Human brain imaging highlights a relationship between excitatory and antioxidant neurochemicals and psychosis

Valerie Sydnor was the lead author on this study. Valerie is a PhD candidate in Ted Satterthwaite’s lab studying how brain plasticity changes throughout neurodevelopment. Valerie aims to uncover how developmental programs contribute to the emergence of youth psychiatric disorders.

or technically,

A meta-analysis of ultra-high field glutamate, glutamine, GABA and glutathione 1HMRS in psychosis: Implications for studies of psychosis risk

[See Original Abstract on Pubmed]

Authors of the study: Valerie Sydnor & David Roalf

PsychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning. is a complex and neurodevelopmental brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. disorder that typically presents in adolescence or early adulthood. Characterized by disorganized thought and behavior, low motivation, and the presence of hallucinations or delusions, psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning. can have a devastating impact on social, occupational, and daily functioning. It’s also more common than you may think. According to the National Alliance on Mental Illness, approximately 100,000 young people experience psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning. each year in the U.S. alone. In addition to affecting basic day-to-day life, episodes of psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning. are associated with changes in both brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. structure and brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. function. For example, psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning. has been linked with changes in the way neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are both connected to (structural change) and communicate with (functional change) one another. Interestingly, these structural and functional changes have been found not only in patients with psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning., but also in youth at genetic or clinical risk for developing psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning.. This finding means that it may be possible to use information about the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to predict and diagnose psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning. as well as to inform psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning. treatment strategies, which represents a huge step forward for psychiatry.

So, what exactly are these psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning.-related brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. changes? Well, Neuroscience Graduate Group (NGG) student Valerie Sydnor, her co-author Dr. David Roalf, and many others in the field, think that a neurochemical called glutamatethe most abundant excitatory neurotransmitter plays a critical role in psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning.. Glutamatethe most abundant excitatory neurotransmitter is the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.’s main excitatory neurotransmitterchemicals released by neurons; can have an excitatory or inhibitory effect, meaning it plays a large role in neuronal communication. (It’s present at approximately 80% of synapsesthe site of transmission of electric nerve impulses between two nerve cells (neurons) that form the basis for neuronal communication, which serve as the point of communication between neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles!) Recently, the receptorsReceives an input some stimulus and transmits a the information to other cells or neurons. that bind glutamatethe most abundant excitatory neurotransmitter to enable this neuronal communication have also been shown to bind drugs, like ketamine, that induce a mental state similar to that of acute psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning.. It is this functional link between glutamatethe most abundant excitatory neurotransmitter receptorsReceives an input some stimulus and transmits a the information to other cells or neurons. and a psychotic-like state that clued Valerie and others into a potential role for glutamatethe most abundant excitatory neurotransmitter in this perplexing disorder. Importantly, in addition to its role in communication throughout the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., glutamatethe most abundant excitatory neurotransmitter can also influence other neurochemicals, including glutamine (a glutamatethe most abundant excitatory neurotransmitter metabolite), gamma aminobutyric acid (GABA; the main inhibitory neurotransmitterchemicals released by neurons; can have an excitatory or inhibitory effect), and glutathione (an antioxidant that protects the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. from oxidative stressdamage done to the body due to a build-up of unstable oxygen-containing molecules). This means that alterations in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. glutamatethe most abundant excitatory neurotransmitter levels, which are thought to occur in psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning., may result in changes in any (or all) of these other three neurochemicals. So, in order to get a complete picture of the relationship between glutamatethe most abundant excitatory neurotransmitter and psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning., it’s necessary to systematically investigate an entire group of neurochemicals.

However, if we want to use these neurochemicals to help predict, diagnose, and treat psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning., we need a way to measure them in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Fortunately, with the development of new technology, we can do just that! Recent advances in ultra-high field MRI technology (think: more than two times stronger than the magnetic field of your average MRI scanner) and proton magnetic resonance spectroscopy (1HMRS) techniques (which enable non-invasive assessment of regional brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. chemistry) allow researchers to more accurately and reliably quantify neurochemical levels in the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of humans. With this promising leap in neurochemical-based brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. imaging, there has been an emergence of research applying the technology to psychiatric disorders like psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning.. To date, nine studies have used ultra-high field 1HRMS to investigate neurochemical concentrations in psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning.. With the goal of synthesizing results across these studies, Valerie and David conducted a meta-analysis. By leveraging available data and quantitatively summarizing the findings, their work provides insight into whether concentrations of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.'s main neurotransmitterschemicals released by neurons; can have an excitatory or inhibitory effect -- glutamatethe most abundant excitatory neurotransmitter and GABA -- and their associated metabolites are altered in psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning..

So, what did Valerie’s meta-analysis find? After combining data from all individuals who participated in the nine available 1HMRS imaging studies, there were a total of 255 individuals with psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning. and 293 healthy participants without psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning.. Comparing metabolite levels for glutamatethe most abundant excitatory neurotransmitter, GABA, glutathione, and glutamine between these two groups, Valerie found that the concentration of both glutamatethe most abundant excitatory neurotransmitter and glutathione was reliably lower in patients with psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning.. This finding adds to a growing body of evidence from animal models, post-mortem brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. tissue, and genetic studies suggesting that glutamatethe most abundant excitatory neurotransmitter system dysfunction contributes to psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning.. It also provides insight into why psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning. may emerge during late stages of neurodevelopment, given that these maturational stages are characterized by extensive changes in neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that communicate using glutamatethe most abundant excitatory neurotransmitter. Valerie’s work paves the way for future research, which could leverage this non-invasive technique to collect longitudinal samples of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. chemistry in order to better understand the developmental time course of these neurochemical alterations. With these kinds of efforts, it won’t be long until concentrations of neurochemicals, like glutamatethe most abundant excitatory neurotransmitter, can be incorporated into individualized psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning. risk calculators, serve as biological predictors of the transition from at-risk for developing psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning. to a formal psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning. diagnosis, and function as druggable targets for decreasing psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways. Psychosis is a complex brain disorder that typically presents in adolescence or early adulthood with devastating impacts on social, occupational, and daily functioning. risk.

About the brief writer: Kara McGaughey

Kara is a PhD candidate in Josh Gold’s lab studying how we make decisions in the face of uncertainty and instability. Combining electrophysiology and computational modeling, she’s investigating the neural mechanisms that may underlie this adaptive behavior.

Want to learn more about imaging neurochemicals in the brain and their implications for mental health? You can find Valerie’s full paper here!

How do the brain’s structure and function develop together through adolescence?

or technically,

Development of structure-function coupling in human brain networks during youth

[See Original Abstract on Pubmed]

Authors of the study: Graham L. Baum, Zaixu Cui, David R. Roalf, Rastko Ciric, Richard F. Betzel, Bart Larsen, Matthew Cieslak, Philip A. Cook, Cedric H. Xia, Tyler M. Moore, Kosha Ruparel, Desmond J. Oathes, Aaron F. Alexander-Bloch, Russell T. Shinohara, Armin Raznahani, Raquel E. Gur, Ruben C. Gur, Danielle S. Bassett, and Theodore D. Satterthwaite

An important part of learning about the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. is not just understanding the way one individual brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region works, but also how different brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions connect to each other. For example, our eyes receive visual information, but you only know what objects you are looking at because that visual information is also associated with your other senses and your memories. The connections between brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions are not completely set once a person is born, they develop as that person grows. There are several ways that these connections can develop. One way is structural, which is the physical connections between regions. These are the white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions connections that stretch from region to region and the synapsesthe point of communication between neurons; the tiny gap between two neurons, where nerve impulses are relayed formed between cells in different regions. Another type of connection between regions is functional. This means that when one region is active and doing a task, the other region is active as well. When the structure between brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions also supports the functional connections between those regions, that is called structure-function coupling. Graham Baum, Neuroscience Graduate Group student and member of the Satterthwaite lab, wanted to know how structure-function coupling develops in youth.

BrainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions can be classified in groups based on what they process. If a brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region only focuses on a single simple thing such as light, heat or taste, then it is called unimodal. If a brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region associates multiple types of information that come from different brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions, that brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region can be called transmodal. When children grow up, the senses are among the first parts of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to develop since they are more concrete; they require less abstract thought. The more evolved transmodal parts of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are the ones that develop later in life. It is also possible to measure how much a transmodal region is connected to other brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions, which is called the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region’s participation coefficient. Graham’s study focused on the differences in development of unimodal and transmodal types of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions.

To study structure-function coupling, Graham scanned people from ages 8 to 23 using MRI imaging. He made two maps for each person. The first map was a structural map, made with diffusion weighted imagingA method for imaging and measuring properties of white matter using magnetic resonance imaging.. This map showed the physical connections between regions of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. The next map was a functional map. To make this map, each participant was scanned with a MRI machine while they were doing a task where they needed to remember a number of things and then repeat them back to the experimenter. That allowed Graham to make a map of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to see how each region of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. communicated with every other region of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. during this task. The last step was to correlate the structural connections with the functional connections. Each region in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. then had a number to represent its structure-function coupling. This final value is what Graham measured and compared between participants.

The first thing Graham found was that regions that were unimodal had stronger structure-function coupling compared to transmodal areas. The more regions that one brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region was communicating with, the weaker structure-function coupling it had. This was true across all ages. He next wanted to know how structure-function associations would change with age. To do this, he compared the structure-function coupling between younger participants and older participants. BrainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions that were unimodal did not change much with age. The regions that changed the most with age were the transmodal areas that support complex thought.

These age differences in structure-function coupling were exciting, but they were done across different people of different ages. Graham added to this by scanning a group of participants and then scanning those same participants about 2 years later. For most adolescents, 2 years can be a significant amount of time to change in terms of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development. When Graham scanned the same people twice, he confirmed that transmodal brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions within the same individuals developed stronger structure-function coupling over time.

The last thing Graham wanted to know is whether these structure-function connections would actually be related to behavior. He looked at how people actually did on the behavioral task that he used to make the functional maps. He found that higher structure-function coupling in a region called the rostrolateral prefrontal cortex (rlPFC) was associated with better performance on the task. The structure-function coupling of the rlPFC could also predict how two people of the same age would do on the task.

Graham’s work shows us something we didn’t know before, how the development of white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions helps to support the way that the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. develops its cognitive abilities. This work gives us the ability to predict brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. function as humans age and develop. Additionally, this work can help us try to understand disorders that are defined by the disconnect between structural and functional development such as certain neuropsychiatric disorders.

About the brief writer: Rebecca Somach

Rebecca is a PhD Candidate in Akiva Cohen’s lab. She is interested in using electrophysiology to answer interesting and novel questions in neuroscience. Her current research focuses on how mild traumatic brain injury alters the neuronal circuitry of sleep.

Want to learn more about structure-function coupling, and how it changes as we develop? Check out Graham’s paper here.

Shedding light on migraines: Signals from the eye make people with migraine more sensitive to light

or technically,

Selective amplification of ipRGC signals accounts for interictal photophobia in migraine

[See Original Abstract on Pubmed]

Authors of the study: Harrison McAdams, Eric A Kaiser, Aleksandra Igdalova, Edda B Haggerty, Brett Cucchiara, David H Brainard, Geoffrey K Aguirre

Have you ever stepped outside and had to squint or shield your eyes from the sun? Bright light can be uncomfortable for anyone, but it can be especially painful to those who experience migraines. While headaches are often associated with migraines, another common symptom is photophobia, or sensitivity to light. Harrison McAdams, a neuroscience student in Dr. Geoffrey Aguirre‘s lab at Penn, wanted to find out what part of the eye or brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. might be responsible for the symptom of photophobia in migraines.

In order to discover how photophobia might arise, we need to understand how our eyes allow us to see our surroundings. The first step in vision is when light hits the retina, a sheet of cells that covers the back of the eye. The retina is made of three layers of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles with specific functions. Some of these neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles can detect light: these are the rods and cones, and they become excited by photons, the particles that make up light. Rods work in dim light, while cones work in bright light and can sense red, green, or blue light. This is how we’re able to see in color! Rods and cones talk to other neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the retina like RGCs (retinal ganglion cells), which then send signals out of the eye and to many different areas of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals..

