1. Study suggests ‘bursts’ of beta waves, not sustained rhythms, filter sensory processing in brain

    November 15, 2017 by Ashley

    From the Brown University press release:

    To better understand the brain and to develop potential therapies, neuroscientists have been investigating how “beta” frequency brainwaves help the brain filter distractions to process sensations. A new Brown University study stands to substantially refine what they thought was going on: What really matters is not a sustained elevation in beta wave power, but instead the rate of specific bursts of beta wave activity, ideally with perfect timing.

    The new insight, reported in the journal eLife, arose from the scientists looking beneath the covers of the typical practice of averaging beta brain wave data. With a closer examination, trial-by-trial for each subject, they saw that what really reflected attention and impacted perception were discrete, powerful bursts of beta waves at frequencies around 20 hertz.

    “When people were trying to block distraction in a brain area, the probability of seeing these beta events went up,” said senior author Stephanie R. Jones, an associate professor of neuroscience at Brown. “The brain seemed to be flexibly modulating the expression of these beta events for optimal perception.”

    The findings, made with consistency in humans and mice, can not only refine ongoing research into how beta waves arise and work in the brain, Jones said, but also provide guidance to clinicians as they develop therapies that seek to modulate beta waves.

    Testing touch

    The research team, led by graduate student Hyeyoung Shin, acquired the data through a series of experiments in which they measured beta waves in the somatosensory neocortex of humans and mice in the second leading up to inducing (or not inducing) varying amounts of a tactile sensation. Humans wore a cap of magnetoencephalography sensors, while mice had implanted electrodes. For people, the sensation was a tap on a finger tip or the foot. For mice, it was a wiggle of a whisker.

    Subjects were merely required to report the sensations they felt — people pushed a button, while mice were trained to lick a sensor in exchange for a reward. The researchers tracked the association of beta power with whether subjects accurately detected, or didn’t detect, stimuli. What they found, as expected, is that the more beta activity there was in the corresponding region of cortex, the less likely subjects were to report feeling a sensation. Elevated beta activity is known to help suppress distractions.

    A particularly good example, Shin said, was that in experiments where people were first instructed to focus on their foot, there was more beta power in the hand region of the neocortex. Correspondingly, more beta in the hand region resulted in less detection of a sensation in the hand.

    “We think that beta acts a filter mechanism,” Shin said.

    Beta bursts

    Consistently throughout various iterations of the experiments across both the human and mouse subjects, increases in beta activity did not manifest as a continuously elevated rhythm. Instead, when beta appeared, it quickly spiked in short, distinct bursts of power. Only if a subject’s beta was averaged over many trials would it look like a smooth plateau of high-power activity.

    After discovering this pattern, the researchers performed analyses to determine what features of the bursts best predicted whether subjects would report, or miss, a touch sensation. After all, it could be the number of bursts, their power, or maybe how long they lasted.

    What Shin and the team found is that number of bursts and their timing both mattered independently. If there were two or more bursts any time in the second before a sensation, it was significantly more likely to go undetected. Alternatively, if just one burst hit within 200 milliseconds of the sensation, the stimulus would also be more likely to be overlooked.

    “The ideal case was having large numbers and being close in timing to the stimulus,” Shin said.

    A better idea of beta

    While the study helps to characterize the nature of beta in the somatosensory neocortex, it doesn’t explain how it affects sensations, Jones acknowledged. But that’s why it is important that the results were in lockstep in both mice and in people. Confirming that mice model the human experience means researchers can rely on mice in experiments that delve more deeply into how beta bursts arise and what their consequence are in neurons and circuits. Shin is already doing experiments to dissect how distinct neural subpopulations contribute to beta bursts and somatosensory detection, respectively. Co-author and postdoctoral researcher Robert Law is applying computational neural models that link the human and animal recordings for further discovery.

