BRAINS IN BRIEFS
Scroll down to see new briefs about recent scientific publications by neuroscience graduate students at the University of Pennsylvania. Or search for your interests by key terms below (i.e. sleep, Alzheimer’s, autism).
A gene linked to schizophrenia? New insights and new models for the devastating disorder.
or technically,
Loss of the neurodevelopmental gene Zswim6 alters striatal morphology and motor regulation.
[See Original Abstract on Pubmed]
or technically,
Loss of the neurodevelopmental gene Zswim6 alters striatal morphology and motor regulation.
[See Original Abstract on Pubmed]
Authors of the study: David J. Tischfield, Dave K. Saraswat, Andrew Furash, Stephen C. Fowler, Marc V. Fuccillo, Stewart A. Anderson
Thanks to recent advancements in technology, scientists have been able to identify genesA unit of DNA that encodes a protein and tells a cell how to function that are associated with all sorts of diseases and disorders. Two such studies1,2 have linked ZSWIM6, a geneA unit of DNA that encodes a protein and tells a cell how to function of unknown function, to schizophrenia and other severe neurodevelopmental disordersA disorder in which the development of the central nervous system is disturbed, which often leads to neuropsychiatric problems or impaired function. Building off of these previous studies, David sought to characterize this geneA unit of DNA that encodes a protein and tells a cell how to function in mice and determine its role in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development and disease.
Based on studies performed in humans, we know that patients with schizophrenia often have abnormalities in 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. called the striatumA region in the front of the brain that is critical for motor and reward system - a region that plays a role in regulating voluntary movements. This makes sense as many symptoms of schizophrenia are movement-based: agitation, repetitive movements, lack of restraint, impaired coordination, etc. Interestingly, Zswim6 (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. encoded by the Zswim6 geneA unit of DNA that encodes a protein and tells a cell how to function in mice) is present in very high levels in this region. David therefore wondered if Zswim6 dysfunction in the striatumA region in the front of the brain that is critical for motor and reward system, specifically, could cause developmental brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. abnormalities that could explain some of the symptoms of schizophrenia. To test this, he deleted this geneA unit of DNA that encodes a protein and tells a cell how to function in a group of mice, and then compared the behaviors and brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development of mice with and without Zswim6.
In terms of neurodevelopment, David found that mice lacking Zswim6 had smaller striata than the mice who had normal levels of Zswim6. In line with this, the mice lacking Zswim6 also had a reduced number of medium spiny neuronsA special type of cell located in the human striatum, especially important in the transmission of dopamine. (the main type of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. cell that makes up the striatumA region in the front of the brain that is critical for motor and reward system), as well as significant abnormalities in the structure of these cells. David then performed behavioral experiments on the mice lacking Zswim6 to determine if there were any changes in motor learning and overall behavioral control (remember: the striatumA region in the front of the brain that is critical for motor and reward system is important for regulating movements). Indeed, David found that the mice lacking Zswim6 did show differences in movement-related behavior. Not only did they have a harder time balancing on a rotating "treadmill" of sorts, but the mice without the Zswim6 geneA unit of DNA that encodes a protein and tells a cell how to function also tended to be a lot more hyperactive (think: sprinting around their cage). This hyperactivity was further increased when the mice were given a low dose of amphetamine (a stimulant drug similar to Adderall that speeds up your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. and your movements). However, this increase in hyperactivity with amphetamine was only seen in the mice lacking Zswim6 - low doses of the drug had no effect on regular mice. This finding is important as extreme sensitivity to amphetamines is a common symptom in humans suffering from schizophrenia, and these drugs can actually induce psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways in those who take them. Therefore, this result further links Zswim6 to specific aspects of schizophrenia.
David’s work not only gives us more information about an important geneA unit of DNA that encodes a protein and tells a cell how to function that we previously knew nothing about, but it also provides the field with a new mouse model, the Zswim6 “deleted” mice, that could be extremely useful in future studies of schizophrenia and its related disorders. In particular, this model reproduces the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region abnormalities, movement problems, and hypersensitivity to amphetamines that are seen in humans with schizophrenia. As schizophrenia is chronic, debilitating, and currently without cure, finding effective ways to study it are of the utmost importance. David’s work leads the way towards understanding the science behind such misunderstood and devastating disorders.
About the brief writer: Kelsey Nemec
As a 2nd year NGG student, Kelsey is interested in using neural stem cells to study neurodevelopment and neurodegeneration in various diseases and disorders.
Citations:
Ripke, S., et al., 2013. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45:1150–1159. Read it here.
Schizophrenia Working Group of the Psychiatric Genomics, C, 2014,. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427. Read it here.
Want to learn more about how researchers study neurodevelopmental disorders like schizophrenia? You can find David’s full paper here!
Old genes: how the genetics of aging may play a role in Parkinson’s disease.
or technically,
Distinct cellular and molecular environments support aging-related DNA methylation changes in the substantia nigra.
[See Original Abstract on Pubmed]
or technically,
Distinct cellular and molecular environments support aging-related DNA methylation changes in the substantia nigra.
[See Original Abstract on Pubmed]
Authors of the study: Maria Fasolino, Shuo Liu, Yinsheng Wang and Zhaolan Zhou
Doctors have known what the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of Parkinson’s disease patients look like for a long time. The disease causes brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. cells (neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles) in the substantia nigra, which is a brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. area important for controlling movement, to die. Unfortunately, how this happens is still a mystery, and doctors aren’t sure why the substantia nigra is particularly susceptible. Scientists are taking a closer look at our DNA for more clues about the disease. The DNA inside each of our cells tells them what 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. to “print,” and you can think 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. as the essential machinery of a cell executing its critical functions (enzymes, receptorsA protein on a cell’s surface that binds to specific molecules (i.e. other proteins or chemicals). Typically, a receptor is said to fit with its partner molecule(s) like a lock and key. When bound by the right molecule, receptors often transmit signals to the rest of the cell. and more). Your DNA is passed down from your parents, and scientists used to think that DNA did not change after being inherited (that is, the DNA you’re born with is the DNA you have for life). Over the last few decades, however, geneticists have realized that our DNA can actually be modified by our environment over the course of our lifetime. These chemical modifications to an individual’s DNA are referred to as epigenetics (epi=“on top of”; genetics=“genesA unit of DNA that encodes a protein and tells a cell how to function,” or DNA), and previous research has shown that epigenetic modification onto DNA accumulates over one’s lifetime, particularly in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Changes to DNA alter its ability to print 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 thus can drastically affect the function or survival of a cell. Maria’s main goal was to see if old age causes any epigenetic oddities in the substantia nigra (the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region implicated in Parkinson’s).
One of the many ways DNA can be modified is by a process known as methylation (a direct, chemical modification onto one of the building blocks of DNA). As mentioned above, DNA modifications such as methylation have the ability to affect how certain genesA unit of DNA that encodes a protein and tells a cell how to function are regulated and 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 made by a cell. Recently, researchers discovered that these modifications, such as methylation, aren’t as permanent as they thought. These ‘earmarks’ on our DNA can be kept, erased, or modified into a completely different type of modification, and this entire process can be quite dynamic throughout life!
Maria looked at aging mice to more closely study how the epigenetics of their substantia nigra cells may be changing over time. She found that the methylation marks on the DNA of these substantia nigra cells were much less stable with age when compared to a different brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. area not affected by Parkinson’s. Furthermore, she went on to show that this methylation difference is specific to dopamine neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles, which are the cells in the substantia nigra implicated in Parkinson’s disease. It is not yet clear whether this different epigenetic pattern in the substantia nigra is what makes it particularly susceptible to cell death with aging. This epigenetic effect might be influenced by the presence 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. that methylate DNA (DNMTs) or those that erase methylation (TETs), which could potentially serve as targets for treatment or early detection of the disease. Maria’s study provides us with more information about the cells in the substantia nigra and how they change with age, giving researchers novel insights on why Parkinson’s may specifically target this region of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Millions of people worldwide suffer from Parkinson’s disease, but engineering treatments that target epigenetic marks like methylation could potentially stop Parkinson’s in it tracks.
About the brief writer: Dan Kalamarides
Dan is a third year student still amazed that we can record activity of a single, live neuron. He studies the role of inhibitory plasticity in the addictive properties of opioids and other drugs.
Interested in learning more about the epigenetics of aging? Take a look at Maria’s full paper here!
A hormone called amylin can tell us to stop overeating (even if we really, really love cookies and swear we only want one more)
or technically,
Amylin acts in the lateral dorsal tegmental nucleus to regulate energy balance Through GABA Signaling.
[See Original Abstract on Pubmed]
or technically,
Amylin acts in the lateral dorsal tegmental nucleus to regulate energy balance Through GABA Signaling.