Figure 1: Anatomy of the eye and retina (adapted from webvision.med.utah.edu)

Most RGCs just listen to the rods and cones that talk to them; however, there are special RGCs that are “intrinsically photosensitive” (ipRGCs), which means they can detect light just like rods and cones do. These ipRGCs actually don’t help you see images. Instead, they are responsible for your sense of a day/night cycle and for helping your pupils adjust to the light or dark. There is also evidence that ipRGCs connect to the thalamus, an area of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. which can sense pain. Harrison thought this connection could explain why light can be especially painful to people with migraine.

60 people participated in this study: 40 experienced photophobia from migraines and 20 did not have migraines for comparison. Pulses of different colored light were flashed in one eye to either activate the cones, the ipRGCs, or both. They rated how painful each flash of light was on a scale from 0 to 10, 10 being the most painful. People with photophobia tended to rate the “cone” light as more painful compared to those without, and their rating increased as the light got brighter. Since we know that they’re sensitive to bright light and that cones work in bright light, this makes sense. Interestingly, they also gave higher pain ratings to light which only activated the ipRGCs.

From this test, Harrison knew that ipRGC activity could cause pain. After recording pupil size while the light was flashing, he found no difference in people with or without migraine. This means that not all ipRGC functions are affected: It’s a specific strengthening of the signal from the retina to the pain-sensing area of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals..

Why would our eyes be wired like this? Just like touching a hot stove can damage your hand, staring at the sun or shining a flashlight in your eyes can damage your retinas. And once those neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles are gone, they’re gone for good--so take care of them! Although this signal can be helpful, warning us that what we’re doing is harmful, it seems like when the signal becomes too strong, people can develop migraines. Identifying the root of the problem is the first step in developing treatments to help people who live with this condition.

About the brief writer: Sierra Foshe

Sierra is a PhD student in Josh Dunaief's lab. She is interested in the mechanisms of retinal inflammation and degeneration.

Want to learn more about the role of ipRGCs in photophobia? You can find Harrison’s full paper here!

Nicotine and Booze: Why smoking as a teen can lead to alcohol abuse as an adult

or technically,

Adolescent nicotine exposure alters GABAA receptor signaling in the ventral tegmental area and increases adult ethanol self-administration

[See Original Abstract on Pubmed]

Authors of the study: Alyse M. Thomas, Alexey Ostroumov, Blake A. Kimmey, Madison B. Taormina, William M. Holden, Kristen Kim, Tiffany Brown-Magnum, and John A. Dani

Take a stroll past any neighborhood bar and you are bound to get a whiff of cigarette smoke from a group huddled outside. It is no secret that smoking and drinking often go hand in hand, but can one actually lead to the other? Scientists say yes. Tobacco use, especially as an adolescent, is a strong predictor for alcohol consumption later in life. But why?

While human data shows a strong correlation between smoking and using drugs/alcohol, scientists have turned to rodent models to determine if nicotine is directly causing the addiction-related behaviors. Indeed, previous rodent studies have directly linked nicotine exposure to enhanced drug use. Interestingly, this association is only seen when the nicotine is administered to adolescent rodents; adult rodents exposed to nicotine do not show an increase in drug consumption later on. Given that adolescent brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are more flexible than fully-grown adult brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. (in both rodents and humans!), researchers have hypothesized that nicotine exposure during adolescence may actually lead to long-term changes in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development. However, how these developmental changes lead to excessive drug consumption later in life was still unknown. Enter Alyse Thomas, a University of Pennsylvania researcher in the Dani lab, who was determined to find out.

While previous studies linked adolescent nicotine exposure to increased drug use, Alyse wanted to see if the same phenomenon held true when the rodents were given access to ethanol (the key ingredient in most forms of alcohol). Thinking that it would, Alyse hypothesized that adolescent (but not adult) rats exposed to nicotine would ingest excessive amounts of ethanol. To test this hypothesis, Alyse used a self-administrationa common behavioral task used by researchers to study addiction in animal models, whereby animals push a lever to give themselves a drug behavior paradigm to research the link between nicotine exposure and ethanol ingestion. This paradigm, commonly used by scientists who study drugs and addiction, allows subjects (in this case rats) to consume as much of a substance (in this case ethanol) as they desire. Alyse ran two sets of experiments: one using adolescent rats, and one using adult rats. In both experiments, the rats were injected with either nicotine or salinesalt water; a common control substance intended to have no effect on behavior or physiology for 14 days straight. Four weeks after their last injection, the rats were placed in a self-administrationa common behavioral task used by researchers to study addiction in animal models, whereby animals push a lever to give themselves a drug chamber where they were allowed unlimited access to ethanol. For the next 30 days, Alyse measured the amount of ethanol each of the rats ingested. This allowed her to determine whether short-term nicotine exposure altered ethanol consumption later in the rat’s life. As hypothesized, she found that adolescent (but not adult) rats exposed to nicotine ingested significantly more ethanol than those exposed to salinesalt water; a common control substance intended to have no effect on behavior or physiology. While this finding was expected, Alyse still wanted to know why it was the case. How does two weeks of nicotine exposure alter a rat’s behavior over four months later?

As an expert in her field, Alyse was aware that ethanol consumption is associated with changes in communication between neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. - specifically, the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the ventral tegmental areaa brain region that plays key roles in drug and natural reward response (VTA). This brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region contains two key players: neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that release GABA neurotransmitterschemicals released by neurons; can have an excitatory or inhibitory effect (inhibitory chemicals that “turn off” nearby neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles) and neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that release dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neurotransmitterschemicals released by neurons; can have an excitatory or inhibitory effect (excitatory, “feel good” chemicals). In the VTA, GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles directly communicate with dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles. Typically, GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles release low levels of their inhibitory chemicals, causing dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to stay silent. However, when dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles sense the presence of drugs or alcohol, they overpower the “off” signals sent from GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles and release a flood of “feel good” signals to the rest of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. However, if the communication between these two types of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles was impaired (say, by nicotine), the “feel good” response elicited from ethanol consumption might also be impaired. Indeed, Alyse and her labmates discovered that nicotine causes GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to become overactive, leading to underactive dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles. Therefore, it takes more ethanol to elicit the same “feel good” response that the animal is used to, causing them to consume more.

With another piece of the puzzle in place, Alyse next wanted to know why nicotine causes these GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to become overactive. Perhaps if she could figure out the cause of the overactivation, she could figure out how to stop it. Alyse therefore took the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. from her adolescent nicotine- and salinesalt water; a common control substance intended to have no effect on behavior or physiology-exposed rats and looked directly into their VTA GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles. Fascinatingly, she found that the nicotine-exposed neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles had a significant buildup of chloride ions within them, which could either be caused by too much chloride coming in, or not enough chloride flowing out. Alyse figured out that it was the latter scenario - nicotine-exposed GABA neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles were unable to properly expel chloride ions, causing them to build up and over activate the cell. With this last piece of the puzzle, Alyse was finally able to link adolescent nicotine exposure to increased alcohol consumption in adulthood (Figure 1).

Armed with a full understanding of the pathway, Alyse performed her final (and most important) experiment yet. Knowing that nicotine causes GABA neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles chloride channelsChannels are specialized proteins found on the surface of the cell. They allow molecules (i.e. neurotransmitters, salts, water) to go from outside to inside the cell and vice versa. to stop working, Alyse hypothesized that repairing these channelsChannels are specialized proteins found on the surface of the cell. They allow molecules (i.e. neurotransmitters, salts, water) to go from outside to inside the cell and vice versa. would restore the pathway and lead to a normal level of ethanol ingestion, even when adolescent rats are exposed to nicotine. Sure enough, when Alyse injected a drug that restored the chloride ion expulsion, the rats no longer ingested excessive amounts of ethanol. This finding means that not only did Alyse determine why nicotine exposure leads to excessive alcohol consumption, but she also discovered a potential treatment strategy for those suffering from alcohol addiction. As excessive alcohol consumption is responsible for more than 95,000 deaths per year in the United States alone, Alyse’s work could help reduce many tragic and preventable deaths in the future.

Figure 1. The Neurological Link Between Nicotine and Alcohol Abuse. Adolescent nicotine exposure decreases the ability of GABA neurons to get rid of chloride ions (1), causing a buildup of chloride in the cell (2). The buildup of negative charge causes the GABA neuron to release more neurotransmitter (3). As these neurotransmitters are inhibitory, they decrease the activity of the dopamine neuron that the GABA neuron is communicating with (4). Now in adulthood, the dopamine neuron requires more alcohol (5) in order to feel as “good” as the normal brain does, leading to excessive alcohol consumption.

About the brief writer: Kelsey Nemec

Kelsey is a PhD Candidate in Chris Bennett’s lab. She is interested in understanding how peripheral immune cells infiltrate the brain, with the hopes of harnessing them to treat brain diseases.

Want to learn more about the link between smoking and drinking? You can find Alyse’s full paper here!

Improving how we visualize brain changes from youth to adulthood

or technically,

Adam Pines was the lead author on this study. Adam is a PhD candidate in Ted Satterthwaite's Lab. He is interested in understanding how psychopathology emerges from neurocognitive development

Leveraging multi-shell diffusion for studies of brain development in youth and young adulthood

[See Original Abstract on Pubmed]

Authors of the study: Adam R. Pines, Matthew Cieslak, Bart Larsen, Graham L. Baum, Philip A. Cook, Azeez Adebimpe, Diego G. Dávila, Mark A. Elliott, Robert Jirsaraie, Kristin Murtha, Desmond J. Oathes, Kayla Piiwaa, Adon F.G. Rosen, Sage Rush, Russell T. Shinohara, Danielle S. Bassett, David R. Roalf, Theodore D. Satterthwaite

As people grow from childhood to adolescence, most changes are pretty clear: you might see a niece or nephew again after a couple years and find they have changed quite a bit, whether they are several inches taller or sporting new favorite phrases and hobbies. During this time of growing up, there are many complex changes happening in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. that are less visible.

One of the things that changes across development is the strength of connections between brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions. Why does this matter? Well, different parts of your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. communicate with each other to produce the thoughts and actions that guide our daily life. When a brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region communicates more with a particular brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region than another, that connection gets stronger. The changes in these connections usually follow a reliable pattern across development, with some individual differences based on our unique experiences. It is important to know what changes to expect in the connections between different brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions during development, so that we can learn to spot when things go awry. Adam Pines of the UPenn Neuroscience Graduate Group and member of the Satterthwaite lab was interested in finding the best ways to measure changes in these connections across development by comparing several methods for analysis.

To visualize the connections between brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions, scientists look at a type of tissue called white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions. To understand what white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions is and why it is important, we need to zoom in and start with the basic building block of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.: the neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles. NeuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles are a specialized kind of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. cell. The communication between neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles is what drives most everything we see, think, and do. The part of the neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that makes up white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions is often covered in an insulating coating called myelin. Myelin helps signals travel faster from one end of a neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to the other. Collectively, these connections are called white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions because the coating makes them appear white.

Techniques have been developed to image white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions using an odd-sounding but effective principle: “follow the water.” You may not think of water when you think of the inner-workings of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., but 73% of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. is actually water.¹ In areas of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. without this myelin coating, water is going in all directions. However, myelin is resistant to water, so it essentially forms little water slides in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Only where there is white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions is the water moving in one direction more than all others. Researchers take advantage of this and “follow the water” to measure 1) the direction of the water and 2) how fast it is going. This tells them the direction of the connection between brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions and the strength of those connections. This technique is called diffusion weighted imagingA method for imaging and measuring properties of white matter using magnetic resonance imaging.. With these basic principles, diffusion weighted imagingA method for imaging and measuring properties of white matter using magnetic resonance imaging. is able to map out where white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions is and measure its properties.

Although it is a powerful tool, interpreting the results of diffusion weighted imagingA method for imaging and measuring properties of white matter using magnetic resonance imaging. requires a lot of complex modelling. Not all models are best suited for studying brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development. The best model would be the one that showed changes in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. with age and that was not affected too much by people moving while they were in the scanner (called in-scanner motion). Imaging of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. has the same problem you do when taking a picture of anything moving - things get blurry. Lots of people can get fidgety in the scanner but especially kids, making finding a metric that isn’t affected by in-scanner motion extra important when studying brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development. Adam wanted to figure out which diffusion weighted imagingA method for imaging and measuring properties of white matter using magnetic resonance imaging. measures researchers should be using to study brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development.

