1. Neurobiology: The chemistry of memory

    December 4, 2017 by Ashley

    From the Ludwig-Maximilians-Universitaet Muenchen (LMU) press release:

    Learning requires the chemical adaptation of individual synapses. Researchers have now revealed the impact of an RNA-binding protein that is intimately involved in this process on learning and memory formation and learning processes.

    The formation of memories requires subtle changes in brain structures. This is because learning and memory are the result of the incessant modification of synapses — which provide the functional connections that enable nerve cells to communicate with one another. The long-term molecular alterations involved in this process are encoded by so-called messenger RNAs, which are produced in the nucleus of the neuron and must be transported to the appropriate synapses in order to program the synthesis of specific proteins “on-site.” In previous studies, LMU scientist Michael Kiebler has shown that the RNA-binding protein Staufen2 plays an essential role in conveying these mRNAs to their destinations. But exactly how this molecular process actually affects learning and behavior was not well understood. Now, a study carried out by the Kiebler group, in collaboration with Dusan Bartsch (Mannheim University) and Spanish colleagues (Seville University), has shed new light on this issue. The new work shows, for the first time, that reduced levels of Staufen2 are associated with a specific impairment of memory. The findings appear in the journal Genome Biology.

    The researchers made use of a genetic rat model that has been developed and refined over the past decade, in which the synthesis of Staufen2 can be conditionally and selectively suppressed in nerve cells in the forebrain. They then characterized the effects of reduced levels of Staufen2 protein on memory using behavioral tests that measure the efficacy of spatial, temporal and associative memory. These tasks are known to depend on synaptic plasticity, i.e. the ability to actively adjust the efficiency of communication between specific synaptic networks, in the hippocampus. The results clearly show that the reduction of Staufen2 in the forebrain has a negative impact on several aspects of memory. “Overall, long-term memory continues to function, and the rats remain capable of learning how to find a food source, for instance” — Kiebler says — “but when the mutants are asked to recall what they have learned after longer periods of time, their performance is significantly worse than wild-type animals.”

    Depletion of Staufen2 also has a marked effect on nerve-cell morphology and synapse function. With the aid of electrophysiological measurements, the authors analyzed the efficiency of signal transmission across synapses in the hippocampus, and found that both long-term potentiation (LTP) and long-term depression (LTD) are affected. LTP is a mechanism that results in a long-lasting increase in the efficiency of synaptic transmission, and thus strengthens the functional connections between them. LTD, on the other hand, diminishes transmission efficacies, and effectively disconnects previously established connections. Strikingly, reduced levels of Staufen2 enhance LTP, while they impair LTD. These findings suggest that deficiency of Staufen2 makes synapses more responsive than they would otherwise be. “LTP is regarded as a model of learning at the cellular level. However, our results indicate that it is actually the balance of LTP to LTD that is important. This is clearly perturbed in the absence of Staufen2,” Kiebler points out. The researchers therefore assume that, under these circumstances, synapses become highly responsive, and not enough are repressed. This could imply that information which is normally consolidated in long-term memory is prematurely destabilized or perhaps even wiped out. “This work has enabled us, for the first time, to link a specific molecular factor — the RNA-binding protein Staufen2 — with synaptic plasticity and learning,” Kiebler says. “Furthermore, our approach promises to yield completely new insights into the molecular mechanisms that mediate learning.”


  2. Study suggests Alzheimer’s Tau protein forms toxic complexes with cell membranes

    December 2, 2017 by Ashley

    From the École polytechnique fédérale de Lausanne press release:

    The brains of patients with Alzheimer’s disease contain characteristic tangles inside neurons. These tangles are formed when a protein called Tau aggregates into twisted fibrils. As a result, the neurons’ transport systems disintegrate, essential nutrients can’t move through, and the cells begin to die, affecting the brain’s functions and giving rise to the disease’s symptoms.