    In the clinical realm, Jones said, an improved understanding of how beta works could translate directly into improving therapies such as transcranial magnetic stimulation or transcranial alternating current to treat neurological disorders, such as chronic pain, or depression. Rather than using those technologies to generate a consistent elevation in beta in a brain region, Jones said, it might be more effective to use them to induce (or suppress) shorter, more powerful bursts and to time those to be as close in time to a target brain activity as possible.

    “Typically with non-invasive brain stimulation you are trying to entrain a rhythm,” Jones said. “What our results suggest is that’s not what the brain is doing. The brain is doing this intermittent pattern of activity.”


  2. Higher estrogen levels linked to increased alcohol sensitivity in brain’s ‘reward center’

    November 14, 2017 by Ashley

    From the University of Illinois at Chicago press release:

    The reward center of the brain is much more attuned to the pleasurable effects of alcohol when estrogen levels are elevated, an effect that may underlie the development of addiction in women, according to a study on mice at the University of Illinois at Chicago.

    Led by Amy Lasek, assistant professor of psychiatry in the UIC College of Medicine, researchers found that neurons in a region of the brain called the ventral tegmental area, or VTA (also known as the “reward center”), fired most rapidly in response to alcohol when their estrogen levels were high. This response, according to their findings published online in the journal PLOS ONE, is mediated through receptors on dopamine-emitting neurons in the VTA.

    “When estrogen levels are higher, alcohol is much more rewarding,” said Lasek, who is the corresponding author on the paper and a researcher in the UIC Center for Alcohol Research in Epigenetics. “Women may be more vulnerable to the effects of alcohol or more likely to overindulge during certain stages of their cycle when estrogen levels are higher, or may be more likely to seek out alcohol during those stages.”

    Studies indicate that gender differences in psychiatric disorders, including addiction, are influenced by estrogen, one of the primary female sex hormones. Women are more likely to exhibit greater escalation of abuse of alcohol and other drugs, and are more prone to relapse in response to stress and anxiety.

    The VTA helps evaluate whether something is valuable or good. When neurons in this area of the brain are stimulated, they release dopamine — a powerful neurotransmitter responsible for feelings of wellness — and, in large doses, euphoria. When something good is encountered — for example, chocolate — the neurons in the VTA fire more rapidly, enforcing reward circuitry that encodes the idea that chocolate is enjoyable and something to be sought out. Over time, the VTA neurons fire more quickly at the sight, or even thought of, chocolate, explained Lasek. In addiction, VTA neurons are tuned into drugs of abuse, and fire more quickly in relation to consuming or even thinking about drugs, driving the person to seek them out — often at the expense of their own health, family, friends and jobs.

    Many animal studies have shown that alcohol increases the firing of dopamine-sensitive neurons in the VTA, but little is known about exactly why this occurs.

    Lasek and her colleagues examined the relationship between estrogen, alcohol and the VTA in female mice. They used naturally cycling mice that were allowed to go through their normal estrous cycles, akin to the menstrual cycle in women.

    Mice were evaluated to determine when they entered diestrus — the phase in the estrous cycle when estrogen levels are close to their peak.

    “In mice in diestrus, estrogen levels increase to about 10 times higher than they are in estrus, the phase in which ovulation occurs and estrogen levels drop,” Lasek said.

    VTAs were taken from mice in both estrus and diestrus and kept alive in special chambers. Electrodes recorded the activity of individual dopamine-sensitive neurons in the VTA. Next, the researchers added alcohol to the chamber. Activity increased twice as much in neurons from mice in diestrus compared to the response of neurons from mice in estrus.

    Lasek and her colleagues then blocked estrogen receptors on dopamine-sensitive neurons in VTA in mice in estrus and diestrus. With the blocker present, the response to alcohol in neurons from mice in diestrus was significantly lower compared with neurons where estrogen receptors remained functional. The estrogen receptor blocker reduced the alcohol response to levels seen in mice in estrus. The responses to alcohol in neurons from mice in estrus were unaffected by the estrogen receptor blocker.

    “The increased reward response to alcohol we see when estrogen levels are high is mediated through receptors for estrogen in the VTA,” said Mark Brodie, professor of physiology and biophysics in the UIC College of Medicine and a co-author on the paper.

