A new brain link discovered by the University of California, Irvine researchers can explain how stress and adversity in early life affect the functioning of the brain’s reward circuitry, offering a new therapeutic target for treating mental illness. Impaired function of this circuit is thought to underlie a number of major disorders, such as depression, substance abuse and excessive risk taking.
In an article recently published online i Nature CommunicationDr. Tallie Z. Baram, senior author and UCI Donald Bren Professor and Distinguished Professor in the Departments of Anatomy & Neurobiology, Pediatrics, Neuroscience and Physiology & Biophysics, and Matt Birnie, lead author and postdoctoral researcher, describe the cellular changes in brain circuitry caused by childhood exposure to adversity.
“We know that early life stress affects the brain, but until now, we didn’t know how,” said Baram. “Our team focused on identifying brain pathways that may be sensitive to stress. We discovered a new pathway within the reward circuit that expresses a molecule called corticotropin-releasing hormone that regulates our responses to stress. .”
“These changes in the pathway affect reward behaviors, reducing pleasure and motivation for play, food and sexual cues in mice,” she said. “In humans, such behavioral changes, known as ‘anhedonia’, are associated with emotional disorders. Importantly, we discovered that when we silence ourselves in this way using modern technology, we become normal -restoring the brain’s reward behavior.”
Researchers mapped all the CRH-expressing connections to the nucleus accumbens, a pleasure and motivation hub in the brain, and discovered a previously unknown projection arising from the basolateral amygdala. In addition to CRH, projection fibers co-express gamma-aminobutyric acid. They found that this new pathway, when stimulated, induces several types of rewarding behavior in male mice.
The study involved two groups of male and female mice. One was exposed to distress early in life by living for a week in cages with limited bedding and nesting material, while the other was reared in typical cages. As adults, early-experienced male mice showed little interest in sweet foods or sexual cues compared to normally reared mice. In contrast, women who experienced adversity wanted rich, sweet food. Blocking the pathway restored normal male reward behavior, but had no effect on females.
“We believe that our findings provide ground-breaking insights into the impact of early-life regret on brain development and in particular on the control of reward behaviors that underlie many emotional disorders. It deepens our understanding of this complex mechanism and identifies a significant new therapeutic target.” said Baram. “Future studies are needed to increase our understanding of the diverse and sex-specific effects of early life adversity on behavior.”
Team members include Annabel K. Short, postdoctoral researcher, Lara Taniguchi, graduate student, Aidan Pham, laboratory assistant, and corresponding author Yuncai Chen, project scientist, from the 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 Institutes of Health grants P50 MH096889, MH73136, U01DA053826 NS108296 P50 DA044118, P50 MH096889 Seed Award FG23670, Bren Foundation, George E. Hewitt Research Foundation for Biomedical Support for the Biomedical and Bioendocrine Support Project of Seed Support Britain -5646342.