Adam tested different methods by seeing how the output of each related to age and to in-scanner motion. Each method had a slightly different set of outputs or metrics that he looked at. He found that the metrics of each related to age and in-scanner motion differently. Some metrics were more affected by the age of the participant than others whereas other metrics were more affected by in-scanner motion. Remember, in order to study brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development, the best metrics would be the ones that were most affected by age and least affected by in-scanner motion. Adam found that each metric varied quite a bit in how well it was associated with age. However, he found that one particular method, the Laplacian-regularized Mean Apparent Propagator (MAPL), was less affected by in-scanner motion than the other methods he tested. MAPL is a relatively new method and, before Adam’s study, no one was sure how well it would work for measuring brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development.

Based on Adam’s work, other researchers now know what metrics are best to study white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions to determine what is happening in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. during development. This work is important because it allows future research on brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development to be more reliable by leading researchers away from model metrics that would miss the effects they are most interested in. By looking at white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions during development using previous methods, researchers have already discovered different pathways that are related to normal development, anxiety and depression, and more. Adam’s work will allow for many more future discoveries like these that help us better understand problems that occur during development!

About the brief writer: Sara Taylor

Sara Taylor is a PhD Candidate in Ted Brodkin’s lab. She is interested in understanding how behaviors associated with Autism Spectrum are related to each other as well as their genetic basis.

Citations:

1. Mitchell, H. H., Hamilton, T. S., Steggerda, F. R., & Bean, H. W. (1945). The chemical composition of the adult human body and its bearing on the biochemistry of growth. Journal of Biological Chemistry, 158(3), 625-637.

   
   You can find the paper here.

Want to learn more about how these methods for studying brain development work? You can find Adam Pines’ full paper here!

The key to assessing Alzheimer’s disease treatments? Test them in Parkinson’s disease patients.

David Dai was the lead author on this study, and was the writer of this brief. David is a MD/PhD student in Eddie Lee's lab. He is interested in understanding the mechanisms underlying neurodegenerative diseases.

or technically,

ADNC-RS, a clinical-genetic risk score, predicts Alzheimer’s pathology in autopsy-confirmed Parkinson’s disease and Dementia with Lewy bodies

[See Original Abstract on Pubmed]

Authors of the study: David L Dai, Thomas F Tropea, John L Robinson, Eunran Suh, Howard Hurtig, Daniel Weintraub, Vivianna Van Deerlin, Edward B Lee, John Q Trojanowski, Alice S Chen-Plotkin

In a world full of uncertainty, the only thing we can be sure of is that time will go on. And with time, unfortunately, comes disease. Age is the greatest risk factor for neurodegenerativebrain diseases characterized by the progressive loss of neurons over time. diseases which are characterized by the progressive loss of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles. Three of the most common neurodegenerativebrain diseases characterized by the progressive loss of neurons over time. diseases are AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease, Parkinson’s disease, and dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms.. Together they affect more than 6 million Americans, and that number is expected to reach over 9.8 million by 2030. To effectively diagnose and treat these diseases, it is vital to develop tools that can accurately predict who will develop disease. However, efforts to predict disease development, especially in AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease, have largely been unsuccessful, despite advancements in our understanding of the genetic risk factors for AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease.

In all three diseases, abnormal proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregate, injure brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. cells, and lead to neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles death, resulting in the symptoms that patients experience -- loss of memory, cognition, and movement. Doctors do their best to diagnose patients, but diagnoses are not confirmed until after patients die, when their brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are autopsied, and the presence of abnormal proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates confirms which disease the patients experienced during life. In AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease, these abnormal proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates are called amyloid-beta plaques (Aβ) and tau neurofibrillary tangles. In Parkinson’s disease and dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms., these proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates are called Lewy bodies. Because of their similarities, Parkinson’s disease and dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms. are both included in a group of diseases called Lewy body diseases (LBD).

Although AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s and LBD are traditionally thought of as separate diseases, patients with LBD often have AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. 50-80% of patients with a primary diagnosis of LBD also exhibit Aβ and tau proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates at autopsy-- hallmarks of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. Up to 40% of patients with a primary diagnosis of Parkinson’s have enough Aβ and tau aggregates in their brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. for a secondary diagnosis of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. As only 10% of people age 65 and older have AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease in the United States, it may not just be a coincidence that Parkinson’s patients commonly also have AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. Patients with Parkinson’s or dementia with Lewy bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms. may actually be at increased risk for developing AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease. This is important for clinicians to recognize when caring for LBD patients!

Taking advantage of LBD patients’ increased risk for developing AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s hallmarks, David Dai and the Chen-Plotkin Lab at the University of Pennsylvania asked: Can we predict which Parkinson’s/dementia with Lewy Bodiesneurodegenerative disorder characterized by neuronal Lewy bodies comprised of alpha-synuclein. Differentiated from Parkinson’s disease based on the relative onset of motor versus cognitive symptoms. patients are likely to develop AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s hallmarks using known AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s genetic risk factors? They gathered various demographic and genetic variables that could impact AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s development and used a machine learning approach to identify the specific factors important for predicting AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status.

They found that using only 4 pieces of information (age of onset and 3 pieces of genetic information), they could predict AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status to a modest degree. They transformed this information into a risk score, called the AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s Disease Neuropathological Change – Risk Score, that provides a continuous assessment of individuals’ risk for developing the hallmarks of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. A continuous risk score is useful because it reflects individuals’ incremental differences in disease development likelihood and allows researchers to set specific, numerical thresholds when predicting which patients are likely or unlikely to develop disease. They checked the effectiveness of their risk score in two additional groups and achieved comparable results. These additional validation steps were important because they showed that the risk score worked not only in the population that was used to build it but also in two other, unrelated groups. In other words, by showing that the risk score succeeded in three distinct groups, the researchers demonstrated that the AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s Disease Neuropathological Change -- Risk Score is a tool that could be successfully used in the general population.

These results have important scientific and clinical implications! By studying how the model made successful predictions, the scientists found that not all genetic information is equal when it comes to predicting AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status in Parkinson’s/dementia with Lewy body patients. They identified three genetic locations that were particularly important for predicting AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s status in this group of individuals. They hope that further investigation will reveal why these locations are so crucial for the model’s predictions. If they are found to increase the development of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s hallmarks in Parkinson’s and dementia with Lewy body patients, then treatments can be designed to block these genetic locations’ functions and maybe prevent AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease development in this subset of patients!

Given that the toxic proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. aggregates Aβ and tau accumulate in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. decades before patients develop symptoms, the medical community is trying to remove the aggregates as early as possible in the disease development process. However, this is extremely difficult because we don’t know who will develop AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s, and we don’t know if removing the aggregates even helps patients! This new risk score could help solve that problem. On average, patients receive clinical diagnoses of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s at ~80 years old, while Parkinson’s patients receive their diagnoses at ~60 years old. That means, using this risk score, we may be able to identify future AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s patients at least a decade before they develop symptoms, allowing us to first assess the effectiveness of Aβ and tau targeting treatments in a group of patients with increased risk of developing AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s. If those treatments are proven to work, we may finally be able to slow the progression of AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease!

Citations:

1. Alzheimer’s Association. 2020 Alzheimer’s Disease Facts and Figures. Alzheimer’s Dement 2020;16(3):391+. You can find the report here.

2. Parkinson’s Foundation. Statistics. Parkinson’s Foundation. 2019 September 19. You can read the article here.

Want to learn more about developing a risk score to predict disease development? You can find the group’s full paper here!

How is the brain fighting HIV?

or technically,

Neuroinflammation associates with antioxidant heme oxygenase-1 response throughout the brain in persons living with HIV

[See Original Abstract on Pubmed]

Authors of the study: Analise L. Gruenewald, Yoelvis Garcia-Mesa, Alexander J Gill, Rolando Garza, Benjamin B. Gelman, Dennis L. Kolson

You might be familiar with Human Immunodeficiency Virus (HIV), but did you know that approximately half of those living with HIV also experience impairments in cognition?¹ HIV is a virus capable of invading our cells, specifically those that play vital roles in our immune system. The immune system is the body’s security force, fighting off invaders and preventing you from getting sick. If HIV is not treated, it will progress into Acquired Immunodeficiency Syndrome (AIDS), in which the immune system is severely weakened and patients become highly vulnerable to complications from other illnesses. While untreated HIV/AIDS is fatal, there have been amazing scientific developments in antiretroviral therapies, which substantially prevent the progression of HIV into AIDS. This therapy prevents the virus from making lots of copies of itself inside cells so that the immune system does not get overwhelmed and can still do its job.² Despite these advancements, there is still much more progress that needs to be made to improve HIV treatment. At the end of 2019, there were roughly 38 million people suffering from HIV/AIDS around the world, and over half a million people died from illnesses related to AIDS. While therapies such as antiretroviral therapy can be successful, a third of people living with HIV still do not have access to these life-saving treatments.³

But how does HIV impact your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.? Besides weakening the immune system, HIV can also impact cognition (the way our brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. thinks and functions). About half of people with HIV also suffer from HIV-associated neurocognitive disorder (HAND). HAND can impair memory, attention, and decision making. How much a person’s cognition is impaired can vary widely, with mild effects in some cases but detrimental effects to a person’s life in others, such as being unable to learn new things or remember important dates and appointments. Why some with HIV develop HAND, and others do not, is still not well understood, but discoveries made by scientists are starting to shed some light on this question.

Dr. Analise Gruenewald is a recent graduate of the Neuroscience Graduate Group at the University of Pennsylvania and member of the Kolson Lab who is intent on building science’s understanding of why HAND develops in only a subset of people living with HIV. Previous work in the Kolson Lab has suggested that a proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. called heme-oxygenase 1 (HO-1) might be key. HO-1 helps the body handle both oxidative stressdamage done to the body due to a build-up of unstable oxygen-containing molecules and inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system, which are both responses of the body to HIV that are thought to contribute to some of its harmful effects. Those with HAND have been shown to have a lower amount of HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in a specific brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region called the prefrontal cortex.⁴ The prefrontal cortex is a part of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. that is important for decision making, which is disrupted in HAND. Analise built upon these findings to understand how HO-1 might be important in the development of HAND in HIV patients. Specifically, Analise sought to determine how much HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. is in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. tissue of patients and how this relates to signs of inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system.

Analise examined the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. tissue of those who had HIV (but specifically did not have HAND) compared to those who did not have HIV. By examining the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of those who had HIV but not HAND, she aimed to identify a particular factor that may function to prevent or protect against it. She first observed that the amount of HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of those with HIV but not HAND was higher than the amount in those without HIV. This exciting finding supports the hypothesis that HO-1 is an important factor in how our brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. defend against HIV, suggesting high levels of HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. provide protection against the development of HIV-related HAND. Further understanding of HO-1’s role in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.’s defense against HAND could enable the development of preventative treatments. Encouraged, Analise decided to explore the connection between HO-1 and HIV-related brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system.

Figure 1: Potential mechanism by which HO-1 prevents development of HAND. 

HIV leads to inflammation (which involves immune cell activation), and whether or not the individual then develops HAND might depend on the level of HO-1 protein they have. (A) If an individual has a high level of HO-1 protein this might enable them to maintain normal cognition. (B) An individual with a low level of HO-1 protein might not be able to properly respond to the inflammation, and will develop HAND. Image created with BioRender.com

To explore this idea further, Analise investigated how the amount of HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. correlated with the presence of inflammatory signals. If HO-1 prevents HAND by mediating the body’s response to infection, one might expect these two to be connected. She chose to measure the levels of various proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. involved in inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system – so if the levels of these proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. are higher, that would indicate that there is more inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system present. She found that if the levels of these inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system-related proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. were higher in a given individual, the amount of HO-1 also tended to be higher. These findings provided even stronger support for Analise’s hypothesis that HO-1 might be important in preventing HAND via compensating for the body’s inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system.

To recap how this might work: HIV causes an inflammatory response in infected patients. HO-1 is a proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. that is important for ensuring the body can be healthy even during this inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system. Higher HO-1 levels should be protective and allow a person to successfully handle high levels of inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system without a lot of serious negative effects (such as on cognition). In those without HAND, this appears to hold true: if the patient has high inflammationthe state of the body when it is fighting an infection, characterized by the release of specific chemicals and the activation of the immune system, they also have high levels of HO-1.

Analise’s work provides a fascinating insight into a poorly understood yet critical topic: why some people with HIV develop HAND, but others don’t. There is still more work to be done to fully confirm her initial findings; however, her work presents a strong foundation for future research. Her findings indicate that HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. might be critical in preventing the development of HAND. Not only is this work thrilling in terms of simply furthering scientific understanding of HAND, but it also has promising therapeutic potential. If HO-1 is important for preventing HAND, this opens up the exciting possibility that a treatment that increases the amount of HO-1 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in those with HIV could prevent HAND. Analise’s work is a wonderful step toward significantly improving the lives of millions of people affected by HIV around the world.