[See Original Abstract on Pubmed]
Authors of the study: David J. Reiner, Elizabeth G. Mietlicki-Baase, Diana R. Olivos, Lauren E. McGrath, Derek J. Zimmer, Kieran Koch-Laskowski, Joanna Krawczyk, Christopher A. Turner, Emily E. Noble, Joel D. Hahn, Heath D. Schmidt, Scott E. Kanoski, Matthew R. Hayes
Here’s how this could work: after a meal, your pancreas produces a hormone called amylin that travels through your bloodstream into your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Once it’s in your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., amylin binds to 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. called “amylin receptorsA protein on a cell’s surface that binds to specific molecules (i.e. other proteins or chemicals). Typically, a receptor is said to fit with its partner molecule(s) like a lock and key. When bound by the right molecule, receptors often transmit signals to the rest of the cell..” BrainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. areas that contain these receptorsA protein on a cell’s surface that binds to specific molecules (i.e. other proteins or chemicals). Typically, a receptor is said to fit with its partner molecule(s) like a lock and key. When bound by the right molecule, receptors often transmit signals to the rest of the cell. can sense amylin, which tells them that you are full. Dave found that there are amylin receptorsA protein on a cell’s surface that binds to specific molecules (i.e. other proteins or chemicals). Typically, a receptor is said to fit with its partner molecule(s) like a lock and key. When bound by the right molecule, receptors often transmit signals to the rest of the cell. in a reward area called the lateral dorsal tegmental nucleus (LDTg). This made Dave wonder what amylin might be doing in the LDTg. He was especially curious because the LDTg is best known as a reward area, not as 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 controls hunger or metabolism. To test this, Dave used a drug to turn on the amylin receptorsA protein on a cell’s surface that binds to specific molecules (i.e. other proteins or chemicals). Typically, a receptor is said to fit with its partner molecule(s) like a lock and key. When bound by the right molecule, receptors often transmit signals to the rest of the cell. specifically in the LDTg of rats. And what he saw was really exciting: rats that received the drug ate less food and lost weight (when compared with rats that received a placebo).
This finding leads to another interesting question -- how does amylin in the LDTg limit food intake and cause weight loss? Dave didn’t do any experiments to figure this out, but he did have an idea of how it might work: because the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. cells inside the LDTg are inhibitory (this means they send “stop” signals to other brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. cells), Dave hypothesized that these “stop” signals are what caused the rats (and could cause you) to eat less. These findings could be really important for many Americans (over a third of the total US population) who struggle with obesity. If we can understand how hormones act in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to make us feel hungry or full, we can potentially create new treatments for healthy weight management.
How support cells in the brain support sleep.
or technically,
Endocytosis at the Drosophila blood-brain barrier as a function for sleep.
[See Original Abstract on Pubmed]
or technically,
Endocytosis at the Drosophila blood-brain barrier as a function for sleep.
[See Original Abstract on Pubmed]
Authors of the study: Gregory Artiushin, Shirley L Zhang, Hervé Tricoire, Amita Sehgal
Although neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles are important in mediating sleep, the non-neuronal support cells of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. (known as glial cells) have also been linked to sleep regulation. Glial cells are a class of cells that surround all neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles and are critical for their survival; they perform important ‘maintenance’ tasks for neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles including providing them with nutrients and oxygen, insulating their electrical connections, and clearing dead cells and waste from their surroundings. Glial cells may help with waste clearance in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. during sleep, and can also release molecules that promote sleep2. In order to carry out their functions properly, glial cells have to move cargo into and out of the cell. This is mainly done through endocytosis, where things outside of the cell are captured into sacs and brought into the cell, much like packaging something important for transport. Although this process of endocytosis is important for glial cell performance overall, scientists still aren’t sure if endocytosis in glial cells is important for sleep. Additionally, it is not known which of the many types of glial cells are important in regulating sleep (there are over four main classes of glia).
Greg decided to use fruit flies to study the importance of endocytosis in sleep. Yes, flies sleep too! Not only are their sleeping patterns similar to that of humans, with a long period of sleep at night, but their genesA unit of DNA that encodes a protein and tells a cell how to function can also be easily manipulated in order to help scientists establish which genesA unit of DNA that encodes a protein and tells a cell how to function are important in regulating sleep. About 75% of known human disease genesA unit of DNA that encodes a protein and tells a cell how to function have a recognizable match in the genetic code of fruit flies3. These qualities make them a popular ‘model’ amongst scientists for studying sleep and its underlying mechanisms. To understand how endocytosis changed with increased sleep need, Greg deprived flies of sleep and then looked at how endocytosis was affected in their glial cells. He found that endocytosis was increased after sleep deprivation, and that this correlated with how sleep-deprived the flies were. Since this suggested that endocytosis was somehow linked to sleep, Greg wanted to explore this link further by blocking endocytosis entirely and seeing what happened to sleep. To do this, he generated a mutated form of a geneA unit of DNA that encodes a protein and tells a cell how to function that is critical for endocytosis in flies, allowing him to effectively block endocytosis in these animals. By mutating this geneA unit of DNA that encodes a protein and tells a cell how to function only in glial cells, Greg was able to block endocytosis exclusively in glial cells of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Interestingly, he saw that this increased how long the flies slept, suggesting that endocytosis in glia somehow controls the process of sleep.
Since there are many types of glial cells, Greg wanted to next understand which type of glial cells were important in sleep. Using the same genetic mutation strategy, Greg blocked endocytosis in each specific type of glial cell: he expressed the mutation in one type of glial cell at a time while leaving endocytosis in all of the other types of glia intact. This allowed him to determine which type of glial cell(s) was responsible for the effects he saw when he blocked endocytosis in all glial cells. He found that endocytosis in one particular type of glial cell was linked to sleep duration. This type of glial cell makes up the blood-brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. barrier in flies. The blood-brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. barrier, or BBB, is composed of tightly-linked glial cells that separate the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. from the rest of the body. This barrier acts as a roadblock that prevents many substances from getting into the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., which is crucial for protecting the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. from pathogens or toxins. Greg found that blocking endocytosis only in the BBB glial cells caused changes in the structure of the barrier and increased sleep. However, blocking endocytosis in other types of glia did not affect the BBB or sleep.
Greg’s work suggests that endocytosis in the glial cells of the BBB of the fly is an important regulator of sleep, identifying a specific mechanism that may also be crucial in human sleep. Exactly how endocytosis at the BBB affects sleep duration remains unknown, but it is possible that this process may be important in waste clearance or maintenance of the BBB. If endocytosis is disrupted, these processes may be impaired leading us to sleep longer as a way of compensating. Future studies will aim to address why disrupting endocytosis in these BBB glial cells messes up the sleep cycle. Greg’s findings in this study (and future experiments) are important because they allow researchers to understand exactly how these processes at the BBB could be important for human brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. function, and how they may be altered in sleep deprivation and sleep disorders, such as insomnia. Scientists might finally be on track to figure out why pulling an all-nighter turns us into sleep-deprived zombies!
About the brief writer: Claudia Lopez
Claudia is a fourth year Neuroscience graduate student studying HIV-related neurodegeneration. She uses cell culture system to study how HIV infection leads to neuronal dysfunction.
Citations:
Shokri-Kojori E, Wang G, Wier CE, Demiral SB, Guo M, Kim SW . . . Volkow ND. (2018). β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proceedings of the National Academy of Sciences, 115(17): 4483-4488. You can find the paper here.
Halassa MM, Florian C, Fellin T, Munoz JR, Lee S, Abel T . . . Frank MG. (2009). Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron, 61(2): 213-219. You can find the paper here.
Pandey UB & Nichols CD. (2001). Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacological Reviews, 11(6): 1114-1125. You can find the paper here.
Brains get denser during adolescence--and that might not be a bad thing!
or technically,
Age-Related Effects and Sex Differences in Gray Matter Density, Volume, Mass, and Cortical Thickness from Childhood to Young Adulthood [See Original Abstract on Pubmed]
Efstathios (Stathis) Gennatas was the lead author on this study.
or technically,
Age-Related Effects and Sex Differences in Gray Matter Density, Volume, Mass, and Cortical Thickness from Childhood to Young Adulthood
[See Original Abstract on Pubmed]
Authors of the study: Gennatas ED, Avants BB, Wolf DH, Satterthwaite TD, Ruparel K, Ciric R, Hakonarson H, Gur RE, Gur RC.
BrainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. tissue can be divided into two types: gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain and 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. Gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain is a thick layer of cells, much of which tiles the surface of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Depending on the location, gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain is thought to process emotion, speech, decision-making, movement, self-control, and more. 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 made of the connections that act as highways among regions of gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain. Because of the fatty biological materials making up these highways, 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 looks white!
As you grow and learn, new connections form. So, it would make sense for the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to grow in size. Yet, this is not the case! Stathis Gennatas, a former neuroscience graduate student under the direction of Dr. Ruben Gur at the University of Pennsylvania, wondered if we were missing the full story.
There are two common ways to measure how much gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain someone has, using a technique called magnetic resonance imagingA common brain imaging method that exploits different magnetic reactions of brain tissue to take pictures of the brain (MRI), which uses large magnets to make a 3D image of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. One way to measure gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain is to calculate its volume from the MRI image. The second way is to measure the thickness of the gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain. Over and over, teams of scientists have found that both of these measures show a dramatic decline during adolescence, despite rapid improvements in tests of memory and learning.1
Stathis and his team used MRI to scan the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of 1189 children and adolescents from the Philadelphia area. As in prior studies, he found that both cortical thickness and gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain volume did indeed decline during adolescence. However, he also looked at another measure called gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density, which measures how tightly packed gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain is in the cortex. Gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density has not historically been examined in studies of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development, which have focused on measures of volume and thickness. Stathis actually found increases in gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density with increasing age; in fact, gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density actually showed the strongest age-related effects, meaning that it changed the most with age. This suggests that perhaps gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain is not being lost during adolescence, but rather, simply being reorganized in a more tightly packed manner.
Stathis found another interesting twist in his study of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. structure during adolescence. The brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of boys and girls appeared to be growing differently. Males at this age tend to be bigger and taller, and therefore have larger brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. and more gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain compared to girls. During adolescence, when gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain volume decreases, female brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. start out with less gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain volume. Stathis found, though, that females have higher gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density on average than males, possibly compensating for their smaller average gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain volume.
