Theta phase-targeted prefrontal stimulation modulates amygdala gamma oscillations and alleviates depressive-like...

Depression is a prevalent and treatment-resistant disorder often linked to dysfunctional communication between the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). A key mechanism involves impaired inhibitory control from the mPFC, leading to aberrant theta and gamma oscillations in the BLA. Although current treatments can partially ameliorate theta-band hyperactivity, persistently elevated gamma oscillations (70-120 Hz) remain a major therapeutic challenge.

We applied electrical stimulation targeted to the instantaneous phase of theta oscillations in the mPFC and tested its effects in rats with chronic unpredictable mild stress (CUMS) model of depression. During the open-field test, local field potentials from mPFC and BLA were recorded. Subsequent analyses included behavioral assessment, neural oscillation pattern, and phase-amplitude coupling.

The theta-phase-targeted stimulation of the mPFC significantly suppressed gamma oscillations in the BLA (70-120 Hz; p < 0.001). The intervention effectively reversed depressive-like behaviors across multiple paradigms. In contrast, control (non-phase-targeted) stimulation produced no significant behavioral improvement or modulation of BLA high-gamma power. Furthermore, theta-gamma phase-amplitude coupling between the mPFC and BLA was restored, indicating a normalization of cross-region interactions.

Our findings suggest that theta-phase-specific neuromodulation of the mPFC could represent a potential circuit-based therapy for depression, potentially by rectifying dysfunctional cross-frequency coupling.