Chronic stress reconfigures microcircuits of prefrontal cortex via divergent remodeling of pyramidal neurons and...

Major depressive disorder (MDD) is a debilitating psychiatric condition associated with the dysfunction of the medial prefrontal cortex (mPFC). While the excitation-inhibition (E/I) imbalance is considered a hallmark of MDD, the precise cell-type-specific microcircuit remodeling and its consequences on network dynamics remain poorly understood.

We employed the chronic unpredictable mild stress (CUMS) paradigm to induce depression-like behaviors in mice. 16-channel microelectrode arrays were used to record single-unit activity and local field potentials (LFPs) in the mPFC of freely moving animals.

CUMS mice exhibited an aberrant E/I state, characterized by excitatory pyramidal neurons (PYR) hypoactivity with irregular firing and inhibitory interneurons (INT) hyperactivity with more regular firing. Circuit connectivity analysis indicated a specific reduction in putative PYR-INT excitatory connections, concurrent with an increased spike suppression probability in putative INT-PYR inhibitory connections in CUMS mice. At the population level, these cellular and connection changes were accompanied by a significant decrease in pairwise synchrony among PYR ensembles. Additionally, LFP recordings revealed frequency-specific alterations, including suppressed gamma (γ) oscillations and enhanced delta (δ) and beta (β) power.

Our findings delineate a sequential pathology where chronic stress disrupts the reciprocal PYR and INT microcircuit via decoupled excitation and enhanced inhibition, potentially contributing to the degradation of mPFC network coding. Restoring this specific connectional balance may represent a novel therapeutic strategy for depression.