Increasing gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density provides an important piece of the puzzle as to why gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain volume or cortical thickness decreases in adolescence. This is important because currently, gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density is not routinely considered in studies of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development in childhood and adolescence, when many psychiatric disorders emerge. Gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density is highly sensitive to changes with age, and thus may help us glean new insight into what changes in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. structure accompany the development of mental disorders. These findings might also help us understand why the effects of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. disorders on females and males differ during the rapid changes of adolescence. Examining gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density could also be really important for understanding the relationship between brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. structure and cognitive performance. More densely packed gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain may allow more processing for less space, thus improving learning and memory abilities. In summary, your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. shrinking during adolescence might not be such a bad thing.
About the brief writer: Ursula Tooley
Ursula is a PhD Candidate in Allyson Mackey’s and Danielle Bassett’s labs. How does our brain change as we develop from young children to adults, and what functional networks support our ability to learn and reason about the world? How does our early environment shape this? Ursula is a fourth year student interested in the answers to these questions.
Citations:
Akshoomoff, N., Newman, E., Thompson, W. K., McCabe, C., Bloss, C. S., Chang, L., ... & Gruen, J. R. (2014). The NIH Toolbox Cognition Battery: Results from a large normative developmental sample (PING). Neuropsychology, 28(1), 1.
Highway to the brain: cells responsible for touch need a support system to grow really long distances during development
or technically,
Roof Plate-Derived Radial Glial-like Cells Support Developmental Growth of Rapidly Adapting Mechanoreceptor Ascending Axons
[See Original Abstract on Pubmed]
or technically,
Roof Plate-Derived Radial Glial-like Cells Support Developmental Growth of Rapidly Adapting Mechanoreceptor Ascending Axons
[See Original Abstract on Pubmed]
Authors of the study: Kim Kridsada, Jingwen Niu, Zhiping Wang,Parthiv Haldipur, Long Ding, Jian J. Li, Anne G. Lindgren, Eloisa Herrera, Gareth M. Thomas, Victor V. Chizhikov, Kathleen J. Millen, and Wenqin Luo
Kim noticed that during development, the mechanoreceptorA type of neuron (nerve cell) that senses mechanical stimuli like touch (“touch”) cell 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 had to travel the farthest (e.g. from hands and feet to the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.) also seemed to grow closer to a group of specialized cells in the spinal cord compared to cells that didn’t have as far to go. She thought that maybe these specialized cells could be guiding cells (aka acting as a highway) and also sending signals (aka “road signs”) out to the touch cell 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 helped them grow through the spinal cord to eventually reach the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Kim found that these support cells indeed sent out signals, in the form of specific growth-promoting 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 could be used by the touch neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to grow in the correct directions. The support cells that Kim found surrounding these touch cells were part of a particular class of cells known as radial glial-like cells (RGLCs), which are cells that can help with growth and development of neuronal cells. Kim wondered how important these RGLCs were for the touch cells - did the touch cells need them to grow along this highway to reach the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.? She hypothesized that without this RGLC highway, the touch cells wouldn't grow as far. To test whether RGLCs are truly needed in the body for touch cells to grow long distances, Kim studied mice that did not have any RGLCs but still had touch cells that were capable of growing. Interestingly, she found that in mice that had no RGLCs, their touch cells axonsA specialized part of a neuron that sends electrical and chemical signals to other cells. Axons are typically long and thin like a wire. were much shorter and 40% of their touch cells did not grow long enough to reach their correct destination in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.! Taken together, these findings suggest that RGLCs are really important in the body for helping touch cells axonsA specialized part of a neuron that sends electrical and chemical signals to other cells. Axons are typically long and thin like a wire. eventually make their way to the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals..
Overall, Kim discovered a previously unknown group of support cells (RGLCs) in the spinal cord that help touch cell axonsA specialized part of a neuron that sends electrical and chemical signals to other cells. Axons are typically long and thin like a wire. make connections over long distances, from the periphery of the body to eventually the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. These findings are really important not only for our understanding of how we develop a very important sense (touch), but could also be used to improve regeneration in people who have suffered injuries and have, as a result, lost their sense of touch. Thanks to Kim’s work, we now know that these spinal cord cells help certain touch cells grow long distances, so we could try to develop drugs or therapies that target them so that growth of touch cells during regeneration happens more easily.
About the brief writer: Elelbin Ortiz
Elelbin is a PhD Candidate in Michael Granato’s lab. She is interested in understanding how animals set behavioral thresholds, or ways to decide whether information from the environment requires a response or not. She is interested in understanding how an animal's genes (DNA) influence how these behavioral thresholds are set.
Do you want to learn more about touch, RGLCs, and development? You can read Kim’s whole paper here.
Humans use previous experience with categories of sounds to categorize new sounds as best as they can
or, technically,
Characterizing the impact of category uncertainty on human auditory categorization behavior.[See the original abstract on PubMed]
or, technically,
Characterizing the impact of category uncertainty on human auditory categorization behavior.[See the original abstract on PubMed]
Authors: Adam M. Gifford, Yale E. Cohen, Alan A. Stocker
Brief prepared by: Adam Gifford & Kate Christison-Lagay
Brief approved by: Peter Dong
Section Chief: Yunshu Fan
Date posted: May 3, 2016
Brief in Brief (TL;DR)
What do we know: We can group and split up sounds (and other things) into different categories, which allows us to identify and understand what is in the environment. However, choosing the best category for a sound can be difficult because sounds can belong to more than one category. For example, both dogs and wolves can howl, and incorrectly categorizing a wolf’s howl as a dog’s can be dangerous.
What don’t we know: How we use past experience with similar sounds to categorize new, unfamiliar sounds.
What this study shows: We use previous experience with similar sounds to make a best guess on how to categorize new sounds. Our brain isn’t perfect, though—it has a lot of activity that isn’t related to what we’re experiencing (this is called noise), so our performance isn’t perfect. But it is as good as it can be given the noise in the brain.
What we can do in the future because of this study: Record from neurons in different parts of the brain to determine where experience with previous sounds and their categories are stored, and how and where the brain uses that information to choose a category for new sounds.
Why you should care: Understanding how humans use prior experience to categorize new information will allow us to determine what goes wrong when we make categorization errors. This understanding could also be used to develop tools that can allow computers to perform the same kinds of categorizations, which would be useful for automated object or voice recognition.
Brief for Non-Neuroscientists
The ability to group and segregate sounds (or objects) into different categories is an important process that allows us to simplify and understand the environment. However, determining the best category for a sound can be difficult, as some sounds can belong to multiple categories. For example, both dogs and wolves can howl, and incorrectly categorizing a wolf’s howl as a dog’s can be dangerous. To solve this problem, the brain must use information learned from experience in categorizing similar sounds in the past. We expected that humans would use previous experience to decide on the best category for a new sound, minimizing the chance that they chose wrong. However, we found that humans did not seem to use the best decision strategy that minimized categorization errors. But if we assume that there is noise in the brain that limits the ability to accurately keep track of previous experience, humans’ category choices can be consistent with the best decision strategy.
Brief for Neuroscientists
Categorization is an important process that allows us to simplify, extract meaning from, and respond to sounds (or other objects) in the environment. However, categorization is complicated because a sound can belong to multiple categories. Thus, to choose the best category for a new sound, we must make use of prior information on the categories of similar sounds. Given the importance of categorization, we hypothesized that humans utilize the best decision strategy for making categorical judgments that allows us to minimize categorization errors. However, we found that humans did not minimize errors in their categorization behavior, similar to behaviors exhibited in other perceptual and cognitive tasks. We then explored the bases for this sub-optimal behavior and found that it can be consistent with the best strategy if we assume that humans have trial-by-trial noise in components of the judgment process.
There's a new janitor in town: cleaning up the mess in ALS
or, technically,
Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation [See the original abstract on PubMed]
or, technically,
Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation [See the original abstract on PubMed]
Authors: Yvette C. Wong, Erika L.F. Holzbaur
Brief prepared by: Shachee Doshi and Patti Murphy
Brief approved by: Peter Dong
Section Chief: Shachee Doshi
Date posted: March 8, 2017
Brief in Brief (TL;DR)
What do we know: Mitochondria are machines in our cells that produce energy. When mitochondria get damaged, healthy cells break down the damaged mitochondria and throw them away. In neurodegenerative diseases like ALS (Lou Gehrig's disease), damaged mitochondria inside neurons are not broken down, and this might be one way in which neurons die.
What don’t we know: Why are damaged mitochondria not broken down inside neurons in people with neurodegenerative diseases? Can we find ways to help these people's neurons break down damaged mitochondria?
What this study shows: A protein called optineurin helps cells break down damaged mitochondria. When there isn't enough optineurin or the optineurin is abnormal (like it is in some cases of ALS), damaged mitochondria are no longer broken down and build up in the neuron.
What we can do in the future because of this study: We could design drugs to make optineurin even better at breaking down damaged mitochondria. These drugs would first be tested to see if they help animals with neurodegenerative diseases and then if they help humans with these diseases.
Why you should care: Neurodegenerative diseases (Alzheimer's Disease, ALS, Frontotemporal Dementia) cause a lot of pain to patients and their families and cost a lot of money to society as a whole. Damaged mitochondria are found in neurons of patients in all these diseases. Finding ways to help cells break down damaged mitochondria can help us treat patients with these diseases.
