tag:theconversation.com,2011:/id/topics/mouse-model-33968/articlesMouse model – The Conversation2023-07-26T12:15:25Ztag:theconversation.com,2011:article/2100362023-07-26T12:15:25Z2023-07-26T12:15:25ZFragile X syndrome often results from improperly processed genetic material – correctly cutting RNA offers a potential treatment<figure><img src="https://images.theconversation.com/files/538608/original/file-20230720-23-yssm44.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2308%2C1298&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">For many people with fragile X, the mutated gene that causes symptoms is active rather than silenced.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/fragile-x-chromosome-illustration-royalty-free-illustration/1407268269">Thom Leach/Science Photo Library</a></span></figcaption></figure><p><a href="https://www.cdc.gov/ncbddd/fxs/features/fragile-x-five-things.html">Fragile X syndrome</a> is a genetic disorder caused by a mutation in a gene that lies at the tip of the X chromosome. It is linked to autism spectrum disorders. People with fragile X experience a range of symptoms that include cognitive impairment, developmental and speech delays and hyperactivity. They may also have some physical features such as large ears and foreheads, flabby muscles and poor coordination.</p>
<p>Along with our colleagues <a href="https://scholar.google.com/citations?user=fbDXtcUAAAAJ&hl=en">Jonathan Watts</a> and <a href="https://www.rushu.rush.edu/faculty/elizabeth-m-berry-kravis-md-phd">Elizabeth Berry-Kravis</a>, <a href="https://profiles.umassmed.edu/display/133116">we are</a> <a href="https://scholar.google.com/citations?user=syYm8JMAAAAJ&hl=en">a team</a> of scientists with expertise in molecular biology, nucleic acid chemistry and pediatric neurology. We recently discovered that the mutated gene responsible for fragile X syndrome is active in most people with the disorder, not silenced as previously thought. But the affected gene on the X chromosome is still unable to produce the protein it codes for because the <a href="https://doi.org/10.1073/pnas.2302534120">genetic material isn’t properly processed</a>. Correcting this processing error suggests that a potential treatment for symptoms of fragile X may one day be available.</p>
<h2>Repairing faulty RNA splicing</h2>
<p>The <a href="https://doi.org/10.1038/s41583-021-00432-0">FMR1 gene encodes a protein</a> that regulates protein synthesis. A lack of this protein leads to overall excessive protein synthesis in the brain that results in many of the symptoms of fragile X. </p>
<p>The mutation that causes fragile X results in extra copies of a DNA sequence called a <a href="https://doi.org/10.1038/s41583-021-00432-0">CGG repeat</a>. Everyone has CGG repeats in their FMR1 gene, but typically fewer than 55 copies. Having 200 or more CGG repeats silences the FMR1 gene and results in fragile X syndrome. However, we found that <a href="https://doi.org/10.1073/pnas.2302534120">around 70% of people</a> with fragile X still have an active FMR1 gene their cellular machinery can read. But it is mutated enough that it is unable to direct the cell to produce the protein it encodes.</p>
<p>Genes are transcribed into another form of genetic material called RNA that cells use to make proteins. Normally, genes are processed before transcription in order to make a readable strand of RNA. This involves removing the <a href="https://www.genome.gov/genetics-glossary/Intron">noncoding sequences</a> that interrupt genes and splicing the genetic material back together. For people with fragile X, the cellular machinery that does this cutting incorrectly splices the genetic material, such that the protein the FMR1 gene codes for is not produced.</p>
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<figcaption><span class="caption">Fragile X syndrome is the most common inherited form of intellectual disability.</span></figcaption>
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<p>Using cell cultures in the lab, we found that <a href="https://doi.org/10.1073/pnas.2302534120">correcting this missplice</a> can restore proper RNA function and produce the FMR1 gene’s protein. We did this by using short bits of DNA called <a href="https://doi.org/10.3390%2Fjcm9062004">antisense oligonucleotides, or ASOs</a>. When these bits of genetic material bind to RNA molecules, they change the way the cell can read it. That can have effects on which proteins the cell can successfully produce.</p>
<p>ASOs have been used with spectacular success to treat other childhood disorders, such as <a href="https://doi.org/10.1016/j.tins.2020.11.009">spinal muscular atrophy</a>, and are now being used to treat <a href="https://doi.org/10.1146/annurev-pharmtox-010919-023738">a variety of neurological diseases</a>.</p>
<h2>Beyond mice models</h2>
<p>Notably, fragile X syndrome is most often <a href="https://doi.org/10.1242/dmm.049485">studied using mouse models</a>. However, because these mice have been genetically engineered to lack a functional FMR1 gene, they are quite different from people with fragile X. In people, it is not a missing gene that causes fragile X but mutations that lead the existing gene to lose function. </p>
<p>Because the mouse model of fragile X lacks the FMR1 gene, the RNA is not made and so cannot be misspliced. Our discovery would not have been possible if we used mice.</p>
<p>With further research, future studies in people may one day include injecting ASOs into the cerebrospinal fluid of fragile X patients, where it will travel to the brain and hopefully restore proper function of the FMR1 gene and improve their cognitive function.</p><img src="https://counter.theconversation.com/content/210036/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Joel Richter receives funding from NIH and FRAXA. </span></em></p><p class="fine-print"><em><span>Sneha Shah receives funding from the FRAXA Research Foundation.</span></em></p>Fragile X syndrome is the most common inherited form of intellectual disability. Using short bits of DNA to fix improperly transcribed genes may one day be a potential treatment option.Joel Richter, Professor of Neuroscience, UMass Chan Medical SchoolSneha Shah, Assistant Professor of Molecular Medicine, UMass Chan Medical SchoolLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1882072022-08-31T12:27:02Z2022-08-31T12:27:02ZExpanding Alzheimer’s research with primates could overcome the problem with treatments that show promise in mice but don’t help humans<figure><img src="https://images.theconversation.com/files/481658/original/file-20220829-8371-fvt75z.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1412&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Rhesus macaques experience an aging process similar to people's.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/rhesus-macaque-royalty-free-image/993621062">Goddard Photography/E+ via Getty Images</a></span></figcaption></figure><p>As of 2022, an estimated <a href="https://doi.org/10.1002/alz.12638">6.5 million Americans</a> have Alzheimer’s disease, an illness that robs people of their memories, independence and personality, causing suffering to both patients and their families. That number may double by 2060. The U.S. has made <a href="https://doi.org/10.1126/science.361.6405.838">considerable investments</a> in Alzheimer’s research, having allocated <a href="https://www.alz.org/news/2022/increase-in-federal-alzheimers-and-dementia-resear">US$3.5 billion in federal funding</a> this year. </p>
<p>Why, then, are researchers no closer to a cure today than they were 30 years ago? </p>
<p>Back in 1995, researchers created the <a href="https://doi.org/10.1038/373523a0">first transgenic mouse model</a> of Alzheimer’s disease, which involved genetically modifying mice to carry a gene associated with early-onset Alzheimer’s. Myriad studies have since focused on mouse models that accumulate <a href="https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease">abnormal proteins</a> in their brains, a hallmark of the disease. Although these studies made great strides in understanding specific mechanisms involved in the disease, they have <a href="https://doi.org/10.1002/trc2.12114">failed to translate</a> into effective treatments.</p>
<p>As <a href="https://scholar.google.com/citations?user=LWCllSsAAAAJ">research</a> <a href="https://scholar.google.com/citations?hl=en&user=0tW5idcAAAAJ">scientists</a> <a href="https://psych.wisc.edu/staff/bennett-allyson/">working</a> with nonhuman primates, we believe that part of the problem is that mice don’t reflect the full spectrum of Alzheimer’s disease. A more complementary animal model, however, could help researchers better translate the results from animal studies to humans. </p>
<h2>Why animal models?</h2>
<p>A critical aspect of understanding what goes awry in Alzheimer’s disease is the relationship between brain and behavior. Researchers rely heavily on animal models to do these types of studies because <a href="https://grants.nih.gov/grants/policy/air/why.htm">ethical and practical issues</a> make them impossible to conduct in people.</p>
<p>In recent years, researchers have developed <a href="https://doi.org/10.15252/embj.2021110002">alternative methods</a> to study Alzheimer’s, such as computer models and cell cultures. Although these options show promise for advancing Alzheimer’s research, they don’t supersede the need for animal models because of important limitations.</p>
<p>One is their inability to replicate the complexity of the human brain. The human brain has an estimated <a href="https://doi.org/10.1002/cne.21974">86 billion neurons</a> that perform highly complex computations. While computer models can simulate the workings of specific neural circuits, they are unable to fully capture these complex interactions and work best when used <a href="https://doi.org/10.1016/j.neuron.2021.07.015">in concert with animal models</a>.</p>
<p>Similarly, cell cultures and brain organoids – miniature brains derived from human stem cells – are <a href="https://doi.org/10.3389/fphar.2020.00396">unable to adequately mimic</a> the aging process and all the ways the components of the human body interact with one another.</p>
<p>As a result of these limitations, researchers turn to animal models that better reflect human biology and disease processes.</p>
<h2>The problem with mice</h2>
<p>According to the National Association for Biomedical Research, approximately <a href="https://www.science.org/content/article/how-many-mice-and-rats-are-used-us-labs-controversial-study-says-more-100-million">95% of lab research conducted in animals in the U.S.</a> is done in mice and rats. Alzheimer’s is no exception: For more than 25 years, research on Alzheimer’s has <a href="https://doi.org/10.1002/cpns.81">focused on using transgenic mice</a> to better understand the biological changes associated with the disease.</p>