    Lasek believes that the increased sensitivity to alcohol in the VTA when estrogen levels peak may play a significant role in the development of addiction in women.

    “We already know that binge drinking can lead to lasting changes in the brain, and in women, those changes may be faster and more significant due to the interaction we see between alcohol, the VTA and estrogen,” Lasek said. “Binge drinking can increase the risk of developing alcoholism, so women need to be careful about how much alcohol they drink. They should be aware that they may sometimes inadvertently over-consume alcohol because the area of the brain involved in alcohol reward is responding very strongly.”


  3. Study suggests brain activity is inherited, may inform treatment for ADHD, autism

    November 13, 2017 by Ashley

    From the Oregon Health & Science University press release:

    Every person has a distinct pattern of functional brain connectivity known as a connectotype, or brain fingerprint. A new study conducted at OHSU in Portland, Oregon, concludes that while individually unique, each connectotype demonstrates both familial and heritable relationships. The results published today in Network Neuroscience.

    “Similar to DNA, specific brain systems and connectivity patterns are passed down from adults to their children,” said the study’s principal investigator Damien Fair, Ph.D., P.A.-C., associate professor of behavioral neuroscience and psychiatry, OHSU School of Medicine. “This is significant because it may help us to better characterize aspects of altered brain activity, development or disease.”

    Using two data sets of functional MRI brain scans from more than 350 adult and child siblings during resting state, Fair and colleagues applied an innovative technique to characterize functional connectivity and machine learning to successfully identify siblings based on their connectotype.

    Through a similar process, the team also distinguished individual sibling and twin pairs from unrelated pairs in both children and adults.

    “This confirms that while unique to each individual, some aspects of the family connectome are inherited and maintained throughout development and may be useful as early biomarkers of mental or neurological conditions,” said lead author Oscar Miranda-Dominguez, Ph.D., research assistant professor of behavioral neuroscience, OHSU School of Medicine.

    Overall, the connectotype demonstrated heritability within five brain systems, the most prominent being the frontoparietal cortex, or the part of the brain that filters incoming information. The dorsal attention and default systems, important for attention or focus and internal mental thoughts or rumination, respectively, also showed significant occurrences.

    “These findings add to the way we think about normal and altered brain function,” said Fair. “Further, it creates more opportunity for personalized and targeted treatment approaches for conditions such as ADHD or autism.”


  4. Study suggests malfunctions in communication between brain cells could be at root of autism

    November 11, 2017 by Ashley

    From the Washington University School of Medicine press release:

    A defective gene linked to autism influences how neurons connect and communicate with each other in the brain, according to a study from Washington University School of Medicine in St. Louis. Rodents that lack the gene form too many connections between brain neurons and have difficulty learning.

    The findings, published Nov. 2 in Nature Communications, suggest that some of the diverse symptoms of autism may stem from a malfunction in communication among cells in the brain.

    “This study raises the possibility that there may be too many synapses in the brains of patients with autism,” said senior author Azad Bonni, MD, PhD, the Edison Professor of Neuroscience and head of the Department of Neuroscience at Washington University School of Medicine in St. Louis. “You might think that having more synapses would make the brain work better, but that doesn’t seem to be the case. An increased number of synapses creates miscommunication among neurons in the developing brain that correlates with impairments in learning, although we don’t know how.”

    Autism is a neurodevelopmental disorder affecting about one out of every 68 children. It is characterized by social and communication challenges.

    Among the many genes linked to autism in people are six genes that attach a molecular tag, called ubiquitin, to proteins. These genes, called ubiquitin ligases, function like a work order, telling the rest of the cell how to deal with the tagged proteins: This one should be discarded, that one should be rerouted to another part of the cell, a third needs to have its activity dialed up or down.

    Patients with autism may carry a mutation that prevents one of their ubiquitin genes from working properly. But how problems with tagging proteins affect how the brain is hardwired and operates, and why such problems may lead to autism, has remained poorly understood.

