BRAINS IN BRIEFS
Scroll down to see new briefs about recent scientific publications by neuroscience graduate students at the University of Pennsylvania. Or search for your interests by key terms below (i.e. sleep, Alzheimer’s, autism).
A mouse model for autism and ADHD can mimic sex differences in sleep
or technically,
Hyperactivity and male-specific sleep deficits in the 16p11.2 deletion mouse model of autism.
[See Original Abstract on Pubmed]
or technically,
Hyperactivity and male-specific sleep deficits in the 16p11.2 deletion mouse model of autism.
[See Original Abstract on Pubmed]
Authors of the study: Angelakos CC, Watson AJ, O'Brien WT, Krainock KS, Nickl-Jockschat T, Abel T.
Falling asleep at night is something we look forward to at the end of the day, restoring our energy for the new day ahead. However, a good night's rest isn’t guaranteed for everyone as many people across the country have trouble sleeping. This is especially true for people diagnosed with autism spectrum disorders (ASD) and attention deficit-hyperactivity disorder (ADHD) who often have trouble falling asleep and staying asleep. Up to 80% of individuals diagnosed with ASD and 55% of children with ADHD suffer from sleep problems. Sleep disturbances can worsen other symptoms common in these disorders such as repetitive behaviors, attention, and communication. Christopher Angelakos, a graduate student in Dr. Ted Abel’s lab, wanted to understand why sleep disturbances are common in ASD and ADHD. In order to answer this question, Christopher turned to established models of ASD/ADHD. He reasoned that mice that have ASD/ADHD-like symptoms might also have sleep disturbances.
Patients with disorders like ASD/ADHD often have changes in the number of copies they have for a geneA unit of DNA that encodes a protein and tells a cell how to function. Typically, for each geneA unit of DNA that encodes a protein and tells a cell how to function there are two copies - one from each parent. Therefore, individuals with ASD/ADHD can have more copies, or fewer copies (also known as a deletion). One of these changes is a deletion in chromosomal region 16p11.2. People that have a deletion in this region are more likely to have ASD and ADHD. Previous research has shown that mice with a deletion in the 16p11.2 region show symptoms similar to ASD/ADHD like differences in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. structure, cognitive ability, and communication. However, sleep problems remained largely unexplored, a problem that Christopher wanted to address.
Christopher observed that these animals were hyperactive, a behavior that is observed in individuals diagnosed with ADHD. He tracked all of the movements of the mice in their cages, observing an increase in activity in the 16p11.2 deletion mice throughout the day, and a robust increase during the dark (active) phase of their cycle. This led him to think that something may be altered in their circadian rhythms. To investigate this he monitored them for 24hrs and measured their sleep and activity to determine if it was normal.
He also examined their sleep cycles using polysomnography, which tracks brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. waves, eye movements, and limb movement during sleep. He wanted to know whether this was a problem of initiating sleep or maintaining sleep. He found that once the animals were asleep, they usually remained asleep for the same amount of time indicating that there was not a problem of staying asleep. On the other hand, once an animal was awake, it was usually awake for a longer period of time, indicating that it may have had trouble with initiating sleep. When Christopher further analyzed the data, he saw male mice with the 16p11.2 deletion spent a longer amount of time awake than regular mice. Coupled with his finding that these mice stay asleep as long as the regular mice, this suggests that they had a hard time falling asleep, rather than that they were waking up multiple times and having brief amounts of wakefulness. Interestingly, these disorders are more commonly found in males rather than females. Males are four times more likely to be diagnosed with ASD and three times more likely to be diagnosed with ADHD.
Issues with sleep in people that are diagnosed with autism or ADHD is a problem that needs to be addressed. Christopher asked whether we can use a mouse to model sleep problems in autism? He showed in his paper that the 16p11.2 deletion mouse can model sleep disturbances that are seen in humans. He is excited to see future work using this mouse model to uncover specific brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. circuits that may be involved and better treatment for sleep problems. Now that we have this experimental mode, we can determine if improving sleep quality will improve other psychiatric symptoms.
Patients with disorders like ASD/ADHD often have changes in the number of copies they have for a geneA unit of DNA that encodes a protein and tells a cell how to function. Typically, for each geneA unit of DNA that encodes a protein and tells a cell how to function there are two copies - one from each parent. Therefore, individuals with ASD/ADHD can have more copies, or fewer copies (also known as a deletion). One of these changes is a deletion in chromosomal region 16p11.2. People that have a deletion in this region are more likely to have ASD and ADHD. Previous research has shown that mice with a deletion in the 16p11.2 region show symptoms similar to ASD/ADHD like differences in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. structure, cognitive ability, and communication. However, sleep problems remained largely unexplored, a problem that Christopher wanted to address.
Christopher observed that these animals were hyperactive, a behavior that is observed in individuals diagnosed with ADHD. He tracked all of the movements of the mice in their cages, observing an increase in activity in the 16p11.2 deletion mice throughout the day, and a robust increase during the dark (active) phase of their cycle. This led him to think that something may be altered in their circadian rhythms. To investigate this he monitored them for 24hrs and measured their sleep and activity to determine if it was normal.
He also examined their sleep cycles using polysomnography, which tracks brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. waves, eye movements, and limb movement during sleep. He wanted to know whether this was a problem of initiating sleep or maintaining sleep. He found that once the animals were asleep, they usually remained asleep for the same amount of time indicating that there was not a problem of staying asleep. On the other hand, once an animal was awake, it was usually awake for a longer period of time, indicating that it may have had trouble with initiating sleep. When Christopher further analyzed the data, he saw male mice with the 16p11.2 deletion spent a longer amount of time awake than regular mice. Coupled with his finding that these mice stay asleep as long as the regular mice, this suggests that they had a hard time falling asleep, rather than that they were waking up multiple times and having brief amounts of wakefulness. Interestingly, these disorders are more commonly found in males rather than females. Males are four times more likely to be diagnosed with ASD and three times more likely to be diagnosed with ADHD.
Issues with sleep in people that are diagnosed with autism or ADHD is a problem that needs to be addressed. Christopher asked whether we can use a mouse to model sleep problems in autism? He showed in his paper that the 16p11.2 deletion mouse can model sleep disturbances that are seen in humans. He is excited to see future work using this mouse model to uncover specific brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. circuits that may be involved and better treatment for sleep problems. Now that we have this experimental mode, we can determine if improving sleep quality will improve other psychiatric symptoms.
About the brief writer: Felicia Davatolhagh
Felicia is a PhD Candidate in Marc Fuccillo’s lab. She is a seventh year studying the impact of neuropsychiatric disease on synaptic connectivity and synaptic function.
Want to learn more about sex differences in neurodevelopmental disorders? You can read Christopher’s whole paper here.
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]
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.
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.
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:
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.
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.