<p>Because mice do not naturally get Alzheimer’s, they are genetically engineered to develop <a href="https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease">abnormal proteins</a> known as amyloid plaques and neurofibrillary tau tangles to mimic Alzheimer’s in their brains. These protein accumulations impair brain function and are associated with memory impairment. While studies on <a href="https://doi.org/10.1038/35050110">treatments that remove these proteins</a> have been able to improve cognition in mice, similar interventions have failed in people.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Four white mice in a cage" src="https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Many Alzheimer’s studies have been conducted in transgenic mice.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/white-research-mice-royalty-free-image/170617385">filo/E+ via Getty Images</a></span>
</figcaption>
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<p>This highlights the challenge of <a href="https://doi.org/10.1002/trc2.12114">translating animal research</a> in the lab to people in the clinic. Mouse studies often mirror only a single aspect of the disease that may not be directly relevant to people. For example, most transgenic mouse models focus on amyloid protein buildup while <a href="https://mitpress.mit.edu/9780262546010/how-not-to-study-a-disease/">neglecting other crucial aspects</a> of the disease, such as overall neurodegeneration. Such limitations have led some scientists to <a href="https://doi.org/10.3390/ijms222313168">question the value of using mouse models for Alzheimer’s research</a>. </p>
<p>It is important to recognize, however, that scientific knowledge often advances in <a href="https://www.statnews.com/2015/12/02/science-groundbreaking/">incremental steps</a> through the collective results of many studies using different methods and models. Rodent studies provide the necessary foundation for animal models that better mimic the full scope of Alzheimer’s – such as nonhuman primates.</p>
<h2>Nonhuman primates offer a closer model</h2>
<p>The specific features of a species – including brain structure, cognitive ability, life span and the extent to which they show the hallmarks of Alzheimer’s – determine how suitable it is for specific research questions. Based on these factors, we believe that nonhuman primates are particularly well suited for Alzheimer’s research.</p>
<p><a href="https://primate.wisc.edu/primate-info-net/pin-factsheets/">Primates</a> are a diverse group of mammals that includes humans, apes, monkeys and prosimians. Nonhuman primates are particularly valuable for understanding <a href="https://doi.org/10.1002/ajp.23309">human aging</a> and <a href="https://doi.org/10.1073/pnas.1912954116">Alzheimer’s disease</a> because their genetic makeup, brain, behavior, physiology and aging process closely resemble those of people. Aging monkeys experience cognitive, physical and sensory decline as well as a variety of illnesses, such as cancer and cardiovascular disease, much like aging people. Perhaps most critical for Alzheimer’s research, nonhuman primates live much longer than rodents and can <a href="https://doi.org/10.1002/ajp.23299">naturally develop some of the hallmarks associated with Alzheimer’s</a> as they get older. </p>
<p>Using nonhuman primates in research <a href="https://www.nature.com/articles/d41586-021-01894-z">faces some challenges</a>. Compared to mice, nonhuman primates are more expensive to house and feed, and face a growing shortage in research facilities. Nonhuman primates are also prime targets for activists seeking to stop the use of animals in research. Yet, in light of ongoing failures with rodent models, nonhuman primates could significantly help scientists better understand and treat Alzheimer’s. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Scientist looking at brain MRIs on multiple computer screens" src="https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Animal models pave the way for clinical research in humans.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/female-radiologist-analysing-the-mri-image-of-the-royalty-free-image/1326240246">simonkr/E+ via Getty Images</a></span>
</figcaption>
</figure>
<p>Scientists study Alzheimer’s in nonhuman primates in a number of ways.</p>
<p>In one approach, researchers examine species with short life spans, such as <a href="https://doi.org/10.1002/ajp.23337">gray mouse lemurs</a> or <a href="https://doi.org/10.1002/ajp.23271">common marmosets</a>, to measure how brain and behavior naturally change with age and identify potential predictors of disease. Other researchers may instead accelerate the disease process by <a href="https://doi.org/10.1002/ajp.23289">inducing plaque</a> or <a href="https://doi.org/10.1002/alz.12318">tangle formation</a> in the brains of longer-lived species, like rhesus macaques. These approaches yield studies that are particularly promising for testing treatments in a short time frame.</p>
<p>A third approach takes advantage of recent advances in genomics to study marmosets <a href="https://doi.org/10.1002/alz.049952">born with genetic mutations</a> involved in Alzheimer’s. This method provides the opportunity to test preventive treatments during early life, well before any sign of the disease appears. </p>
<p>Lastly, <a href="https://doi.org/10.1002/ajp.23254">comparing Alzheimer-like patterns across primate species</a> may help reveal critical risk factors for developing the disease, which could be reduced to promote healthy aging.</p>
<p>We believe that research in nonhuman primates, when conducted with the highest <a href="https://doi.org/10.1016/j.neuroimage.2020.117700">ethical standards</a>, provides the best chance to understand how and why Alzheimer’s disease progresses, and to design treatments that are safe and effective in people.</p><img src="https://counter.theconversation.com/content/188207/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Agnès Lacreuse receives funding from NIH, serves on the American Psychological Association Committee for Animal Research and Ethics and volunteers for Speaking of Research</span></em></p><p class="fine-print"><em><span>Allyson Bennett serves on the Board of Directors for Public Responsibility for Medicine & Research and volunteers for Speaking of Research.
</span></em></p><p class="fine-print"><em><span>Amanda M. Dettmer volunteers for Speaking of Research.</span></em></p>Nonhuman primates like rhesus monkeys share certain characteristics with people that may make them better study subjects than mice for research on neurodegenerative diseases.Agnès Lacreuse, Professor of Behavioral Neuroscience, UMass AmherstAllyson J. Bennett, Professor of Psychology, University of Wisconsin-MadisonAmanda M. Dettmer, Associate Research Scientist, Yale UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1657272021-09-02T12:24:09Z2021-09-02T12:24:09ZResearchers trained mice to control seemingly random bursts of dopamine in their brains, challenging theories of reward and learning<figure><img src="https://images.theconversation.com/files/418141/original/file-20210826-19-ar18hi.jpeg?ixlib=rb-1.1.0&rect=5%2C0%2C740%2C591&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The brains of mice randomly produce large bursts of dopamine that could produce feelings of hope.</span> <span class="attribution"><span class="source">Julia Kuhl</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><p><em>The <a href="https://theconversation.com/us/topics/research-brief-83231">Research Brief</a> is a short take about interesting academic work.</em></p>
<h2>The big idea</h2>
<p>My colleagues and I recently found that we were able to train mice to voluntarily increase the <a href="https://doi.org/10.1016/j.cub.2021.06.069">size and frequency of seemingly random dopamine impulses in their brains</a>. Conventional wisdom in neuroscience has held that dopamine levels change solely in response to cues from the world outside of the brain. Our new research shows that increases in dopamine can also be driven by internally mediated changes within the brain.</p>
<p>Dopamine is a small molecule found in the brains of mammals and is associated with feelings of reward and happiness. In 2014, my colleagues and I invented a new method to <a href="https://doi.org/10.1038/nmeth.3151">measure dopamine in real time in different parts of the brains of mice</a>. Using this new tool, my former thesis student, Conrad Foo, found that neurons in the brains of mice release large bursts of dopamine – called impulses – <a href="https://doi.org/10.1016/j.cub.2021.06.069">for no easily apparent reason</a>. This occurs at random times, but on average about once a minute. </p>
<p>Pavlov was famously able to train his dogs to salivate at the sound of a bell, not the sight of food. Today, scientists believe that the bell sound <a href="https://doi.org/10.1016/j.tics.2013.06.010">caused a release of dopamine to predict the forthcoming reward</a>. If Pavlov’s dogs could control their cue-based dopamine responses with a little training, we wondered if our mice could control their spontaneous dopamine impulses. To test this, our team designed an experiment that rewarded mice if they increased the strength of their spontaneous dopamine impulses. The mice were able to not only increase how strong these dopamine releases were, but also how often they occurred. When we removed the possibility of a reward, the dopamine impulses returned to their original levels.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/418263/original/file-20210827-4978-16rkim3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="An image showing a dog salivating when offered food, not salivating when a bell is rung, then salivating when a bell is rung and food is offered and finally salivating when just a bell is rung." src="https://images.theconversation.com/files/418263/original/file-20210827-4978-16rkim3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/418263/original/file-20210827-4978-16rkim3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=353&fit=crop&dpr=1 600w, https://images.theconversation.com/files/418263/original/file-20210827-4978-16rkim3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=353&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/418263/original/file-20210827-4978-16rkim3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=353&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/418263/original/file-20210827-4978-16rkim3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=444&fit=crop&dpr=1 754w, https://images.theconversation.com/files/418263/original/file-20210827-4978-16rkim3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=444&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/418263/original/file-20210827-4978-16rkim3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=444&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Pavlov famously showed that cues – like food or a bell – produce a response, but new mouse research shows that dopamine impulses can occur in the absence of a cue.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Pavlov%27s_dog_conditioning.svg#/media/File:Pavlov's_dog_conditioning.svg">Maxxl²/WikimediaCommons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
