Behavioral susceptibility and resilience following early-life stress are associated with sex-dependent locus coeruleus noradrenergic signatures in adulthood

Abstract

Child adversity (CA), encompassing emotional, physical, and sexual maltreatment or abuse, affects a substantial number of children worldwide. Moreover, it is the leading predictor of psychiatric disorders such as major depressive disorder (MDD), anxiety, and suicidal behavior. Despite the robust link between CA and psychopathology, individual outcomes vary significantly, with some children demonstrating resilience. Resilience is an adaptive and dynamic process, which mitigates the long-term effects of CA, suggesting potential protective mechanisms that remain underexplored. This study investigates behavioural susceptibility and resilience following early life stress (ELS) and examined whether these outcomes are associated with sex-dependent alteration of the locus coeruleus-norepinephrine (LC-NE) system, a critical modulator of stress, cognition, and emotion. Using a maternal deprivation model combined with limited nesting and bedding, we examined sex-dependent behavioral, physiological, and neurobiological markers associated with ELS outcomes in mice. Behavioral clustering revealed distinct phenotypes: resilient, anxious, and anhedonic-like with sex-specific differences in distribution. Early markers, including body weight and ultrasonic vocalization (USV) patterns, were linked to long-term susceptibility. Neuroanatomical analyses identified sex-specific LC-NE activation patterns associated with resilient and susceptible phenotype, particularly within the caudal-dorsal LC. These findings highlight sex-dependent behavioural trajectories of ELS that are associated with distinct LC-NE activation patterns, offering insights into potential interventions targeting resilience mechanisms in children exposed to CA.