Sharafuddin Khairuddin Wei Ling Lim Yasin Temel Lee Wei Lim



Electrical stimulation has been proposed as a potential therapy for patients with treatment resistant depression. In this study, we investigate the effects of highfrequency stimulation (HFS) in different brain regions on various depressive-like behaviors using the stress resilience and vulnerable rat depression models.


Rats were exposed to chronic unpredictable stress procedures (CUS) for 3 weeks. Vulnerable and resilience animals were characterized based on their sucrose consumption levels during CUS procedures. CUS-treated rats received HFS in the lateral habenula (LHb), ventromedial prefrontal cortex (vmPFC), nucleus accumbens (NAc) and they were tested for depressivelike behavioral experiments. The morphological changes of dopaminergic neuron and hippocampal neuroplasticity were determined by immunohistochemical labeling methods.


CUS exposure for 3 weeks increased number of animals (51%) exhibiting reduced sucrose consumption, separating the resilience and vulnerable group of CUS-induced model. CUS vulnerable sham animals demonstrated anxiety-like behavior, decreased motivation and increased immobility compared to that of the resilience group, implicating high susceptibility of vulnerable individuals to the CUS procedure. Interestingly, vmPFC HFS significantly reduced anxiety response, increased hedonia and motivation levels for food intake in the vulnerable group compared to the resilience group, while HFS in other brain regions did not show difference. HFS in vmPFC and LHb also showed reduced behavioral despair in both CUS vulnerable and resilience group. In histochemistry, our results demonstrate that vmPFC HFS rescued the stressinduced dopamine neuron degeneration in the dorsal raphe nucleus, as well as increased hippocampal neurogenesis of stress vulnerable animals.


These results suggest that vmPFC HFS effectively restores depressive-like behaviors by mechanisms of dorsal raphe dopaminergic neurons restoration and enhanced hippocampal neuroplasticity 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.


Supplementary Issue