    To understand the role of ubiquitin genes in brain development, Bonni, first author Pamela Valnegri, PhD, and colleagues removed the ubiquitin gene RNF8 in neurons in the cerebellum of young mice. The cerebellum is one of the key brain regions affected by autism.

    The researchers found that neurons that lacked the RNF8 protein formed about 50 percent more synapses — the connections that allow neurons to send signals from one to another — than those with the gene. And the extra synapses worked. By measuring the electrical signal in the receiving cells, the researchers found that the strength of the signal was doubled in the mice that lacked the protein.

    The cerebellum is indispensable for movement and learning motor skills such as how to ride a bicycle. Some of the recognizable symptoms of autism — such as motor incoordination and a tendency to walk tippy-toed — involve control of movement.

    The animals missing the RNF8 gene in the neurons of their cerebellum did not have any obvious problems with movement: They walked normally and appeared coordinated. When the researchers tested their ability to learn motor skills, however, the mice without RNF8 failed miserably.

    The researchers trained the mice to associate a quick puff of air to the eye with the blinking of a light. Most mice learn to shut their eyes when they see the light blink, to avoid the irritation of the coming air puff. After a week of training, mice with a functioning copy of the gene closed their eyes in anticipation more than three quarters of the time, while mice without the gene shut their eyes just a third of the time.

    While it is best known for its role in movement, the cerebellum is also important in higher cognitive functions such as language and attention, both of which are affected in autism. People with autism often have language delays and pay unusually intense attention to objects or topics that interest them. The cerebellum may be involved not only in motor learning but in other features of autism as well, the researchers said.

    Of course, there is a world of difference between a mouse that can’t learn to shut its eyes and a person with autism who struggles to communicate. But the researchers said the findings suggest that changing how many connections neurons make with each other can have important implications for behavior.

    Since this paper was written, Bonni and colleagues have tested the other autism-associated ubiquitin genes. Inhibition of all genes tested cause an increase in the number of synapses in the cerebellum.

    “It’s possible that excessive connections between neurons contribute to autism,” Bonni said. “More work needs to be done to verify this hypothesis in people, but if that turns out to be true, then you can start looking at ways of controlling the number of synapses. It could potentially benefit not just people who have these rare mutations in ubiquitin genes but other patients with autism.”


  5. Locus coeruleus activity linked with hyperarousal in PTSD

    November 9, 2017 by Ashley

    From the Elsevier press release:

    A new study in Biological Psychiatry has linked signs of heightened arousal and reactivity — a core symptom of posttraumatic stress disorder (PTSD) — to overactivity of the locus coeruleus (LC), a brain region that mediates arousal and reactivity. By combining bodily responses and brain imaging data, the new paper by Dr. Christoph Mueller-Pfeiffer at the University of Zurich, Switzerland and colleagues is the first to provide direct human evidence for a theory over 30 years old. Pinpointing the origin of symptoms in the brain is a major step in efforts to improve treatment options for patients with the disorder.

    “The authors are to be congratulated on imaging this part of the brain,” said Dr. John Krystal, Editor of Biological Psychiatry. “Demonstrating the presence of LC hyperactivity in PTSD sets the stage for clarifying the relationship of LC activity to stress response, resilience, PTSD symptoms, and the treatment of PTSD,” he added.

    In the study, first author Christoph Naegeli, also of University of Zurich, and colleagues analyzed 54 participants who had been exposed to trauma, about half of whom developed PTSD. When the participants listened to random bursts of white noise, those who were diagnosed with PTSD had more frequent eye blinks, and increased heart rate, skin conductance and pupil area responses — indicators of the body’s autonomic response — than participants without PTSD.

    Using functional magnetic resonance imaging to measure brain activity, Naegeli and colleagues found that patients with PTSD had larger brain responses in the LC and other regions wired to the LC that control alertness and motor preparation. According to Mueller-Pfeiffer, the increased brain activity and autonomic responses measured in the participants provide a biologically plausible explanation for hypervigilance and exaggerated startle responses in PTSD. However, LC activation was not directly associated with arousal symptoms. Thus, direct links between LC hyperactivity and PTSD symptom severity still need to be demonstrated.

