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

or technically,

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

[See Original Abstract on Pubmed]

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

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

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

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

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

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

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

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

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

About the brief writer: Brenna Shortal

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

Citations:

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

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

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

Why does a brain with dementia make a person forgetful?

or technically,

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

[See Original Abstract on Pubmed]

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

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

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

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

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

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

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

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

About the brief writer: Lyles Clark

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

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

or technically,

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

[See Original Abstract on Pubmed]

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

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

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

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

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

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

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

About the brief writer: Sara Taylor

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

Citations:

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

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

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]

Authors of the study: David J. Tischfield, Dave K. Saraswat, Andrew Furash, Stephen C. Fowler, Marc V. Fuccillo, Stewart A. Anderson

Hallucinations, delusions, and paranoia. Agitation, depression, and trouble sleeping. The symptoms of schizophrenia vary from person to person, but one fact remains the same: there is currently no known cure for the disorder that affects over 77 million people worldwide. Due in large part to its incredibly diverse set of symptoms, schizophrenia is an extremely challenging disorder to study. David Tischfield, a neuroscience graduate student working in the laboratory of Dr. Stewart Anderson at the University of Pennsylvania, tackled this problem by studying the relationship between a recently identified neurodevelopmental geneA unit of DNA that encodes a protein and tells a cell how to function and its contribution to normal and abnormal brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. function.

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 studies^1,2 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:

1. Ripke, S., et al., 2013. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45:1150–1159. Read it here. 

2. 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]

Authors of the study: Maria Fasolino, Shuo Liu, Yinsheng Wang and Zhaolan Zhou

Have you ever wondered about the cause of Parkinson’s disease and what researchers are doing to improve treatment? First described in the 1800s, this devastating neurological disorder is currently estimated to affect seven to ten million people worldwide (with some of the more recognizable victims including Michael J. Fox, Muhammad Ali, and Robin Williams). Symptoms of the disease include motor dysfunction (shaking, rigidity, difficulty walking, etc), depression, and dementia. Although there are ways to slow disease progression, there is presently no cure available, and the average life expectancy is only 7-14 years after diagnosis. We still have a lot to learn about what makes certain people susceptible to the disorder and how we can improve treatment options. With this in mind, UPenn neuroscience graduate student Maria Fasolino and her team in the Zhou lab set out to learn more about what changes take place in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. during aging that might correlate to the development of Parkinson’s disease.

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]

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

Have you ever had one too many chocolate chip cookies? Maybe you’ve eaten so much that you felt sick? Sometimes we eat when we’re not hungry. This is because, in addition to filling us up, delicious food activates the parts of our brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. that make us feel pleasure (also known as the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.’s “reward areas”). Dave Reiner, a neuroscience graduate student in Matt Hayes’s lab, wondered if some people feel the rewarding effects of food more strongly than others. To figure this out, he asked whether one of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.’s specialized reward areas can sense a hormone called amylin, which gets released when you’re full. Dave thought that if the reward areas could sense amylin, then they might be able to tell you to stop eating, no matter how delicious your grandma’s cookies are....

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]

Authors of the study: Gregory Artiushin, Shirley L Zhang, Hervé Tricoire, Amita Sehgal

Almost every day of our lives we close our eyes, count a few sheep, and drift off to sleep. If we don’t get enough sleep, our brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. doesn’t work as well and its normal functions, such as attention and decision-making, are affected. But why does this happen? Why is sleep so important? Although not everything about sleep is known, what scientists do know is that sleep is necessary to maintain the health of the cells in our body, especially the cells in our brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. NeuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles perform essential processes during sleep that they can’t do as efficiently while awake, such as consolidating memories and clearing waste. For this reason, sleep deprivation has serious consequences including build-up of toxic proteins¹. Therefore, neuroscientists have been curious about the mechanisms of sleep for quite some time. Gregory Artiushin, a UPenn neuroscience graduate student in the lab of Amita Sehgal, was interested in understanding this sleep process a little deeper, specifically thinking about how different cells in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. may contribute to sleep function.

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:

1. 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.

2. 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.

3. 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!

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.

Have you ever wondered what happens to your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. during the tumultuous ride of adolescence? Along with dramatic changes of the body, there are considerable changes of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. We all know that the ability to think, learn, and make decisions improves as children grow up, so it is quite surprising to learn that parts of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are actually getting smaller during this time.

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:

1. 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]

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

Have you ever thought about going on a cross-country road trip, perhaps from Washington D.C to San Francisco? To make traveling such a long distance easier, you may need road signs telling you where to go and highways to make your journey more direct. In the same way that we need directions and fuel for a long trip, the neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that mediate our sense of touch (also known as mechanoreceptorA type of neuron (nerve cell) that senses mechanical stimuli like touch cells) need a way to get their axonsA specialized part of a neuron that sends electrical and chemical signals to other cells. Axons are typically long and thin like a wire. from the periphery of your body (e.g., hands, toes, and legs) to their final destination, the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.! During nervous system development, it’s really important for these cells to reach the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. in order to provide us with a proper sense of touch; these cells help you feel the carpet under your feet as you get out of bed, the fork in your hand as you eat your lunch, and even that light tap on your shoulder when somebody is trying to get your attention. So how exactly do these touch neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles axonsA specialized part of a neuron that sends electrical and chemical signals to other cells. Axons are typically long and thin like a wire. travel so far to ultimately reach the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.? Kim Kridsada, a neuroscience graduate student in Wenqin Luo’s lab, sought to figure this out.

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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.