Early-life stress can disrupt maturation of brain's reward circuits,
promoting disorders
New therapeutic target for treating mental illness

Date:
February 27, 2023
Source:
University of California - Irvine
Summary:
A new brain connection can explain how early-life stress and
adversity trigger disrupted operation of the brain's reward
circuit, offering a new therapeutic target for treating mental
illness. Impaired function of this circuit is thought to underlie
several major disorders, such as depression, substance abuse and
excessive risk-taking.


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FULL STORY ==========================================================================
A new brain connection discovered by University of California, Irvine researchers can explain how early-life stress and adversity trigger
disrupted operation of the brain's reward circuit, offering a new
therapeutic target for treating mental illness. Impaired function of
this circuit is thought to underlie several major disorders, such as depression, substance abuse and excessive risk-taking.


==========================================================================
In an article recently published online in Nature Communications,
Dr. Tallie Z.

Baram, senior author and UCI Donald Bren Professor and Distinguished
Professor in the Departments of Anatomy & Neurobiology, Pediatrics,
Neurology and Physiology & Biophysics, and Matt Birnie, lead author and
a postdoctoral researcher, describe the cellular changes in the brain's circuitry caused by exposure to adversity during childhood.

"We know that early-life stress impacts the brain, but until now,
we didn't know how," Baram said. "Our team focused on identifying
potentially stress- sensitive brain pathways. We discovered a new
pathway within the reward circuit that expresses a molecule called corticotropin-releasing hormone that controls our responses to
stress. We found that adverse experiences cause this brain pathway to
be overactive." "These changes to the pathway disrupt reward behaviors, reducing pleasure and motivation for fun, food and sex cues in mice,"
she said. "In humans, such behavioral changes, called 'anhedonia,' are associated with emotional disorders. Importantly, we discovered that when
we silence this pathway using modern technology, we restore the brain's
normal reward behaviors." Researchers mapped all the CRH-expressing connections to the nucleus accumbens, a pleasure and motivation hub in
the brain, and found a previously unknown projection arising from the basolateral amygdala. In addition to CRH, projection fibers co-expressed gama-aminobutyric acid. They found that this new pathway, when stimulated, suppresses several types of reward behaviors in male mice.

The study involved two groups of male and female mice. One was exposed to adversity early in life by living for a week in cages with limited bedding
and nesting material, and the other was reared in typical cages. As
adults, the early adversity-experiencing male mice had little interest in
sweet foods or sex cues compared to typically reared mice. In contrast, adversity-experiencing females craved rich, sweet food. Inhibiting the
pathway restored normal reward behaviors in males, yet it had no effect
in females.

"We believe that our findings provide breakthrough insights into the
impact of early-life adversity on brain development and specifically on
control of reward behaviors that underlie many emotional disorders. Our discovery of the previously unknown circuit function of the basolateral amygdala-nucleus accumbens brain pathway deepens our understanding of
this complex mechanism and identifies a significant new therapeutic
target." Baram said. "Future studies are needed to increase our
understanding of the different and sex-specific effects of early-life
adversity on behavior." Team members include Annabel K. Short,
postdoctoral researcher, Lara Taniguchi, graduate student, Aidan Pham,
lab assistant, and co-corresponding author Yuncai Chen, project scientist,
from Department of Pediatrics; Gregory B. de Carvalho, graduate student, Benjamin G. Gunn, assistant project scientist; Christy A.

Itoga, researcher; Xiangmin Xu, professor; Lulu Y. Chen, assistant
professor; from the Department of Anatomy & Neurobiology; and Stephen
V. Mahler, associate professor from the Department of Neurobiology
and Behavior.

This work was supported by National Institute of Health grants
P50 MH096889, MH73136, U01DA053826 NS108296 P50 DA044118, P50
MH096889 Seed Award FG23670, The Bren Foundation, a George E. Hewitt
Foundation for Biomedical Research Fellowship and a British Society for Neuroendocrinology Project Support Grant BSN-5646342.

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========================================================================== Story Source: Materials provided by
University_of_California_-_Irvine. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Matthew T. Birnie, Annabel K. Short, Gregory B. de Carvalho, Lara
Taniguchi, Benjamin G. Gunn, Aidan L. Pham, Christy A. Itoga,
Xiangmin Xu, Lulu Y. Chen, Stephen V. Mahler, Yuncai Chen, Tallie
Z. Baram.

Stress-induced plasticity of a CRH/GABA projection disrupts
reward behaviors in mice. Nature Communications, 2023; 14 (1) DOI:
10.1038/ s41467-023-36780-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/02/230227161434.htm

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