Citations:

1. Saylor, D., Dickens, A. M., Sacktor, N., Haughey, N., Slusher, B., Pletnikov, M., Mankowski, J. L., Brown, A., Volsky, D. J., & McArthur, J. C. (2016). HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nature reviews. Neurology, 12(4), 234–248. https://doi.org/10.1038/nrneurol.2016.27

2. Deeks, S., Overbaugh, J., Phillips, A. & Buchbinder, S. (2015). HIV infection. Nat Rev Dis Primers, 1, 15035. https://doi.org/10.1038/nrdp.2015.35

3. The Global HIV/AIDS Epidemic. (2020, November 25). HIV.gov. Retrieved January 2, 2021, from https://www.hiv.gov/hiv-basics/overview/data-and-trends/global-statistics

   Gill, A. J., Kovacsics, C. E., Cross, S. A., Vance, P. J., Kolson, L. L., Jordan-Sciutto, K. L., Gelman, B. B., & Kolson, D. L. (2014). Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders. The Journal of clinical investigation, 124(10), 4459–4472. https://doi.org/10.1172/JCI72279

About the brief writer: Katie Copley

Katie is a PhD student in Dr. Jim Shorter’s lab.

Do you want to learn more of the details of Analise’s work? You can find her full paper here.

A mouse model for autism and ADHD can mimic sex differences in sleep

or technically,

Hyperactivity and male-specific sleep deficits in the 16p11.2 deletion mouse model of autism.

[See Original Abstract on Pubmed]

Authors of the study: Angelakos CC, Watson AJ, O'Brien WT, Krainock KS, Nickl-Jockschat T, Abel T.

Falling asleep at night is something we look forward to at the end of the day, restoring our energy for the new day ahead. However, a good night's rest isn’t guaranteed for everyone as many people across the country have trouble sleeping. This is especially true for people diagnosed with autism spectrum disorders (ASD) and attention deficit-hyperactivity disorder (ADHD) who often have trouble falling asleep and staying asleep. Up to 80% of individuals diagnosed with ASD and 55% of children with ADHD suffer from sleep problems. Sleep disturbances can worsen other symptoms common in these disorders such as repetitive behaviors, attention, and communication. Christopher Angelakos, a graduate student in Dr. Ted Abel’s lab, wanted to understand why sleep disturbances are common in ASD and ADHD. In order to answer this question, Christopher turned to established models of ASD/ADHD. He reasoned that mice that have ASD/ADHD-like symptoms might also have sleep disturbances.

Patients with disorders like ASD/ADHD often have changes in the number of copies they have for a geneA unit of DNA that encodes a protein and tells a cell how to function. Typically, for each geneA unit of DNA that encodes a protein and tells a cell how to function there are two copies - one from each parent. Therefore, individuals with ASD/ADHD can have more copies, or fewer copies (also known as a deletion). One of these changes is a deletion in chromosomal region 16p11.2. People that have a deletion in this region are more likely to have ASD and ADHD. Previous research has shown that mice with a deletion in the 16p11.2 region show symptoms similar to ASD/ADHD like differences in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. structure, cognitive ability, and communication. However, sleep problems remained largely unexplored, a problem that Christopher wanted to address.

Christopher observed that these animals were hyperactive, a behavior that is observed in individuals diagnosed with ADHD. He tracked all of the movements of the mice in their cages, observing an increase in activity in the 16p11.2 deletion mice throughout the day, and a robust increase during the dark (active) phase of their cycle. This led him to think that something may be altered in their circadian rhythms. To investigate this he monitored them for 24hrs and measured their sleep and activity to determine if it was normal.

He also examined their sleep cycles using polysomnography, which tracks brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. waves, eye movements, and limb movement during sleep. He wanted to know whether this was a problem of initiating sleep or maintaining sleep. He found that once the animals were asleep, they usually remained asleep for the same amount of time indicating that there was not a problem of staying asleep. On the other hand, once an animal was awake, it was usually awake for a longer period of time, indicating that it may have had trouble with initiating sleep. When Christopher further analyzed the data, he saw male mice with the 16p11.2 deletion spent a longer amount of time awake than regular mice. Coupled with his finding that these mice stay asleep as long as the regular mice, this suggests that they had a hard time falling asleep, rather than that they were waking up multiple times and having brief amounts of wakefulness. Interestingly, these disorders are more commonly found in males rather than females. Males are four times more likely to be diagnosed with ASD and three times more likely to be diagnosed with ADHD.

Issues with sleep in people that are diagnosed with autism or ADHD is a problem that needs to be addressed. Christopher asked whether we can use a mouse to model sleep problems in autism? He showed in his paper that the 16p11.2 deletion mouse can model sleep disturbances that are seen in humans. He is excited to see future work using this mouse model to uncover specific brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. circuits that may be involved and better treatment for sleep problems. Now that we have this experimental mode, we can determine if improving sleep quality will improve other psychiatric symptoms.

About the brief writer: Felicia Davatolhagh

Felicia is a PhD Candidate in Marc Fuccillo’s lab. She is a seventh year studying the impact of neuropsychiatric disease on synaptic connectivity and synaptic function.

Want to learn more about sex differences in neurodevelopmental disorders? You can read Christopher’s whole paper here.

How neurons regulate transport on the microtubule highway system.

or technically,

alpha-Tubulin Tyrosination and CLIP-170 Phosphorylation Regulate the Initiation of Dynein-Driven Transport in Neurons.

[See Original Abstract on Pubmed]

Authors of the study: Jeffrey J. Nirschl, Maria M. Magiera, Jacob E. Lazarus, Carsten Janke, Erika L.F. Holzbaur

The longest neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the human body are the motor neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that help you wiggle your toes. These neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles extend long branches, called axonsA specialized part of a neuron that sends electrical and chemical signals to other cells. Axons are typically long and thin like a wire., that travel from the spinal cord in your lower back all the way down to your toes. These axonsA specialized part of a neuron that sends electrical and chemical signals to other cells. Axons are typically long and thin like a wire. are often a few feet long (maybe even longer if you’re a professional basketball player like Shaquille O’Neal)! To maintain the ability to wiggle your toes, these neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles need to be able to transport important molecules down the entire length of their axonA specialized part of a neuron that sends electrical and chemical signals to other cells. Axons are typically long and thin like a wire.. Thankfully, all neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles have a highway system made of microtubulesMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. (which is just a fancy scientific way to say “tiny tubes”) that they can use to transport molecules down their axonsA specialized part of a neuron that sends electrical and chemical signals to other cells. Axons are typically long and thin like a wire.. A proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. called dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   walks along these microtubulesMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. and carries other molecules or “cargo” with it. In this way, dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   is like a truck that pulls trailers throughout the neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles on the microtubuleMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. highway system. These trailers contain specific cargo that the neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles needs in different places.

NeuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles need to maintain tight control over what gets transported on this microtubuleMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. highway system. They do this by modifying proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. that attach the dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   motor proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. to the microtubulesMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization.. You can think of these proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. as traffic conductors controlling which cars (and therefore what cargo) get onto the highway. NeuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles throughout the body need to be able to control when and where dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   gets onto the microtubuleMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. highway and what cargo it is carrying. Scientists know that when neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles lose control of the microtubuleMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. highway system, it can cause problems and may even result in neurological disorders like Parkinson’s Disease. But how the cell regulates dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   is not yet understood. Jeffrey Nirschl, a neuroscience graduate student at the University of Pennsylvania in Erika Holzbaur’s lab, was interested in figuring out how neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles regulate dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.

 . DyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   can be placed onto the microtubuleMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. highway by specific proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in the cell such as CLIP-170 (you can remember that it “clips” dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   onto the microtubuleMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. highway). Jeffrey thought that CLIP-170 was the key player in regulating when and where dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   gets “clipped” onto the microtubulesMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization.. The cool thing about CLIP-170 is that it has a brake mechanism, called a phosphorylationA post-translational protein modification in which a phosphate group is added to alter the activity or location of proteins within the cell. tag, that prevents CLIP-170 from attaching dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   to the microtubulesMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization.. When this phosphorylationA post-translational protein modification in which a phosphate group is added to alter the activity or location of proteins within the cell. tag is removed (or when CLIP-170 is dephosphorylated), CLIP-170 is activated. In other words, removal of the brake on CLIP-170 allows it to clip dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   onto microtubulesMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization.. Through his work, Jeffrey discovered that the CLIP-170 regulates when dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   is attached to the microtubuleMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. highway.

Jeffrey also hypothesized that the microtubuleMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. highway itself could be modified to regulate when and where dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   can get on the highway, much like traffic cones regulate where cars can go. Tubulin is the proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. building block of microtubulesMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization.. Many tubulin proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. come together and bind end-to-end to form long (but tiny) tubes that run the entire length of the axonA specialized part of a neuron that sends electrical and chemical signals to other cells. Axons are typically long and thin like a wire.. Modification of tubulin building blocks changes the structure and function of the microtubuleMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. highway. One way in which the highway can be modified is called tyrosinationA post-translational protein modification in which the amino acid tyrosine is added to the protein to alter its function., in which the amino acid tyrosine is reversibly added to the tubulin making up the microtubuleMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. highway. The process of tyrosinationA post-translational protein modification in which the amino acid tyrosine is added to the protein to alter its function. can be thought of as road workers putting cones on the highway during construction periods. But unlike traffic cones, tyrosinationA post-translational protein modification in which the amino acid tyrosine is added to the protein to alter its function. increases the ability of dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   to get on the highway and transport its cargo. Jeffrey was able to demonstrate that microtubuleMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. tyrosinationA post-translational protein modification in which the amino acid tyrosine is added to the protein to alter its function. regulates where dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   is put onto the microtubuleMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. highway.

By looking at living neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles and proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies., Jeffrey showed that CLIP-170 regulates when dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   gets on the microtubuleMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. highway and microtubuleMicroscopic tubular structures in the cells made of the protein tubulin that form a skeleton or highway system to help the cell maintain structure and organization. tyrosinationA post-translational protein modification in which the amino acid tyrosine is added to the protein to alter its function. determines where dyneinA motor protein that moves along microtubules and helps carry cargo to various parts of the cell.   gets on the highway. This allows neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to control the location of proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. and molecules in the neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in time and space so it can always function. We are grateful the motor neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles running all the way from our lower back to our toes can do this so we can wiggle our toes every morning.

About the brief writer: Rachel Cerón

Rachel is a PhD Candidate co-mentored by Robert Heuckeroth and Roberto Dominguez. She is studying molecular mechanisms that underlie human diseases in the gastrointestinal system including those that affect the enteric nervous system (the brain in your gut).

Want to learn more about molecular transport in neurons? You can find Jeffrey’s paper here.

An itch we can't scratch ... yet

or technically,

TRPC3 Is Dispensable for β-Alanine Triggered Acute Itch.

[See Original Abstract on Pubmed]

Authors of the study: Peter Dong, Changxiong Guo, Shengxiang Huang, Minghong Ma, Qin Liu & Wenqin Luo

You’re sitting peacefully on your couch and all of a sudden your nose itches. Annoying, right? Why does this happen? More importantly, how can our bodies sense this itch in the first place? This “itch” sensation, also known as pruritoception, has evolved in humans and other animals as an important alarm system for possible threats. These include anything from small microbes to poisons/toxins that can come from plants, food, and even some medications. Although we know that this sensation exists, neuroscientists don’t know much about how the cells in our brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. (neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles) sense itch in the first place.

The skin is the largest organ of the human body, and within it lie many different sensors for detecting stimuli from the outside world. One class of these sensors - called nociceptors - send information to the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. about pain, temperature, and, you guessed it, itch. One important nociceptor for itch is called the “Mas-related G-proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. coupled receptorReceives an input some stimulus and transmits a the information to other cells or neurons. member D” (yikes!), we’ll call that the MRGPRD receptorReceives an input some stimulus and transmits a the information to other cells or neurons. from now on. The reason it’s important for itch is because it detects the itch-inducing chemical, 𝛽-alanine. MRGPRD is broadly expressed, which just means scientists find a lot of this receptorReceives an input some stimulus and transmits a the information to other cells or neurons. in certain parts of the spinal cord. The spinal cord is an organ that is really important for touch and itch because it allows the body to communicate with the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. However, in order for information from organs such as the skin to reach the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., it needs specific “decoder proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies.” that will convert this initial information at the level of the spinal cord into a format the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. will understand. You can think of these decoder proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. as being analogous to Google Translate. If you’re visiting a foreign country and need to translate a word you’ve read, you can use your Google Translate app to translate it into English, a language you understand. However, scientists don’t really know which proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. are functioning as decoders to convert the information the MRGPRD detects to the kind of information that the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. can understand. Peter Dong, a neuroscience graduate student working with Dr. Wenqin Luo at UPenn, set out to try to address this question in his research.

One family of “decoder proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies.” that have been shown to play a role in the detection of many senses such as temperature, pressure, and pain is known as the “transient receptorReceives an input some stimulus and transmits a the information to other cells or neurons. potential” (TRP, pronounced “trip”) family. However, the exact role of TRP proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in decoding itch sensations remains uncertain. Peter chose to test one proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in this family, called TRPC3, to determine whether or not it was the “translator” of information being detected by MRGPRD. Why TRPC3? Well, TRPC3 has been shown to respond to touch sensation, and in Peter’s study, the data showed that TRPC3 is present in the same neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that contain MRGPRD. The next question Peter wanted to ask was whether MRGPRD-containing cells needed TRPC3 in the spinal cord in order to properly translate their messages for the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. So he studied a mouse that did not have any TRPC3 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. anywhere in its body, including the spinal cord. We’ll call this the TRPC3 “knockout” mouse. Peter found that even in mice without TRPC3, MRGPRD was still present. This suggests that TRPC3 is not needed for normal MRGPRD presence and functioning.

So what does this mean? Is TRPC3 the proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. converting itch signals from MRGPRD to the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. or not? Peter and his colleagues addressed this question by doing behavioral studies on their TRPC3 knockout mice. They injected 𝛽-alanine (the itch-inducing chemical) into the back or cheek of mice lacking TRPC3 proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies., and then measured how much they scratched to test if TRPC3 is required for itch sensation. They found that normal mice and TRPC3 knockout mice both still scratched a lot. This suggests that TRPC3 alone is not needed for itch, because the mice lacking TRPC3 were still very itchy.

Though Peter wanted to scratch his itch of knowing which proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. translates sensory information from MRGPRD to the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., TRPC3 is not it. Although he was a little disappointed, this is actually a really good thing to know! This finding will give insight to researchers that can try to study other types of proteinsAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in the TRP family as well as additional groups of proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. families! This research not only helps us understand why and how humans evolved to detect itch, but it also provides a stepping stone for the development of treatments for patients who suffer chronic itch as a symptom of diseases such as multiple sclerosis, neuropathy or shingles. Currently there are no good medications to relieve chronic itch, therefore, knowing more about how we detect itch at a molecular level will help scientists develop medications to improve the quality of life of these patients.

About the brief writer: Solymar Rolon

Solymar is a PhD Candidate in Maria Geffen’s lab. She is studying the role of amygdala-thalamic projections in auditory behavior.

Want to learn more about what TRPC3 does in itch modulation? Check out Peter’s full paper here.

I can almost see it now: How having a more vivid visual imagination makes us less willing to wait.

or technically,

The Vivid Present: Visualization Abilities Are Associated with Steep Discounting of Future Rewards.

[See Original Abstract on Pubmed]

Authors of the study: Trishala Parthasarathi, Mairead H. McConnell, Jeffrey Luery, Joseph W. Kable

Most of us struggle to make better life choices. We may be trying to lose weight, but those cookies look delicious. We probably should get a good night’s rest, but Netflix is already loading the next episode of our favorite show. In each of these situations we have to decide between two different types of rewards: one that is instantly gratifying but may not improve our life in the long run, and one that won’t pay off immediately but could ultimately be more satisfying. Often we end up choosing the short-term and potentially less rewarding option. How do people make these decisions? Is there something we can do to make it easier to wait for a reward?

To answer these questions, researchers have started to investigate what things make people choose short-term or long-term rewards. The primary result found by these studies is that people are more willing to wait for future rewards when they are instructed to imagine the future before making their choice. Researchers have suggested that imagining the future makes long-term rewards seem more attainable or less far away in time, so people are more willing to wait for them. Given this hypothesis, Trish Parthasarathi, a graduate student in Dr. Joe Kable’s lab, made two predictions. First, she predicted that people who had more vivid visual imaginations, and therefore could more easily imagine the future, would be more willing to wait for future rewards. Second, she predicted that training people to improve their visual imaginations, and thus making it easier to imagine the future, would also make them more willing to wait for future rewards. Testing this second prediction was very important as it would establish whether people who happened to have more vivid visual imaginations just happened to be more willing to wait for rewards (that is, that the two are correlated) or if people were more willing to wait for rewards because they had a more vivid visual imagination (that is, one causes the other).

Trish designed a study to test her two predictions. At the beginning of the study, she used a well-established questionnaire to measure the vividness of each participant’s imagination. Then, to evaluate how patient they were at waiting for future rewards, Trish had each participant do a task in which they were repeatedly asked to choose between a smaller monetary reward that they would receive immediately and a larger reward that they would receive later. The immediate rewards ranged between $10 and $34. The delayed rewards were either $25, $30, or $35 and were always larger than the immediate reward. The wait time ranged from one day to 6 months. For example, one choice might be whether to receive $11 immediately, or $30 in 24 days.

After participants had performed this task once to assess their patience for reward, they were randomly assigned to either a control relaxation training or visual imagination training group. In both groups, participants were led through mindfulness meditations. In these meditations, individuals are asked to bring awareness to their bodies, breathing, and the physical sensations they are currently experiencing and to use this awareness to help them relax in the present moment. In the imagination training group, participants were also asked to focus on a goal that they would like to achieve in the future. Specifically, they were led through two vivid scenarios in which they could imagine overcoming potential obstacles and experience the feelings of achieving their goal. Thus, the main difference between the two groups is that the control group was asked to think about the present only while the training group was specifically asked to think about the future. After 4 weeks of training, all participants redid the questionnaire to see if their visual imagination had improved and redid the decision task to see what effect the training had on their ability to wait for rewards.

Trish and her colleagues predicted three results from these experiments. First, they predicted that people who had more vivid imaginations would be more likely to choose the larger, later rewards in the task. Next, they predicted that the participants who went through the visual imagination training would have more vivid imaginations. Finally, they predicted that those individuals who had improved the vividness of their imaginations would be more likely to choose the larger later reward than before they had completed the training.

Surprisingly, Trish’s findings were the exact opposite of two of these predictions! She observed that people who had more vivid visual imaginations were actually less likely to choose to wait for the larger, later reward in the task. She also found that while the visualization training program did successfully improve participants' visual imagination compared to the control relaxation training group, these individuals became more impatient: they were now less likely than they were before training to choose to wait for the later reward in the task.

Trish and her colleagues offered a couple of possible explanations for why they observed these unexpected results. One explanation is that the visual imagination training actually ended up making future results seem as though they were further away or had already been achieved, thus pushing people towards focusing on the present. In other words: people might imagine the obstacles so clearly that they wouldn’t want to face them, or they might imagine the reward so vividly that they felt that it was already achieved. Either of these imagined scenarios could lead them to refocus on the present reality instead of the future reward. The other explanation Trish and her colleagues proposed is that we can use our imagination to imagine the present or the future, but the present is often already more vivid and easily imagined. Thus, when people were trained to visualize more effectively, the present actually became even easier to imagine and thus people were biased towards the present. Finally, they also noted that although we often think of being less patient as a bad thing, there are times when choosing the more immediate option may be beneficial. Always waiting for the perfect option can cause us to be indecisive and miss out on certain opportunities. This visualization training could be beneficial for helping people overcome indecision, but another study would have to be done to see if this is true.

There are two important points to take away from this study. First, this study demonstrates that unfortunately, sometimes the strategies that seem to make a lot of sense for improving our behavior don’t actually work. Fortunately, we can design scientific studies to test these strategies and make sure we aren’t following bad advice. Second, next time you are trying to stop yourself from grabbing some cookies or watching another hour of your show, trying to more vividly imagine how you would feel if you made each choice may not be the best way to go!

About the brief writer: Ron DiTullio

Ron is a PhD Candidate in the Cohen Lab and Balasubramanian Group whose work revolves around determining how the brain processes and stores information about the external world. Specifically, he focuses on how we are able to hear and recognize sounds as well as how we remember directions and events of our life.

To learn more about this exciting work, check out Trish’s full paper here.

Cognitive reserve: keeping your mind young while your brain ages.

Katerina Placek was the lead author on this study.

or technically,

Cognitive reserve in frontotemporal degeneration.

[See Original Abstract on Pubmed]

Authors of the study: Katerina Placek, Lauren Massimo, Christopher Olm, Kylie Ternes, Kim Firn, Vivianna Van Deerlin, Edward B. Lee, John Q. Trojanowski, Virginia M.-Y. Lee, David Irwin, Murray Grossman, Corey T. McMillan

We’ve all heard the stories of the 90-year-old who is as spry as they were at 50. The internet is teeming with theories as to what keeps these people so sharp in their old age. It turns out that the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of a 90-year-old chess champion may look the same as a 70-year-old with late-stage dementia. So, what’s the difference? To begin to get at this question, scientists are beginning to study “cognitive reserve”. Cognitive reserve refers to the observation that people who have amassed more “experiential resources”, such as education, social interactions or occupation, remain cognitively normal even when their brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. show significant degeneration. In other words, people with greater cognitive reserve are less susceptible to the memory loss and dementia that comes with old age.

The relationship between cognitive reserve and AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease has been well studied. Katerina Placek, a neuroscience graduate student at Penn in Corey McMillan's lab, wondered how cognitive reserve affects people with another common form of dementia caused by frontotemporal lobar degeneration (FTLD). As its name suggests, FTLD is characterized by a loss of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the frontal lobe and temporal lobe of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., which leads to behavioral, social and language impairments. Unlike in AlzheimerA disease (typically in older people) in which neurons die, causing people to lose their memories.’s disease, memory remains relatively intact in FTLD. To understand how FTLD and cognitive reserve interact, Katerina asked patients with FTLD to perform a cognitive task and compared this to their cognitive reserve score. Katerina found that patients with higher cognitive reserve performed better on a cognitive test of their language abilities. Specifically, participants in Katerina’s study were asked to name as many words as they could starting with the letters F”, “A”, and “S” for 1 minute each (these letters were chosen because they are some of the most common in the English language - try it yourself and see how you do!). Katerina first found that FTLD patients perform worse on this task than healthy participants, which is not surprising given the known language deficits associated with FTLD. Interestingly, Katerina found that among FTLD patients, those with higher cognitive reserve were able to name more words than patients with lower cognitive reserve for each letter. Katerina also looked at the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of these patients using an MRI, and she saw that those with higher cognitive reserve also had less degeneration in their frontal and temporal lobes, the most affected regions in FTLD.

While your genesA unit of DNA that encodes a protein and tells a cell how to function may play a role in cognitive reserve, Katerina’s finding tells us that there are environmental factors at play too. Maybe you’ve heard of one of the many apps and games (Lumosity and Cognifit are two examples) that claim to improve your memory or your cognition. There is not yet consensus among scientists about the efficacy of these games, but in general, be wary of such claims. Instead, continue to learn, have interesting conversations with friends, and seek out experiences that challenge you to think. By doing so, we make our brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. stronger and more resilient to the detrimental effects of aging.

About the brief writer: Emily Feierman

Emily is a second year graduate student interested in understanding how complex learning processes are disrupted in neuropsychiatric disease.

Want to learn how to keep your brain strong and nimble? Find  Katerina Placek’s full paper here!

A medication for opioid addiction may also help people suffering from depression.

or technically,

A role for the mu opioid receptor in the antidepressant effects of buprenorphine.

[See Original Abstract on Pubmed]

Authors of the study: Shivon A. Robinson, Rebecca L. Erickson, Caroline A. Browne, Irwin Lucki

Do you know someone frustrated by ineffective antidepressant treatment? Nearly one-third of patients with depression will not find relief with current antidepressant medication¹. Creating new medications for depression is tricky, because we still do not completely understand what is happening in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Furthermore, even if we developed a new antidepressant today, it would take over a decade for that medicine to become available to patients due to FDA regulations. To get around this issue, researchers are interested in finding new applications for drugs that have already been FDA approved for other illnesses. Repurposing an already-approved medication can greatly reduce the amount of time it takes for patients to receive effective treatment! Buprenorphine is a medication currently approved for the treatment of opioid addiction. Shivon Robinson, a neuroscience graduate student in Irwin Lucki’s lab, investigated whether buprenorphine could also be used to fight depression.