    Given its role in the pathology of Alzheimer’s disease, Tau protein has been extensively investigated. With several clinical trials of amyloid-targeting therapies failing recently, Tau has become one of the most actively pursued therapeutic targets for Alzheimer’s disease. However, questions still remain about how Tau spreads in the brain and kills neurons. The cell membrane has been shown to play a role in regulating Tau’s aggregation properties and physiological functions, but we still do not understand how the interplay between Tau and lipid membranes can lead to the loss of neurons seen in Alzheimer’s disease.

    Now, the lab of Hilal Lashuel at EPFL, in collaboration with the lab of Thomas Walz at the Rockefeller University, found that individual Tau proteins interact with and disrupt the cell membrane of neurons. This disruption gives rise to highly stable complexes made up of several Tau proteins as well as fat molecules (phospholipids) from the membrane.

    Subsequent studies showed that the protein/phospholipid complexes are more readily taken up by neurons compared to the fibril form of the protein, and induce toxicity in primary neurons of the hippocampus in vitro. The hippocampus is where memory is processed, and loss of hippocampal neurons is a classic symptom of Alzheimer’s disease. The complexes were detectable with an antibody (MC-1) that is used as a standard for detecting pathological conformations of Tau, meaning that they share some features of the pathological form of the protein.

    “Our goal was to identify the sequence and structural factors that drive Tau interaction with membranes and the formation of these complexes so that we can develop strategies to interfere with their formation and block their toxicity,” says Nadine Ait Bouziad, the PhD student who led the study.

    In collaboration with Professor David Eliezer at Weill Cornell School of Medical Sciences in New York, the researchers used Nuclear Magnetic Resonance (NMR) to gain insight into the structure of Tau in the core of the complexes. This revealed that the cores are made up of two small peptides, each only six amino acids long. These peptides are called PHF6* and PHF6, and they play important roles in driving Tau aggregation and assembly into fibrils. Their presence connects the protein/phospholipid complexes with the development of Alzheimer’s disease.

    Building on their findings, the researchers were able to produce mutant Tau protein. The introduced mutations disrupted Tau’s ability to interact with cell membranes, but did so without interfering with its ability to form fibrils. The idea behind this is that such mutants can be used to uncouple these two processes, which would allow researchers to investigate the effect that these membrane interactions have on the function, aggregation and toxicity of Tau in primary neuron cultures. This would be a first step in gaining a clearer picture of how Tau tangles begin to form, which would be critical if we are to develop efficient therapies to counteract their toxicity.

    “Our findings point toward a novel form of Tau protein/phospholipid complexes that might be part of a membrane-dependent mechanism that regulates Tau structure, oligomerization, toxicity, and possibly its normal and aberrant trafficking between and within neurons,” says Hilal Lashuel. “By developing tools that allow us to detect, disrupt and/or target these complexes, we hope to identify novel strategies to inhibit Tau aggregation, toxicity, and pathology spreading in the Alzheimer’s brain.”


  3. Dementia study sheds light on how damage spreads through brain

    December 1, 2017 by Ashley

    From the University of Edinburgh press release:

    Insights into how a key chemical disrupts brain cells in a common type of dementia have been revealed by scientists.

    Brain tissue from people with Dementia with Lewy Bodies (DLB) showed that the protein builds up in vital parts of neurons that connect cells and may jump from one cell to another through these connections.

    Scientists say the findings shed light on the causes of DLB and will help to accelerate the search for a treatment.

    The study, co-led by the University of Edinburgh, focused on synapses – shared connection points between brain cells that allow chemical and electrical signals to flow between cells. These signals are vital for forming memories and are key to brain health, experts say.

    Researchers showed that synapses in five people who had died with DLB contained clumps of the damaging protein, known as alpha-synuclein, which could contribute to dementia symptoms.

    Toxic alpha-synuclein was spotted in both sides of the synapses, suggesting that it may jump between cells through these connections. This sheds light on how damage could be spread through the brain.