Brief for Non-Neuroscientists
Mitochondria are the energy powerhouses of the cell. They make the fuel for all the cellular machinery to run smoothly. Accumulation of damaged and dysfunctional mitochondria has been observed in many neurodegenerative diseases, including ALS, Alzheimer's disease and Parkinson's disease.
While it is unknown how mitochondria become damaged, it is known that accumulation of malfunctioning mitochondria is one of the factors contributing to neuronal cell death. Normally, a cell discards its damaged parts by a process known as autophagy. When it is mitochondria that are being discarded, this process is called mitophagy.
One reason damaged mitochondria might build up in neurodegenerative diseases is defective mitophagy. If there were a way to rescue this defect, it could help cells get rid of these damaged mitochondria. This study identifies a pathway to do just that. The authors find that a protein called optineurin can be recruited to the mitochondria, which in turn leads to the recruitment of autophagosomes. Autophagosomes are special structures that envelop and engulf damaged cellular material to degrade it. If optineurin is removed from the cell, autophagosomes are no longer recruited to damaged mitochondria. Adding normal optineurin back into the cell can rescue autophagosome recruitment, but adding back an altered (mutated) form of optineurin that is found in ALS cannot rescue autophagosome recruitment.
This study tells us that it may be possible to treat neurodegenerative diseases by increasing the amount of normal optineurin available in cells.
Brief for Neuroscientists
Mitochondrial dysfunction is a hallmark of many neurodegenerative diseases including ALS, frontotemporal dementia and Alzheimer's disease, and is implicated in disease pathophysiology. While mitophagy is a well-understood quality control mechanism that can degrade dysfunctional mitochondria, it seems to be compromised in these diseases. Optineurin is a protein that binds ubiquitin and the autophagosome via its LC3-binding domain, thus acting as an autophagy receptor. Mutations in optineurin have been found in familial cases of ALS. This paper describes a parkin-dependent role for optineurin in mitophagy in vitro. Using HeLa cells and confocal microscopy, the authors find that parkin is required to stabilize optineurin on the mitochondrial membrane, which in turn recruits the protein LC3 to initialize autophagosome formation. Depleting optineurin prevents autophagosome recruitment and mitochondrial turnover. This can be rescued by expressing wild type optineurin but not an ALS-linked mutant optineurin. Further, deleting autophagy receptor p62 did not prevent autophagosome formation, indicating a specific role for optineurin in initiating mitophagy. This study presents evidence for the contribution of mitochondrial dysfunction to cell death in neurodegeneration, and describes a mechanistic role for optineurin in mitophagy.
Recycling centers in the cells of Alzheimer’s patients are less acidic than normal and this impairs their function
or, technically,
Lysosomal alkalization and dysfunction in human fibroblasts with the Alzheimer’s disease-linked presenilin 1 A246E mutation can be reversed with cAMP [See the original abstract on PubMed]
or, technically,
Lysosomal alkalization and dysfunction in human fibroblasts with the Alzheimer’s disease-linked presenilin 1 A246E mutation can be reversed with cAMP [See the original abstract on PubMed]
Authors: Erin E. Coffey, Jonathan M. Beckel, Alan M. Laties, Claire H. Mitchell
Brief prepared by: Alice Dallstream
Brief approved by: Ari Kahn
Section Chief: Alyse Thomas
Date posted: June 8, 2016
Brief in Brief (TL;DR)
What do we know: Alzheimer’s disease is the leading cause of dementia and can be inherited through changes in a gene called PS1. These changes makes it hard for neurons and other cells to get rid of their waste, and make the cells less healthy.
What don’t we know: We don’t know how these changes in the PS1 gene impairs waste recycling in cells.
What this study shows: In cells from patients who have changes in PS1, the part of the cell responsible for recycling is not as acidic as normal recycling centers, making them less effective. If you make these recycling cell parts more acidic in PS1 cells, they regain their function.
What we can do in the future because of this study: We have more information on what is going wrong in the messed up PS1 neurons and can use this information to develop therapy for Alzheimer’s patients.
Why you should care: Alzheimer’s disease currently has no cure and is increasingly common among the elderly. By figuring out what goes wrong in the cells of Alzheimer’s patients, we can find potential ways to treat it.
Brief for Non-Neuroscientists
There is a mutation in a gene called presenilin 1 (PS1) that is one of the leading causes of familial Alzheimer’s disease. This mutation in PS1 makes it hard for cells to clear their waste and recycle these molecules to stay healthy. The major “waste facility” of the cell is an organelle called the lysosome. When the lysosome becomes less acidic than normal, it struggles to clear and recycle the waste building up in the cell. This study explored whether there is a change in acidity in the lysosome in cells with the PS1 mutation. Using a new and very sensitive technique to measure acidity changes in the lysosomes of the skin cells in patients with the PS1 mutation and in healthy controls, the researchers were able to see that the PS1 lysosomes were less acidic than healthy lysosomes. This reduction in acidity was shown to impair the lysosome’s ability to recycle and breakdown waste products. The scientists then used a molecule called cAMP to restore the typical acidity in the PS1 lysosomes, and this helped to improve the function of the lysosomes in taking care of the waste products. The researchers suggest that this might be a new way of treating Alzheimer’s disease in patients with the PS1 mutation.
Brief for Neuroscientists
Impairments in autophagy in neurons is characteristic of many neurodegenerative diseases, including Alzheimer’s disease. A transmembrane protein in the lysosome called presenilin 1 (PS1) is one of the most common mutations in early-onset Alzheimer’s. The mutation in PS1 creates autophagy pathology and leads to buildup of amyloid beta, but the mechanism behind this pathology is not well understood. Using a novel technique to measure subtle pH differences in the lysosome, the authors examined the lysosomal pH found in skin fibroblasts of PS1 patients and found a slight alkalization of lysosomal pH previously undetectable with other measurements of intracellular pH. The expression levels of both mRNA and protein for genes involved in autophagy were shown to be increased in the PS1 fibroblasts, suggesting that a lysosomal pH compensation mechanism may explain the delay in pathology of a PS1 mutation. In particular, lysosomal alkalization impaired the maturation process of cathespin D, a lysosomal protease. The authors introduced cAMP to the PS1 fibroblasts to re-acidify lysosomal pH, resulting in partial rescue of cathepsin D maturation and autophagic function. This suggests that cAMP or another small molecule may acidify lysosomal pH and serve as an avenue for treatment of early-onset Alzheimer’s disease caused by PS1 mutation.
A misbehaving catalyst acts on motor proteins to mess up shipping of materials inside neurons
or, technically,
Stress-induced CDK5 activation disrupts axonal transport via Lis1/Ndel1/Dynein [See the original abstract on PubMed]
or, technically,
Stress-induced CDK5 activation disrupts axonal transport via Lis1/Ndel1/Dynein [See the original abstract on PubMed]
Authors: Eva Klinman, Erika L. Holzbaur
Brief prepared by: Eva Klinman
Brief approved by: Felicia Davatolhagh
Section Chief: Alyse Thomas
Date posted: May 13, 2016
Brief in Brief (TL;DR)
What do we know: Cargos move up and down axons normally, and this is disrupted when axons become stressed or ill (like in ALS, Alzheimer’s, and Parkinson’s).
What don’t we know: We don’t understand what regulates the movement along the axon (what controls the motor proteins dynein and kinesin), and how we can fix this process when it goes wrong.
What this study shows: This study shows how CDK5 over-activation causes disrupted cargo transport through changes in motor protein activity. CDK5 alters motor proteins indirectly, through proteins Ndel1 and Lis1. Reducing CDK5 activity restores cargo transport to normal in mouse models of ALS.
What we can do in the future because of this study: We can figure out what else is affecting cargo transport in neurons (it isn’t just CDK5!), and in the future attempt to treat sick mice by reducing CDK5 to see if they live longer.
Why you should care: Understanding how tiny cargo move in neurons is awesome! Also, if we can figure out how disrupted cargo transport contributes to disease, we can develop better treatments.
Brief for Non-Neuroscientists
Neurons are the longest cells in the body, with axons that can stretch from your spine to your foot. Proteins and organelles made in the cell body need to be transported to the end of the axon (led by the motor protein kinesin), and old organelles need to be transported back up the axon to be degraded (dragged along behind the motor protein dynein). This transport up and down the axon is disrupted in neurodegenerative diseases like ALS, Alzheimer’s, and Parkinson’s. Scientists do not know how exactly transport is being disrupted, or what we can do to fix it. We found that a neuronal-specific kinase, CDK5, which is over-activated in all of these diseases, is responsible for disrupting transport. High activity of CDK5 causes organelles to wiggle back-and-forth rather than moving smoothly. However, this kinase does not phosphorylate either motor protein directly, rather, we found that it acts on Ndel1, a protein which binds another protein (Lis1) to interfere with dynein-drive transport from the end of the axon to the cell body. Therefore, CDK5 acts indirectly to disrupt transport. Reducing CDK5 activity in neurons from an ALS mouse model helped restore transport.