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<h2>Why it matters</h2>
<p>In the 1990s, neuroscientist Wolfram Schultz discovered that an animal’s brain will <a href="https://doi.org/10.1523/jneurosci.13-03-00900.1993">release dopamine if the animal expects a reward</a>, not just when receiving a reward. This showed that dopamine can be produced in response to the expectation of a reward, not just the reward itself – the aforementioned modern version of Pavlov’s dog. But in both cases dopamine is produced in response to an outside cue of some sort. While there is always a small amount of random <a href="https://doi.org/10.1152/jn.1990.63.3.592">background dopamine “noise” in the brain</a>, <a href="https://doi.org/10.1152/physrev.00023.2014">most</a> neuroscience <a href="https://doi.org/10.1038/nn.4173">research</a> had <a href="https://doi.org/10.1146/annurev-neuro-072116-031109">not considered</a> the possibility of random dopamine impulses large enough to produce changes in brain function and memory. </p>
<p>Our findings challenge the idea that dopamine signals are deterministic – produced only in response to a cue – and in fact challenge some fundamental theories of learning which currently have no place for large, random dopamine impulses. Researchers have long thought that dopamine enables animals to determine which cues can guide them toward a reward. Often a sequence of cues is involved – for example, an animal may be attracted to the sound of running water that only later leads to the reward of drinking. </p>
<p>Our observation of spontaneous bursts of dopamine – not ones that occur in response to a cue – don’t fit neatly with this framework. We suggest that large spontaneous impulses of dopamine could break these chains of events and impair an animal’s ability to connect indirect cues to rewards. The ability to actively influence these dopamine bursts could be a mechanism for mice to minimize this hypothesized problem in learning, but that remains to be seen. </p>
<h2>What still isn’t known</h2>
<p>My colleagues and I still need to connect the current findings with parts of the brain <a href="https://doi.org/10.1038/s41586-019-1261-9">known to signal with dopamine</a>.
In terms of behavior – such as foraging or navigating a maze in the laboratory – what is the effect of spontaneous impulses on the ability to learn? It is tempting to wonder whether spontaneous impulses could act as a false expectation of reward. It may be the case that spontaneous impulses give animals hope that a reward of some sort is “out there.” We plan to test whether there is a causal link between the spontaneous impulses of dopamine and mice venturing out to explore their surroundings. Finally, it is unknown whether the impulses help or hinder mental ability. Since the <a href="https://doi.org/10.1016/j.phrs.2018.12.001">dopamine receptors in the cortex</a> are the same <a href="https://doi.org/10.1073/pnas.97.14.7673">receptors that are overexpressed in schizophrenia</a>, we wonder whether there is a connection between spontaneous impulses and mental health.</p>
<p>[<em>Over 110,000 readers rely on The Conversation’s newsletter to understand the world.</em> <a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=100Ksignup">Sign up today</a>.]</p><img src="https://counter.theconversation.com/content/165727/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>David Kleinfeld receives funding from the National Institutes of Health. </span></em></p>Mouse brains produce random, strong bursts of dopamine and are able to control them. This may challenge many long-held ideas about learning and motivation.David Kleinfeld, Professor of Physics and Neurobiology, University of California, San DiegoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1594222021-05-04T18:37:56Z2021-05-04T18:37:56ZAre graphene-coated face masks a COVID-19 miracle – or another health risk?<figure><img src="https://images.theconversation.com/files/397937/original/file-20210429-19-1kv1qr.jpg?ixlib=rb-1.1.0&rect=3%2C0%2C2118%2C1411&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Officials in Quebec, Canada recently removed graphene-coated face masks from schools and daycare centers.</span> <span class="attribution"><span class="source">Ridofranz/iStock via Getty Images</span></span></figcaption></figure><p>As a <a href="https://doi.org/10.7326/M20-2496">COVID-19</a> and <a href="https://doi.org/10.1111/j.1365-2796.2006.01713.x">medical device</a> researcher, I understand the importance of <a href="https://www.cdc.gov/media/releases/2020/p0714-americans-to-wear-masks.html">face masks</a> to prevent the spread of the coronavirus. So I am intrigued that some mask manufacturers have begun adding graphene coatings to their face masks to inactivate the virus. Many <a href="https://dx.doi.org/10.1016%2Fj.mtchem.2020.100385">viruses, fungi and bacteria</a> are incapacitated by graphene in laboratory studies, including <a href="https://dx.doi.org/10.1016%2Fj.mehy.2020.110031">feline coronavirus</a>. </p>
<p>Because SARS CoV-2, the coronavirus that causes COVID-19, can <a href="https://www.dhs.gov/science-and-technology/sars-calculator">survive on the outer surface of a face mask for days</a>, people who touch the mask and then rub their eyes, nose, or mouth may risk getting COVID-19. So these manufacturers seem to be reasoning that graphene coatings on their reusable and disposable face masks will add some anti-virus protection. But in March, the <a href="https://www.cbc.ca/news/canada/montreal/masks-early-pulmonary-toxicity-quebec-schools-daycares-1.5966387">Quebec provincial government</a> removed these masks from schools and daycare centers after Health Canada, Canada’s national public health agency, warned that inhaling the graphene could lead to asbestos-like lung damage.</p>
<p>Is this move warranted by the facts, or an over-reaction? To answer that question, it can help to know more about what graphene is, how it kills microbes, including the SARS-COV-2 virus, and what scientists know so far about the potential health impacts of breathing in graphene.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/398491/original/file-20210503-15-p9z6x3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Hand wearing blue vinyl protective glove holding a small tube." src="https://images.theconversation.com/files/398491/original/file-20210503-15-p9z6x3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/398491/original/file-20210503-15-p9z6x3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/398491/original/file-20210503-15-p9z6x3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/398491/original/file-20210503-15-p9z6x3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/398491/original/file-20210503-15-p9z6x3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/398491/original/file-20210503-15-p9z6x3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/398491/original/file-20210503-15-p9z6x3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Batch samples of nano-scale graphene material at a graphene processing factory.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/batch-samples-of-graphene-nano-material-in-graphene-royalty-free-image/578461001?adppopup=true">Monty Rakusen/Getty Images</a></span>
</figcaption>
</figure>
<h2>How does graphene damage viruses, bacteria and human cells?</h2>
<p>Graphene is a thin but strong and conductive <a href="https://doi.org/10.1007/s40820-019-0237-5">two-dimensional sheet of carbon atoms</a>. There are three ways that it can help prevent the spread of microbes:</p>
<p>– Microscopic graphene particles have <a href="https://doi.org/10.1080/10807039.2012.702039">sharp edges</a> that mechanically damage viruses and cells as they pass by them. </p>
<p>– Graphene is negatively charged with highly mobile electrons that electrostaticly trap and inactivate some viruses and cells. </p>
<p>– Graphene causes cells to generate oxygen free radicals that can damage them and <a href="https://dx.doi.org/10.1016%2Fj.mehy.2020.110031">impairs their cellular metabolism</a>. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/2fNKgCO1p4E?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Dr. Joe Schwarcz at McGill University explains graphene.</span></figcaption>
</figure>
<h2>Why graphene may be linked to lung injury</h2>
<p>Researchers have been studying the potential negative impacts of inhaling microscopic graphene on mammals. In one 2016 experiment, <a href="https://doi.org/10.1080/15459624.2015.1076162">mice with graphene placed in their lungs</a> experienced localized lung tissue damage, inflammation, formation of granulomas (where the body tries to wall off the graphene), and persistent lung injury, similar to what occurs when humans <a href="https://dx.doi.org/10.1080%2F15459624.2015.1076162">inhale asbestos</a>. A different study from 2013 found that when <a href="https://doi.org/10.1080/10807039.2012.702039">human cells were bound to graphene</a>, the cells were damaged.</p>
<p>In order to mimic human lungs, scientists have developed biological models designed to simulate the impact of high concentration aerosolized graphene – graphene in the form of a fine spray or suspension in air – on industrial workers. One such study published in March 2020 found that a <a href="https://doi.org/10.1016/j.mtbio.2020.100050">lifetime of industrial exposure</a> to graphene induced inflammation and weakened the simulated lungs’ protective barrier. </p>
<p>It’s important to note that these models are not perfect options for studying the dramatically lower levels of graphene inhaled from a face mask, but researchers have used them in the past to learn more about these sorts of exposures. A study from 2016 found that a <a href="https://dx.doi.org/10.1080%2F15459624.2015.1076162">small portion of aerosolized graphene nanoparticles</a> could move down a simulated mouth and nose passages and penetrate into the lungs. A 2018 study found that brief exposure to a lower amount of aerosolized graphene did not notably <a href="https://doi.org/10.1016/j.carbon.2018.05.012">damage lung cells</a> in a model. </p>
<p>From my perspective as a researcher, this trio of findings suggest that a little bit of graphene in the lungs is likely OK, but a lot is dangerous.</p>
