“Braking” the Prefrontal Cortex: The Role of Glucocorticoids and Interneurons in Stress Adaptation and Pathology

The medial prefrontal cortex (mPFC) receives information regarding stimuli and appropriately orchestrates neurophysiological, autonomic, and behavioral responses to stress. The cellular and neurochemical heterogeneity of the mPFC and its projections are key to fine-tuning of stress responses and adaptation. Output of the mPFC is mediated by glutamatergic pyramidal neurons whose activity is coordinated by an intricate network of interneurons. Excitatory/inhibitory (E/I) balance in the mPFC is critical for appropriate responsiveness to stress, and E/I imbalance occurs in numerous neuropsychiatric disorders that co-occur with chronic stress. Moreover, there is mounting data suggesting that chronic stress may precipitate E/I imbalance. This review will provide information regarding the cellular and anatomical makeup of the mPFC and discuss the impact of acute and chronic stress in adulthood and early life on interneuron function, with implications for E/I balance affecting functional connectivity. Specifically, the review will highlight the importance of interneuron type, connectivity, and location (both layer- and subregion-specific). The discussion of local mPFC networks will focus on stress context, including stressor duration (acute vs. chronic) and timing (early life vs. adulthood), as these factors have significant implications for the interpretation of experiments and mPFC E/I balance. Indeed, interneurons appear to play a prominent role in prefrontal adaptation, and a better understanding of the interactions between stress and interneuron function may yield insight to the transition from adaptation to pathology. Ultimately, determining the mechanisms mediating adaptive versus pathologic plasticity will promote the development of novel treatments for neuropsychiatric disorders related to prefrontal E/I imbalance.