Learning the wiring diagram for autism spectrum disorders
New study uncovers brain circuit involved in dysfunctional social,
repetitive, and inflexible behaviors characteristic of ASD
Date:
July 15, 2020
Source:
UT Southwestern Medical Center
Summary:
Researchers have identified brain circuitry that plays a key role
in the dysfunctional social, repetitive, and inflexible behavioral
differences that characterize autism spectrum disorders (ASD). The
findings could lead to new therapies.
FULL STORY ==========================================================================
A team led by UT Southwestern researchers has identified brain circuitry
that plays a key role in the dysfunctional social, repetitive, and
inflexible behavioral differences that characterize autism spectrum
disorders (ASD). The findings, published online this week in Nature Neuroscience, could lead to new therapies for these relatively prevalent disorders.
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The Centers for Disease Control and Prevention estimate that about 1 in
54 children in the U.S. have ASD, a broad range of neurodevelopmental conditions thought to be caused by a combination of genetic and
environmental factors.
Although researchers have identified some key genes and pathways that contribute to ASD, the underlying biology of these disorders remains
poorly understood, says Peter Tsai, M.D., Ph.D., assistant professor
in the departments of neurology and neurotherapeutics, neuroscience, pediatrics, and psychiatry at UT Southwestern Medical Center and a member
of the Peter O'Donnell Jr. Brain Institute.
However, Tsai explains, one key brain region that's been implicated in
ASD dysfunction is the cerebellum, part of the hindbrain in vertebrates
that holds about three-quarters of all the neurons in the body and has traditionally been linked with motor control. Recent studies by Tsai
and his colleagues have demonstrated that inhibiting activity in a
region of the cerebellum known as Rcrus1 can cause altered social and repetitive/inflexible behaviors reminiscent of ASD in mice. Their work
also found that stimulation of this area could rescue social behaviors in
an ASD-relevant model but was unable to improve repetitive or inflexible behaviors. Together, these studies suggested that additional regions of
the cerebellum might also regulate repetitive and/or inflexible behaviors.
In addition, how these cerebellar regions might regulate these
ASD-relevant behaviors remained unknown. To learn more about the brain circuitry controlling these behaviors, Tsai and his colleagues worked
with mice genetically engineered to reduce the activity of Purkinje cells, specialized cells that turn down the activity of other brain regions. When
they examined the activity of the rest of the brain, they saw increased activity in the medial prefrontal cortex (mPFC), another region previously implicated in ASD. Behavioral tests showed that these animals displayed characteristic social and repetitive/ inflexible behaviors reminiscent
of ASD. When the researchers inhibited mPFC activity in these animals,
both social impairments and repetitive/inflexible behaviors improved.
Because the cerebellum and the mPFC are on opposite ends of the brain,
Tsai and his colleagues used microscopic imaging to trace how these
regions are linked.
They found connections specifically between Rcrus1 and the mPFC in
these animals, with decreased Rcrus1 activity leading to increased
mPFC activity.
Further investigation showed that connectivity in this region wasn't just disrupted in these particular mice. It also existed in about a third of
94 different mouse lines carrying autism-related mutations and in two independent cohorts of people with ASD.
Looking further to better determine the anatomical connections between
these regions, the researchers saw that signals from Rcrus1 appear to
be routed to the mPFC through an area known as the lateral nucleus;
however, modulation of this region was only sufficient to improve social behaviors in their genetic mouse model while repetitive/inflexible
behaviors remained abnormal. Thus, Tsai and colleagues interrogated other cerebellar regions and found that modulation of another ASD-implicated cerebellar region, the posterior vermis, results in improvement in
repetitive and inflexible behaviors. They then asked whether this
cerebellar region also targets the mPFC and found that both posterior
vermis and Rcrus1 converge on the mPFC through another intermediate
region, the ventromedial thalamus.
Each of these regions could play a key role in potential future
therapies for ASD, Tsai explains. And because their experiments could
improve dysfunctional social and repetitive/inflexible behaviors even
in adult animals, it raises the possibility that therapies that target
this circuit in humans might be able to improve ASD-related dysfunction
even into adulthood.
Just as an electrician can repair a home's wiring once he or she
understands the wiring diagram, these findings give us potential hope
for improving dysfunctional activity in the circuits involved in ASD,"
Tsai says.
Other UTSW researchers who contributed to this study include Elyza Kelly, Fantao Meng, Yasaman Kazemi, Chongyu Ren, Christine Ochoa Escamilla,
Jennifer M. Gibson, Sanaz Sajadi, Robert J. Pendry, Tommy Tan, and Brad
E. Pfeiffer.
This study was performed with critical contributions from scientists
at the University of Toronto as well as Oxford, American, and Johns
Hopkins Universities, among others, and was supported by funding from
the National Institute of Neurological Disorders and Stroke (NS083733, NS107004, NS095232, and NS105039), the National Institute of Mental Health (MH116882 and MH094268), the Tuberous Sclerosis Alliance, the Department
of Defense, Autism Speaks, the Canadian Institutes of Health Research, the Ontario Brain Institute, and the National Institutes of Health (MH106957).
========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Elyza Kelly, Fantao Meng, Hirofumi Fujita, Felipe Morgado, Yasaman
Kazemi, Laura C. Rice, Chongyu Ren, Christine Ochoa Escamilla,
Jennifer M. Gibson, Sanaz Sajadi, Robert J. Pendry, Tommy Tan,
Jacob Ellegood, M.
Albert Basson, Randy D. Blakely, Scott V. Dindot, Christelle
Golzio, Maureen K. Hahn, Nicholas Katsanis, Diane M. Robins, Jill
L. Silverman, Karun K. Singh, Rachel Wevrick, Margot J. Taylor,
Christopher Hammill, Evdokia Anagnostou, Brad E. Pfeiffer, Catherine
J. Stoodley, Jason P.
Lerch, Sascha du Lac, Peter T. Tsai. Regulation of autism-relevant
behaviors by cerebellar-prefrontal cortical circuits. Nature
Neuroscience, 2020; DOI: 10.1038/s41593-020-0665-z ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2020/07/200715095504.htm
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