• Human gene variant produces attention de

    From ScienceDaily@1:317/3 to All on Thursday, April 07, 2022 22:30:40
    Human gene variant produces attention deficit disorder-like problems in
    mice

    Date:
    April 7, 2022
    Source:
    Florida Atlantic University
    Summary:
    Mutant mice are providing scientists with a new neurobiological
    framework to understand the brain changes observed in distractible
    humans who carry a common gene variant whose frequency has been
    associated with Attention Deficit Hyperactivity Disorder (ADHD). The
    scientists demonstrate that mice that express the variant adopt
    an inattentive phenotype similar to that seen in humans.



    FULL STORY ========================================================================== Mutant mice are providing scientists with a new neurobiological framework
    to understand the brain changes observed in distractible humans who carry
    a common gene variant whose frequency has been associated with Attention Deficit Hyperactivity Disorder (ADHD). The scientists demonstrate that
    mice that express the variant adopt an inattentive phenotype similar to
    that seen in humans.


    ==========================================================================
    The study, led by researchers from the University of Michigan in
    collaboration with Florida Atlantic University, Temple University, and
    the National Institute on Deafness and Other Communication Disorders,
    National Institutes of Health, used genetically engineered mice to
    examine the neural and behavioral effects of a choline transporter (CHT) variant. Prior work by the team has shown that the variant associated
    with heightened distractibility in humans, though whether the variant
    was itself causal for inattention was unclear.

    In the new study, researchers made a single change in the gene encoding
    the neuronal CHT and then searched for physiological changes in the
    brain, focusing on their ability to sustain production and release of the powerful brain chemical acetylcholine, which is synthetized from choline.

    In humans, disruption of acetylcholine signaling impairs one's capacity
    to filter distractors and to perform focus-demanding tasks. A total
    loss of CHT function in mice and people leads to early death due to the
    role played by acetylcholine in muscle contraction, particularly the
    muscles that control breathing. Lesser reductions in CHT activity allow
    for normal growth and movement, but mice with these changes exhibit
    premature fatigue when made to run on a treadmill. Work from the new
    study reveals that the mice show signs of mental fatigue as well.

    Results of the study, published in The Journal of Neuroscience,indicate
    that the CHT gene variant known as Val89, reduces the rate of choline
    uptake and the capacity to sustain acetylcholine production during attention-demanding conditions, effects that lead to diminished cognitive performance when the mice are faced with attentional challenges. Evidence
    from the mouse studies provides direct evidence that Val89 drives
    increased vulnerability to distraction and provides a mechanistic basis
    for the diminished frontal cortex activation observed in Val89-expressing humans.

    "Our mouse studies, along with prior behavioral and brain imaging
    studies, indicate that a single copy of the variant is sufficient to
    change acetylcholine availability and its resulting cognitive effects,"
    said Randy D.

    Blakely, Ph.D., co-author, executive director of the FAU Stiles-Nicholson
    Brain Institute and professor, FAU Schmidt College of Medicine. "Seeing
    effects from a single copy of Val89 suggests that choline transport may be mediated by a pair of CHT proteins such that one poorly functioning copy
    can impact the normal function of the other, leading to stronger effects
    than expected from simply having one copy compromised." This finding
    has been reported before in people with neuromuscular disorder causing
    CHT mutations, but this also appears to be the case for brain function.



    ========================================================================== "Val89 mice lack cognitive flexibility in response to an attentional challenge," said Eryn Donovan, lead author and a graduate student in
    the Department of Psychology, University of Michigan. "Our findings
    from this mouse model suggest the potential for a more complete
    investigation of the effects of the CHT Val89 mutation in the brain
    as well as the development of therapeutic strategies for those with
    disrupted acetylcholine signaling." According to the United States
    Centers for Disease Control and Prevention, the estimated number of
    children ever diagnosed with ADHD, according to a 2016 parent survey,
    is 6.1 million. This same survey shows that 6 in 10 children with ADHD
    had at least one other mental, emotional or behavioral disorder and 62
    percent were taking ADHD medication. Although ADHD most often occurs in children, it also can be diagnosed in adulthood.

    "We think that the CHT Val89 mouse can be a valuable model to study
    heritable risk for cognitive disorders that arise from cholinergic dysfunction," said Blakely. "We now can gain much more insight into
    the brain effects of the Val89 variant in ways that cannot be done in
    humans and possibly lead to new ways to treat disorders associated with
    brain acetylcholine signaling that appear in childhood, such as ADHD,
    or during aging, as with Parkinson's disease and Alzheimer's disease."
    In addition to new insights into a potential risk factor for psychiatric
    and neurological disorders, Martin Sarter, Ph.D., a professor of
    psychology and neuroscience at the University of Michigan and the
    communicating author of the study says that their findings explain why
    healthy humans expressing this genetic variant exhibit robust attentional vulnerabilities.

    "As this genetic variant is quite common, occurring in about 9 to 10
    percent of humans, we now understand exactly how this variant influences
    the brain mechanisms that are essential for paying attention," said
    Sarter.

    Other study co-authors are Cassandra Avila, a graduate student and Sarah Klausner, an undergraduate student, Department of Psychology, University
    of Michigan; Vinay Parikh, Ph.D., an associate professor of psychology
    and neuroscience, Temple University; Maria Cristina Fenollar Ferrer,
    Ph.D., Laboratory of Molecular Genetics, Section of Human Genetics,
    National Institute on Deafness and Other Communication Disorders.


    ========================================================================== Story Source: Materials provided by Florida_Atlantic_University. Original written by Gisele Galoustian. Note: Content may be edited for style
    and length.


    ========================================================================== Journal Reference:
    1. Eryn Donovan, Cassandra Avila, Sarah Klausner, Vinay Parikh,
    Cristina
    Fenollar-Ferrer, Randy D. Blakely, Martin Sarter. Disrupted
    choline clearance and sustained acetylcholine release in vivo by
    a common choline transporter coding variant associated with poor
    attentional control in humans. The Journal of Neuroscience, 2022;
    JN-RM-1334-21 DOI: 10.1523/ JNEUROSCI.1334-21.2022 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220407161941.htm

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