<p>Although it might seem obvious to compare inhaling graphene to the well-known harms of breathing in asbestos, the two substances behave differently in one key way. The body’s natural system for disposing of foreign particles cannot remove asbestos, which is why long-term exposure to asbestos can lead to the cancer <a href="https://dx.doi.org/10.21037%2Fatm.2017.03.74">mesothelioma</a>. But in studies using <a href="https://doi.org/10.1021/acsnano.8b04758">mouse models</a> to measure the impact of high dose lung exposure to graphene, the body’s natural disposal system does remove the graphene, although it occurs very slowly over 30 to 90 days.</p>
<p>The findings of these studies shed light on the possible health impacts of breathing in microscopic graphene in either small or large doses. However, these models don’t reflect the full <a href="https://doi.org/10.1002/jcph.1569">complexity of human experiences</a>. So the strength of the evidence about either the benefit of wearing a graphene mask, or the harm of inhaling microscopic graphene as a result of wearing it, is very weak. </p>
<h2>No obvious benefit but theoretical risk</h2>
<p>Graphene is an intriguing scientific advance that may speed up the demise of COVID-19 virus particles on a face mask. In exchange for this unknown level of added protection, there is a theoretical risk that breathing through a graphene-coated mask will liberate graphene particles that make it through the other filter layers on the mask and penetrate into the lung. If inhaled, the body may not remove these particles rapidly enough to prevent lung damage.</p>
<p>The health department in Quebec is erring on the side of caution. Children are at very low risk of COVID-19 mortality or hospitalization, although they may infect others, so the theoretical risk from graphene exposure is too great. However, adults at <a href="https://www.cdc.gov/coronavirus/2019-ncov/daily-life-coping/deciding-to-go-out.html">high immediate risk of harm from contracting COVID-19</a> may choose to accept a small theoretical risk of long-term lung damage from graphene in exchange for these potential benefits.</p>
<p>[<em>Explore the intersection of faith, politics, arts and culture.</em> <a href="https://theconversation.com/us/newsletters/this-week-in-religion-76/?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=religion-explore">Sign up for This Week in Religion.</a>]</p><img src="https://counter.theconversation.com/content/159422/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>C. Michael White does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Some face masks now come with a coating of graphene, a substance that can kill microbes. Is it safe to breathe it in?C. Michael White, Distinguished Professor and Head of the Department of Pharmacy Practice, University of ConnecticutLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1062832018-11-27T14:16:00Z2018-11-27T14:16:00ZCould this be a solution for the obesity crisis?<figure><img src="https://images.theconversation.com/files/247258/original/file-20181126-140507-1rdi7hr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/187634345?src=iaoSivmZYXtcQUAGRirxMQ-2-17&size=medium_jpg">TAGSTOCK1/Shutterstock</a></span></figcaption></figure><p>Obesity is a disease where people accumulate more and more fat. When they reach a certain point, their fat stops working and they develop disease, such as type 2 diabetes. But not all fat is bad. The fat that accumulates in obesity is called white fat, but a second form of fat (brown fat) could actually be used to treat obesity. </p>
<p>Brown fat has evolved to turn fuel into heat. In small animals, like mice and voles, brown fat makes heat that helps them survive, even in freezing temperatures. </p>
<p>Brown fat can burn a stupendous amount of energy. When fully activated, just 100g of brown fat can burn 3,400 calories a day – nearly double most people’s daily food intake and more than enough to rapidly combat obesity. Even better, for reasons we don’t yet understand, when brown fat burns fuel, the body doesn’t sense it, meaning the person doesn’t eat more food to stay at the same weight. </p>
<p>While babies have a lot of brown fat, most adults have very little and, worse still, it is almost always inactive. However, <a href="http://diabetes.diabetesjournals.org/content/65/5/1179.long">recent studies</a> have shown we can develop more brown fat, making it an attractive approach to treat obesity. </p>
<h2>How to make more brown fat</h2>
<p>Unfortunately, the only reliable way to both increase the amount and activity of brown fat is to mimic a harsh winter – one without central heating and warm clothes. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/247266/original/file-20181126-140507-1lwjeag.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/247266/original/file-20181126-140507-1lwjeag.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/247266/original/file-20181126-140507-1lwjeag.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/247266/original/file-20181126-140507-1lwjeag.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/247266/original/file-20181126-140507-1lwjeag.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=425&fit=crop&dpr=1 754w, https://images.theconversation.com/files/247266/original/file-20181126-140507-1lwjeag.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=425&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/247266/original/file-20181126-140507-1lwjeag.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=425&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A reliable but unpleasant way to increase brown fat.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/1020235939?src=_elJYp2zPGuhzbeCVROEjw-1-1&size=medium_jpg">Petrushin Evgeny/Shutterstock</a></span>
</figcaption>
</figure>
<p>Placing people in the cold tells their body they need more heat and <a href="https://www.physiology.org/doi/full/10.1152/physrev.00015.2003">their nervous system tells brown fat to both turn on and become larger</a>. But putting people in a cold room for days is impractical, not to mention really unpleasant. </p>
<p>One option is to mimic the nervous signals that turn on brown fat using drugs. But the drugs that turn on brown fat also <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298351/">increase blood pressure and heart rate</a>. This has the side effect of causing heart attacks, particularly in obese people, whom brown fat is supposed to treat. </p>
<p>The final problem with activating brown fat is that even if we could make every white fat cell in the body brown, it would not necessarily help. Brown fat needs an excellent blood supply to provide all those calories it can burn. It also needs nerves to contact the brown fat cells to switch them on.</p>
<h2>BMP8b: a potentially game-changing molecule</h2>
<p>A few years ago, we <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383997/">identified</a> a molecule in mice called BMP8b. BMP8b is found at much higher levels in brown fat than in white fat, and the amount of it increased when we put mice in the cold. </p>
<p>Importantly, humans also have BMP8b. We discovered that deleting BMP8b in mice prevented brown fat from functioning. Because BMP8b is found in the blood, it could be used as a drug to increase the amount of brown fat in humans as well as its activity. </p>
<p>Before testing BMP8b in humans, we wanted to investigate the effect of boosting BMP8b in mice – that is, would it increase brown fat function? We genetically engineered the white fat of mice to have as much BMP8b as the brown fat of normal mice.</p>
<p>We <a href="https://www.nature.com/articles/s41467-018-07453-x">found</a> that increasing BMP8b levels made white fat browner and increased its activity. BMP8b does this by making mice more sensitive to the signals from nerves that activate brown fat. What was more unexpected was that BMP8b also increased the number of blood vessels and the number of nerves in white and brown fat. </p>
<p>This combination of factors was really exciting as BMP8b could make humans have more brown fat that has a good fuel supply. Increasing the number of nerves in brown fat would also mean any signals from the brain to activate brown fat would be amplified. Finally, because BMP8b makes brown fat more sensitive to signals from the nerves that activate brown fat, it may be possible to use drugs that mimic these signals at lower doses – even below the levels that cause heart attacks. </p>
<p>While our results are promising, more work will be needed to test if BMP8b can change brown fat function in humans.</p><img src="https://counter.theconversation.com/content/106283/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Samuel Virtue receives funding from the British Heart Foundation, Medical Research Council and The Wellcome Trust. </span></em></p><p class="fine-print"><em><span>Antonio Vidal-Puig receives funding from MRC, BHF, Wellcome Truts, ERC and Horizon 2020</span></em></p><p class="fine-print"><em><span>Vanessa Pellegrinelli receives funding from the British Heart Foundation, Medical Research Council,The Wellcome Trust and WHRI-ACADEMY.</span></em></p>Scientists manage to boost brown fat in mice with a molecule called BMP8b. Could this be the future for treating obesity?Samuel Virtue, Senior Research Associate, University of CambridgeAntonio Vidal-Puig, Professor of Molecular Nutrition and Metabolism, University of CambridgeVanessa Pellegrinelli, Researcher, University of CambridgeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1022892018-08-29T18:02:01Z2018-08-29T18:02:01ZBrain implant could stop epilepsy seizures<figure><img src="https://images.theconversation.com/files/234039/original/file-20180829-195328-f75rh5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/344282432?src=0qMPwIzLEtNMAGGfywpNHw-1-88&size=medium_jpg">SpeedKingz/Shutterstock</a></span></figcaption></figure><p>For many people who suffer from neurological disorders, such as epilepsy, there are no viable treatment options. In our <a href="http://advances.sciencemag.org/content/4/8/eaau1291">latest research</a>, we developed an implantable device that may one day offer relief. We show that the implant can treat problems in the brain, such as epileptic seizures, by delivering brain chemicals – known as neurotransmitters – directly to the cells in the brain that cause the problem.</p>
<p>The implant works by using an electric field to push neurotransmitters out of the device from an internal reservoir. This process, known as <a href="https://www.thoughtco.com/electrophoresis-definition-4136322">electrophoresis</a>, allows for precise control over the dose and timing of drug delivery, which is important for addressing intermittent disorders such as epilepsy. </p>
<p>This way of delivering drugs also has the advantage of not increasing the local pressure where the drug exits the device because the drug molecules are not in a solvent – they exit the device “dry”. This is important because it means the drug molecules (neurotransmitters in this case) can interact directly with the tissue surrounding the implant without causing damage to those cells or the surrounding tissue.</p>
