Deep Brain Stimulation of Lateral Habenula Ameliorates Depression-like Symptoms in Rats: Involvement of Mesolimbic Circuit

Abstract

Deep brain stimulation (DBS) is a promising approach for the treatment of psychiatric disorders including depression, and various targets have been tested for their usefulness. Among these lateral habenula (LHb), a critical site linked to depression, has attracted considerable attention in recent years. DBS at LHb produced antidepressant activity by modulating the monoamine levels. However, the precise circuitry that mediates the positive effects have not been clarified. Herein we employed chronic unpredictable mild stress (CUMS) protocol to generate rats with depression-like phenotype. These animals showed (a) reduced sucrose intake and locomotion, (b) increased immobility in forced swim test, (c) reduction in GAD67 mRNA and increase in VGLUT2 mRNA in the LHb tissue, (d) an increase in glutamate and GABA level in the ventral tegmental area (VTA), and (e) reduction in dopamine in the microdialysates collected from nucleus accumbens shell (AcbSh). Application of DBS, targeted unilaterally at the LHb for 1 h each day for 14 days, resulted in reversal of almost all the above parameters suggesting anti-depressive like action. With a view to dissect the role of GABA in LHb, bicuculline (GABA-A receptor antagonist), administered intra-LHb to CUMS rats, reduced sucrose preference in spite of the application of DBS. We suggest that DBS at LHb may (a) upregulate GABAergic system in LHb, (b) reduce the control exercised by the LHb over VTA via glutamatergic system, and (c) upregulate VTA-Acb pathway. The series of changes finally leading to the increase in DA in Acb, may lead to anti-depressive action.