ROLE OF THE LOCUS COERULEUS NORADRENERGIC SYSTEM IN SUSCEPTIBILITY AND RESILIENCE FOLLOWING EARLY LIFE STRESS IN MALE AND FEMALE MICE

Child adversity (CA), including emotional, physical, and sexual maltreatment, affects a large proportion of children worldwide and represents a major risk factor for psychiatric disorders such as major depressive disorder (MDD), anxiety, and suicidal behavior. However, despite the strong association between CA and later psychopathology, outcomes are highly heterogeneous, with a subset of individuals exhibiting resilience. Resilience is a dynamic adaptive process that can buffer the long-term consequences of early adversity, yet the underlying protective mechanisms remain poorly understood. In this study, we investigated the involvement of the locus coeruleus–norepinephrine (LC–NE) system, a key regulator of stress responses, cognition, and emotional processing, in mediating vulnerability and resilience following early life stress (ELS).
We employed a mouse model combining maternal deprivation with limited nesting and bedding to assess behavioral, physiological, and neurobiological correlates of ELS in both males and females. Behavioral clustering identified distinct outcome phenotypes: resilient, anxious, and depressive-like with sex-specific differences. Early-life indicators, including body weight and ultrasonic vocalization profiles, were predictive of long-term susceptibility.
Neuroanatomical analyses revealed sex-dependent patterns of LC–NE activation associated with resilience and vulnerability. In particular, the caudal-dorsal region of the LC emerged as a key region, linked to anxious phenotypes in males and resilient phenotypes in females.
Together, these findings demonstrate that ELS induces enduring, sex-specific alterations in the LC–NE system that shape adaptive and maladaptive behavioral trajectories. This work provides novel insight into neurobiological mechanisms of resilience and suggests potential targets for interventions in vulnerable populations exposed to CA.