    Similar findings were not seen in brain tissue from people who had died with Alzheimer’s disease or those without dementia.

    The discovery was made with extremely powerful technology, used in DLB for the first time, which allowed the scientists to view detailed images of over one million single synapses. Individual synapses are around 5000 times smaller than the thickness of a sheet of paper.

    Although alpha-synuclein clumps had been previously identified in DLB, their effects on synapses were unknown because of difficulties in studying them due to their tiny size.

    DLB is the third most common form of dementia after Alzheimer’s and vascular dementias, affecting around 100,000 people in the UK. It can cause severe memory loss as well as movement problems and there is no cure.

    Professor Tara Spires-Jones, Programme Lead at the UK Dementia Research Institute at the University of Edinburgh, who co-led the study, said: “DLB is a devastating condition and our findings suggest that it is at least partly driven by damage to synapses. These discoveries should invigorate the search for therapies aimed at reducing synaptic damage and open the possibility of targeting the spread of alpha-synuclein through the brain, which could stop disease progression in its tracks.”

    Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK, said: “This exciting research using cutting-edge technology sheds new light on the progression of DLB in the brain. The results provide convincing, measurable and visual evidence that toxic alpha-synuclein is disrupting synapses that could potentially contribute to the devastating symptoms of the disease.

    “We are extremely pleased our funding has helped produce these important results which demonstrate potential avenues for much-needed new treatments for people who are living with DLB. The research we fund would not be possible without the work of our tireless supporters who go to extraordinary lengths to allow talented researchers to make important new discoveries like these.”


  4. Study suggests potential treatment for autism, intellectual disability

    November 26, 2017 by Ashley

    From the University of Nebraska Medical Center (UNMC) press release:

    A breakthrough in finding the mechanism and a possible therapeutic fix for autism and intellectual disability has been made by a University of Nebraska Medical Center researcher and his team at the Munroe-Meyer Institute (MMI).

    Woo-Yang Kim, Ph.D., associate professor, developmental neuroscience, led a team of researchers from UNMC and Creighton University into a deeper exploration of a genetic mutation that reduces the function of certain neurons in the brain.

    Dr. Kim’s findings were published in this week’s online issue of Nature Neuroscience.

    “This is an exciting development because we have identified the pathological mechanism for a certain type of autism and intellectual disability,” Dr. Kim said.

    Recent studies have shown that the disorder occurs when a first-time mutation causes only one copy of the human AT-rich interactive domain 1B (ARID1B) gene to remain functional, but it was unknown how it led to abnormal cognitive and social behaviors.

    Autism spectrum disorder (ASD) impairs the ability of individuals to communicate and interact with others. About 75 percent of individuals with ASD also have intellectual disability, which is characterized by significant limitations in cognitive functions and adaptive behaviors.

    There are no drugs or genetic treatments to prevent ASD or intellectual disability; the only treatment options focus on behavioral management and educational and physical therapies.

    The team created and analyzed a genetically modified mouse and found that a mutated Arid1b gene impairs GABA neurons, the ‘downer’ neurotransmitter, leading to an imbalance of communication in the brain.

    GABA blocks impulses between nerve cells in the brain. Low levels of GABA may be linked to anxiety or mood disorders, epilepsy and chronic pain. It counters glutamate (the upper neurotransmitter), as the two mediate brain activation in a Yin and Yang manner. People take GABA supplements for anxiety.

    “In normal behavior, the brain is balanced between excitation and inhibition,” Dr. Kim said. “But when the inhibition is decreased, the balance is broken and the brain becomes more excited causing abnormal behavior.

    “We showed that cognitive and social deficits induced by an Arid1bmutation in mice are reversed by pharmacological treatment with a GABA receptor modulating drug. And, now we have a designer mouse that can be used for future studies.”

    Next steps for Dr. Kim and his team are to even further refine the specific mechanism for autism and intellectual disability and to identify which of the many GABA neurons are specifically involved.


