Neural oscillations in the nucleus accumbens-dorsal hippocampal circuits and behavioral effects of acute fluoxetine administration during the Tail suspension test in mice.

Major depressive disorder (MDD) involves dysregulation of limbic circuits mediating stress and reward processing. While selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine typically require chronic administration for clinical efficacy, preclinical studies suggest that a single dose can rapidly modulate neural activity and produce antidepressant-like effects. The present study examined the effects of a single oral dose of fluoxetine (20 mg/kg) on behavioral and neural dynamics in mice undergoing the tail suspension test (TST), a validated paradigm of despair-like behavior. Electrodes were implanted in the nucleus accumbens (NAc) and dorsal hippocampus (dHP), and LFPs were recorded during resting and TST conditions. Behavioral assessments demonstrated that fluoxetine increased locomotor activity during resting and significantly reduced immobility during TST. Spectral analysis revealed that fluoxetine enhanced high-frequency gamma oscillations in the NAc and dHP during both mobility and immobility states, while attenuating stress-induced reductions in gamma power observed in the control group. Coherence analysis indicated that fluoxetine enhanced NAc-dHP functional connectivity, particularly in theta and low gamma bands, during both rest and TST. These effects were state- and region-specific, suggesting selective modulation of mesolimbic-hippocampal circuits. Collectively, these findings demonstrate that acute fluoxetine administration alters neural dynamics associated with behavioral despair and supports the hypothesis that early network-level changes contribute to the antidepressant-like effects observed in preclinical models. This work highlights oscillatory biomarkers and circuit-level targets relevant to fast-acting antidepressant responses.