<p>Researchers have <a href="http://advances.sciencemag.org/content/1/4/e1500039">previously shown</a> that this method for delivering drugs can be used to manage pain, with an implant that was placed in the spinal cord of rats. The novelty of our work, published in Science Advances, was to engineer an implant small enough to be implanted in the brain of mice. We also incorporated tiny sensors into the implant to allow us to monitor the local brain activity where the device was implanted. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/234041/original/file-20180829-195298-10bkxsr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/234041/original/file-20180829-195298-10bkxsr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=375&fit=crop&dpr=1 600w, https://images.theconversation.com/files/234041/original/file-20180829-195298-10bkxsr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=375&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/234041/original/file-20180829-195298-10bkxsr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=375&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/234041/original/file-20180829-195298-10bkxsr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=471&fit=crop&dpr=1 754w, https://images.theconversation.com/files/234041/original/file-20180829-195298-10bkxsr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=471&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/234041/original/file-20180829-195298-10bkxsr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=471&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Neurotransmitters are the brain’s chemical messengers.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/432573415?src=dOOXsUyelZUo17hUgHiTKQ-1-1&size=medium_jpg">Andrii Vodolazhskyi/Shutterstock.com</a></span>
</figcaption>
</figure>
<p>Using the on-board sensors, we could see the onset of seizure-like activity in mice. After a seizure was detected, we told the implant to send out inhibitory neurotransmitters to the brain tissue at the centre of the seizures. The neurotransmitters tell the cells in that tissue to stop propagating the seizure message to other cells. This stopped the seizures.</p>
<p>After finding that we could stop seizures, we wanted to see if we could prevent seizures altogether, rather than stop them after they have started. To test this, we started delivering the neurotransmitters before a dose of seizure-inducing chemicals was injected into the brain with a separate implant. These experiments showed that our implant could prevent any seizure-like activity from happening.</p>
<h2>Platform technology</h2>
<p>We are very excited because this is the first time anyone has seen that an electrophoretic drug delivery device can stop or prevent seizure-like activity. Also, we see this as a platform technology that could be adapted to help treat many different neurological disorders including epilepsy, Parkinson’s disease and brain tumours.</p>
<p>It is important to note that, so far, this device has only been tested in mice and rats. Judging from the time it has taken for other technologies to go from this stage to widespread clinical use, it is likely to be at least a decade before this technology would be widely available for humans. During this time much work will be done to prove the long-term viability of these implants for treating epilepsy as well as other neurological disorders.</p><img src="https://counter.theconversation.com/content/102289/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Christopher Proctor receives funding from the University of Cambridge where he is a research associate and Borysiewicz Biomedical Sciences fellow in the Department of Engineering.
</span></em></p>New approach to preventing seizures proves effective in mice.Christopher Proctor, Research Associate in the Fabrication and Validation of Implantable Ion Pumps, University of CambridgeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1014092018-08-21T16:14:35Z2018-08-21T16:14:35ZDiabetes: new test could detect the disease much earlier<figure><img src="https://images.theconversation.com/files/232098/original/file-20180815-2897-5ozz84.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/750940015?src=4ug-v-ZCvEmyXpFIZKQN9A-1-4&size=medium_jpg">Egoreichenkov Evgenii/Shutterstock.com</a></span></figcaption></figure><p>The glucose tolerance test is the standard method for detecting diabetes. But our <a href="https://www.cell.com/cell-reports/fulltext/S2211-1247(18)31166-5">new study suggests</a> that a different test can identify the disease earlier than the glucose tolerance test.</p>
<p>Diabetes <a href="http://www.euro.who.int/en/health-topics/noncommunicable-diseases/diabetes/data-and-statistics">kills 3.4m</a> people worldwide each year, and this figure is expected to continue rising. It kills people by causing secondary diseases, such as heart disease, stroke and kidney failure. And the longer diabetes remains untreated, the greater the risk of developing these diseases, so early detection is vital. </p>
<p>Diabetes is detected when the body can no longer regulate its own blood sugar levels. Blood sugar is controlled by insulin, a hormone made in the pancreas. This hormone lowers blood glucose by making the body’s cells take it up, where it is stored or used for energy. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/232727/original/file-20180820-30608-1xi2874.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/232727/original/file-20180820-30608-1xi2874.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/232727/original/file-20180820-30608-1xi2874.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/232727/original/file-20180820-30608-1xi2874.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/232727/original/file-20180820-30608-1xi2874.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/232727/original/file-20180820-30608-1xi2874.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/232727/original/file-20180820-30608-1xi2874.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption"></span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/editor/image/how-does-insulin-work-illustrated-vector-792237640">VectorMine/Shutterstock.com</a></span>
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</figure>
<p>There are two major forms of diabetes: type 1 and type 2. Type 1 is an autoimmune disease where the body destroys the cells in the pancreas that produce insulin. Type 2 is a progressive disease where the body first becomes resistant to insulin. Initially, the body makes more insulin to keep blood sugar levels in check, but the pancreas then wears out and blood glucose levels become dangerously high. </p>
<h2>Fat as the new marker</h2>
<p>In type 2 diabetes, the body’s cells become resistant to the effects of insulin before diabetes develops. This made us wonder whether we could detect earlier stages of the disease, when the body is insulin resistant but before the pancreas has worn out and blood glucose levels have increased. We focused on investigating how the body becomes unresponsive to insulin. And to do so, we considered fat, not glucose. </p>
<p>Obesity is now established as the leading cause of <a href="https://www.diabetes.co.uk/diabetes-and-obesity.html">type 2 diabetes</a>. One of the main ways that obesity is thought to cause diabetes is by the body fat (adipose tissue) not <a href="http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0060237">working properly</a>. </p>
<p>Healthy adipose tissue takes up the fat we consume and stores it until it is needed for fuel, such as at night when we are asleep. When obese people eat a meal their adipose tissue does not take up the fat. Instead, the fat is directed into other organs, such as the liver and muscle where it causes insulin resistance. </p>
<p>Insulin acts as a signal and attaches to a receiver on the outside of cells called the insulin receptor. The insulin receptor activates lots of other signals inside the muscles or liver that tell them what to do, such as: take up glucose. But when the cell is full of fat, it muffles the signals, making them quieter. The fact the cells don’t respond to insulin makes them “insulin resistant”. The body tries to get around this by turning up the amount of insulin to make the cells take up the right amount of glucose, overcoming the effects of the fat.</p>
<h2>Strong evidence</h2>
<p>The concept that faulty adipose tissue can cause insulin resistance and diabetes is strongly <a href="http://joe.endocrinology-journals.org/content/207/3/245.long">supported by evidence</a> from people with lipodystrophy – a condition where the body has no adipose tissue. People with this condition have severe insulin resistance and diabetes.</p>
<p>Importantly, the adipose tissue of obese people is also bad at releasing fat when they are asleep, meaning that obese people have to use lots of glucose when they are sleeping to provide energy. </p>
<p>The test doctors use to diagnose diabetes is called the glucose tolerance test. It is usually performed in the morning before people have eaten. The person is then given a drink containing glucose (sugar), and blood samples are taken over the next two hours. </p>
<p>People (and mice) are classed as having diabetes if they show high blood glucose levels during the test. But we suspected that some obese people would pass the test because their adipose tissue does not release enough fat and their body is primed to use glucose in fasted states, such as when they are asleep. </p>
<p>Conversely, if we gave obese people a large meal, the fat they should store in adipose tissue would go to organs, such as muscle, and cause insulin resistance, causing them to have high blood glucose. </p>
<h2>Milkshake test</h2>
<p>To study how fat causes insulin resistance and diabetes, we used mice lacking a gene called PPARy2. Removing the gene PPARy2 prevents adipose tissue from both taking up and releasing fat, mimicking what is seen in obese people. </p>
<p>Despite their fat not working properly, we already know that mice lacking PPARy2 appear healthy according to the glucose tolerance test. We now wanted to see if we could detect their defective fat using a large meal test. But there was a problem: how do you get a mouse to eat more food? </p>
<p>We exploited the fact that mice are normally fed a very boring diet, similar to rusks. When we switched mice to a tastier diet, high in fat, we realised they ate twice as much as normal for the first 24 hours after receiving the diet. We collected blood samples before and after the 24-hour overfeeding period to see if blood glucose and insulin increased. </p>
<p>We tested both normal mice and mice lacking PPARy2 with our overfeeding challenge. Normal mice increased their insulin levels twofold and kept their blood glucose levels normal. But mice lacking PPARy2 increased their insulin levels tenfold following the overfeeding challenge and had increased blood glucose levels, indicating that they were metabolically impaired. </p>