  5. Injury from contact sport has harmful, though temporary effect on memory

    November 22, 2017 by Ashley

    From the McMaster University press release:

    McMaster University neuroscientists studying sports-related head injuries have found that it takes less than a full concussion to cause memory loss, possibly because even mild trauma can interrupt the production of new neurons in a region of the brain responsible for memory.

    Though such losses are temporary, the findings raise questions about the long-term effects of repeated injuries and the academic performance of student athletes.

    The researchers spent months following dozens of athletes involved in high-contact sports such as rugby and football, and believe that concussions and repetitive impact can interrupt neurogenesis — or the creation of new neurons — in the hippocampus, a vulnerable region of the brain critical to memory.

    The findings were presented today (Tuesday, November 14th) at the Society for Neuroscience’s annual conference, Neuroscience 2017, in Washington D.C.

    “Not only are newborn neurons critical for memory, but they are also involved in mood and anxiety,” explains Melissa McCradden, a neuroscience postdoctoral fellow at McMaster University who conducted the work. “We believe these results may help explain why so many athletes experience difficulties with mood and anxiety in addition to memory problems.”

    For the study, researchers administered memory tests and assessed different types of athletes in two blocks over the course of two years. In the first block, they compared athletes who had suffered a concussion, uninjured athletes who played the same sport, same-sport athletes with musculoskeletal injuries, and healthy athletes who acted as a control group.

    Concussed athletes performed worse on the memory assessment called a mnemonic similarity test (MST), which evaluates a person’s ability to distinguish between images that are new, previously presented, or very similar to images previously presented.

    In the second study, rugby players were given the MST before the season started, halfway through the season, and one month after their last game. Scores for injured and uninjured athletes alike dropped midseason, compared to preseason scores, but recovered by the postseason assessment.

    Both concussed and non-concussed players showed a significant improvement in their performance on the test after a reprieve from their sport.

    For the concussed athletes, this occurred after being medically cleared to return to full practice and competition. For the rugby players, they improved after approximately a month away from the sport.

    If neurogenesis is negatively affected by concussion, researchers say, exercise could be an important tool in the recovery process, since it is known to promote the production of neurons. A growing body of new research suggests that gentle exercise which is introduced before a concussed patient is fully symptom free, is beneficial.

    “The important message here is that the brain does recover from injury after a period of reprieve,” says McCradden. “There is a tremendous potential for the brain to heal itself.”


  6. Researchers develop way to stimulate formation of new neural connections in adult brain

    November 16, 2017 by Ashley

    From the University of Idaho press release:

    A team led by University of Idaho scientists has found a way to stimulate formation of new neural connections in the adult brain in a study that could eventually help humans fend off memory loss, brain trauma and other ailments in the central nervous system.

    Peter G. Fuerst, an associate professor in the College of Science’s Department of Biological Sciences and WWAMI Medical Education Program, and a team that included lead author doctoral student Aaron Simmons, were able to stimulate growth of new neural connections in mice that are needed to connect the cells into neural circuits. Their study, which included scientists from the University of Louisville and University of Puerto Rico-Humacao, is titled “DSCAM-Mediated Control of Dendritic and Axonal Arbor Outgrowth Enforces Tiling and Inhibits Synaptic Plasticity.” It was published today in the Journal Proceedings of the National Academy of Sciences.

    “The paper is a study into factors that prevent adult neurons from making new connections,” Fuerst said. “Regulation of this process is important to prevent several disorders, such as autism, but is also related to the inability of the adult nervous system to readily recover from damage.”

    Researchers studied a cell population that has the unusual ability to make new connections into adulthood, but under normal conditions does not grow the needed axons or dendrites. The team was able to genetically manipulate the cell population in the mice to induce axon and dendrite outgrowth. They found this induced the formation of stable, functional connections with new cells.

    “The idea is that one could stimulate the nervous system to make new connections if there was some kind of trauma,” Fuerst said. “Maybe this is the way to reactivate the cell to build those new connections that we can take advantage of clinically.”

