NAcLat-DBS reduces GABA_B expression of dopamine neurons to correct depressive symptoms in CMS mice

Hypodopaminergic activity within the mesolimbic circuitry is recognized as a typical characteristic in severe and refractory depression. Deep brain stimulation (DBS) of the nucleus accumbens (NAc) has shown therapeutic potential for treatment-resistant depression (TRD), yet its underlying molecular mechanism remains incompletely defined. We used chronic mild stress (CMS) combining fiber photometry recording, pharmacological interventions and genetic manipulations in freely moving mice to examine the variation of dopamine (DA) activity in the ventral tegmental area (VTA) and the potential roles of GABA_B receptor (GABA_B) in mediating the effects of lateral nucleus accumbens shell (NAcLat)-targeted DBS. We performed in vivo fiber photometry recordings to track glutamatergic inputs onto the VTA after NAcLat-DBS. Immunofluorescence and in situ hybridization techniques were used to unravel GABA_B1 expression of the DA and GABA neurons in the VTA. The results have determined that long-term NAcLat-DBS decreases DA GABA_B1 expression and alleviates depressive-like behaviors in CMS mice. Importantly, selective overexpression of DA GABA_B1 in VTA-NAcLat pathway reversed the behavioral benefits of DBS. This reduced DA GABA_B1 expression was necessary for the antidepressant effects of DBS. Further, pharmacological blockade of GABA_B by CGP reproduced the antidepressant effects of DBS in CMS mice. Mechanistically, the enhanced excitation of glutamatergic input in the VTA involved in correcting dopaminergic activity and potentially involved in GABA_B expression alteration during NAcLat-DBS. These findings identify a previously unrecognized role of GABA_B in mediating the antidepressant outcome of NAcLat-DBS and suggest that modulation of the DA GABA_B1 in VTA-NAcLat pathway could represent a pharmacological target for treatment-resistant depression.