Deep brain stimulation in experimental stress animal model of depression

Abstract

INTRODUCTION: Deep brain stimulation has been proposed as a potential therapy for patients with treatment-resistant depression. In this study, we investigated the effects of high-frequency stimulation (HFS) in specific brain regions on various depressive-like behaviors using the stress resilience and vulnerable rat depression models. METHODS: Animals were exposed to chronic unpredictable stress procedures (CUS) and tested for depressive-like behaviors after receiving HFS in the lateral habenula, ventromedial prefrontal cortex (vmPFC), and nucleus accumbens. Vulnerable and resilience animals were characterized based on their sucrose consumption levels during CUS procedures. The investigation on changes of midbrain dopaminergic and serotonergic neurons, and hippocampal neuroplasticity were performed using both molecular and immunohistological labeling methods. RESULTS AND DISCUSSION: Our results demonstrated that electrical stimulation targeting specifically the vmPFC, most effectively treats symptoms of mood-related behaviors, as compared to several potential antidepressant stimulated-brain regions. Further, our results have shown that it could also be used to enhance the growth of brain cells in the hippocampus, which mitigates the harmful effects of dementia-related conditions and improve the learning and memory functions in object recognition and Morris water maze tests. Our data showed a remarkable increase of hippocampal neural progenitors, surviving BrdU-positive cells, and dendritic arborization after vmPFC stimulation as compared to the sham. Interestingly, vmPFC HFS also rescued the stress-induced midbrain dopamine neuron degeneration, as well as evoked a specific brain circuitry modulation of the serotonergic pathway, which linked to the dorsal raphe nucleus in regulation of mood-related and hippocampal-dependent memory behaviors. Overall, our results suggest that vmPFC HFS effectively restores depressive-like behaviors by mechanisms of hippocampal neuroplasticity, serotonergic neurotransmission, and dopaminergic neurons restoration in the vulnerable CUS-induced model. Further studies are needed to understand the underlying mechanisms of HFS on the resilience and vulnerable group of CUS-induced depression models.