Loss of pleasure (Anhedonia): A sex-dependent, cross-species consequence of unpredictable signals to the perinatal brain.

Reward seeking is an essential component of human behavior. Anhedonia (reduced motivation for and pleasure in reward) is a core feature of several mental illnesses. Early life adversity associates with later impairments in reward behaviors and related psychopathology; however, specific aspects of early adversity that lead to disrupted reward behaviors are unknown. Capitalizing on evidence that unpredictable signals to the developing brain constitute adversity and influence neurodevelopment, we examined whether exposure to perinatal unpredictable maternal signals associated with diminished reward responsivity, and probed causality using experiments in mice. We analyzed a longitudinal human study (N=158 mother/child dyads) and a controlled prospective mouse study (N=111 pups; 17 litters). In humans, exposure to unpredictable signals during late gestation was assessed by maternal mood entropy (a measure of how disordered or random signals are). In mice, unpredictable maternal care behaviors were experimentally induced during the neonatal period, and maternal care entropy was similarly computed. Aspects of anhedonia were determined by adolescent self-report and diminished behavioral responses to palatable food in young adult mice. Across species, unpredictable maternal signals were associated with reduced reward responsivity in males, but not females. Associations persisted after accounting for income and maternal psychopathology in humans, and for cohort and litter effects in mice. These findings indicate a robust, sex-dependent link between early exposure to maternal unpredictability and disrupted reward processing. The convergence of cross-species results indicates that unpredictability of maternal signals plays a role in shaping reward behaviors in males, with implications for the developmental origins of mental illness.