NORADRENERGIC MODULATION OF STRESS RESILIENCE AND SUSCEPTIBILITY IN LEARNED HELPLESSNESS

Stress is a major risk factor for depression and related mood disorders. Individual variability in behavioral outcomes following stress exposure suggests that neuromodulatory control systems play a critical role in determining whether stress leads to adaptive coping or maladaptive affective outcomes. The locus coeruleus-noradrenergic (LC-NE) system is a central regulator of adaptive responses to aversive stimuli, but whether region-specific NE dynamics contribute to stress resilience or susceptibility remains unclear. To address this question, we combined fiber photometry, genetic and chemogenetic manipulations in mice exposed to a learned helplessness paradigm. Real-time calcium activity in LC-NE neurons and extracellular NE release in the mPFC and amygdala were monitored during inescapable shock training and subsequent escape testing. Behavioral performance during escape trials (latency and failure rate) was subjected to k-means clustering to classify animals as stress-resilient or stress-susceptible. At the circuit level, resilient and susceptible mice displayed marked differences in LC activity and region-specific NE dynamics, quantified as area under the curve of photometry signals. In parallel, we used mice with VMAT2 depletion selectively in dopamine-β-hydroxylase-expressing neurons, effectively abolishing vesicular NE release. These mice exhibited more rapid extinction of the susceptible phenotype compared to wild-type controls. Consistently, acute chemogenetic inhibition of LC-NE neurons via DREADDs significantly reduced escape failures relative to sham-treated animals, promoting a resilient behavioral profile. Together, these findings provide insights into the role of noradrenergic signaling in shaping behavioral responses to stress and advance our understanding of neuromodulatory mechanisms implicated in stress-related disorders.