Acute and chronic gene expression activation following medial forebrain bundle DBS and selective dopamine pathway stimulation

Deep brain stimulation (DBS) of the medial forebrain bundle (mfb) demonstrated anti-depressant effects both clinically and experimentally. Modulation of mesocorticolimbic dopaminergic (DA) activity could contribute-in part-to the therapeutic effects. By comparing selective and pathway specific midbrain DA optogenetic stimulation with the global, non-pathway specific mfb-DBS, the study explored changes in gene-expression of key biomarkers associated with neurocircuitry of depression. Rats received either optogenetic DAergic or mfb-DBS, delivered as acute/single or chronic/repeated stimulation. Micro-dissected regions were prepared for in situ hybridization targeting biomarkers of GABAergic, glutamatergic, and dopaminergic systems. Mfb-DBS mediated DA independent pathway increased GABAergic biomarkers (GABAA, GAD1) in frontal and accumbal regions, not in midbrain. The combinations of low frequency/high pulse width and high frequency/low pulse width stimulation generally increased biomarker expression similarly, but chronic/repetitive stimulation had no accumulative effect. Interestingly, unilateral stimulation had bilateral effects, but stimulation modalities had little impact on DAT and Vglut2 expression. In conclusion, both low and high frequency, acute/single and chronic/repetitive mfb-DBS-but not selective optogenetic stimulation -activated gene expression of biomarkers associated with GABAergic transmission. The increased expression was transitory and less chronic than predicted. Importantly, the study provides evidence that the anti-depressant therapeutic effects of clinical medial forebrain bundle DBS occurs-in part-be via modulation of GABAergic signalling which in turn could regulate the release of dopamine in frontal and accumbal regions. In addition, clinical implication of the data is that unilateral stimulation had bilateral consequences on the gene expression, although the physiological and functional sequelae of this are yet unknown.