Brief for Neuroscientists
Axonal transport is disrupted in neurodegenerative disease, but we don’t know how transport is regulated in healthy or diseased neurons. The kinase CDK5 is overactivated in stressed neurons because its normal activator (p35, membrane bound) is cleaved (p25, membrane-free), and this cleavage product is spatially and temporally deregulated. We found that expressing the stress activator (p25) in healthy neurons caused disruption of transport for a wide range of cargos including lysosomes, autophagosomes, mitochondria, and signaling endosomes. Previous labs have determined that CDK5 does not directly phosphorylate kinesin or dynein. However, we determined that CDK5 phosphorylates Ndel1, which binds Lis1 to regulate the retrograde processivity of dynein. Without Ndel1, CDK5 cannot disrupt motility. Moreover, similar disruptions are found in neurons taken from SOD1 mice, an ALS mouse model. Reducing CDK5 activity in these neurons returns transport to normal, implying that CDK5 over-activity is responsible for disrupting transport.
Genetic mutations related to Huntington’s disease disrupt the transport and breakdown of unwanted materials in the cell
or, technically,
The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. [See the original abstract on PubMed]
or, technically,
The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. [See the original abstract on PubMed]
Authors: Yvette C. Wong, Erika L. Holzbaur
Brief prepared by: Sarah Ly
Brief approved by: Isaac Perron
Section Chief: Alyse Thomas
Date posted: May 3, 2016
Brief in Brief (TL;DR)
What do we know: Healthy cells need to get rid of materials that they can no longer use. In Huntington’s disease (HD), cells aren’t able to get rid of unwanted stuff and scientists think this is one reason why the disease destroys the brain.
What don’t we know: The specific ways that HD causes cells to be unable to get rid of unwanted material.
What this study shows: In HD, what may be happening is that cells with mutated htt protein can’t transport unwanted stuff to where it needs to go because normally in a healthy cell the htt protein and its partner protein help move junk from one end of the neuron (the tip of the axon) to the other end (the cell body).
What we can do in the future because of this study: We can continue to study cell transport and find new ways to treat HD.
Why you should care: There is currently no cure for HD. By improving our understanding of what goes wrong in the brain during HD, scientists can work towards developing new treatments for the disease.
Brief for Non-Neuroscientists
Healthy cells need to get rid of materials that they can no longer use. Huntington’s disease (HD) is a devastating disease where sufferers lose brain function and are unable to control their own body movements. In the brains of patients with HD, the neurons — the main cells in the brain — aren’t able to get rid of unwanted junk or waste. Scientists believe this may be the reason why neurons die in the brain in HD. In a healthy neuron, waste gets packaged and transported from one end of the cell (the tip of the axon) back to the other end of the cell (the cell body). Scientists are still trying to figure out what specifically goes wrong in this process that causes cells to die in HD. This study shows that normal huntingtin protein helps move things from the axon to the cell body with the help of a partner protein. Thus, having abnormal huntingtin protein, which is the cause of HD, prevents cells from moving waste back to the cell body and this waste is now not efficiently degraded. This is important to know because it shows us that in HD, the problem with getting rid of junk is that the junk can’t travel to where it needs to go! If cells are no longer able to move stuff that it no longer needs to places where it can get broken down, these things can build up and cause cells to die.
Brief for Neuroscientists
Healthy cells must regularly degrade nonessential proteins in a process known as autophagy. Defects in autophagy have been implicated in the neurodegenerative disorder Huntington’s disease (HD), which is caused by a polyglutamine expansion in the huntingtin (htt) gene. The precise mechanisms that underlie autophagosomal defects in HD are not fully understood. In healthy neurons, autophagosomes form at the axon tip and are transported toward the cell body. By live-imaging cells with GFP-labeled autophagosomes, we found that both the htt protein and its adaptor protein huntingtin-associated protein-1 (HAP1) physically associate with autophagosomes in neurons and are necessary for proper retrograde transport of autophagosomes along the axon. This retrograde transport is impaired when neurons express the mutant htt protein. The expression of mutant htt in neurons is also associated with the accumulation of dysfunctional mitochondrial cargo within the autophagosomes, suggesting that defective autophagosome transport is linked to defects in autophagic degradation. The role of htt and HAP1 in promoting transport of autophagosomes may explain how mutations in htt contribute to neurodegeneration and cell death in HD.
Different types of neurons within the substantia nigra may play different roles in human behavior
or, technically,
Electrophysiological evidence for functionally distinct neuronal populations in the human substantia nigra. [See the original abstract on PubMed]
or, technically,
Electrophysiological evidence for functionally distinct neuronal populations in the human substantia nigra. [See the original abstract on PubMed]
Authors: Ashwin G. Ramayya, Kareem A. Zaghloul, Christoph T. Weidemann, Gordon H. Baltuch and Michael J. Kahana
Brief prepared by: Yin Li
Brief approved by: Hannah Shoenhard
Section Chief: Ryan Natan
Date posted: July 12, 2016
Brief in Brief (TL;DR)
What do we know: The brain area called the substantia nigra (SN) plays important roles in trial-and-error learning and the control of movement. The movement disorder Parkinson's disease is caused by the loss of SN cells that release dopamine, known as DA cells. The SN also contains a different type of cells known as GABA cells. From animal studies, it is known that DA and GABA cells have different functions in the SN.
What don’t we know: Whether, in the human SN, these two cell types also serve different functions.
What this study shows: When humans play a game that involves trial-and-error learning, DA and GABA cells respond differently to rewarding experiences.
What we can do in the future because of this study: Having established that there are distinct groups of neurons, we can begin to explore how they each contribute to normal and abnormal brain function.
Why you should care: Dysfunction of the SN occurs in many brain disorders, including Parkinson's disease (in which DA cells die) and schizophrenia. Understanding the normal functions of the cells that make up the SN can thus help us understand and potentially treat these brain disorders.
Brief for Non-Neuroscientists
The substantia nigra (SN) has at least two neuron types: DA neurons, which release the neurotransmitter dopamine, and GABA neurons, which release the neurotransmitter GABA. Animal studies indicate that these cells play distinct roles in a variety of tasks, including trial-and-error learning and motor control. Animal studies have also shown that these neurons have different electrical properties. For example, DA cells tend to fire more slowly than GABA cells. In this study, the scientists recorded from the SN of human patients undergoing surgery for Parkinson's disease while the subjects played a video game involving trial-and-error learning. In the past, it has been difficult to study the activity of DA cells versus GABA cells in the human brain because these cells are anatomically intermingled. This challenge was overcome by using the distinct electrical properties of DA and GABA cells in the SN, rather than physical features or location, to classify them. They found that human DA and GABA cells do indeed respond differently when patients encounter positive experiences in their video game. This result confirms that there are two subpopulations of cells with different roles in the human SN and gives neuroscientists a new tool to distinguish these subpopulations in future studies.
Brief for Neuroscientists
The substantia nigra (SN) is composed of two anatomically intermingled subareas known as the pars compacta and the pars reticulata, which are key nodes of the basal ganglia system for learning from trial-and-error (reinforcement learning) and controlling movement. Pars compacta and pars reticulata are preferentially enriched for neurons that release the neurotransmitters DA and GABA, respectively. Non-human studies indicate that DA and GABA cells in these two areas play functionally distinct roles in the basal ganglia; however, it is not known whether the same is true in the human brain, partly because these cells tend to be anatomically intermingled. In this study, Ramayya and colleagues recorded from the SN of human patients undergoing surgery for Parkinson's disease, which involves placement of microelectrodes near the SN. The patients played a video game in which they had to learn by trial-and-error which symbols on the screen would give them the most number of virtual points. After each choice, subjects were given either positive or negative feedback. Recorded cells were classified as DA or GABA cells based on their firing rate and waveform: from animal studies, DA cells are known to have low firing rates and wide spike waveforms, whereas GABA cells have tonically high firing rates and narrower spike waveforms. They found that DA and GABA cells differed in their responses to positive feedback in the game. Whereas DA cells tended to respond with a quick burst of activity soon after feedback (within ~250-500 ms), GABA cells responded more slowly, with elevated firing rates that occurred up to 1000 ms after feedback. These results confirm the existence of two functionally distinct subpopulations of neurons in the human substantia nigra and suggest that a combination of firing rate and waveform may be a useful way to classify DA and GABA cells in vivo for future studies.
Monkeys hear things the same way as people so we can use them as a model to figure out what the brain is doing when we hear stuff
or, technically,
Behavioral correlates of auditory streaming in rhesus macaques. [See the original abstract on PubMed]
or, technically,
Behavioral correlates of auditory streaming in rhesus macaques. [See the original abstract on PubMed]
Authors: Kate L. Christison-Lagay, Yale E. Cohen
Brief prepared by: Kate Christison-Lagay
Brief approved by: Bri Jeffrey
Section Chief: Ryan Natan
Date posted: May 3, 2016
Brief in Brief (TL;DR)
What do we know: We can hear individual sounds from a background of sounds; we know some stuff about noises that help us hear sounds separately from other sounds
What don’t we know: How the brain does this; if animals hear the same way
What this study shows: Animals (monkeys) hear sounds the same way as people
What we can do in the future because of this study: Record from neurons in different parts of the brain to see how the brain is figuring out how we hear things in our world
Why you should care: We don’t know how we *normally* perceive sounds, so we don’t really know how we can fix things when stuff goes wrong with our hearing on the brain-side (instead of the ear-side) of things. This helps us figure out how the brain normally hears things, so we can start to address what to do when it’s not working normally.
Brief for Non-Neuroscientists
We hear individual sounds because our brains can either group or separate noises in our environment--a process we call ’auditory streaming’. For many years, scientists have used a particular stimulus--one in which two tones alternate--to figure out what cues in sounds help us group them together or separate them apart. However, because we cannot record from neurons (cells in the brain) in people, and because it is hard to train animals to do this task, we do not know what the brain is doing while we hear this set of sounds. Before we can record from neurons in animals, we have to make sure that they hear and decide about the sounds in this task the same way people do. We found that monkeys make the same kind of decisions in this task as people. We can now record from neurons while monkeys are doing this task, and determine how neurons in different parts of the brain respond.