<p>Importantly, we conducted these tests in young mice, equivalent to people in their early twenties and at an age when their glucose tolerance tests were normal. Finally, we determined that when mice with defective adipose tissue reached middle age they became metabolically ill, even if they ate a healthy diet. </p>
<p>Our study suggests that it may be possible to detect some people with metabolic disease earlier by replacing the glucose in a glucose tolerance test with a calorific milkshake containing glucose, fat and protein. The next step will be to compare the ability of the glucose tolerance test and the milkshake test to predict future diabetes development in humans.</p><img src="https://counter.theconversation.com/content/101409/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Samuel Virtue receives funding from the British Heart Foundation, Medical Research Council and The Wellcome Trust. </span></em></p>New mouse study suggests that a heavy meal may be a better test than the glucose tolerance test.Samuel Virtue, Senior Research Associate, University of CambridgeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/850662017-12-05T04:07:42Z2017-12-05T04:07:42ZA new collaborative approach to investigate what happens in the brain when it makes a decision<figure><img src="https://images.theconversation.com/files/197377/original/file-20171202-5392-1edrpfm.jpg?ixlib=rb-1.1.0&rect=1319%2C238%2C2973%2C2330&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">What's going on in there when you decide?</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/businesswoman-making-decision-360687236">Sergey Nivens/Shutterstock.com</a></span></figcaption></figure><p>Decisions span a vast range of complexity. There are really simple ones: Do I want an apple or a piece of cake with my lunch? Then there are much more complicated ones: Which car should I buy, or which career should I choose?</p>
<p>Neuroscientists like me have identified some of the individual parts of the brain that contribute to making decisions like these. Different areas <a href="https://doi.org/10.1038/nature12077">process sounds</a>, <a href="https://doi.org/10.1523/JNEUROSCI.0105-17.2017">sights</a> or pertinent <a href="https://doi.org/10.7554/eLife.05457">prior knowledge</a>. But understanding how these individual players work together as a team is still a challenge, not only in understanding decision-making, but for the whole field of neuroscience.</p>
<p>Part of the reason is that until now, neuroscience has operated in a traditional science research model: Individual labs work on their own, usually focusing on one or a few brain areas. That makes it challenging for any researcher to interpret data collected by another lab, because we all have slight differences in how we run experiments.</p>
<p>Neuroscientists who study decision-making set up all kinds of different games for animals to play, for example, and we collect data on what goes on in the brain when the animal makes a move. When everyone has a different experimental setup and methodology, we can’t determine whether the results from another lab are a clue about something interesting that’s actually going on in the brain or merely a byproduct of equipment differences.</p>
<p><a href="https://www.braininitiative.nih.gov/">The BRAIN Initiative</a>, which the Obama administration launched in 2013, started to encourage the kind of collaboration that neuroscience needs. I just think it hasn’t gone far enough. So I co-founded a project called the <a href="https://www.internationalbrainlab.com/">International Brain Laboratory</a> – a virtual mega-laboratory composed of many labs at different institutions – to show that the proverb “alone we go fast, together we go far” holds true for neuroscience. The first question the collaboration is tackling focuses on decision-making by the brain.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/193460/original/file-20171106-1046-ehjqn2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/193460/original/file-20171106-1046-ehjqn2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/193460/original/file-20171106-1046-ehjqn2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/193460/original/file-20171106-1046-ehjqn2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/193460/original/file-20171106-1046-ehjqn2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/193460/original/file-20171106-1046-ehjqn2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/193460/original/file-20171106-1046-ehjqn2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/193460/original/file-20171106-1046-ehjqn2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">We know a lot, but not enough, about how the cogs all fit together.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/p_revagar/28777007826">Piyushgiri Revagar</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span>
</figcaption>
</figure>
<h2>The brain’s decision team</h2>
<p>Individual neuroscience labs have already uncovered a lot about how particular brain areas contribute to decision-making.</p>
<p>Say you’re choosing between an apple or a piece of cake to go with lunch. First, you need to know that apples and cake are the two options. That requires action from brain areas that process sensory information – your eyes see the apple’s bright red skin, while your nose takes in the sweet smell of cake.</p>
<p>Those sensory areas often connect to what we call association areas. Researchers have traditionally thought they play a role in <a href="https://doi.org/10.1038/nn.3865">putting different pieces of information</a> together. By collating information from the eyes, the ears and so on, the association areas may give a more coherent, <a href="https://doi.org/10.1038/nature14066">big-picture view</a> of what’s happening in the world. </p>
<p>And why choose one action over another? That’s a question for the brain’s <a href="https://doi.org/10.1016/j.conb.2008.08.003">reward circuitry</a>, which is critical in <a href="https://doi.org/10.1038/nrn2357">weighing the value of different options</a>. You know that the cake will taste sweetly delicious now, but you might regret it when you’re heading to the gym later.</p>
<p>Then, there’s the frontal cortex, which is believed to play a <a href="https://doi.org/10.1038/35036228">role in controlling voluntary action</a>. Research suggests it’s involved in committing to a particular action once enough incoming information has arrived. It’s the part of the brain that might tell you the piece of cake smells so good that it’s worth all of the calories.</p>
<p>Understanding how these different brain areas typically work together to make decisions could help with understanding what happens in diseased brains. Patients with disorders such as autism, schizophrenia and Parkinson’s disease often use sensory information in an unusual way, especially if it’s complex and uncertain. Research on decision-making may also inform treatment of patients with other disorders, such as substance abuse and addiction. Indeed, <a href="https://archives.drugabuse.gov/NIDA_Notes/NNVol18N4/DirRepVol18N4.html">addiction is perhaps a prime example</a> of how decision-making can go very wrong.</p>
<h2>A lab collaborative spread around the world</h2>
<p>Right now, neuroscientists are taking lots of closeup snapshots of what happens in particular areas of the brain when it makes a decision. But they aren’t coordinating with each other much, so these closeup pieces don’t fit together to give us the big picture of decision-making that we need. </p>
<p>That’s why a team of us joined up to form the International Brain Laboratory. With support from the International Neuroinformatics Coordinating Facility, the Wellcome Trust, and the Simons Foundation (also a funder of The Conversation US), we aim to create that big picture by designing one large-scale experiment that uses the exact same approach to study many different brain areas. Because the brain is so complex, we need the expertise of many different labs that each specialize in particular brain areas. But we need them to coordinate and use the same approach so that we can put all of their different pieces of the picture together. </p>
<p>We’re bringing together a team of 21 scientists who will work very closely to understand how billions of neurons work together in a single brain to make decisions. About a dozen different labs will each do part of one big experiment by measuring neuron activity in animals engaged in exactly the same game. Our team members will record activity from hundreds of neurons in each animal’s brain. We’ll collect tens of thousands of neuronal recordings that we can analyze together.</p>
<h2>Keep it simple</h2>
<p>In real-world decisions, you’re combining lots of different pieces of information – your sensory signals, your internal knowledge about what’s rewarding, what’s risky. But implementing that in a laboratory context is pretty hard.</p>
<p>We’re hoping to recreate a mouse’s natural foraging experience. In real life, there are many different paths an animal can take as it navigates the world looking for something to eat. It wants to find food, because food is rewarding. It uses incoming sensory cues, like, “Oh, I see a cricket over there!” An animal might combine that with a memory of reward, like, “I know this area has lush berry bushes, I remember that from yesterday, so I’ll go there.” Or, “I know over here there was a cat last time, so I’d better avoid that area.”</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/189663/original/file-20171010-17462-7i2day.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/189663/original/file-20171010-17462-7i2day.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/189663/original/file-20171010-17462-7i2day.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=417&fit=crop&dpr=1 600w, https://images.theconversation.com/files/189663/original/file-20171010-17462-7i2day.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=417&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/189663/original/file-20171010-17462-7i2day.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=417&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/189663/original/file-20171010-17462-7i2day.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=525&fit=crop&dpr=1 754w, https://images.theconversation.com/files/189663/original/file-20171010-17462-7i2day.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=525&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/189663/original/file-20171010-17462-7i2day.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=525&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Imagining the world from a mouse’s perspective is essential for International Brain Laboratory scientists when picking a lab task that mimics a real-world decision.</span>
