Microcircuits of Stress Sensitization in the Nucleus Accumbens

Abstract

There is a well-established link between childhood adversity and the lifetime risk of psychiatric disorders. Human and animal studies indicate that early-life stress (ELS) increases the risk for depression by sensitizing individuals to later stress, which then precipitates the onset of symptoms, but the mechanisms underlying this relationship are unclear. ELS alters short- and long-term activity in the nucleus accumbens (NAc), which also shows altered function during depressive periods. This suggests that the NAc may be mechanistically involved in the process of stress sensitization. This thesis investigated the hypothesis that the reactivation of ELS-responsive microcircuits in the NAc is a necessary component of the sensitized behavioral response to adult stress. Utilizing a novel transgenic mouse line, we expressed an inhibitory DREADD (Designer Receptor Exclusively Activated by Designer Drugs) in experience-responsive cells in the NAc of juvenile mice during ELS or standard (Std) enrichment conditions. We conducted a pilot study in WT mice to ensure that our ligand of choice, olanzapine (OLZ), does not induce behavioral effects in the absence of DREADDs. We then investigated the effect of inhibiting experience-responsive microcircuits during adult chronic social defeat stress (CSDS) on subsequent anxiety- and depression-like behavior. As hypothesized, ELS sensitized the animals to adult stress, rendering more animals stress-susceptible with vehicle treatment while Std animals remained resilient or indifferent. Microcircuit inhibition with OLZ treatment inverted these proportions, yielding more resilient animals in the ELS cohort and more susceptible animals in the Std cohort. These data suggest that inhibitory DREADDs were expressed in distinct microcircuits in the NAc, responsive to either ELS or reward, and that inhibition of these circuits during CSDS dampened or enhanced the stress experience, respectively. I conclude that cellular reactivation in the NAc may be an important component of stress sensitization and propose future avenues of investigation to build on this work. Finally, I discuss the utility of animal models in neuropsychiatric research and their relevance to the goal of lessening the global health burden of major depressive disorder.