    The study may also reveal new avenues for treating these common and disabling symptoms of PTSD. “Our results suggest that targeting locus coeruleus system hyperactivity with new pharmacological or psychotherapeutic interventions are approaches worthy of further investigation,” said Dr. Mueller-Pfeiffer.


  6. Study suggests gene therapy protecting against age-related cognitive, memory deficits

    November 4, 2017 by Ashley

    From the Universitat Autònoma de Barcelona press release:

    Researchers from the Institute of Neurosciences at the Universitat Autònoma de Barcelona (INc-UAB) and the Vall d’Hebron Research Institute (VHIR) are the first to demonstrate that regulation of the brain’s Klotho gene using gene therapy protects against age-related learning and memory problems in mice.

    The study, published in Molecular Psychiatry (Nature group), opens the door to advancing in the research and development of therapies based on this neuroprotective gene.

    Researchers from the UAB demonstrated in a previous study that Klotho regulates age-associated processes, increasing life expectancy when over-expressed and accelerating the development of learning and memory deficiencies when inhibited.

    Now they have demonstrated in vivo for the first time that one dose of this gene injected into the central nervous system prevents the cognitive decline associated with aging in old animals which were treated at a younger age.

    The results, which form part of the PhD thesis of Anna Massó, first author of the article, are part of a study led by INc-UAB researchers Dr Miguel Chillón, ICREA researcher at the Department of Biochemistry and Molecular Biology of the UAB and the VHIR; Dr Lydia Giménez-Llort from the Department of Psychiatry and Legal Medicine of the UAB; and with the collaboration of Dr Assumpció Bosch, also from the Department of Biochemistry and Molecular Biology.

    “The therapy is based on an increase in the levels of this protein in the brain using an adeno-associated viral vector (AAV). Taking into account that the study was conducted with animals which aged naturally, we believe this could have the therapeutic ability to treat dementia and neurodegenerative disorders such as Alzheimer’s or multiple sclerosis, among others,” Miguel Chillón points out.

    The researchers patented their therapy and have licensed it to Kogenix Therapeutics. The company includes UAB participation and is based in the United States. It was launched by Dr Miguel Chillón and Dr Assumpció Bosch, together with the entrepreneur Menachem Abraham and Dr Carmela Abraham, professor of Biochemistry and Pharmacology at the Boston University School of Medicine, a pioneering centre in the study of Klotho in the central nervous system for more than a decade.

    The objective of Kogenix is to achieve the initial capital needed to advance in the pre-clinical trials already being conducted with animal models of Alzheimer’s disease. This will give way to the development of a drug to be used in gene therapy against neurodegenerative diseases based on small molecules which enhance the expression of the gene and/or the use of fragments of the Klotho protein itself.

    “In basic research studies and clinical trials the AAVs have shown to be safe and effective in the implementation of a central nervous system gene therapy. In fact, the Food and Drug Administration made the first gene therapy available in the United States in August and additional approvals are expected,” Dr Assumpció Bosch states.


  7. Study finds mapping brain connectivity with MRI may predict outcomes for cardiac arrest survivors

    November 3, 2017 by Ashley

    From the Johns Hopkins Medicine press release:

    A new study led by Johns Hopkins researchers found that measures of connectivity within specific cerebral networks were strongly linked to long-term functional outcomes in patients who had suffered severe brain injury following a cardiac arrest.

    A description of the findings, published in October in the journal Radiology, suggests that mapping and measuring such connectivity may result in highly accurate and reliable markers of long-term recovery trajectories in people with neurological damage caused by heart attacks, strokes, brain hemorrhage or trauma.

    “By analyzing functional MRI data we are able to see where brain network disruption is occurring, and determine how these changes relate to the likelihood of recovery from brain damage,” says Robert Stevens, M.D., associate professor of anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine, and the paper’s senior author.