<span class="attribution"><span class="source">Elena Nikanorovna</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>At first pass, the setup we’re using for the International Brain Laboratory doesn’t look very natural at all. The mouse has a little device that it uses to report decisions – it’s actually a wheel from a Lego set. For example, it might learn that when it sees an image of a vertical grating and turns the wheel until the image is centered, it gets a reward. If you think about what foraging is – exploring the environment, trying to find rewards, making use of sensory signals and prior knowledge – this simple Lego wheel activity does capture its essence.</p>
<p>We really had to think about the trade-off between having a behavior that was complex enough to give us insight into interesting neural computations, and one that was simple enough that it could be implemented in the same way in many different experimental laboratories. The balance we struck was a decision-making task that starts simple and becomes more and more complex as an individual animal achieves different stages of training. </p>
<p>Even in the simplest, very earliest stage we’re looking at, where the animals are just making voluntary movements, they’re deciding when to make a movement to harvest a reward. I’m sure we can go much further, but even if that’s as far as we get, having neural measurements from all over the brain during a simple behavior like this will be very interesting. We don’t know how it happens in the brain that you decide when to take a particular action and how to execute that action. Having neural measurements from all over the brain of what happened just before the animal spontaneously decided to go and get a reward will be a huge step forward.</p><img src="https://counter.theconversation.com/content/85066/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Anne Churchland receives funding from NIH, Simons Foundation, The Office of Naval Research, the Pew Trusts and the Klingenstein-SImons Foundation. </span></em></p>A new initiative called the International Brain Laboratory is tackling this fundamental mystery of neuroscience in an unusual way.Anne Churchland, Associate Professor of Neuroscience, Cold Spring Harbor LaboratoryLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/835282017-09-07T11:18:31Z2017-09-07T11:18:31ZEating oily fish during pregnancy could prevent schizophrenia in the child, new study suggests<figure><img src="https://images.theconversation.com/files/185996/original/file-20170914-9015-18bc7f.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/450048262?src=K3CJAc8vRWnZPawTZ83wCw-1-21&size=medium_jpg">dangdumrong/Shutterstock</a></span></figcaption></figure><p>Mice that are deprived of an essential fatty acid, called docosahexaenoic acid (DHA), during pregnancy, are more likely to produce pups that display schizophrenia-like symptoms as adults, according to a <a href="https://www.nature.com/tp/journal/v7/n9/full/tp2017182a.html">new study</a> from Japan. </p>
<p>DHA is an essential fatty acid – “essential” because our bodies can’t produce it. It must be obtained from food. Oily fish, such as salmon and sardines, are good sources of dietary DHA. It is well understood that DHA plays a role in brain development. It is especially important during the last three months of pregnancy, and in the first two years of adolescence. </p>
<p>Studies have shown that babies fed on DHA-supplemented formula milk display higher visual acuity and <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757317/">problem-solving at 10 to 12 months</a>. In an animal study, rats deprived of DHA – resulting in a 50-80% reduction in DHA levels in the brain – were shown to have <a href="https://www.ncbi.nlm.nih.gov/pubmed/11080210">impaired learning and memory</a>. Conversely, dietary DHA supplementation has been shown to <a href="https://www.ncbi.nlm.nih.gov/pubmed/15672635">improve learning and memory</a> in brain damaged lab rats. </p>
<iframe src="https://www.facebook.com/plugins/video.php?href=https%3A%2F%2Fwww.facebook.com%2FKeeleUniversity%2Fvideos%2F10155126927223337%2F&show_text=0&width=560" width="100%" height="420" style="border:none;overflow:hidden" scrolling="no" frameborder="0" allowtransparency="true" allowfullscreen="true"></iframe>
<p>In the Japanese study, conducted by researchers at the RIKEN Brain Science Institute in Tokyo, mice were fed on a diet free from DHA, prior to conception and up to the point the offspring had been weaned. The mouse pups were then given a standard diet, containing DHA, and tested at eight weeks, which roughly translates to human adolescence. </p>
<p>The cognitive function of the mice was assessed using standard mazes; they needed to find and remember the location of a food reward. And depression and motivation were assessed by monitoring the mice’s general activity and how quickly they avoided open spaces in special mazes (mice prefer enclosed spaces). </p>
<p>Mice born from mothers fed on a diet that excluded DHA showed significantly lower performance on the range of tests, compared with mothers fed on a standard diet. Consequently, these mice displayed schizophrenia-like symptoms including, impaired cognitive function, and reduced motivation; characteristic of the early stage of disorder. This led the study’s authors to suggest that getting enough DHA during pregnancy may protect against schizophrenia-like symptoms in the offspring. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/184976/original/file-20170906-18486-8fk3lp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/184976/original/file-20170906-18486-8fk3lp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=473&fit=crop&dpr=1 600w, https://images.theconversation.com/files/184976/original/file-20170906-18486-8fk3lp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=473&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/184976/original/file-20170906-18486-8fk3lp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=473&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/184976/original/file-20170906-18486-8fk3lp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=594&fit=crop&dpr=1 754w, https://images.theconversation.com/files/184976/original/file-20170906-18486-8fk3lp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=594&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/184976/original/file-20170906-18486-8fk3lp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=594&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Mice were tasked with locating a food reward.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/3142630?src=wHl8YjQcdfLtZKY_fRK4ig-1-5&size=medium_jpg">OZ photo/Shutterstock</a></span>
</figcaption>
</figure>
<h2>The role of epigenetics</h2>
<p>The mechanisms underlying how diet can play such an important role in brain function and health are poorly understood. The dogma of genetics being entirely based on what we inherit, rather than the environment we are exposed to, has been questioned by scientists in recent years. The advent in understanding of the concept of <a href="https://www.whatisepigenetics.com/fundamentals/">epigenetics</a> has revolutionised the field of genetic science and provided a potential mechanism through which the environment exerts an influence on genes.</p>
<p>Under epigenetic modification, certain <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107542/">mechanisms</a> can change the way a gene functions, or is expressed – without changing DNA itself – resulting in vastly different outcomes. These mechanisms are in turn activated by environmental factors, including <a href="https://www.ncbi.nlm.nih.gov/pubmed/22415078">diet</a>. </p>
<p>In the Japanese study, the researchers investigated the levels of two genes (<a href="http://www.sciencedirect.com/science/article/pii/S0301008208000464">Rxr and Ppar</a>), known to be associated with schizophrenia in humans. They found evidence that these genes had been modified by epigenetic factors, resulting in lower activity in the mice that displayed schizophrenia-like symptoms. </p>
<p>It’s very difficult to draw a direct comparison between evidence gained from studies in mice, to humans. However, the study identified similar low levels of the RxR and Ppar gene in hair follicle samples obtained from schizophrenic patients. This suggests that adequate levels of DHA in the maternal diet protects normal gene function, which in turn protects against expression of genes associated with schizophrenia. </p>
<p>Ultimately, given that epigenetic modifications to genes can also be passed on to future offspring, this study provides further evidence for the critical role dietary levels of DHA play in brain function and health. Also, given that epigenetic modifications to genes can be passed on, adequate maternal nutrition is not just essential to their offspring, but also to future generations.</p><img src="https://counter.theconversation.com/content/83528/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>David Mazzocchi-Jones receives funding from the Medical Research Council, and the Ramacoitti Foundation. He is also a Labour Party Borough (Newcastle-under-Lyme) and County Councillor (Staffordshire). </span></em></p>The offspring of mice who don’t get enough DHA during pregnancy are more likely to have pups that display schizophrenia-like symptoms.David Mazzocchi-Jones, Lecturer in Neuroscience, Keele UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/817022017-07-28T10:12:18Z2017-07-28T10:12:18ZLosing weight without a diet: manipulating a type of brain cell gets results in mice<figure><img src="https://images.theconversation.com/files/180053/original/file-20170727-27682-1wo3mnt.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Evidence for a link between obesity and brain inflammation is getting stronger.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/394863769?src=Q23R3mkddZz9ElmqVQUDdg-1-1&size=medium_jpg">Suzanne Tucker/Shutterstock</a></span></figcaption></figure><p>A new <a href="http://www.sciencedirect.com/science/article/pii/S155041311730339X">study</a> has found something remarkable: the activation of a particular type of immune cell in the brain can, on its own, lead to obesity in mice. This striking result provides the strongest demonstration yet that brain inflammation may be a cause, rather than a consequence, of obesity. It also provides promising leads for new anti-obesity therapies. </p>
<p>The <a href="http://www.nature.com/nrendo/journal/v11/n6/abs/nrendo.2015.48.html">evidence</a> linking brain inflammation to obesity has been building for some time. Consistent overeating causes stress and damage to cells in the body and brain. This damage results in a response from the immune system that has a wide range of <a href="http://www.ucl.ac.uk/ucl-press/browse-books/a-conversation-about-healthy-eating">effects</a>. </p>