Brief for Neuroscientists
Our ability to hear sounds as distinct units arises from our ability to segregate and group acoustic features--a process called streaming. Although an ’auditory streaming’ task has been used extensively to study these perceptual processes in humans, we do not know the neural correlates of this ability, in part because all neurophysiological animal studies using this stimulus have been done while animals are passively listening or sedated. Before using this task to examine the neural correlates of auditory streaming, we had to establish whether animals performed the task similarly to humans. We found that monkeys’ behavioral reports were qualitatively consistent with those of human listeners, thus this task may be used in future neurophysiological studies.
An 'unexpected' outcome: many parts of our brain, not just a few areas, learn and adapt from unanticipated results
or, technically,
Expectation modulates neural representations of valence throughout the human brain [See the original abstract on PubMed]
or, technically,
Expectation modulates neural representations of valence throughout the human brain [See the original abstract on PubMed]
Authors: Ashwin G. Ramayya, Isaac Pedisich, Michael J. Kahana
Brief prepared by: Ryan G. Natan
Brief approved by: Shivon Robinson
Section Chief: Isaac Perron
Date posted: March 24, 2017
Brief in Brief (TL;DR)
What do we know: We try to make choices that will lead to the best outcomes, but when results are different than expected, we learn from our experience. Research has shown that the frontal cortex, the brain region in control of decision making, detects these unexpected outcomes.
What don’t we know: The frontal cortex uses our experiences—expected or unexpected—to learn, thus shaping our future decisions. However, recent research has shown that many more brain regions are capable of detecting expected negative and positive outcomes. Therefore, it is possible that brain regions beyond the frontal cortex could also detect unexpected outcomes.
What this study shows: The scientists found that many parts of the cerebral cortex respond to unexpected outcomes, which is surprising because these brain regions are not directly involved in decision making. This study suggests that these brain regions also play a different role in learning from experience.
What we can do in the future because of this study: Next, we can test if these brain regions actually contribute to learning from experience, and whether these different brain regions learn differently. This would help us figure out how the brain breaks down information in order to learn.
Why you should care: In many forms of mental illness, people lose the ability to learn from their experience, leading to poor decision making. In order to figure out how to help these patients, it is important to understand how healthy individuals learn. Studies like these help us figure out what parts of the brain might be malfunctioning during mental illness, and point us to brain areas that need treatment.
Brief for Non-Neuroscientists
We typically choose behaviors based on what we expect will lead to the best outcomes. Reinforcement learning occurs when we encounter an unexpected outcome; if we expect a large reward but instead receive punishment or trivial reward, we use this information to update our beliefs and shape our future behavior. While human subjects learn to play a game involving high- and low-probability outcomes, the unexpected outcomes lead to strong activity in brain regions that control decision making, such as the frontal cortex. In other words, frontal cortex 'encodes' unexpected outcomes and uses this information to guide reinforcement learning.
However, a recent experiment demonstrated that expected rewards and punishments lead to strong activity in many regions throughout the brain, not just the frontal cortex, opening the possibility that other brain regions are also involved in reinforcement learning. To test if they also encode unexpected outcomes, Ramayya et al. recorded electrical signals from the cortex of epilepsy patients, who already have an array of electrodes directly contacting their brain for medical treatment, while they learned a probabilistic choice game. Similar to the previous findings, 19 out of 21 cortical regions across the brain encoded expected rewards or penalties. More interestingly, 9 of the regions encoded unexpected outcomes, including regions of the cortex not thought to be directly related to decision making. Specifically, regions within the occipital, parietal and temporal lobes (classically considered important for vision, sensation, and language/memory, respectively) showed heightened brain activity during unexpected outcomes in this task. This experiment will shape future work in the field because it shows that many more brain regions may be involved in reinforcement learning than previously thought.
Brief for Neuroscientists
We typically choose behaviors based on what we expect will lead to the best outcomes, and reinforcement learning supports our ability to improve these choices. During unexpected outcomes, reward prediction error (i.e., the difference between the predicted result and the actual result) represent the strongest driver of reinforcement learning. While subjects perform active learning tasks, functional MRI (fMRI) and single neuron studies show that frontal cortex and other brain regions associated with executive control appear to encode reward prediction error. These results point to exclusive control of reinforcement learning by the executive control network. However, recent fMRI studies demonstrate that expected reward and punishment signals are present throughout the brain, raising the possibility that non-executive control regions may support reinforcement learning by encoding reward prediction error. To test this, Ramayya et al. used intracranial electroencephalography to measure gamma-band oscillatory activity (70-200 Hz) in epilepsy patients while they learned a probabilistic two-alternative forced-choice task. Supporting previous findings, 50% of the 4,306 recording sites and 19 out of 21 cortical regions encoded expected rewards or penalties. Confirming the authors' hypothesis, 10% of recording sites and 9 brain regions encoded reward prediction error, including regions in the occipital, parietal, and temporal lobes. Further, the strength of the reward prediction error signals strongly correlated with the subjects' task performance. These results demonstrate that learning related signals are distributed widely across the brain, beyond the executive control network. This study will shape future work in the field by widening the brain regions studied toward understanding reinforcement learning.
Linking TrkB to Zzz’s: How one protein may help us understand the intersection of depression and sleep disorders
or, technically,
The truncated TrkB receptor influences mammalian sleep. [See the original abstract on PubMed]
or, technically,
The truncated TrkB receptor influences mammalian sleep. [See the original abstract on PubMed]
Authors: Adam J. Watson, Kyle Henson, Susan G. Dorsey, Marcos G. Frank
Brief prepared by: Adam Watson & Isaac Perron
Brief approved by: Carolyn Keating
Section Chief: Isaac Perron
Date posted: May 20, 2016
Brief in Brief (TL;DR)
What do we know: Our brain tries to maintain balance: the longer we stay awake, the more we need to sleep. However, we know very little about what signals in the brain help us maintain this balance. We know of one protein, called BDNF, that accumulates in the brain the longer you stay awake, which could be a signal that tells your brain that you have been awake for a long time and need to sleep. Consistent with this, putting BDNF into the brain promotes sleep. We also know that BDNF tends to function when it interacts with its receptor, called TrkB.
What don’t we know: It is unknown how BDNF and its receptor, TrkB, increase sleep.
What this study shows: The researchers found that getting rid of one type of the TrkB receptor causes mice to have increased sleep/wake fragmentation (i.e., frequent flip-flopping between sleep and wakefulness). They also found that these mice spend more time in REM sleep (the stage of sleep when you dream) and enter REM sleep more quickly. These effects on REM sleep are interesting because they are similar to sleep changes observed in depressed people.
What we can do in the future because of this study: Future studies could show if BDNF still causes sleepiness in mice lacking the TrkB receptor. Also, it is possible that changing TrkB activity might improve sleep quality, which may be relevant for the depressed population.
Why you should care: Although every animal sleeps, we know very little about why we sleep and what makes us sleepy. This study not only helps us better understand what in our brains makes us sleepy, but may help shed light on mental health disorders, such as depression.
Brief for Non-Neuroscientists
Most animals, including humans, cycle between wakefulness and two different types of sleep—rapid eye movement (REM) sleep and non-REM sleep (NREM). However, little is known about how our brain regulates wake, REM, and NREM onset and offset, and how much REM and NREM sleep we need to feel well rested. Scientists are beginning to figure out which brain areas and which signaling molecules are important for sleep regulation. One signaling molecule, BDNF, is produced in the brain during wakefulness and high levels of BDNF can induce sleep. It is unknown, however, how BDNF causes sleepiness. There are different types of BDNF receptors (i.e., anything that binds to BDNF, thus propagating the signal), so this study explored the importance of one type of BDNF receptor—TrkB.T1—on sleep regulation. The researchers performed experiments with a mouse strain lacking only the TrkB.T1 receptor with other types of BDNF receptors unaffected. They were surprised to find that overall wake and NREM time were normal in mice without the TrkB.T1 receptor. However, the researchers found that these mutant mice had many abnormalities regarding REM sleep; specifically, TrkB.T1 knockout mice entered REM sleep sooner and spent more time in REM sleep compared to control mice. These effects on REM sleep are especially interesting because psychiatric illnesses, including depression, are associated with these same types of sleep changes. Moreover, some people who commit suicide have reduced levels of TrkB.T1 in certain areas of their brain, suggesting a potential link between sleep disturbances and major depressive disorder. Therefore, it is possible that this study discovered why some mentally ill people have abnormal sleep, which helps future studies design better, more targeted therapeutics.