In her paper, Shivon demonstrated that buprenorphine reduced measures of depression in mice and she wanted to know how buprenorphine was having these effects. To assess depression-like symptoms in mice, she used what is called the “novelty-induced hypophagia” test, or NIH. NIH involves placing yummy treats (in this case, peanut butter chips) in the middle of an open, brightly lit chamber. Mice are generally wary of bright, open spaces so they will take some time to investigate the rest of the chamber before going to snack on the peanut butter chips. Conventional antidepressant medications will reduce the amount of time it takes for the mouse to approach the peanut butter chips, so other medications that do the same thing are thought to have similar effects as traditional antidepressants. She found that giving buprenorphine to mice before the test reduced the amount of time it took for the mice to approach the treats – just like current antidepressants!

After establishing that buprenorphine mimics traditional antidepressants in this task, Shivon wanted to know what buprenorphine was doing in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to help reduce depression-like symptoms in mice. Drugs interact with the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. by binding to receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron., which convey chemical messages to neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles and other cells. There are many different types of receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. produced by cells, and they only respond to specific drugs and molecules. When buprenorphine reaches the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., it binds to several types of receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron., two of which are kappa opioid receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. and mu opioid receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron.. Shivon wondered if buprenorphine binding to one of these receptorA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. types was important for the antidepressant effects they observed. She found that buprenorphine reduced depression-like behaviors in mice by binding to the mu opioid receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron., not the kappa opioid receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron.. She further validated this finding by using a different drug, cyprodime, that binds exclusively to mu opioid receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron.. Cyprodime also reduced the amount of time it takes for mice to approach the peanut butter chips, supporting the idea that activation of mu opioid receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. by buprenorphine is important for antidepressant effects on this task.

This study represents an important step towards finding a potential new treatment for depression, an illness that affects nearly 7 million Americans annually. Depression is a disease that affects many different parts of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Shivon’s work demonstrates that mu opioid receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. may play an important role in depression. Uncovering new ways that depression affects the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. can help us find effective treatments for patients that fail to respond to current antidepressants.

Meet the brief writer: Lexi Ellis

Citations:

1. Ionescu DF, Rosenbaum JF, Alpert JE. Pharmacological approaches to the challenge of treatment-resistant depression. Dialogues Clin Neurosci. 2015;17(2):111–126.

If you are interested, check out this cited paper here.

Are teens uniquely susceptible to long-term effects of stress?

or technically,

Adolescent Chronic Unpredictable Stress Exposure Is a Sensitive Window for Long-Term Changes in Adult Behavior in Mice.

[See Original Abstract on Pubmed]

Authors of the study: Nicole L Yohn & Julie A Blendy

Stress happens. Whether it’s a dead car battery or a looming work deadline, stress is a fact of life. However, the types of stressors we experience and how they might affect us are constantly changing. Adolescence is one stage of life where these changes are particularly apparent. Most of us can appreciate how the nature of stressors change during adolescence (school pressures, dating and friendships, availability of drugs/sex/alcohol, huge physical and emotional developments, etc.), but less appreciated are the ways in which teens may be uniquely susceptible to the long-term and detrimental effects of these stressors.

This question of if and why adolescents are especially sensitive to stress shaped Nicole Yohn’s research at the University of Pennsylvania in the laboratory of Dr. Julie Blendy. Previous research has shown that human brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development is not fully completed until about the age of 25. In this sense, our brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are still undergoing tremendous remodeling during our teenage years. Nicole wondered if exposure to stress during this period of continuing brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development may contribute to the increase in mental disorders, like anxiety, depression, and drug abuse, which often emerge during these years. This was an important question-- even though there’s plenty of research linking stress to mental disorders, there are very few studies looking at how the two are connected. Nicole set out to bridge that gap.

One of the most important (and most frustrating) aspects of stress is that it’s both chronic and unpredictable. In order to best model these aspects of stress in the lab, Nicole created a mouse model and designed her experiment such that each mouse was exposed to three different types of stressors a day for twelve consecutive days. These stressors consisted of things like food restriction, exposure to cold temperatures, isolation, and other unpleasant situations. To ask whether exposure to stress during adolescence is more damaging than exposure to stress during adulthood, Nicole compared two groups of mice-- one that faced these chronic and unpredictable stressors during puberty and one that experienced the stressors during adulthood. Both groups of mice were tested for behaviors associated with anxiety and depression, the most prevalent stress-related disorders.

So, does stress during particular stages of development alter susceptibility to mental illness? Nicole found that it seems to depend on exactly which mental illness we’re talking about. For example, Nicole observed depression-like behaviors in all mice exposed to stress, regardless of whether they experienced that stress during puberty or adulthood. In contrast, anxiety behaviors only appeared if stress occurred during adolescence, not adulthood. The sex of the mice also seemed to be an important factor in effects of stress on behavior. In one behavioral assessment, female mice showed more anxiety than males. This might mean that how we respond to stress may have something to do with sex-specific hormonesA substance produced in the body that controls or regulates the activity of certain cells or organs. Many hormones are produced by special glands and travel through the blood to reach the location in the body where they act..

Speaking of hormonesA substance produced in the body that controls or regulates the activity of certain cells or organs. Many hormones are produced by special glands and travel through the blood to reach the location in the body where they act. and chemicals, Nicole wanted to look for a chemical that might underlie the different effects stress has on adolescents versus adults. One chemical she chose to investigate was corticotropin releasing factor (Crf) -- a hormoneA substance produced in the body that controls or regulates the activity of certain cells or organs. Many hormones are produced by special glands and travel through the blood to reach the location in the body where they act. that’s released in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. when we feel stressed. Crf is responsible for the extra alertness or the feeling of butterflies in our stomachs we might notice before doing something important, like giving a presentation. While a short-term boost of Crf might be helpful in focusing our attention on the task at hand, too much Crf can be a bad thing. When looking at Crf levels in the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of her mice, Nicole found increases only in mice that were exposed to stress during adolescence. Interesting, right? It seems like this increase in Crf could be what’s causing the development of anxiety in adolescent but not adult animals.

What do we know for sure? Nicole’s work suggests that mice are especially susceptible to stress during adolescence. She also showed that being female might make you even more susceptible to the long-lasting effects of stress. While more research is needed to determine whether these findings hold true for humans, Nicole has established a good model for future studies to look into how stress affects us throughout our lives, and how we might be able to prevent or lessen the damage it causes.

About the brief writer: Kara McGaughey

Fascinated by the long-standing linguistic connection between the gut and the brain ("gutsy," "gut feeling," "gut instinct," etc.), Kara is using her second year in NGG to examine the interplay between microbiota and brain development.

Can anti-diabetes drugs be repurposed to treat cocaine addiction?

or technically,

Glucagon-like peptide-1 receptor activation in the ventral tegmental area attenuates cocaine seeking in rats.

[See Original Abstract on Pubmed]

Authors of the study: Nicole S. Hernandez, Kelsey Y. Ige, Elizabeth G. Mietlicki-Baase, Gian Carlo Molina-Castro, Christopher A. Turner, Matthew R. Hayes, & Heath D. Schmidt

Addiction is a disease affecting the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., and neuroscientists have been trying to figure out how to best treat it. Cocaine addiction is a major problem in the United States. Cocaine is the second deadliest illicit drug following opioids and actually claims more lives than opioids in certain racial groups.¹ Unfortunately, people facing cocaine addiction today have very few treatment options. Nicole Hernandez, a graduate student in Heath Schmidt’s lab, studies cocaine addiction using rats as a model to try to find effective treatments. In 2015, Dr. Schmidt’s lab discovered a drug already used to treat diabetes actually reduces the amount of cocaine rats will consume.² These experiments were done when the rats had free access to cocaine. The major hurdle in the treatment of cocaine addiction, however, is preventing relapse after quitting because of drug cravings. Nicole wondered how this drug might affect the amount rats will work to obtain cocaine when it is not readily available. Seeking to answer this question, she tested if the drug could potentially reduce cocaine craving and relapse.

So what is this drug, and how does it work? In the last decade, the FDA approved several drugs for the treatment of Type II Diabetes. One of these drugs, Exendin-4, works by acting like a hormoneA substance produced in the body that controls or regulates the activity of certain cells or organs. Many hormones are produced by special glands and travel through the blood to reach the location in the body where they act. that is released by cells in the intestine and neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., called glucagon-like peptide-1 (GLP-1). In the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., GLP-1 binds to GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. and activates them, which stimulates neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that reduce food intake. Exendin-4, the drug used in Nicole’s study, also activates GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. and therefore has the same effect as GLP-1 itself. GLP-1, aside from reducing food intake, also affects the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.'s reward system. Since drugs of abuse act on this system, Dr. Schmidt’s lab tested whether Exendin-4 would affect the rewarding properties of cocaine. Indeed, Exendin-4 decreased the amount of cocaine rats took when given free access to the drug. However, it still wasn’t clear how Exendin-4 would affect cocaine craving. Craving can be measured by determining how hard rats are willing to work to get more cocaine, which they call cocaine seeking behavior. Specifically, they tested how many times rats would press a lever that was previously paired with cocaine but was no longer. Nicole found that treating rats given Exendin-4 did not work as hard to seek out cocaine: there was a decrease in cocaine seeking. This suggested that rats did not crave cocaine as much after receiving Exendin-4. Interestingly, this was the case even when given doses of Exendin-4 that were too low to affect food intake and body weight, suggesting that this medication may be used in cocaine addicts without any adverse effects such as weight loss or changes in appetite. As such, maybe Exendin-4 could be a first step in curbing drug relapse!

Armed with this interesting finding, Nicole tried to understand where this drug might be acting in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. She thought it might be acting in the ventral tegmental area (VTA). The VTA is a region of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. rich in GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. and part of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.’s reward system that is very active in response to cocaine. To see if Exendin-4 might be acting in the VTA to reduce cocaine seeking, she blocked GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in the VTA and repeated the experiment. When GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in the VTA were blocked, Exendin-4 no longer reduced cocaine seeking. Remember, Exendin-4 normally activates GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron., so this result suggests that in order for Exendin-4 to reduce cocaine seeking, it needs to be able to activate GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in the VTA. This is very strong evidence that Exendin-4 reduces cocaine seeking by activating GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions involved in reward.

This study uncovered a possible new use for drugs that activate GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron., like Exendin-4. It also opens the door to several future experiments. For example, while Nicole showed that activating GLP-1 receptorsA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. in the VTA might reduce cocaine seeking, it is still not clear how this happens. The VTA is a region of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. that produces dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion.. DopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. is a chemical typically released during pleasurable experiences, such as food consumption and social interactions. Cocaine and other drugs of abuse hijack this system, increasing dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. signalling, which promotes addiction. It is possible that GLP-1 receptorA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. activation decreases the amount of dopamineA neurotransmitter produced by neurons in the brain that regulates movement and emotion. that is released to the rest of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. , which might blunt the addictive property of cocaine. While more research is needed to support this hypothesis, Nicole’s study sheds light on a possible new use for GLP-1 receptorA molecule that binds to a chemical signal and causes a change inside a cell. For example, a receptor on the outside of a neuron can bind to a neurotransmitter released from a different neuron. activators such as Exendin-4, already on the market to treat diabetes, in the treatment of cocaine addiction.

About the brief writer: Nitsan Goldstein

Nitsan is a third year graduate student in Nick Betley’s lab. She is interested in how the brain senses the energy needs of the body and coordinates appropriate behaviors

Citations:

1. Warner M, Trinidad JP, Bastian BA, et al. Drugs most frequently involved in drug overdose deaths: United States, 2010–2014. National vital statistics reports; vol 65 no 10. Hyattsville, MD: National Center for Health Statistics. 2016.

2. Schmidt HD, Mietlicki-Baase EG, Ige KY, Maurer JJ, Reiner DJ, Zimmer DJ, et al. Glucagon-like peptide-1 receptor activation in the ventral tegmental area decreases the reinforcing efficacy of cocaine. Neuropsychopharmacology. 2016;41:1917–1928.

Formatted link to the paper goes here.

