Stress vulnerability in adolescent mice is characterized by a distinct neurotrophic imbalance in the amygdala and prefrontal cortex.

Abstract

Adolescence is a critical neurodevelopmental window characterized by heightened plasticity and increased vulnerability to affective disorders. Brain-derived neurotrophic factor (BDNF) signaling through its high-affinity receptor, Tyrosine Kinase B (TRKB), plays a central role in synaptic plasticity and stress adaptation. While dysregulation of TRKB signaling has been implicated in affective pathology, its region-specific association with stress vulnerability during adolescence remains poorly understood. Exposure to stress during this period yields highly heterogeneous outcomes, and the molecular profiles that distinguish vulnerability from resilience remain unclear. Using an unpredictable chronic mild stress (UCMS) paradigm in adolescent C57BL/6 mice, stressed animals were stratified into stress-resilient (S_RES) and stress-vulnerable (S_VUL) subgroups based on anxiety-like behavior. Our findings demonstrate that stress vulnerability is associated with a pronounced, region-specific dissociation in neurotrophic signaling, characterized by reduced expression of TRKB in the prefrontal cortex (PFC) alongside elevated TRKB expression in the amygdala. These alterations are accompanied by changes in BDNF expression and markers of stress reactivity and neuroinflammation. Multivariate analyses revealed that vulnerability and resilience are not defined by uniform stress-induced effects, but rather by distinct, system-level molecular configurations across corticolimbic circuits. These results suggest that a disrupted neurotrophic balance across the PFC and the amygdala is associated with stress susceptibility during adolescence. By demonstrating that vulnerability is linked with coordinated, region-specific molecular states rather than global dysregulation, this work advances a region-informed framework for understanding individual differences in stress outcomes and highlights potential targets for early intervention.