Sex-dependent consequences of early life adversity on reward circuitry and opioid reward-related behaviors

In humans, early-life adversity (ELA) such as trauma, poverty, and chaotic environment is linked to increased risk of later-life emotional disorders including depression and substance use disorders. These disorders involve underlying disruption of reward circuits and likely vary by sex. However, the neurobiological mechanisms by which this occurs are unknown. The work presented here examines effects of ELA on drug-seeking behavior and reward circuit function in rats, in pursuit of a mechanistic understanding that will inform novel translational intervention or prevention strategies for opioid addiction and other negative outcomes of early life adversity. To this end, I employ a transdisciplinary approach to dissecting neural circuit mechanisms of ELA-induced reward seeking dysfunction. Specifically, I combine a robust translational model of ELA with sophisticated behavioral methods including analysis of economic demand for opioids, a measure also used to quantify addiction severity in humans. These behavioral assays are combined with tract tracing, multi-region analysis of neuronal activation, and molecular analyses of endogenous opioid system. The results of these experiments demonstrate sex-divergent consequences of ELA on the reward circuit: females are prone to addiction-like behaviors whereas males instead develop an anhedonic phenotype. Underlying mechanisms include sex-dependent alterations in gene expression of select opioid receptors and neuronal activation in the nucleus accumbens and its glutamatergic afferents. Through this work, I establish novel mechanisms by which developmental stressors sex-dependently alter reward circuit function, identifying potential new targets for future interventions