Stress and medial prefrontal cortex: Sex-dependent effects in rodent models

Chronic stress significantly alters rodent medial prefrontal cortical (mPFC) structure and function, contributing to cognitive and affective dysfunction associated with stress-related psychiatric disorders. Although the effects of stress on the male mPFC have been extensively characterized, growing evidence demonstrates that females exhibit distinct behavioral, structural, and molecular responses to chronic stress. This review synthesizes current findings regarding sex differences in stress-induced plasticity within the adult mPFC, discussing the behavioral outcomes, activation, and neural plasticity of the region in response to stress exposure. Across stress paradigms, males generally exhibit earlier dendritic retraction, spine loss, and impairments in cognitive flexibility, whereas females often demonstrate delayed mPFC effects despite persistent affective behavioral deficits. Emerging evidence suggests that females may recruit compensatory inhibitory mechanisms, particularly through parvalbumin neuron activation, that transiently buffer pyramidal cells from stress-induced remodeling. In contrast, stress in males may influence mPFC structure and function via somatostatin interneuron signaling, glucocorticoid receptor-mediated pathways, and microglial-dependent synaptic remodeling. However, sex differences are strongly influenced by stress modality, duration, and intensity, which contributes to variability across studies. Despite this variability, patterns in the literature suggest that males and females recruit distinct mPFC mechanisms in response to stress. Improved understanding of sex-specific stress adaptations may inform the development of targeted interventions for stress-related psychiatric disorders.