Role of the locus coeruleus noradrenergic system in susceptibility and resilience following early life stress in male and female mice

BackgroundChild 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 the role of the locus coeruleus-norepinephrine (LC-NE) system, a critical modulator of stress, cognition, and emotion, in mediating resilience and susceptibility following early life stress (ELS). MethodsUsing a maternal deprivation model combined with limited nesting and bedding, we examined behavioral, physiological, and neurobiological markers associated with ELS outcomes in mice of both sex. ResultsBehavioral clustering revealed distinct phenotypes: resilient, anxious, and depressive-like with sex-specific differences in distribution. Early markers, including body weight and ultrasonic vocalization (USV) patterns, predicted long-term susceptibility. Neuroanatomical analyses identified sex-specific LC-NE activation patterns associated with resilience and susceptibility, highlighting the caudal-dorsal LC as a critical region in males and females in different phenotypes, anxious in males and resilient in females. ConclusionThese findings highlight the impact of ELS on the LC-NE system and its role in shaping adaptive and maladaptive trajectories, offering insights into potential interventions targeting resilience mechanisms in children exposed to CA.