    Their efforts included research through the regional WWAMI Medical Education Program at the University of Washington and could have wide ramifications for other adult neurological conditions that prevent human brains from making those needed connections as an adult.

    “In children in early development it’s very easy to make new connections, but adults lose that ability, and we want to see why that is,” he said.

    The genetic manipulation used in mice as part of the study wouldn’t work in humans. Instead, Fuerst and his team would next like to test small-molecule drugs that regulate these central nervous system processes — currently used to combat cancer in humans — to see if they can help the nervous system make new connections in mice.

    “These contributions by Peter and his team right here at the University of Idaho are helping advance global neurological research,” said Janet Nelson, vice president for research and economic development. “I’m excited by the potential impact of this research on the understanding of the brain and in advancing human health.”


  7. Neuroscientists identify source of early brain activity

    November 15, 2017 by Ashley

    From the University of Maryland press release:

    Some expectant parents play classical music for their unborn babies, hoping to boost their children’s cognitive capacity later in life. While some research supported a link between prenatal sound exposure and improved brain function, scientists had not identified any structures responsible for this link in the developing brain.

    A new study led by University of Maryland neuroscientists is the first to identify a mechanism that could explain such an early link between sound input and cognitive function, often called the “Mozart effect.” Working with an animal model, the researchers found that a type of cell present in the brain’s primary processing area during early development, long thought to form structural scaffolding with no role in transmitting sensory information, may conduct such signals after all.

    The results, which could have implications for the early diagnosis of autism and other cognitive deficits, were published in the online early edition of the Proceedings of the National Academy of Sciences on November 6, 2017.

    “Previous research documented brain activity in response to sound during early developmental phases, but it was hard to determine where in the brain these signals were coming from,” said Patrick Kanold, a professor of biology at UMD and the senior author of the research paper. “Our study is the first to measure these signals in an important cell type in the brain, providing important new insights into early sensory development in mammals.”

    Working with young ferrets, Kanold and his team directly observed sound-induced nerve impulses in subplate neurons for the first time. During development, subplate neurons are among the first neurons to form in the cerebral cortex — the outer part of the mammalian brain that controls perception, memory and, in humans, higher functions such as language and abstract reasoning. Subplate neurons help guide the formation of neural circuits, in the same way that a temporary scaffolding helps a construction crew build walls and install windows on a new building.

    Much like construction scaffolding, the role of subplate neurons is thought to be temporary. Once the brain’s permanent neural circuits form, most of the subplate neurons die off and disappear. According to Kanold, researchers assumed that subplate neurons had no role in transmitting sensory information, given their temporary structural role.

    Conventional wisdom suggested that mammalian brains transmit their first sensory signals in response to sound after the thalamus fully connects to the cerebral cortex. In many mammals used for research, the connection of the thalamus and the cortex also coincides with the opening of the ear canals, which allows sounds to activate the inner ear. This coincident timing provided further support for the traditional model of when sound processing begins in the brain.

    However, researchers had struggled to reconcile this conventional model with observations of sound-induced brain activity much earlier in the developmental process. Until his group directly measured the response of subplate neurons to sound, Kanold said, the phenomenon had largely been overlooked.

    “Our work is the first to suggest that subplate neurons do more than bridge the gap between the thalamus and the cortex, forming the structure for future circuits,” Kanold said. “They form a functional scaffolding that actually processes and transmits information before other cortical circuits are activated. It is likely that subplate neurons help determine the early functional organization of the cortex in addition to structural organization.”

    By identifying a source of early sensory nerve signals, the current study could lead to new ways to diagnose autism and other cognitive deficits that emerge early in development. Early diagnosis is an important first step toward early intervention and treatment, Kanold noted.

    “Now that we know subplate neurons are transmitting sensory input, we can begin to study their functional role in development in more detail,” Kanold said. “What is the role of sensory experience at this early stage? How might defects in subplate neurons correlate with cognitive deficits and conditions like autism? There are so many new possibilities for future research.”