Brief for Neuroscientists
Sleep timing is regulated by both circadian rhythms and poorly-understood homeostatic processes. The neurotrophin BDNF may be a key player in sleep homeostasis since interstitial BDNF levels rise after prolonged wakefulness and intracerebroventricular infusion of BDNF promotes sleep. However, it is unclear which signaling pathways are responsible for mediating the sleep-promoting effects of BDNF. The high-affinity receptor for BDNF—TrkB—has at least two major isoforms: a kinase-containing full-length isoform, TrkB.FL, and a truncated, kinase-lacking isoform, TrkB.T1. The function of TrkB.T1 is far less-well understood, but it has comparable brain expression to TrkB.FL and is enriched in brain areas critical for normal sleep/wake regulation. Therefore, the authors hypothesized that BDNF promotes sleep through the TrkB.T1 receptor. To test this hypothesis, they performed polysomnographic (EEG) sleep/wake recordings in TrkB.T1 constitutive knockout mice. Surprisingly, TrkB.T1 knockout (KO) mice exhibit normal amounts of wakefulness and NREM sleep, although wake and NREM sleep fragmentation is increased (i.e., shorter bouts and more transitions between sleep and wake). Further, TrkB.T1 KO mice spend more time in REM sleep, enter REM sleep sooner, and have longer REM bouts compared to wildtype controls. These results suggest that BDNF acting through the TrkB.T1 receptor suppress REM sleep. These results are relevant for the REM sleep abnormalities associated with several psychiatric disorders, as reduced BDNF levels correlate with depression and reduced TrkB.T1 receptor expression is associated with increased suicide mortality. Collectively, this study demonstrates one pathway by which BDNF influences sleep expression, which may also be relevant for understanding the role of neurotrophins in mental illnesses.
How our brains combine simple concepts into more complex ideas
or, technically,
Converging evidence for the neuroanatomic basis of combinatorial semantics in the angular gyrus. [See the original abstract on PubMed]
or, technically,
Converging evidence for the neuroanatomic basis of combinatorial semantics in the angular gyrus. [See the original abstract on PubMed]
Authors: Amy R. Price, Michael F. Bonner, Jonathan E. Peelle, Murray Grossman
Brief prepared by: Meghan Healey
Brief approved by: Shivon Robinson
Section Chief: Isaac Perron
Date posted: May 3, 2016
Brief in Brief (TL;DR)
What do we know: Humans are able to represent individual concepts and combine them into more complex concepts. For example, we can take the concepts “wet” and “leaf” and combine them to form another meaningful concept: “wet leaf.” While this seems intuitive to most people, some patients with dementia have difficulty combining concepts into meaningful ideas.
What don’t we know: Scientists do not know how the brain does this and which regions are involved.
What this study shows: The researchers found a specialized brain region, termed the angular gyrus, that supports the process of conceptual combination. This is true in both healthy adults and patients with neurodegenerative diseases.
What we can do in the future because of this study: Future studies can examine other factors, like grammatical category (e.g. nouns vs adjectives) or type of input (e.g. words vs pictures), that may affect an individual’s ability to combine concepts.
Why you should care: By learning more about the brain basis of conceptual combination, we may be able to develop new ways to improve language comprehension in patients with dementia.
Brief for Non-Neuroscientists
Humans can build an unlimited number of concepts by combining individual concepts into more complex representations. For example, the concepts “plaid” and “jacket” can be represented independently, or integrated into a more complex and more meaningful representation: “plaid jacket”. While previous studies have examined the cognitive processes that may be involved in this type of conceptual combination, very few studies have examined what parts of the brain support this fundamental process. In this study, researchers used both classic and functional magnetic resonance imaging (MRI) to observe brain structure and activity, respectively, to determine which brain regions are necessary to complete a conceptual combination task. The results showed that a specific brain region—the angular gyrus—is active during a conceptual combination task and its atrophy is correlated with decreased ability to perform this task. This finding adds a new role for the angular gyrus, which was already known to connect language regions, sensory regions, and motor regions of the brain. This allows us to better understand the brain circuitry that supports advanced linguistics and semantics, which may allow the development of better therapies to treat patients with dementia or other disorders affecting word comprehension.
Brief for Neuroscientists
Combinatorial semantics refers to the ability to construct complex concepts from individual constituents. For example, the basic concepts “plaid” and “jacket” can be integrated into a more sophisticated representation: “plaid jacket.” While theories of semantic memory have addressed how and where individual concepts may be represented in the brain, surprisingly little is known about the neuroanatomic basis of more complex representations. Here, researchers investigated the hypothesis that conceptual combination is dependent not only on primary sensory and motor cortices, as is the case with individual concepts, but also high-level association cortices. Using two complementary neuroimaging techniques (functional neuroimaging in healthy adults and structural neuroimaging in patients with focal neurodegenerative disease), Price et al. found that the angular gyrus, which has extensive connections to sensorimotor and language regions throughout the brain, plays a critical role in conceptual combination. Delineating the neural substrates supporting combinatorial semantics may have future implications for the treatment of individuals with semantic dementia.
Abnormal antibodies: what happens to healthy neurons when important signaling proteins are targeted for disposal
or, technically,
Acute mechanisms underlying antibody effects in anti-N-methyl-D-aspartate receptor encephalitis. [See the original abstract on PubMed]
or, technically,
Acute mechanisms underlying antibody effects in anti-N-methyl-D-aspartate receptor encephalitis. [See the original abstract on PubMed]
Authors: Emilia H. Moscato, Xiaoyu Peng, Ankit Jain, Thomas D. Parsons, Josep Dalmau, Rita J. Balice-Gordon
Brief prepared by: Kim Kridsada
Brief approved by: Hannah Shoenhard
Section Chief: Chris Palmer
Brief posted: May 3, 2016
Brief in Brief (TL;DR)
What do we know: Our immune systems produce particles known as antibodies that bind to harmful or foreign matter in our bodies, targeting them for removal. Sometimes these antibodies incorrectly tag normal healthy things in our bodies as “bad,” like proteins on the surface of our neurons. This mistake can lead to diseases, such as a swelling of the brain called encephalitis.
What don’t we know: We don’t yet understand what happens to the neurons that antibodies mistakenly identify as “bad,” and whether those neurons still work well after this process.
What this study shows: When antibodies mistakenly tag a protein found on neurons that is important for learning and memory known as a NMDA receptor, the protein is sucked back into the cells and chewed up for disposal. In addition, affected neurons try to make up for these changes by changing their connections to other neurons.
What we can do in the future because of this study:By understanding how these misbehaving antibodies cause brain swelling and change the connections between neurons, we can develop better medicines to restore normal brain function in patients.
Why you should care: Currently, there are no good treatments for this kind of immune disease that changes brain function. Through a better understanding of what happens to the neurons and their connections to each other during this process, we hope to develop a new and better treatment for people with this disease.
Brief for Non-Neuroscientists
Encephalitis or brain inflammation can have various causes, including autoimmune disease. In this study, scientists look at a form of autoimmune encephalitis that targets specific proteins on neurons called NMDA receptors, which are important for memory, learning, and communication between neurons. They find that patients with this form of autoimmune encephalitis have antibodies that specifically target NMDA receptors, particularly in the hippocampus, a part of the brain that is best known for its role in short- and long-term memory. Targeted NMDA receptors are internalized by the neurons and are recycled or degraded. Since NMDA receptors are important for communication between neurons, reducing their numbers can change communication efficiency, and ultimately, brain function. The brain tries to compensate for these changes by modifying how the affected neurons are connected to other neurons. From this study, we have a better understanding of the disease mechanism of autoimmune encephalitis, and can develop better ways to treat patients with this, and similar, diseases.
Brief for Neuroscientists
In recent years, autoimmune encephalitides (believe it or not, this is a real word) have been found to attack synaptic proteins, affecting both signal transmission and synaptic function. In one type of encephalitis, the immune system targets synaptic NMDA receptors, which are necessary for glutamatergic transmission involved in plasticity, memory and learning. Patients suffering from this disorder exhibit behavioral and memory dysfunction. This study shows that patients with this form of encephalitis develop antibodies against the GluN1 subunit of NMDA receptors, present at a very high density in the hippocampus. Although the antibodies bind to an NMDA receptor region containing the ligand-binding domain, neurons treated with the antibodies do not exhibit electrophysiological changes before significant receptor internalization has occurred. Receptor hypofunction is primarily induced by internalization of NMDA receptors in both excitatory and inhibitory hippocampal neurons. The internalized NMDA receptors are trafficked to lysosomes and endosomes at an increasing rate over time, independently of receptor activity. Homeostatic regulation triggers changes in the inhibitory synaptic density of the hippocampus to partially compensate for the altered NMDA receptor activity, while gene transcription of the receptor remains unchanged. Ultimately, the findings here reveal molecular mechanisms that potentially underlie the behavioral and symptomatic changes experienced by patients with autoimmune encephalitis.
Understanding how a few neurons in a tiny worm control eating under multiple conditions
or, technically,
Neural and genetic degeneracy underlies Caenorhabditis elegans feeding behavior. [See the original abstract on PubMed]
or, technically,
Neural and genetic degeneracy underlies Caenorhabditis elegans feeding behavior. [See the original abstract on PubMed]
Authors: Nick F. Trojanowski, Olivia Padovan-Merhar, David M. Raizen, Chris Fang-Yen
Brief prepared by: Nick Trojanowski
Brief approved by: Alyse Thomas
Section Chief: Chris Palmer
Date posted: May 3, 2016
Brief in Brief (TL;DR)
What do we know: Only a few neurons control worm eating behavior. Even when you destroy most of them, the system still works properly.
What don’t we know: The purpose and function of these neurons, since the system seems to work fine without most of them.
What this study shows: Many of these neurons are capable of making the worm eat under some but not all conditions, ensuring that eating continues even when some parts of the system are changed.
What we can do in the future because of this study:We can better understand how the worm decides which neurons to use during different conditions to ensure organism survival.
Why you should care: We don’t really understand what causes most mental illnesses, but we think it has to do with systems of neurons malfunctioning. If we understand how a worm keeps working even when some parts of the nervous system break, we can better understand how to fix people’s brains when things go wrong during mental illness.
