Early life stress can disrupt maturing of brain reward circuits, promoting disorders
UC Irvine discovery offers new therapeutic target for treating mental illness
February 27, 2023
"We discovered that when we silence this pathway using modern technology, we restore the brain’s normal reward behaviors," said Dr. Tallie Z. Baram. Photo by Steve Zylius/UC Irvine
Irvine, Calif. — A new brain connection discovered by University of California, Irvine researchers can explain how early life stress and adversity disrupt the brain’s reward circuits, offering a new therapeutic target to treat mental illness.
Impaired function of this circuit is thought to underlie several major disorders, such as depression, substance abuse and excessive risk-taking.
The cellular changes in the brain’s circuitry caused by exposure to adversity during childhood are described in an article published recently in the journal Nature Communications by senior author Dr. Tallie Z. Baram, a Donald Bren Professor and Distinguished Professor in the UCI School of Medicine's departments of Anatomy & Neurobiology, Pediatrics, Neurology and Physiology & Biophysics, and Matt Birnie, lead author and a postdoctoral researcher.
“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, which controls our responses to stress. We found that adverse experiences cause this brain pathway to be overactive.”
Reward behaviors affected
“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 corticotropin-releasing hormone (CRH) 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.
Response differs in males, females
The study involved two groups of male and female mice. One group was exposed to adversity early in life by living for a week in cages with limited bedding and nesting material; 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 with 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," Baram said. "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."
Future studies are needed to increase understanding of the different and sex-specific effects of early life adversity on behavior, she added.
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 & Neurobiolgy; and Stephen V. Mahler, associate professor from the Department of Neurobiology and Behavior.
This research 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.
About UCI’s Brilliant Future campaign: Publicly launched on Oct. 4, 2019, the Brilliant Future campaign aims to raise awareness and support for UCI. By engaging 75,000 alumni and garnering $2 billion in philanthropic investment, UCI seeks to reach new heights of excellence in student success, health and wellness, research and more. The School Medicine plays a vital role in the success of the campaign. Learn more about our https://brilliantfuture.uci.edu/uci-school-of-medicine" target="_blank">Brilliant Future campaign.
About the University of California, Irvine: Founded in 1965, UCI is a member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by U.S. News & World Report. The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. Visit www.uci.edu to learn more about UC Irvine.
For more information, contact: