Modulation of Depression-like Behaviors by RASD2 through Regulation of Dopaminergic Signaling from the Rostral VTA to D1 Neurons in the NAc Shell

RASD2 (Rhes), a crucial modulator of striatal dopamine signaling, has established functions in the NAc core, yet its regulation of DRD1 circuits driven by the distinct rostral VTA (rVTA) within the functionally unique NAc shell (NAcs) remains undefined. To address this, using an unpredictable mild stress paradigm, we characterized this specific rVTA-NAcs pathway and identified RASD2 as a "molecular brake" compromised by stress. Stress downregulated RASD2, which released intrinsic inhibitory constraints and triggered an aberrant upregulation of the NAc DRD1-DARPP-32 signaling axis. Optogenetic stimulation of the rVTA-NAcs pathway restored phasic dopamine release and rescued depressive-like behaviors. Crucially, overexpression of RASD2 specifically in D1-expressing neurons recapitulated these antidepressant effects by normalizing the dysregulated DRD1-cAMP-PKA-DARPP-32 axis. Collectively, our results reveal RASD2 as a vital upstream regulator that maintains striatal signaling stability. Its stress-induced loss initiates a maladaptive cascade, while its restoration presents a promising therapeutic strategy for early-stage depression.