    Cardiac arrest, or the sudden loss of heart function, affects an estimated 535,000 people in the United States each year, according to the American Heart Association. The loss of blood flow, and its restoration through resuscitation, is associated with rapid and widespread damage to the brain, leading to disabling neurological and cognitive problems in survivors.

    Several modifiable factors, such as timeliness and quality of cardiac resuscitation and the strict control of body temperature to avoid fever, strongly influence the magnitude of brain damage and the prospects for recovery, says Stevens.

    He adds that current methods to predict how an individual will recover over time are limited, but advanced imaging techniques such as quantitative brain mapping using MRI data could transform practice by allowing clinicians to make better-informed decisions about care. MRI can specifically and accurately identify changes in tissue structure, blood flow and functional activation. Functional connectivity is determined by analyzing the temporal correlation of functional activation in different parts of the brain, thereby establishing the strength of connections between anatomically distinct regions. Clusters of brain regions that are highly correlated are called networks, and the degree of correlation can be measured within and between networks.

    For their study, the Hopkins researchers and their colleagues assessed the brain’s functional activation in 46 patients who were in a coma after cardiac arrest between July 2007 and October 2013. MRI was performed on all patients on average 12.6 days after cardiac arrest, and the analysis focused on four networks in the brain: dorsal attention network (DAN, which is active when a person uses energy to focus attention); default mode network (DMN, which is active when an individual is at rest); executive control network (ECN, which is active while initiating tasks and is associated with reward and inhibition); and salience network (SN, a network that determines the importance of stimuli and may direct activation of other cognitive networks). Of the participants, 32 were men, and the average age was 49.

    One year after the patients’ cardiac arrests, the researchers assessed survivors with the Cerebral Performance Category (CPC) Scale, a commonly used measure of neurological function following cardiac arrest. The test uses a scale from 1 to 5, with 1 indicating minimal to no disability and 5 indicating brain death. Eleven of the 46 patients who had favorable outcomes (a score of 1 or 2) showed higher connectivity within the DMN network, as well as greater anti-correlation (when one is active the other is not) between the SN and ECN and the SN and DMN, when compared with patients who had an unfavorable outcome (CPC greater than 2). Remarkably, the functional connectivity markers predicted outcomes more accurately when compared with structural measures of, for example, tissue damage, used in conventional MRI scans.

    “These findings highlight a potential realm of precision medicine using brain network biomarkers that are discriminative and predictive of outcomes,” says Haris Sair, M.D., interim director of neuroradiology at the Johns Hopkins University School of Medicine and the study’s lead author. “In the future, connectivity biomarkers may help guide new therapies for targeted treatment to improve brain function.”


  8. Study suggests people with psychotic-like experiences spend less time in healthy brain states

    November 2, 2017 by Ashley

    From the Elsevier press release:

    Healthy people experiencing subtle symptoms observed in psychotic disorders, such as hallucinations and delusions, have altered brain dynamics, according to a new study published in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. The alterations were found in patterns of brain activity that reoccur, or “states” that the brain moves in and out of over time. The participants who reported the psychotic-like experiences (PLEs) — considered to be at the low end of the psychosis spectrum — spent less time in a brain state reflecting healthier brain network activity.

    Previous studies of PLEs have found alterations in specific brain networks, but the findings reveal that it is not just about damaged connections — the amount of time spent in uncommon brain states may contribute to psychosis..

    “These altered brain dynamics are important because they provide a new biomarker for subclinical psychosis,” said Dr. Anita Barber of the Feinstein Institute for Medical Research in New York, first author of the study. The participants were all considered healthy, yet their subtle symptoms demonstrated unique brain fluctuations that could potentially be used to identify signs of psychosis.

    In the study, Dr. Barber and colleagues analyzed brain imaging data from the Human Connectome Project of 76 otherwise healthy participants reporting PLEs and 153 control participants. Those experiencing PLEs spent less time in a more “typical” reoccurring brain state involving cognitive networks. They also spent more time in a state characterized by excessive communication in visual regions of the brain, which could be the basis for visual hallucinations experienced in psychosis. The study didn’t include people with a psychotic disorder, but the findings line up with brain alterations found in patients with schizophrenia.