Brief for Non-Neuroscientists
For animals to survive and reproduce, it’s very important that they are able to ingest food. A microscopic worm, one that’s been studied by neuroscientists for 40 years, has a small system of neurons that controls feeding. When you individually destroy most of these neurons, the worm still eats properly. We wanted to define the purpose of the neurons that don’t seem to be critical for eating. To do this, we used a technique called optogenetics, which allows us to turn on neurons by shining a blue light on them. By turning on the neurons one by one, we found that many of the individual neurons initiate eating behavior. This result explains why previous studies found no change in eating after destroying individual neurons: some neurons can do the same job as other neurons, depending on the conditions. We also found that under certain conditions, destroying some of these neurons did affect eating, so these neurons don’t always have exactly the same functions. Understanding how systems of neurons in this small worm have evolved to maintain function when some neurons are destroyed will help researchers understand how systems of neurons in other animals, such as humans, respond to changes or injuries. We hope that this will eventually allow us to understand how neurons controlling behaviors associated with mental illness go wrong and why.
Brief for Neuroscientists
Degenerate networks, in which structurally distinct elements can perform the same function or yield the same output, are ubiquitous in biology and likely provide systems the ability to ensure organism survival under various conditions. Degeneracy contributes to the robustness and adaptability of networks in varied environmental and evolutionary contexts. However, how degenerate neural networks regulate behavior in vivo is poorly understood, especially at the genetic level. Here, we identify degenerate neural and genetic mechanisms that underlie excitation of the pharynx (feeding organ) in the nematode Caenorhabditis elegans using cell-specific optogenetic excitation and inhibition. We show that the pharyngeal neurons MC, M2, M4, and I1 form multiple direct and indirect excitatory pathways in a robust network for control of pharyngeal pumping. I1 excites pumping via MC and M2 in a state-dependent manner. We identify nicotinic and muscarinic receptors through which the pharyngeal network regulates feeding rate. These results identify two different mechanisms by which degeneracy is manifest in a neural circuit in vivo.
Activation of the brain's stress response in the 'mood center' of the brain produces sex-dependent changes
or, technically,
Sex Differences in Corticotropin-Releasing Factor Receptor-1 Action Within the Dorsal Raphe Nucleus in Stress Responsivity [See the original abstract on PubMed]
or, technically,
Sex Differences in Corticotropin-Releasing Factor Receptor-1 Action Within the Dorsal Raphe Nucleus in Stress Responsivity [See the original abstract on PubMed]
Authors: Alexis R. Howerton, Alison V. Roland, Jessica M. Fluharty, Anikò Marshall, Alon Chen, Derek Daniels, Sheryl G. Beck, Tracy L. Bale
Brief prepared by: Felicia Davatolhagh
Brief approved by: Elaine Liu & Carolyn Keating
Section Chief: David Reiner
Date posted: August 10, 2017
Brief in Brief (TL;DR)
What do we know: Women are twice as likely as men to suffer from stress-related disorders, such as depression and anxiety. A hormone called CRF is involved in the stress response and can act in in the 'mood center' of the brain, a region called the dorsal raphe.
What don’t we know: Does CRF act differently within the dorsal raphe in males and females?
What this study shows: CRF in the dorsal raphe does work differently in males and females. Females have a decreased response to CRF, compared to males.
What we can do in the future because of this study:We can better understand sex differences that exist in stress-related disorders and improve how we treat men and women that have these disorders.
Why you should care: CRF-targeting drugs, which are used to treat disorders such as depression, anxiety, and addiction, are sometimes unsuccessful in patients. Identifying and addressing sex differences in the brain's stress response might help fix this.
Brief for Non-Neuroscientists
In the United States, women are twice as likely as men to be afflicted by a stress-related affective disorder. Corticotropin-releasing factor (CRF) is a peptide hormone and neurotransmitter that mediates stress response through signaling in an area of the brain called the dorsal raphe (DR). CRF receptor-1 (CRFr1) inactivators have been extensively studied in the hope that they can alleviate symptoms of stress-related affective disorders; however, none has been successful in clinical trials. Differences in stress response circuitry between males and females might account for these unsatisfactory results. This study found that in males, infusions of a CRFr1 antagonist into the DR reduced production of the stress hormone corticosterone and alleviated anxiety-like behavior. On the other hand, the CRFr1 antagonist did not affect corticosterone levels or behavior in females. These results suggest sex-dependent differences in CRFr1 activity in the DR. Overall, these findings warrant further investigation into pharmacological therapies tailored toward sex-dependent differences in the brain's stress response system.
Brief for Neuroscientists
The prevalence of affective disorders is twice as high in women as it is in men. Corticotropin-releasing factor (CRF) has been shown to contribute to the development of affective disorders through excessive activation of its receptor CRFr1. The dorsal raphe (DR) is implicated in the central stress pathway response, through activation of CRFr1. This study aimed to elucidate the sex differences within the DR in response to stress, specifically examining CRF modulation in the DR circuits. Infusion of the CRFr1 antagonist NBI35965 (NBI) or CRF into the DR, resulted in robust bidirectional modulation of corticosterone production and behavioral stress response in males, while females were minimally responsive. Furthermore, male mice showed enhanced membrane excitability following CRF application, but the response in female mice was blunted. Therefore, these sex differences in stress circuitry might explain why CRFr1 antagonists have been unsuccessful in clinical trials. These studies warrant further investigation into pharmacological treatments directed at addressing sex differences in the CRF system.
Deep Brain Stimulation: A potential treatment for cocaine relapse
or, technically,
Deep brain stimulation of the nucleus accumbens shell attenuates cue-induced reinstatement of both cocaine and sucrose seeking in rats [See the original abstract on PubMed]
or, technically,
Deep brain stimulation of the nucleus accumbens shell attenuates cue-induced reinstatement of both cocaine and sucrose seeking in rats [See the original abstract on PubMed]
Authors: Leonardo A. Guercio, Heath D. Schmidt, R. Christopher Pierce
Brief prepared by: Leonardo Guercio
Brief approved by: Ari Kahn
Section Chief: David Reiner
Date posted: April 11, 2017
Brief in Brief (TL;DR)
What do we know: Drug relapse in humans and animal models can be produced by three major factors: stress, drug-associated cues (environments and items), and re-exposure to the drug itself. The nucleus accumbens is a brain region that is critically involved in drug addiction and relapse. Deep brain stimulation (DBS), a Food and Drug Administration (FDA)-approved treatment for Parkinson's disease, of the nucleus accumbens can block cocaine relapse that is triggered by re-exposure to cocaine in animal models of addiction.
What don’t we know: Can DBS of the nucleus accumbens also block cocaine relapse triggered by cocaine-associated cues, such as environments associated with drug use?
What this study shows: We can effectively use DBS in the nucleus accumbens to block cocaine relapse triggered by cocaine-associated cues. However, DBS in this brain region may also affect the ability to seek naturally rewarding substances, such as sugar.
What we can do in the future because of this study:We can figure out if DBS can become an FDA-approved treatment for drug addiction. Future findings may also help determine what other brain areas are involved in the different types of relapse, and whether DBS can be an effective treatment in all types of drug relapse.
Why you should care: There are very few treatment options for drug addiction in general and there are no FDA-approved treatments for cocaine addiction. Existing FDA-approved treatments like DBS may be effective in treating relapse to cocaine and other drugs.
Brief for Non-Neuroscientists
A major problem facing cocaine addicts is the discouragingly high rate of relapse. Cocaine relapse in humans can be precipitated by three major factors: stress, drug-associated cues and contexts, and re-exposure to the drug itself. We can model cocaine relapse using these same factors in an animal behavior model called reinstatement. Briefly, animals are placed in an operant chamber where they can press a lever to self-administer cocaine. This is done daily for about 3 weeks, then the drug is removed and animals undergo a period of withdrawal. After approximately 1 week of withdrawal, the animals are placed back in the operant chamber, and cocaine seeking is reinstated either by an injection of cocaine, exposure to lights and tones previously paired with cocaine infusions, or a stressor.
This reinstatement model is extremely useful for determining brain regions and neurotransmitters involved in cocaine relapse, with the hopes of developing a treatment for cocaine addiction and relapse. Currently, there are no FDA-approved therapies for cocaine addiction and relapse. Deep brain stimulation (DBS) is an FDA-approved treatment for Parkinson's disease. By applying DBS to the nucleus accumbens, a brain region critically involved in drug addiction and relapse, we were able to block cocaine reinstatement triggered by cocaine-associated cues. However, DBS in this brain region also blocked responding for sugar as well, so it may affect natural reward processing. Understanding how DBS can affect the brain regions and circuits involved in cocaine relapse may lead to repackaging DBS as a treatment for drug addiction.
Brief for Neuroscientists
Our lab has previously shown that deep brain stimulation (DBS) of the nucleus accumbens shell attenuates the priming-induced reinstatement of cocaine seeking, without perturbing sucrose reinstatement. In this study, we examined whether deep brain stimulation (DBS) can modulate cue-induced reinstatement of cocaine and sucrose seeking. We found that DBS of the accumbens shell attenuated cue-induced reinstatement of cocaine seeking. However, DBS in this region also attenuated cue-induced sucrose reinstatement, suggesting that the effects of DBS may not be drug-specific when suppressing cue-induced relapse. Further studies will examine the efficacy of DBS as a potential therapeutic avenue for cocaine reinstatement.