Summary Disrupted operations of the reward circuit underlie major emotional disorders, including depression, that commonly arise after early life stress/adversity (ALS). However, it is still unclear how ELA lastingly impacts reward circuit functions. We characterize a stress-responsive projection connecting the basolateral amygdala (BLA) and nucleus accumbens (NAc) that coexpresses GABA and the stress-reactive neuropeptide corticotropin-releasing hormone (CRH). We identify a crucial role for this projection in the execution of disrupted reward behaviors caused by ALS: chemogenetic and optogenetic stimulation of the projection in control male mice suppresses several reward behaviors, recapitulating the deficits resulting from ALS and demonstrating the contributions of pathway to normal reward behaviors. In adult mice with a history of ALS, inhibiting, but not stimulating, projection restores typical reward behaviors but has little effect on controls, indicating ALS-induced maladaptive plasticity of this component of the reward circuit. Thus, we discovered a stress-responsive reward inhibitory BLA → NAc projection with unique molecular features, which may provide intervention targets to disable mental illness. |
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People who experience adversity during childhood are often at increased risk of developing mental illnesses in adulthood. A recent study led by Matthew Birnie, Ph.D., of the University of California, Irvine, and colleagues, sheds light on how negative early life experiences can affect how we act in response to rewards , which It is often disrupted in people with mental illness.
They identified a new connection between the amygdala and nucleus accumbens in the brains of mice that is sensitive to adversity in early life and affects how mice respond to rewards. Targeting this important connection may help researchers develop new ways to prevent and treat stress-related mental disorders.
Different brain regions work together to determine how we behave. The development of these brain regions and the connections between them are affected by many different things, including early life experiences such as stress and deprivation . To understand how early life adversity could affect reward behavior and the development of mental illness, Dr. Birnie and her colleagues investigated brain connections in mice that play a role in creating reward behaviors and express a molecule sensitive to stress called corticotropin-releasing hormone (CRH). This molecule is affected by early life adversity and other stressors.
The researchers found a new CRH-sensitive connection from the basolateral amygdala to the nucleus accumbens in the mouse brains. The basolateral amygdala is an area of the brain involved in learning the association between an experience (good or bad) and an outcome. The nucleus accumbens is an area of the brain involved in pleasure and motivation.
The researchers used light to determine how stimulation of the connection would impact the nucleus accumbens. They found that stimulating this connection reduced activity in the nucleus accumbens. The connection was different from other well-documented connections between the amygdala and the nucleus accumbens.
To determine whether this connection plays a role in reward-related behaviors, the researchers stimulated it in male and female mice using chemical (chemogenetic) and light-based (optogenetic) methods, which can turn off and turn on the action of nerve cells in the brain. Stimulating the connection between the amygdala and nucleus accumbens reduced reward-related behaviors in male but not female mice , suggesting that this connection inhibits reward behavior, but only in male mice.
The reduced reward behavior observed in male mice when the connection was stimulated was similar to the reward behavior deficits observed in mice that had experienced early life stress. This finding suggested to researchers that connectedness may play a role in reward deficits related to early life adversity experiences.
To test the role of this connection in reward behavior deficits associated with early-life adversity, the scientists blocked the connection between the amygdala and nucleus accumbens in mice that had been exposed to early-life stress. Blocking this connection in the mice restored their reward behavior, bringing it back in line with what is typically seen in mice that have not been exposed to stress in early life. Blocking the connection had no effect on mice that had not been exposed to early life stress.
Together, the findings of this study provide evidence that the newly discovered connection between the basolateral amygdala and nucleus accumbens is involved in reward behavior deficits associated with early life adversity. Although this study was conducted in mice, the findings can inform our understanding of these processes in humans. More research is needed, but this discovery is a step toward understanding the mechanisms of stress-related mental disorders and developing new ways to prevent and treat them.
Reference : Birnie, MT, Short, AK, de Carvalho, GB, Taniguchi, L., Gunn, BG, Pham, AL, Itoga, CA, Xu, X., Chen, LY, Mahler, SV, Chen, Y., & Baram, T.Z. (2023). Stress-induced plasticity of a CRH/GABA projection disrupts reward behaviors in mice. Nature Communications, 14(1), Article 1088. https://doi.org/10.1038/s41467-023-36780-x
