Summary: Researchers have identified a new stress-sensitive pathway in the brain’s reward system that releases the corticotropin-releasing hormone in response to stress. Adverse experiences make this pathway overactive.
Source: UC Irvine
New brain connection discovered by University of California, Irvine researchers may explain how early stress and adversity trigger disrupted functioning of the brain’s reward circuitry, offering a new therapeutic target for the treatment of mental illness . The impaired function of this circuit is believed to underlie several major disorders, such as depression, substance abuse, and excessive risk taking.
In an article recently published online in Nature CommunicationDr. Tallie Z. Baram, lead author and UCI Donald Bren Professor and Emeritus Professor in the Departments of Anatomy and Neurobiology, Pediatrics, Neurology and Physiology and Biophysics, and Matt Birnie, lead author and postdoctoral researcher, describe the cellular changes in brain circuitry caused by exposure to childhood adversity.
“We know that early life stress impacts the brain, but until now we didn’t know how,” Baram said.
“Our team focused on identifying brain pathways potentially sensitive to stress. We discovered a new pathway in the reward circuitry that expresses a molecule called corticotropin-releasing hormone that controls our responses to stress. We found that negative experiences lead to hyperactivity of this brain pathway.
“These pathway changes disrupt reward behaviors, reducing pleasure and motivation for pleasure, food, and sexual cues in mice,” she said.
“In humans, such behavioral changes, called ‘anhedonia’, are associated with emotional disturbances. Importantly, we found that when we silence this pathway using modern technology, we restore the brain’s normal reward behaviors.
The researchers mapped all CRH-expressing connections to the nucleus accumbens, a pleasure and motivation center in the brain, and found a previously unknown projection originating from the basolateral amygdala.
In addition to CRH, projection fibers co-express gamma-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 living for a week in cages with little bedding and nesting material, and the other was raised in typical cages.
In adulthood, male mice experiencing early adversity had little interest in sweet foods or sexual cues compared to typically bred mice. In contrast, women who experienced adversity craved rich, sweet foods. Pathway inhibition restored normal reward behaviors in men, but had no effect in women.
“We believe our findings provide groundbreaking insights into the impact of early life adversity on brain development and specifically the control of reward behaviors that underlie many emotional disorders.
“Our discovery of the previously unknown circuit function of the basolateral cerebral amygdala-nucleus accumbens pathway deepens our understanding of this complex mechanism and identifies an important new therapeutic target.” said Baram.
“Future studies are needed to increase our understanding of the differential and gender-specific effects of early adversity on behavior.”
Team members include Annabel K. Short, postdoctoral researcher, Lara Taniguchi, graduate student, Aidan Pham, laboratory assistant, and co-corresponding author Yuncai Chen, project scientist, from the Department of Pediatrics; Gregory B. de Carvalho, graduate student, Benjamin G. Gunn, project scientific assistant; Christy A. Itoga, researcher; Xiangmin Xu, teacher; Lulu Y. Chen, assistant professor; from the Department of Anatomy and Neurobiology; and Stephen V. Mahler, associate professor in the Department of Neurobiology and Behavior.
Funding: This work was supported by National Institute of Health Grants P50 MH096889, MH73136, U01DA053826 NS108296 P50 DA044118, P50 MH096889 Seed Award FG23670, Bren Foundation, George E. Hewitt Foundation Fellowship for Research biomedical and a BSN grant supporting the British Society for Neuroendocrinology project -5646342.
About this stress research news
Author: Patricia Harman
Source: UC Irvine
Contact: Patricia Harriman – UC Irvine
Picture: Image is in public domain
Original research: Free access.
“Stress-induced plasticity of a CRH/GABA projection disrupts reward behaviors in mice” by Tallie Z. Baram et al. Nature Communication
Stress-induced plasticity of a CRH/GABA projection disrupts reward behaviors in mice
Disrupted operations of the reward circuitry underlie major emotional disturbances, including depression, which usually occur after early stress/adversity (ELA). However, the lasting impact of ELA on reward circuit functions remains unclear.
We characterize a stress-responsive projection linking the basolateral amygdala (BLA) and nucleus accumbens (NAc) that co-expresses GABA and the stress-responsive neuropeptide corticotropin-releasing hormone (CRH).
We identify a crucial role for this projection in the execution of ELA-induced disrupted reward behaviors: chemogenetic and optogenetic stimulation of projection in control male mice suppresses several reward behaviors, recapitulating deficits resulting from ELA and demonstrating pathway contributions to normal reward behaviors.
In adult ELA mice, inhibiting – but not stimulating – projection restores typical reward behaviors but has little effect in controls, indicating ELA-induced maladaptive plasticity of this component of the reward circuitry.
Thus, we uncover a stress-responsive and reward-inhibiting BLA → NAc projection with unique molecular characteristics, which may provide intervention targets for disabling mental illnesses.