Amygdalar Modulation of Medial Prefrontal Cortex Neuronal Subtypes Orchestrates Stress-induced Depressive-like Behavior

Abstract

Aberrant interactions between the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) are a hallmark of major depressive disorder (MDD), yet the underlying circuit-level mechanisms remain poorly defined. Here, I identify a pathway by which hyperactivity in the BLA suppresses prefrontal excitatory output via recruitment of local inhibitory interneurons. Using anatomical tracing and immunohistochemistry, I confirmed robust glutamatergic projections from the BLA to the mPFC. Optogenetic stimulation of BLA terminals in the mPFC induced pronounced depression-like behaviors, including behavioral despair and anhedonia, whereas chemogenetic silencing of mPFC GABAergic neurons significantly attenuated these effects. Chronic activation of BLA excitatory neurons recapitulated core behavioral and physiological features of depression, characterized by reduced activity of mPFC excitatory neurons and enhanced recruitment of local inhibitory neurons, as shown by in-vivo calcium and ex vivo electrophysiological recordings. Further analyses identified a subset of mPFC interneurons expressing cholecystokinin (CCK) as key mediators of this circuit, as targeted inhibition of these cells was sufficient to reverse depression-like behaviors. Together, these findings delineate a cell-type-specific circuit through which amygdala hyperactivity disrupts prefrontal excitatory-inhibitory balance, providing mechanistic insight into affective dysfunction in depression.

Date of Award	12 Dec 2025
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Jufang HE (Supervisor)