    Kanold’s findings are already drawing interest from researchers who study sensory development in humans. Rhodri Cusack, a professor of cognitive neuroscience at Trinity College Dublin, in Ireland, noted that the results could have implications for the care of premature infants.

    “This paper shows that our sensory systems are shaped by the environment from a very early age,” Cusack said. “In human infants, this includes the third trimester, when many preterm infants spend time in a neonatal intensive care unit. The findings are a call to action to identify enriching environments that can optimize sensory development in this vulnerable population.”


  8. Study suggests spending decisions are influenced by adaptation in neural circuits

    November 12, 2017 by Ashley

    From the Washington University School of Medicine press release:

    The British have a pithy way of describing people who dither over spending 20 cents more for premium ice cream but happily drop an extra $5,000 for a fancier house: penny wise and pound foolish.

    Now, a new study suggests that being penny wise and pound foolish is not so much a failure of judgment as it is a function of how our brains tally the value of objects that vary widely in worth.

    Researchers at Washington University School of Medicine in St. Louis have found that when monkeys are faced with a choice between two options, the firing of neurons activated in the brain adjusts to reflect the enormity of the decision. Such an approach would explain why the same person can see 20 cents as a lot one moment and $5,000 as a little the next, the researchers said.

    “Everybody recognizes this behavior, because everybody does it,” said senior author Camillo Padoa-Schioppa, PhD, an associate professor of neuroscience, of economics and of biomedical engineering. “This paper explains where those judgments originate. The same neural circuit underlies decisions that range from a few dollars to hundreds of thousands of dollars. We found that a system that adapts to the range of values ensures maximal payoff.”

    The study is available online in Nature Communications.

    While you are contemplating whether to order a scoop of vanilla or strawberry ice cream, a part of your brain just above the eyes is very busy. Brain scans have shown that blood flow to a brain area known as the orbitofrontal cortex increases as people weigh their options.

    Neurons in this part of the brain also become active when a monkey is faced with a choice. As the animal tries to decide between a sip of, say, apple juice or grape juice, two sets of neurons in its orbitofrontal cortex fire off electrical pulses. One set reflects how much the monkey wants apple juice; the other set corresponds to the animal’s interest in grape juice. The faster the neurons fire, the more highly the monkey values that option.

    A similar process likely occurs as people make decisions, the researchers said. But what happens to firing rates when a person stops thinking about ice cream and starts thinking about houses? A house might be hundreds of thousands of times more valuable than a cup of ice cream, but neurons cannot fire pulses 100,000 times faster. The speed at which they can fire maxes out at about 500 spikes per second.

    To find out how neurons cope with different values, Padoa-Schioppa and colleagues repeatedly gave monkeys a choice between two juices, offered in the range of 0 to 2 drops. After a break, the same two juices were offered in the range of 0 to 10 drops. The researchers recorded which neurons were active — and how quickly they were firing — as the monkeys made their choices.

    The researchers discovered that the neurons’ firing rates reset between the two sessions. In the first session the maximum firing rate corresponded to the option of two drops of juice, and in the second it corresponded to 10 drops of juice. In other words, the same change in how rapidly the neuron fired corresponded to a fine distinction in value when the range was narrow, and a coarse distinction when the range was broad.

    “As we adapt to large values, we lose some ability to consider smaller values,” Padoa-Schioppa said. “This is why salesmen try so hard to sell you upgrades when you’re buying a car. Spending $100 to add on a radio seems like no big deal if you’re already spending $20,000 on a car. But if you already have a car and you are thinking of spending $100 for a radio, suddenly it seems like a lot. They know that people don’t come back and buy the radio later.”