    According to Dr. Cameron Carter, Editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, the study is an important example of how more sophisticated approaches to analyzing brain imaging data examining transitions between mental states over time can measure altered brain dynamics that can identify subtle risk states or even track the transition from subclinical to clinical psychopathology.

    “This has implications for improving health and well-being and for preventing conversion to a psychotic disorder,” said Dr. Barber. PLEs affect many more people than the number who will be diagnosed with a psychotic disorder, and can cause impairments in social and occupational functioning similar to, though less severe than, those experienced by people with psychosis. “The findings suggest that therapies encouraging greater engagement of goal-directed behaviors and less engagement of visual sensory processing could improve outcomes,” said Dr. Barber.


  9. Study suggests brain’s response to mid-life surge in cell aging starts or ends a path to dementia

    by Ashley

    From the University of Texas Health Science Center at Houston press release:

    Researchers at The University of Texas Health Science Center at Houston (UTHealth) School of Dentistry and McGovern Medical School have discovered a previously unknown characteristic of brain-cell aging that could help detect late-onset Alzheimer’s disease decades before symptoms begin.

    The study, “Interleukin33 deficiency causes tau abnormality and neurodegeneration with Alzheimer-like symptoms in aged mice,” appeared online in the journal Translational Psychiatry earlier this year.

    Working with mice, the UTHealth team found that neurons in the brain experienced a sudden increase in aging around the mouse equivalent of age 40 in humans. Normal mice responded with a surge of interleukin33, a protein that activates the body’s repair mechanisms to make the neurons healthy again. Mice lacking the IL33 gene didn’t experience the surge and continued to decline, eventually developing dementia at an age roughly equivalent to 68 in humans.

    “We think we’re getting old gradually, but when we’re talking about these cells, we’ve discovered that it’s not that way,” said Yahuan Lou, Ph.D., a professor in the Department of Diagnostic and Biomedical Sciences at the School of Dentistry.

    Late-onset sporadic Alzheimer’s disease occurs after age 65 and represents approximately 95 percent of all cases, with the other 5 percent believed to be genetic. By the time symptoms appear, the brain has already lost massive numbers of neurons. The UTHealth researchers believe the surge at age 40 may be an ideal time to look for biomarkers that predict Alzheimer’s long before the damage begins.

    Lou first detected the power of IL33 while studying premature ovarian failure in mice. “We observed that when we removed IL33, the ovary shrank much faster than normal. So we wondered: If IL33 does this in the ovary, what does it do in the brain? The brain has an abundance of IL33.”

    Looking for collaborators who could test that question, Lou was surprised to learn that researchers from McGovern Medical School’s Department of Psychiatry and Behavioral Sciences had recently moved into the new UT Behavioral and Biomedical Sciences Building that he and other dental school researchers had also newly occupied. Among his new neighbors were Department of Psychiatry Professor Joao De Quevedo, M.D., Ph.D., and Assistant Professor Ines Moreno-Gonzalez, Ph.D., of the Mitchell Center for Alzheimer’s Disease, who had the expertise and resources for analyzing rodent behavior and correlating it to humans. A collaborative team soon formed, and their mouse study led to the paper in Translational Psychiatry with plans for follow-up studies to explore the tantalizing results.

    Lou said a group of researchers in Singapore recently conducted an experiment using mice that model familial early-onset Alzheimer’s disease. “When they injected IL33 into the [Alzheimer’s] mice, they saw that the plaque load was reduced, but they didn’t know why,” he said. “We’ve figured out why.”

    The IL33 injections seemed to relieve symptoms temporarily, he added, but did not cure the disease. The effects lasted about two weeks in mice — equal to several months in humans. Lou believes finding a way to enhance the brain’s own supply of IL33 may lead to potential treatments for the disease.