How you find what you’re looking for.

or technically,

Signals in inferotemporal and perirhinal cortex suggest an untangling of visual target information.

[See Original Abstract on Pubmed]

Authors of the study: Marino Pagan, Luke S Urban, Margot P Wohl, Nicole C Rust

Finding Your Keys
You are late and the Uber is already outside. Where are your wallet and keys? You scan the nearest table. A dirty coffee cup, excessive CVS coupons, and at last, you see your wallet and keys, poking out from under a shirt. While this process might seem effortless, quickly finding what you are looking for in a crowded scene -- a process called “visual search” -- is an ability that even sophisticated computer programs have trouble with ¹. Marino Pagan in Nicole Rust’s lab at the University of Pennsylvania spent his PhD studying exactly how our brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. can quickly and flexibly find what we’re looking for out of everything we are looking at.

However, this question has been difficult for scientists to answer. Before Marino performed his experiments, it was unknown which part of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. was responsible for visual search. In other words, scientists hadn’t yet been able to identify neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that specifically respond when what you are looking for matches what you are looking at. Additionally, it was unknown how any brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. area would combine the information about what you are looking for and what you are looking at. How do scientists go about answering where and how the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. identifies different visual search “targets?” Before we tell you the results, we’re going to break down the approach Marino took to answering these questions.

Where in the BrainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.?
Let’s first examine the question of where -- where are the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. that are responsible for identifying visual search targets? We can answer this question by guessing what the activity of a brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. area that identifies search targets would look like and then looking for brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. areas with activity that matches our hypothesis. Like we mentioned before, neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in this area would respond or “turn on” when what you are looking at matches what you are looking for. In our earlier example about getting to your Uber, we would guess that a visual search area would turn on when you were looking at your wallet, or your keys, but not the coffee cup. However, in a different situation--let’s say making coffee--what you are looking for is different. This time, the visual search area would respond when you look at the coffee cup, but not the other items. Essentially, the visual search area should turn on when you are looking at the item you were searching for.

How?
Now let’s examine how the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. figures out whether what you’re looking at matches what you’re looking for. All information in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. is represented as different patterns of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles turning on - or “firing.” For example, a pattern in which all neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles fire could mean something different than a pattern in which only half the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles fire. In order for the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to determine whether what you’re looking for matches what you’re looking at, the pattern of neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles firing in the visual search area must be different for matches versus non-matches. When your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. can differentiate - or separate - the neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles firing patterns for matches and non-matches, you will be able to distinguish between the two categories in the real world! So our question of how now becomes more specific - how does the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. separate patterns of firing for matches and non-matches? It turns out, there are many ways that the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. can separate firing patterns! Learning which ones the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. uses not only teaches us about how our brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. work, but can also help us build better computer algorithms to perform search tasks- not just for finding keys on a table, but for, say, identifying faces in a crowd.

Although the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. has a lot of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles, we’re going to think about different ways to separate firing patterns by pretending there are only two neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. area responsible for visual search. In this situation, one way for the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to determine whether a firing pattern says “match” or “no match” is to make a simple rule that divides the patterns into two groups. One example of a rule could be “If neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles 1 is firing more than neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles 2, you are looking at a match. Otherwise, you are not”. This rule is shown in Fig 1, on the left. Notice how the rule makes it easy to draw a straight line that perfectly puts all matches on one side of the line, and all non-matches on the other. This type of neural firing is said to be linearly separable. It is linear something that can be represented as a straight line on a graph, and directly proportional changes in two related quantities because a simple, straight line can separate the two categories. This way of separating firing patterns is both very reliable and very easy for the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to do! Other ways of separating might require many more complicated rules (an example of this is shown in Fig 1, right). Therefore, linearly separable neural firing is good candidate for how the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. might distinguish between search targets versus other objects.

With all this in mind, Marino Pagan and his PhD advisor Nicole Rust could make hypotheses about how the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. identifies different visual search “targets” and which area of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. is responsible for this: 1) the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.’s “visual search area” would turn on when what you are looking for matches what you are looking at, and 2) neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in this visual search area will have separable firing patterns for matches vs. non-matches. To test these hypotheses, they did one experiment to recreate the process we go through when looking for our keys.

Figure 1

Results
First, Marino trained monkeys to recognize specific, everyday objects (i.e. keys or wallet) in a sequence of images interspersed with other objects (i.e. the coffee cup). They then looked for (1) where in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. there was activity specific to targets and (2) how this region separated its firing patterns for matches and non-matches (i.e. were they linearly separable). They narrowed their search to two regions of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.: the inferior temporal lobe and the perirhinal cortex. The inferior temporal lobe is a part of the visual system and is thought to be the first place that memory (i.e. what you are looking for) and visual information (i.e. what you are looking at) are combined². The perirhinal cortex receives information from the inferior temporal lobe and is necessary for good performance on visual search tasks³.

Marino first asked whether either brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region had activity patterns that were selective for search targets. They found this selectivity to be much stronger in the perirhinal cortex than the inferior temporal lobe, suggesting that the where of visual search is primarily the perirhinal cortex (PRH).

To address how this selective activity arose, Marino then asked if neural firing in response to targets was more linearly separable in one brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region compared to the other. After looking over many neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles, they found that it was much easier to draw a simple line that separated targets from non-targets (similar to Fig 1, left) in perirhinal cortex compared to inferior temporal lobe. Together, Marino’s findings suggest that the perirhinal cortex codes information of the location of the search target, separated from other objects using , linearsomething that can be represented as a straight line on a graph, and directly proportional changes in two related quantities separability.

There are still many exciting questions to answer. What is the inferior temporal lobe doing to combine memory and visual information? How is the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. cell activity different in the inferior temporal lobe compared to perirhinal cortex? Do those differences contribute to the linearsomething that can be represented as a straight line on a graph, and directly proportional changes in two related quantities separability we see in the perirhinal cortex? Marino found that the answer was a bit more complicated. He found that the inferior temporal cortex may use non-linearsomething that can be represented as a straight line on a graph, and directly proportional changes in two related quantities separability, where flexible curves can separate visual and remembered information instead of rigid lines . The inferior temporal cortex then sends this information separable by flexible curves to the perirhinal cortex, which then may transform the information to again be separated by a line.

Conclusion
Like most problems in science, one experiment cannot fully and conclusively reveal everything there is to know about how we “search” with our eyes. However, the work of Marino Pagan and his mentor Nicole Rust takes important steps closer to this understanding, and adds valuable new information about where and how search targets are identified in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Not only does their work shine light on previously mysterious ways the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. supports everyday actions like visual search but it also provides a foundation to engineer computers that can scan and find objects as quickly and flexibly as we do.

Figure 2

About the brief writer: Jeni Stiso

Jeni is a PhD Candidate in Dani Bassett’s lab. Jeni is interested in cognitive and computational neuroscience. She is interested in how changes in the electrical activity of the brain help people learn things.

Citations:

1. https://medium.com/deep-dimension/an-analysis-on-computer-vision-problems-6c68d56030c3

2. Chelazzi, L., & Desimone, R. (1993). A neural basis for visual search in IT. Nature. 363, pages 345–347.

3. Meunier, M., Bachevalier, J., Mishkin, M. & Murray, E.A. Effects on visual recognition of combined and separate ablations of the entorhinal and perirhinal cortex in rhesus monkeys. J. Neurosci. 13, 5418–5432 (1993).

To learn more about how the brain helps us quickly identify what we’re looking for, check out the full paper here.

My back hurts, my hand hurts: is pain different in different parts of the body?

or technically,

Sparse genetic tracing reveals regionally specific functional organization of mammalian nociceptors.

[See Original Abstract on Pubmed]

Authors of the study: William Olson, Ishmail Abdus-Saboor, Lian Cui, Justin Burdge, Tobias Raabe, Minghong Ma, Wenqin Luo

Have you ever wondered why you can feel the details of an object with your fingertips, but not with your elbow? Your body detects sensations including touch and pain using specialized nerves that detect information in your environment and transmit it to your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Together, these nerves are called the “sensory system.” As you may have noticed, however, this system does not treat all body regions the same. This is why your fingertips are much more sensitive to touch stimuli than other parts of your body (imagine trying to feel Braille with the back of your hand). Our fingertips are very sensitive to touch mainly because they contain more ‘touch-sensitive’ nerve endings than other body regions.

Pain perception relies on ‘pain-sensitive’ nerve endings that are distinct from our ‘touch-sensitive’ nerve endings. But just like for touch, certain regions of our body, like our fingertips, are more sensitive to pain than others. Interestingly, unlike for touch, this is not because we have more ‘pain-sensitive’ nerve endings in pain-sensitive areas. In fact, we have relatively few ‘pain-sensitive’ nerve endings in our fingertips -- even though they are extremely sensitive to pain! This observation surprised Will Olson, a neuroscience graduate student in Wenqin Luo’s lab. He wondered how certain parts of the body are more sensitive to pain than others.

To figure this out, he carefully studied the shape and size of pain nerve endings in mice. These nerves are like wires that run all the way from your skin into your spinal cord. This means there are two endings of these nerves: one in the skin and one in the spinal cord. Will took a good look at both ends. He saw that, in general, ‘pain-sensitive’ nerves come in different shapes and sizes depending on where in the body they are found. Interestingly, he found that pain nerve endings have a low density in the mouse paw, just like in the human hand! The pain nerve endings in the paw also looked very similar to pain nerve endings in other parts of the mouse. This surprised Will because he knew that mice have very high pain sensitivity in their paws. He wondered, if the density and the shape of the pain nerves in the paw skin is the same as in other parts of the body, then why are paws so sensitive to pain?! The answer became clear when Will looked at these nerves in the spinal cord -- in the spinal cord, paw pain nerves look completely different from pain nerves that come from other parts of the mouse. Will hypothesized that the special shape of these paw pain nerves could enhance pain sensation in the paw. And in fact, Will found that these paw pain nerves are better at sending information to the spinal cord than pain nerves that come from other parts of the mouse.

While these findings are interesting and could even help some of us decide on the least painful place to get a tattoo, this study might also help people with chronic pain. Chronic pain occurs when people feel pain for weeks, months or even years. Based on this study, we may be able to identify specific causes of chronic pain in different parts of the body. For example, chronic back pain might be very different from chronic joint pain. Our current pain medications are not effective as treatments for many forms of chronic pain. The lack of good treatments has contributed to the increase in opioid prescriptions that led to opioid addiction crisis. Identifying more specific causes of chronic pain could give researchers ideas for better ways to treat it.

About the brief writer: Patti Murphy

Patti is a PhD Candidate in Michael Granato's lab. Patti is interested in understanding and developing therapeutics for functional nerve regeneration, particularly to restore voluntary motor control after spinal cord injury.

Do you want to learn more about how we feel pain? You can read Will’s entire paper here.

It’s all about balance. How a reduction in inhibitory signals in the developing brain could contribute to cognitive deficits in ASD.

or technically,

Exploring the relationship between cortical GABA concentrations, auditory gamma-band responses and development in ASD: Evidence for an altered maturational trajectory in ASD.

[See Original Abstract on Pubmed]

Authors of the study: Russell G. Port, William Gaetz, Luke Bloy, Dah-Jyuu Wang, Lisa Blaskey, Emily S. Kuschner, Susan E. Levy, Edward S. Brodkin, and Timothy P.L. Roberts

Autism spectrum disorder (ASD) is a developmental disorder characterized by difficulty with social communication and repetitive behaviors.¹ ASD persists for one’s entire life, with an estimated 1-2% of children currently diagnosed.¹ This is a twenty- to thirty-fold increase from the prevalence recorded in the late 1960s, when ASD was first characterized.¹ Experts believe that this sharp increase is mainly due to the fact that doctors and parents are more aware of ASD and what the symptoms look like.² Despite the fact that people who have ASD are born with the disorder, ASD is hard to diagnose in babies and is often unnoticed until the child begins falling short of social or academic benchmarks.¹ The ability to detect autism earlier in young children could make a big difference in how much doctors are able to do to improve the lives of those patients. Russ Port and his graduate advisor Timothy Roberts designed this study to learn more about what makes the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of people with ASD different from those of people who do not have ASD. The results of this study show promise for improving our ability to detect ASD earlier than is currently possible.