    While having adaptable neurons allows us effectively to shop for items ranging in value from groceries to cars to houses, it does introduce a theoretical quirk: It should be possible to change someone’s preferences simply by adjusting the range of each option. For example, by offering a large range of apple juice and a small range of grape juice, the researchers could make a drop of apple juice look less valuable than a drop of grape juice, convincing an apple-loving monkey to select grape juice instead.

    When they changed the ranges of the juices, however, the researchers found that the monkeys did not fall for it. Apple-loving monkeys continued to choose apple juice.

    The researchers concluded that making a choice between two juices is not a simple matter of comparing the firing rates of the apple-juice neurons to the firing rates of the grape-juice neurons. Instead, neurons pegged to each option feed into a neural circuit that processes the data and corrects for differences in scale.

    It’s a system optimized for making the best possible choice — the one that reflects true preferences over a vast range of values, even though some detail gets lost at the higher end.

    “It was a puzzle: How does the brain handle this enormous variability?” said Padoa-Schioppa. “We showed that a circuit that has adaptation and corrects for it ensures maximal payoff. And these findings have implications for understanding why people make the choices they do. There’s a good neurological reason for behavior that might seem illogical.”


  9. 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.”


  10. Study indicates sleep deprivation leads to mental lapses

    November 3, 2017 by Ashley

    From the University of California – Los Angeles Health Sciences press release:

    Ever sleep poorly and then walk out of the house without your keys? Or space out on the highway and nearly hit a stalled car?

    A new study is the first to reveal how sleep deprivation disrupts our brain cells’ ability to communicate with each other, leading to temporary mental lapses that affect memory and visual perception.

    “We discovered that starving the body of sleep also robs neurons of the ability to function properly,” said senior author Dr. Itzhak Fried, professor of neurosurgery at the David Geffen School of Medicine at UCLA and Tel Aviv University. “This paves the way for cognitive lapses in how we perceive and react to the world around us.”

    Fried led an international team in studying 12 UCLA epileptic patients who had electrodes implanted in their brains in order to pinpoint the origin of their seizures prior to surgery. Because lack of sleep can provoke seizures, these patients stay awake all night to speed the onset of an epileptic episode and shorten their hospital stay.

    The team asked the patients to categorize a variety of images as fast as possible while their electrodes recorded the firing of nearly 1,500 single brain cells across the group in real time. The scientists zeroed in on the temporal lobe, which regulates visual perception and memory.

    Performing the task grew more challenging as the patients grew sleepier. As the patients slowed down, their brain cells did, too.

    “We were fascinated to observe how sleep deprivation dampened brain cell activity,” said lead author Dr. Yuval Nir of Tel-Aviv University. “Unlike the usual rapid reaction, the neurons responded slowly, fired more weakly and their transmissions dragged on longer than usual.”

    Lack of sleep interfered with the neurons’ ability to encode information and translate visual input into conscious thought.

    The same phenomenon can occur when a sleep-deprived driver notices a pedestrian stepping in front of his car.

    “The very act of seeing the pedestrian slows down in the driver’s over-tired brain,” he explained. “It takes longer for his brain to register what he’s perceiving.”

    In a second finding, the researchers discovered that slower brain waves accompanied sluggish cellular activity in the same regions of the patients’ brains.

    “Slow sleep-like waves disrupted the patients’ brain activity and performance of tasks,” said Fried. “This phenomenon suggests that select regions of the patients’ brains were dozing, causing mental lapses, while the rest of the brain was awake and running as usual,” said Fried.

    The study’s findings provoke questions for how society views sleep deprivation.

    “Inadequate sleep exerts a similar influence on our brain as drinking too much,” said Fried. “Yet no legal or medical standards exist for identifying over-tired drivers on the road the same way we target drunk drivers.”

    Fried and his colleagues plan to dive more deeply into the benefits of sleep. Future studies aim to unravel the mechanism responsible for the cellular glitches that precede mental lapses.

    Previous studies have tied sleep deprivation to a heightened risk of depression, obesity, diabetes, heart attacks and stroke, as well as medical errors.