深部脑刺激治疗抑郁症模型大鼠的作用机制研究

It is important to find safe and effective treatment for treatment-resistant depression (TRD). Many clinical trials have proven deep brain stimulation (DBS) at several different brain targets in TRD patients can effectively relieve depressive symptoms. However, its mechanism of action remains unknown. BDNF plays critical roles in the neuronal survival, differentiation and synaptic plasticity. Previous studies have shown that abnormalities of BDNF-TrkB signaling pathway in the hippocampus and ventral tegmental area (VTA)-nucleus accumbens (NAc) may contribute to the development of depression. Accordingly, we hypothesize that DBS may exert their therapeutic effects through regulating BDNF-TrkB signaling pathway in the hippocampus or VTA-NAc, which is associated with the brain region that electrodes are implanted, and finally result in increased adult hippocampal neurogenesis. To verify this hypothesis, the present study will use DBS to treat chronic unpredictable stress (CUS)-induced depression model rats at two proven effective brain targets in TRD patients, ventromedial prefrontal cortex (vmPFC) and NAc, respectively. We will also use in vivo knockdown or overexpression of BDNF in the hippocampus and VTA to directly explore the role of BDNF-TrkB signaling pathway in antidepressant effects of DBS and related mechanisms. This study will provide the experimental theory for clinic application of DBS to treat depression.

难治性抑郁症（TRD）的治疗是临床工作中亟待解决的问题。多项临床研究表明在不同脑区进行深部脑刺激（DBS）均能有效改善TRD患者的抑郁症状，但相关机制尚不清楚。BDNF广泛参与神经元的存活、分化以及突触可塑性的调节，以往研究表明海马或腹侧被盖区（VTA）-伏隔核（NAc）的BDNF-TrkB信号通路异常可导致抑郁的发生。据此，我们推测DBS可能通过调节上述脑区的BDNF-TrkB信号通路发挥疗效，不同刺激部位影响的靶区不同，而最终途径可能是增强了海马的成体神经再生。为验证上述假说，本研究拟采用慢性不可预知性应激大鼠抑郁模型，选取临床实验已证实有效的刺激部位腹内侧前额叶皮层和NAc分别进行DBS治疗，并利用慢病毒载体分别对海马和VTA进行BDNF过表达或敲减，通过行为学、形态学、分子生物学等手段阐明BDNF-TrkB信号通路在DBS治疗抑郁症中的作用，为DBS的临床应用奠定理论基础。

难治性抑郁症（treatment resistant depression, TRD）的治疗是临床工作中亟待解决的问题。多项临床研究表明在不同脑区进行深部脑刺激（deep brain stimulation, DBS）均能有效改善TRD患者的抑郁症状，但相关机制尚不清楚。海马和腹内侧前额叶皮层（vmPFC）之间的神经元通信可能在与抑郁相关的情绪过程中起重要作用。本项目比较了低强度的高频刺激（HFS，130 Hz，100μA）和高强度的低频刺激（LFS，20 Hz，400μA）两种常用的vmPFC刺激模式对自由活动的慢性不可预知应激（CUS）抑郁大鼠的海马和vmPFC的网络震荡的影响。我们发现vmPFC高频或低频刺激1小时对CUS大鼠具有明显的抗抑郁样作用。对局部场电位（LFP）震荡结果的分析表明，CUS大鼠基线的β和γ震荡显著低于正常对照。vmPFC高频和低频刺激均能引起正常和CUS大鼠海马的自发振荡增加，尤其是β和γ震荡。并且，高频和低频刺激均可增加自由活动大鼠的海马和vmPFC之间的β和γ震荡的同步化活动。此外，高、低频刺激在抗抑郁样效应和对LFP震荡的影响方面没有差异。这些结果表明，高频和低频DBS可能具有共同的抗抑郁机制，其中vmPFC和海马中β和γ震荡的同步化增加可能有助于改善抑郁样行为。另一方面，本项目从突触超微结构、神经递质以及信号通路等角度对低频DBS的作用机制进行了深入的探索。我们发现DBS能够显著增加CUS大鼠海马的突触数目，维持突触结构的完整；提高海马5-羟色胺和去甲肾上腺素的含量；并增强PFC和海马的mTORC1信号通路。