Russ knew that researchers in the field believed that ASD may be related to differences in how cells in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. communicate with one another. The brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. is made up of specialized cells called neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that can send information to one another via electrical and chemical signals. In order for the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to function normally, it must maintain a very careful balance between so-called ‘excitatory’ and ‘inhibitory’ chemical signals. Excitatory signals cause information to move from one neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to the next, while inhibitory signals stop information from moving on to the next neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles (think red/green lights in traffic signals). You need both kinds of signals to make sure that information ends up reaching its proper destination. The most important inhibitory chemical signal is called GABA. Scientists have found that people with ASD have less GABA in their brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. than people who do not have ASD. This leads to an imbalance between those excitatory and inhibitory signals in these people.

The electrical signals made by neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles sending information to one another can be measured from the scalp using electroencephalography. When a large group of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles is working together at the same time, they create waves of electrical signals called brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. waves. One kind of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. wave, gamma-band brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. waves (Gamma) are relatively fast, compared to the others. To get a better sense of what that means, see figure 1 below. You have the most Gamma in your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. when you are really alert: for example, during learning or sensory input (smell, taste, touch, etc.). The creation of Gamma is dependent upon proper levels of GABA during brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development. Since GABA is so important for the creation of Gamma, it may not surprise you to learn that Gamma, like GABA, are also reduced in people with ASD.

Figure 1. Brain waves (waveforms adapted from www.themusiciansbrain.com)

Russ wanted to look at this relationship between GABA and Gamma in his patients with ASD. He confirmed that participants who had ASD had lower levels of both GABA and Gamma than participants who did not have ASD. Interestingly, he also noticed that, in participants without ASD, those with more GABA also had more Gamma, and those with less GABA had less Gamma. In participants with ASD, no such relationship existed.

Excited about this unexpected result, Russ wondered why this relationship between levels of GABA and Gamma was absent in participants with ASD. He thought that it might have something to do with the way the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of people with ASD develop. Therefore, in the next part of the study, he decided to study young people and adults separately. He hypothesized that he would find age-related differences in the relationship between Gamma and GABA that would shed more light on the developmental differences between people with and without ASD. In this part of the study, he found that there was no difference in the levels of Gamma between young people with and without ASD. However, the young people with ASD had lower levels of GABA than those without ASD. We know that GABA is important for the development of Gamma in the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of young people. We also know that adults with ASD do have lower levels of Gamma than adults without ASD. The finding that there is a lower level of GABA in young people with ASD but not a lower level of Gamma is an important finding because it suggests that something happens during brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development that causes levels of Gamma in adults with ASD to be lower than what is seen in adults without ASD.

Russ also found that, in young people without ASD, the older a participant was, the more GABA and Gamma they had. This relationship was not present in young people with ASD. In this group, there was no correlation between levels of GABA or Gamma and age. So, in young people with ASD, there isn’t the same increase in both GABA and Gamma as the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. develops that is seen in young people without ASD. Furthermore, Russ found that there was no relationship between levels of GABA and Gamma with age in either adult group. This suggests that once the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. is finished developing, the levels of GABA and Gamma stop increasing. With low GABA to begin with, young people with ASD are not able to create enough Gamma to match the levels of people without ASD before the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. stops developing. These lower levels of Gamma become permanent in adulthood.

Broadly speaking, these data are a great case study for the importance of balance between inhibitory and excitatory signals in the developing brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Specifically, Russ’s work highlights the importance of the inhibitory signal GABA during early brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development. This work also suggests that monitoring the levels of GABA and Gamma in young children could be used as a possible screening tool to detect ASD earlier. Earlier detection could help doctors develop more effective interventions or strategies for children with ASD and their families.

About the brief writer: Brenna Shortal

Brenna is a third year student in Alex Proekt’s lab. She is studying the similarities and differences between sleep and anesthesia with the goal of understanding how we wake up.

Citations:

1. Autism and Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators. “Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2010.” Morbidity and Mortality Weekly Report: Surveillance Summaries, vol. 63, no. 2, 2014, pp. 1–21. 

2. Stephen J. Blumberg, Matthew D. Bramlett, Michael D. Kogan, Laura A. Schieve, Jessica R. Jones, Michael C. Lu. “Changes in Prevalence of Parent-Reported Autism Spectrum Disorder in School-Aged U.S. Children: 2007 to 2011-2012. National Center for Health Statistics Reports.” National Center for Health Statistics, number 65, 2013.

Do you want to learn more about ASD and development? You can read Russ’s whole paper here.

Why does a brain with dementia make a person forgetful?

or technically,

Differential α‑synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril‑induced toxicity.

[See Original Abstract on Pubmed]

Authors of the study: Esteban Luna, Samantha C. Decker, Dawn M. Riddle, Anna Caputo, Bin Zhang, Tracy Cole, Carrie Caswell, Sharon X. Xie, Virginia M. Y. Lee, Kelvin C. Luk

Why do we become more forgetful as we age? What makes some of us, who develop dementia, become more forgetful than others? Scientists at the University of Pennsylvania think the answers to these questions lie in physical changes that happen inside your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. as you get older. Esteban Luna, a neuroscience graduate student working in the laboratories of Drs. Virginia Lee and Kelvin Luk, set his focus on a particular area of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. called the hippocampus. The hippocampus is well-known for being the site of learning and memory in most mammals - from humans all the way to mice!

So what happens inside the hippocampus that researchers think could cause dementia? Esteban and other scientists think it all comes down to a proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. in your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. not working as it normally does: it doesn’t fold correctly, and becomes “sticky” in this wrong shape. The proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. they think is the culprit in dementia is called alpha-synuclein (we’ll call it aSyn for short). The sticky, misfolded aSyn builds up inside neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles which makes them get sick and even die. When neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. don’t function properly they can’t communicate with the other cells around them, and whole regions (like the hippocampus) can end up being “short-circuited” or impaired! But how do you get lots of the messed up proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. inside neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles? Scientists still don’t really know how that process begins in humans, but they’re trying to figure it out by artificially mimicking this proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. “build-up” in mice in the lab. In order to do that, scientists can begin by injecting a little bit of misfolded aSyn into the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Then, like a snowball effect, once there’s a little bit of the misfolded aSyn, the aSyn already inside the cell also begins to misfold and become sticky. As misfolded aSyn builds up, the cells get sicker and sicker, and can eventually die. What does this cell death have to do with memory? Well, Esteban Luna and colleagues think that when the build-up of misfolded aSyn leads to lots of cell death in the hippocampus (the memory center), we begin to experience problems with memory.

To test this idea, Esteban did just that: he injected a little bit of misfolded aSyn into the hippocampus of some mice and then looked at sections of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. after some time had passed to see what was happening to the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in the hippocampus. One of the first things he noticed was that the different parts of the hippocampus looked different: some areas had lots of misfolded aSyn, some had less, and some parts had barely any! He noticed that this pattern also correlated with the patterns of cell death. In other words, places that had lots of misfolded aSyn were the same places where lots of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles had died, and in places that had very little misfolded aSyn, most of the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles stayed alive.

Next, Esteban wondered if the different parts of the hippocampus had different amounts of normal aSyn to begin with, and if that might be why different areas responded differently to the “sticky” or toxic aSyn he was injecting. His idea was that if some neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles had more regular aSyn to begin with, there would be more proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. available to misfold when he injected the sticky version. The hippocampus is normally made up of many different types of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles, which ends up being really useful for researchers. This allowed Esteban to grow different types of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in a dish and look at how much regular aSyn they had at baseline. When he grew the different kinds of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles, he saw that the cells from the area with lots of misfolded aSyn and lots of cell death had lots of the aSyn to begin with. Remember, this is without any disease or injection of any kind. Similarly, the type of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles from the part of the hippocampus with very little misfolded aSyn and cell death had low levels of regular aSyn at baseline when grown in a dish. So what does all of this mean? It means that Esteban’s idea was right - neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that have more of the regular aSyn to begin with are more susceptible to developing pathology (sticky, misfolded proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies.) and toxicity (cell death) than neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that have less normal aSyn.

Finally, in order to find out if more initial aSyn actually causes the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to accumulate more misfolded aSyn during disease, Esteban performed a really cool experiment where he grew neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles in a dish that completely lacked any aSyn. Then, he gave these neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles a little bit of misfolded aSyn which normally snowballs to cause lots of buildup inside the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles, and eventually leads to cell death. What did he find? There was almost no pathological buildup of misfolded aSyn inside the cell, and almost no cell death either! The toxic aSyn had no regular aSyn inside the cell to trigger misfolding of. This means that expression of regular aSyn inside the cells is required for the cells to develop pathology in response to the misfolded aSyn.

So what does this mean for humans with memory problems and dementia? For certain types of dementia that have buildup of misfolded aSyn and consequent cell death, Esteban’s work sheds light on some of the mechanisms of how that works and why some parts of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are more susceptible to this damage than others. For example, certain areas of the hippocampus have cells that have lots of regular aSyn to begin with, and these are the cells that are susceptible to a toxic buildup of misfolded aSyn and eventual death. Hopefully, his work can help inform other kinds of research aiming to develop drugs that slow/stop the progression of dementia without harming other, healthy parts of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. in the process. Keep an eye out for all the cool work Esteban and his team at UPenn do in the future!

Want to learn more about memory problems in older adults? Check out Esteban Luna’s full paper here.

About the brief writer: Lyles Clark

Lyles is a fourth year student in Amelia Eisch’s lab. Lyles studies how neurons that are born after a traumatic brain injury contribute to pathology and hippocampal circuit dysfunction.

Does connecting with other people get harder as you get older?

or technically,

Social Coordination in Older Adulthood: A Dual-Process Model.

[See Original Abstract on Pubmed]

Authors of the study: Meghan L. Healey and Murray Grossman

Being able to relate to and connect with other people is an important part of staying happy and healthy at any age. Connecting with other people is especially important for your mental health. Having close friendships makes a stressful day not feel as bad and can even make it less likely that you experience anxiety or depression¹. But for older adults, it can become more difficult to stay connected. NGG student Meghan Healey and her mentor Dr. Murray Grossman wanted to ask why that might be- are there any skills that take a hit as you get older and contribute to this increased risk of social isolation?

Social coordination is the process of making sure that you and another person understand a situation or problem that you are working on together. One example of social coordination is giving directions on a road trip. You need to use the information you have available (road signs, landmarks, and the map/GPS) and what you know about what the driver is seeing to get to where you need to go.

Social coordination requires two main skills: working memory and perspective-taking. Working memory is the ability to mentally keep information on-hand for 10 to 60 seconds at a time to easily use when needed. When giving directions, you use your working memory to remember the upcoming turns and whether they are lefts or rights, while also keeping in mind where you currently are. Perspective-taking involves picturing what another person might be seeing as well as considering what they might know or need to know in a particular situation. For example, figuring out which landmarks/road signs the driver can easily see is an example of perspective-taking.

While we don’t know what happens to your social coordination abilities as you get older, working memory and perspective-taking are more studied. Several studies found that working memory gets worse with age. However, the case is still open on whether perspective-taking ability gets better or worse over time. So, Meghan set out to measure how working memory, perspective-taking, and social coordination change as we age.

Meghan came up with a clever way to test each of these skills in the same task. She designed a game where the person playing sees a board with a bunch of objects on it. Next to the board is a cartoon avatar that sometimes can also see the board and sometimes can’t see it as well. It is the player’s job to ‘help’ the avatar by describing which object moves on the board. The amount of information the player gives (too little, too much, or just enough) tests perspective-taking and the number of objects that need to be considered tests working memory. For example, if the avatar is facing the board, then it doesn’t need as much information as when it is facing away from the board. Players that give the too much information when the avatar is facing the board, likely lack perspective taking skills (in this case, the ability to imagine what the avatar can see based on which way it is facing). How well people perform on the game measures social coordination. To test the effect of age on these skills, she asked young adults (20-30 years old) and older adults (56-60 years old) to play this game.

She found that older adults had more difficulty with the parts of the game that tested both working memory and perspective-taking. These results suggest that older adults had worse overall social coordination abilities. Based on what we know from other studies, worse social coordination abilities can lead to difficulties in forming and maintaining relationships. This provides a clue as to why older adults might be more likely to spend time alone than with friends. Based on these findings, we could benefit from future research that tackles how we can improve perspective-taking abilities of older adults to help them build towards healthier social lives.

About the brief writer: Sara Taylor

Sara is a third year graduate student interested in the genetic basis for social behaviors in autism.

Citations:

1. Ganster, D. C., & Victor, B. (1988). The impact of social support on mental and physical health. British Journal of Medical Psychology, 61(1), 17-36.

If you are interested in learning more about how aging changes the way we interact with one another, check out Meghan’s paper here.