Effect of Deep Brain Stimulation in The Ventral Tegmental Area on Neuronal Activity in Local and Remote Brain Regions in Kindled Mice

Objective: The mechanisms behind seizure suppression by deep brain stimulation (DBS) are not fully revealed, andthe most optimal stimulus regimens and anatomical targets are yet to be determined. We investigated the modulatoryeffect of low-frequency DBS (L-DBS) in the ventral tegmental area (VTA) on neuronal activity in downstreamand upstream brain areas in chemically kindled mice by assessing c-Fos immunoreactivity.Materials and Methods: In this experimental study, 4-6 weeks old BL/6 male mice underwent stereotaxic implantationof a unilateral stimulating electrode in the VTA followed by pentylenetetrazole (PTZ) administration every other dayuntil they showed stage 4 or 5 seizures following 3 consecutive PTZ injections. Animals were divided into control,sham-implanted, kindled, kindled-implanted, L-DBS, and kindled+L-DBS groups. In the L-DBS and kindled+L-DBSgroups, four trains of L-DBS were delivered 5 min after the last PTZ injection. 48 hours after the last L-DBS, mice weretranscardially perfused, and the brain was processed to evaluate c-Fos expression by immunohistochemistry.Results: L-DBS in the VTA significantly decreased the c-Fos expressing cell numbers in several brain areas includingthe hippocampus, entorhinal cortex, VTA, substantia nigra pars compacta, and dorsal raphe nucleus but not in theamygdala and CA3 area of the ventral hippocampus compared to the sham group.Conclusion: These data suggest that the possible anticonvulsant mechanism of DBS in VTA can be through restoringthe seizure-induced cellular hyperactivity to normal.