Deep brain stimulation improved depressive-like behaviors and hippocampal synapse deficits by activating the BDNF/mTOR signaling pathway

ABSTR A C T Our previous study demonstrated that acute deep brain stimulation (DBS) in the ventromedial prefrontal cortex (vmPFC) remarkably improved the depressive-like behaviors in a rat model of chronic unpredictable mild stress (CUS rats). However, the mechanisms by which chronic DBS altered depressive-like behaviors and reversed cognitive impairment have not been clarified. Recent work has shown that deficits in brain-derived neurotrophic factor (BDNF) and its downstream proteins, including mammalian target of rapamycin (mTOR), might be involved in the pathogenesis of depression. Therefore, we hypothesized that the antidepressant-like and cogni-tive improvement effects of DBS were achieved by activating the BDNF/mTOR pathway. CUS rats received vmPFC DBS at 20 Hz for 1 h once a day for 28 days. After four weeks of stimulation, the rats were assessed for the presence of depressive-like behaviors and euthanized to detect BDNF/mTOR signaling using immunoblots. DBS at the vmPFC significantly ameliorated depressive-like behaviors and spatial learning and memory deficits in the CUS rats. Furthermore, DBS restored the reduced synaptic density in the hippocampus induced by CUS and increased the expression or activity of BDNF, Akt, and mTOR in the hippocampus. Thus, the antidepressant-like effects and cognitive improvement produced by vmPFC DBS might be mediated through increased activity of the BDNF/mTOR signaling pathway.