    The cause of late-onset Alzheimer’s is a medical mystery with many potential causes under investigation, including neuro-inflammation, abnormal aging, smoking, and infections. IL33 deficiency is another promising lead, with additional studies planned as funding is secured.


  10. Study identifies neurons that rouse the brain to breathe

    November 1, 2017 by Ashley

    From the Beth Israel Deaconess Medical Center press release:

    A common and potentially serious sleep disorder, obstructive sleep apnea affects at least one quarter of U.S. adults and is linked to increased risk of diabetes, obesity and cardiovascular disease. In a paper published in the journal Neuron, researchers at Beth Israel Deaconess Medical Center (BIDMC) identified specific neural circuitry responsible for rousing the brain of mice in simulated apnea conditions. The findings could lead to potential new drug therapies to help patients with obstructive sleep apnea get more rest.

    Often but not always marked by loud snoring, sleep apnea occurs when a sleeping person’s airway collapses and closes off breathing. Dipping oxygen (O2) levels and rising carbon dioxide (CO2) levels in the blood alert the sleeping brain to the problem, rousing the sleeper just long enough to re-establish breathing.

    “A person with apnea wakes up and starts breathing again and this cycle can repeat hundreds of time per night, so the person never gets very deeply asleep,” said senior author Clifford B. Saper, MD, Chair of the Department of Neurology at BIDMC. “In the morning, they may not remember that they have not had a restful night’s sleep but will feel very tired.”

    Fragmented sleep can leave people with apnea with significant impairments to cognition, mood and daytime alertness; it may also increase cardiovascular risk. But what if scientists could prevent the brain from rousing itself hundreds of times per night in response to rising CO2 levels, while allowing it to reestablish regular respiration again?

    “Our goal was to identify the circuitry responsible for waking the brain up during sleep apnea, which is distinct from the part of the brain that controls breathing,” said Saper, who is also the James Jackson Putnam Professor of Neurology and Neuroscience at Harvard Medical School. “If we could keep the brain from waking up during apneas and activate only the part of the brain that opens up the airways, people with obstructive sleep apnea would still be able to get a good night’s rest.”

    Using an enclosure with adjustable atmospheric levels of O2 and CO2, Saper and colleagues mimicked the effects of OSA in mice by changing the ratio of the two gases every five minutes for 30 seconds.

    Then, Saper and colleagues focused on a subset of neurons — called PBelCGRP cells- known to show activity in response to elevated CO2 levels. The team used mice with these cells genetically-altered in such a way that researchers could activate or suppress the neurons at will using light or drugs to trigger genetic switches. Known as optogenetics and chemogenetics, these experiments demonstrated that activating these cells will wake mice up and keep them up for hours. They also showed that suppressing PBelCGRP cells’ activity would let mice sleep even as CO2 levels in the air around them rose. Taken together, these findings show that the PBelCGRP cells wake up the brain and are necessary for arousal.

    In the final experiment, the researchers followed the PBelCGRPneurons’ long-reaching branches (called axons) to the cells they connect with in other regions of the brain. Without disrupting the cells’ entire activity, the researchers switched off PBelCGRPneurons’ connection to a key site in the basal forebrain. That resulted in a nearly complete loss of sensitivity to CO2 arousal.

    Saper and colleagues note that rising CO2 levels may not be the only factor that repeatedly rouses people with sleep apnea throughout the night. Negative air pressure in the collapsed upper airway may also send “wake-up” messages to the brain via another neuronal circuit. Or PBelCGRP neurons may rouse a sleeping brain in response to a variety of stimuli, not just rising CO2 levels, the researchers suggest. Learning which neurons regulate arousal could allow scientists to develop drugs to treat obstructive sleep apnea and other sleep disorders.

    “The long-term goal of this research is to come up with drugs that will affect specific pathways in the brain,” Saper said. “The next step is to see if we can use drugs to prevent the wake-up response while augmenting the opening of the airway. That way, having an apnea won’t wake a person up.”