Mapping the brain's sensory gatekeeper

Date:
July 22, 2020
Source:
Massachusetts Institute of Technology
Summary:
Researchers have mapped the thalamic reticular nucleus in
unprecedented detail, revealing that the region contains two
distinct subnetworks of neurons with different functions. The
findings could offer researchers much more specific targets for
designing drugs that could alleviate attention deficits, sleep
disruption, and sensory hypersensitivity.



FULL STORY ==========================================================================
Many people with autism experience sensory hypersensitivity, attention deficits, and sleep disruption. One brain region that has been implicated
in these symptoms is the thalamic reticular nucleus (TRN), which is
believed to act as a gatekeeper for sensory information flowing to
the cortex.


==========================================================================
A team of researchers from MIT and the Broad Institute of MIT and Harvard
has now mapped the TRN in unprecedented detail, revealing that the region contains two distinct subnetworks of neurons with different functions. The findings could offer researchers more specific targets for designing drugs
that could alleviate some of the sensory, sleep, and attention symptoms
of autism, says Guoping Feng, one of the leaders of the research team.

"The idea is that you could very specifically target one group of neurons, without affecting the whole brain and other cognitive functions," says
Feng, the James W. and Patricia Poitras Professor of Neuroscience at
MIT and a member of MIT's McGovern Institute for Brain Research.

Feng; Zhanyan Fu, associate director of neurobiology at the Broad
Institute's Stanley Center for Psychiatric Research; and Joshua Levin,
a senior group leader at the Broad Institute, are the senior authors of
the study, which appears today in Nature. The paper's lead authors are
former MIT postdoc Yinqing Li, former Broad Institute postdoc Violeta Lopez-Huerta, and Broad Institute research scientist Xian Adiconis.

Distinct populations When sensory input from the eyes, ears, or other
sensory organs arrives in our brains, it goes first to the thalamus, which
then relays it to the cortex for higher-level processing. Impairments
of these thalamo-cortical circuits can lead to attention deficits, hypersensitivity to noise and other stimuli, and sleep problems.



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One of the major pathways that controls information flow between the
thalamus and the cortex is the TRN, which is responsible for blocking
out distracting sensory input. In 2016, Feng and MIT Assistant Professor Michael Halassa, who is also an author of the new Nature paper, discovered
that loss of a gene called Ptchd1 significantly affects TRN function. In
boys, loss of this gene, which is carried on the X chromosome, can lead
to attention deficits, hyperactivity, aggression, intellectual disability,
and autism spectrum disorders.

In that study, the researchers found that when the Ptchd1 gene was knocked
out in mice, the animals showed many of the same behavioral defects seen
in human patients. When it was knocked out only in the TRN, the mice
showed only hyperactivity, attention deficits, and sleep disruption,
suggesting that the TRN is responsible for those symptoms.

In the new study, the researchers wanted to try to learn more about the specific types of neurons found in the TRN, in hopes of finding new
ways to treat hyperactivity and attention deficits. Currently, those
symptoms are most often treated with stimulant drugs such as Ritalin,
which have widespread effects throughout the brain.

"Our goal was to find some specific ways to modulate the function of
thalamo- cortical output and relate it to neurodevelopmental disorders,"
Feng says. "We decided to try using single-cell technology to dissect
out what cell types are there, and what genes are expressed. Are
there specific genes that are druggable as a target?" To explore that possibility, the researchers sequenced the messenger RNA molecules found
in neurons of the TRN, which reveals genes that are being expressed in
those cells. This allowed them to identify hundreds of genes that could
be used to differentiate the cells into two subpopulations, based on
how strongly they express those particular genes.



==========================================================================
They found that one of these cell populations is located in the core
of the TRN, while the other forms a very thin layer surrounding the
core. These two populations also form connections to different parts
of the thalamus, the researchers found. Based on those connections,
the researchers hypothesize that cells in the core are involved in
relaying sensory information to the brain's cortex, while cells in the
outer layer appear to help coordinate information that comes in through different senses, such as vision and hearing.

"Druggable targets" The researchers now plan to study the varying
roles that these two populations of neurons may have in a variety of neurological symptoms, including attention deficits, hypersensitivity,
and sleep disruption. Using genetic and optogenetic techniques, they
hope to determine the effects of activating or inhibiting different TRN
cell types, or genes expressed in those cells.

"That can help us in the future really develop specific druggable
targets that can potentially modulate different functions," Feng
says. "Thalamo-cortical circuits control many different things, such as
sensory perception, sleep, attention, and cognition, and it may be that
these can be targeted more specifically." This approach could also be
useful for treating attention or hypersensitivity disorders even when
they aren't caused by defects in TRN function, the researchers say.

"TRN is a target where if you enhance its function, you might be
able to correct problems caused by impairments of the thalamo-cortical circuits," Feng says. "Of course we are far away from the development of
any kind of treatment, but the potential is that we can use single-cell technology to not only understand how the brain organizes itself, but
also how brain functions can be segregated, allowing you to identify much
more specific targets that modulate specific functions." The research
was funded by the Simons Center for the Social Brain at MIT, the Hock
E. Tan and K. Lisa Yang Center for Autism Research at MIT, the James
and Patricia Poitras Center for Psychiatric Disorders Research at MIT,
the Stanley Center for Psychiatric Research at the Broad Institute,
the National Institutes of Health/National Institute for Mental Health,
the Klarman Cell Observatory at the Broad Institute, the Pew Foundation,
and the Human Frontiers Science Program.


========================================================================== Story Source: Materials provided by
Massachusetts_Institute_of_Technology. Original written by Anne
Trafton. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yinqing Li, Violeta G. Lopez-Huerta, Xian Adiconis, Kirsten
Levandowski,
Soonwook Choi, Sean K. Simmons, Mario A. Arias-Garcia, Baolin Guo,
Annie Y. Yao, Timothy R. Blosser, Ralf D. Wimmer, Tomomi Aida,
Alexander Atamian, Tina Naik, Xuyun Sun, Dasheng Bi, Diya Malhotra,
Cynthia C.

Hession, Reut Shema, Marcos Gomes, Taibo Li, Eunjin Hwang,
Alexandra Krol, Monika Kowalczyk, Joa~o Pec,a, Gang Pan, Michael
M. Halassa, Joshua Z. Levin, Zhanyan Fu, Guoping Feng. Distinct
subnetworks of the thalamic reticular nucleus. Nature, 2020; DOI:
10.1038/s41586-020-2504-5 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200722112653.htm

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