<p>Some of these effects help to reduce the problems caused by overeating, but others seem to make things worse. For example, in the hypothalamus – the part of the brain that controls, among other things, eating and activity – inflammation causes problems such as leptin resistance that interfere with the regulation of body weight. </p>
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<img alt="" src="https://images.theconversation.com/files/180051/original/file-20170727-8525-xlh1cq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/180051/original/file-20170727-8525-xlh1cq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/180051/original/file-20170727-8525-xlh1cq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/180051/original/file-20170727-8525-xlh1cq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/180051/original/file-20170727-8525-xlh1cq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/180051/original/file-20170727-8525-xlh1cq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/180051/original/file-20170727-8525-xlh1cq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">The hypothalamus controls eating and physical activity.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/435142264?src=OuphGGrJ2465SuPozApSXg-1-3&size=medium_jpg">stefan3andrei/Shutterstock</a></span>
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<p>Leptin is a hormone that is released by fat cells and provides the brain with information about the amount of energy stored as body fat. Normally, neurons in the hypothalamus that are sensitive to leptin will use this information to regulate eating and activity as needed to maintain body fat within some desired range. </p>
<p>In obesity, however, these neurons become insensitive to leptin. As a result, they no longer trigger the decrease in hunger and increase in energy expenditure that are necessary to lose excess weight. This is why the vast majority of attempts by obese people to lose weight <a href="http://ajcn.nutrition.org/content/82/1/222S.long">fail</a>– inflammation causes the brain to fight against it every step of the way.</p>
<p>So brain inflammation clearly plays an important role in sustaining obesity. But could it also be one of the primary causes of obesity in the first place? The onset of brain inflammation coincides with the other changes that take place in the body and brain as a result of overeating and weight gain. But whether brain inflammation actually causes the development of obesity is not yet clear. The results of the new study, however, demonstrate that the activation of a particular type of brain immune cell, microglia, initiates a cascade of events that do indeed lead directly to obesity.</p>
<h2>Manipulating microglia in mice</h2>
<p>In the study, researchers at the University of California, San Francisco and the University of Washington performed experiments on mice. They found that altering the activity of microglia in the hypothalamus allowed them to control the body weight of the mice independent of diet. </p>
<p>The researchers began by testing the effects of reducing either the number of microglia or their level of activity. They found that both manipulations cut the weight gain that resulted from putting the mice on high-fat diet in half.</p>
<p>They then tested the effects of increasing the activity of microglia. They found that this manipulation caused obesity even in mice that were on a normal diet. This latter result is particularly surprising. The fact that obesity can be induced through microglia – rather than directly through neurons themselves – is an indication of how strongly the brain’s supporting cells can exert control over its primary functions.</p>
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<img alt="" src="https://images.theconversation.com/files/180052/original/file-20170727-11584-1gnjlhb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/180052/original/file-20170727-11584-1gnjlhb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/180052/original/file-20170727-11584-1gnjlhb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/180052/original/file-20170727-11584-1gnjlhb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/180052/original/file-20170727-11584-1gnjlhb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/180052/original/file-20170727-11584-1gnjlhb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/180052/original/file-20170727-11584-1gnjlhb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Obesity can be induced by manipulating microglia.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/406573030?src=XVFM9UaOAjiBnmGJ4p6B0w-1-1&size=medium_jpg">Janson George/Shutterstock</a></span>
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<p>So artificial brain inflammation <em>can</em> cause obesity in mice. Of course, that doesn’t mean that natural, diet-induced brain inflammation <em>does</em> cause obesity in humans. But these new results suggest that this idea is worth taking seriously, particularly given that fact that potential solutions to the obesity crisis are in short supply. </p>
<p>This new study alone has already identified several possible targets for anti-obesity drugs. Intriguingly, one of the same drugs that was used in the study to decrease activity in microglia is also being tested in human cancer <a href="https://clinicaltrials.gov/ct2/results?cond=&term=plx3397">trials</a>, so initial indications of its effects on body weight should be available soon. But either way, a deeper understanding of the role of brain inflammation will help to clarify the causes of obesity. And hopefully prompt ideas about how it can be avoided in the first place.</p><img src="https://counter.theconversation.com/content/81702/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Nicholas Lesica receives funding from the Wellcome Trust.</span></em></p>Research provides hope for new anti-obesity drugs.Nick Lesica, Wellcome Trust Senior Research Fellow, UCLLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/698232016-12-06T09:22:38Z2016-12-06T09:22:38ZThe link between Parkinson’s disease and gut bacteria<figure><img src="https://images.theconversation.com/files/148692/original/image-20161205-8034-12j4rws.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Antibiotics: a new weapon to fight Parkinson's?</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/528642760?src=7zlpBmZZQhyblJx9vKpWRA-1-29&id=528642760&size=medium_jpg">Alina Kupstova/Shutterstock.com</a></span></figcaption></figure><p>What do the contents of your stomach have to do with Parkinson’s disease? A new <a href="http://www.cell.com/cell/fulltext/S0092-8674(16)31590-2">study</a> from a <a href="https://sarkis.caltech.edu">group of researchers</a> at the California Institute of Technology (CalTech) in Los Angeles suggests more than you might think.</p>
<p>The scientists looked at mice that have been genetically engineered to develop some of the changes in the brain and symptoms that are linked to Parkinson’s disease. This includes the build up in the brain of a sticky protein called alpha synuclein into lumps called Lewy bodies, and the death of cells in a bit of the brain called the <em>substantia nigra</em> (which is important for controlling movement). When this happens in humans, it causes the symptoms that we associate with Parkinson’s, such as shaking or slowed movement. The team at CalTech found that changing the number and type of bacteria in the gut of these mice could influence what happened in the mouse brain.</p>
<p>They used antibiotics to get rid of most of the bacteria in the gut of the mice, or used mice that don’t have any bacteria in their stomachs at all. In these mice, they found that accumulation in the brain of alpha synuclein was decreased. They also found that there was less of an immune response (one of the main ways that the body reacts to damage) in the brain, and that the mice had fewer problems with their movement.</p>
<p>Intriguingly, this isn’t the first time that links between the brain and the stomach have been reported in Parkinson’s. One of the first symptoms of Parkinson’s disease is constipation, which doctors think is caused by the brain cells that control bowel movement <a href="http://onlinelibrary.wiley.com/doi/10.1002/mds.26866/full">dying or going wrong</a>. Another link, which might be important for the experiments from the Californian group, is that the build up of the sticky alpha synuclein lumps that are linked to cells dying in the brain doesn’t start in the brain. It starts in the <a href="http://link.springer.com/article/10.1007/s00441-004-0956-9">gut and appears to spread to the brain later</a>.</p>
<h2>Important new avenue</h2>
<p>Why are these experiments important? At the moment, there aren’t any drugs available that can slow down the progression of Parkinson’s – once you start developing symptoms, they get progressively worse as time goes by. The more we understand what causes the changes in the brain that lead to Parkinson’s, the more likely it is that we can identify a process that we can use drugs to stop or slow down. This will help patients who develop Parkinson’s, or perhaps even stop them developing the disease in the first place.</p>
<p>The results from the mice that had had their stomach bacteria removed means we need to look a lot closer at what is happening in the stomachs of people with Parkinson’s. Perhaps there is a slightly different mix of bacteria in people who develop the disease, or maybe we can change the bacteria in the stomachs of people who have Parkinson’s to slow down the changes in their brain. </p>
<p>It is important to remember that there is a lot of work that needs to be done before we fully understand what these results mean. All of the experiments done by the group at CalTech were done in mice. There are some big differences between the laboratory mice that researchers use to look at Parkinson’s and what happens in humans with the disease, so we need to be a little bit cautious about reading too much into these results. But this is still a very interesting and exciting study, and has the potential to open up a new front in the fight to develop drugs for Parkinson’s.</p><img src="https://counter.theconversation.com/content/69823/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Patrick Lewis receives funding from the UK Medical Research Council and Biotechnology and Biological Sciences Research Council, the US National Institutes of Health and the Michael J. Fox Foundation. He has previously received an honorarium from Astex Pharmaceuticals He is affiliated with the Biochemical Society, the Society for Neuroscience, the Royal Institution and the Fabian Society. </span></em></p>A mouse study suggests that Parkinson’s might start in the gut and later spread to the brain.Patrick Lewis, Associate Professor in Cellular and Molecular Neuroscience, University of ReadingLicensed as Creative Commons – attribution, no derivatives.