Adolescent and adult stress alter excitatory-inhibitory network dynamics in the medial prefrontal cortex

Abstract Stress is a major risk factor for psychiatric disorders, with the timing of exposure critically shaping its neural and behavioral consequences. Here, we investigated how stress during adolescence or adulthood affects neuronal activity and oscillatory dynamics in the medial prefrontal cortex (mPFC) of rats. Animals were exposed to a combined footshock and restraint stress protocol during adolescence (postnatal days PNDs 31 to 40) or adulthood (PNDs 65 to 74). In vivo electrophysiological recordings of putative glutamate pyramidal neurons, Gamma-Aminobutyric Acid (GABA) interneurons, and local field potentials were performed 1 to 2 and 5 to 6 wk post-stress to evaluate both short- and long-term effects. Adolescent stress induced increases in pyramidal neuron firing rates and sustained elevations in interneuron burst activity that persisted into adulthood, accompanied by long-lasting reductions in mPFC gamma oscillations. These alterations point to enduring disruptions in excitatory–inhibitory balance and impaired network coordination. In contrast, adult stress produced no persistent changes in pyramidal neuron activity but caused transient increases in interneuron excitability and selective reductions in theta oscillatory power, suggesting temporary inhibitory dysfunction. These findings highlight adolescence as a critical window during which stress triggers enduring, cell-type-specific changes in cortical circuitry, whereas changes induced by adult stress are transient, potentially reflecting recovery mechanisms. Collectively, our results underscore the importance of developmental timing in determining stress outcomes, providing mechanistic insight into how adolescent stress may contribute to long-lasting cortical dysfunction and psychiatric disease risk, and informing the timing of potential preventive or therapeutic interventions.