γ神经网络振荡在深部脑刺激改善抑郁症状中的作用研究

Studies have shown that deep brain stimulation (DBS) can effectively improve the symptoms of patients with depression, but the specific mechanism is not clear, which may be related to the neuronal activity. The gamma oscillations mediated by the intermediate neurons are involved in the synaptic regulation and are regulated by several neurotransmitters. Clinical studies suggested that the decrease of gamma oscillations in the brain of the depressive patients was associated with the severity of depression. We also found that the gamma oscillations in the prefrontal cortex and hippocampal significantly decreased in the depression model rats. Accordingly, we hypothesize that DBS promote the antidepressant effects through the increase of gamma oscillations to increase synaptic plasticity by maintaining the homeostasis of neurotransmitters. In this study, we verify the antidepressant effect of DBS through various behavioral tests in normal and depressive rats. We used in vivo multi-channel recording technology to observe the effect of DBS on gamma oscillations, and used molecular biology technology to observe the effect of DBS on synaptic function. We further define the role of gamma oscillations in the effect of DBS by increasing the emotion related brain region gamma oscillation (photo genetic technology) or blocking the gamma oscillation (GABA receptor antagonist) to explore the mechanism of DBS. We studied the mechanism of the oscillatory and synaptic function of the gamma neural network in the antidepressant effect of DBS from molecular cell to whole level, and provided a new perspective for the targets of DBS.

深部脑刺激(DBS)能有效改善抑郁症患者的症状，但机制不明。研究表明DBS可影响神经元同步化活动，与参与突触调节的γ振荡关系密切。临床研究提示抑郁患者脑中γ振荡减少，其减少程度与抑郁的严重程度有关。我们前期发现抑郁模型大鼠前额叶皮层和海马γ振荡相比正常大鼠明显减少。据此我们假设DBS对抑郁症状的改善有可能通过增加脑区间γ振荡并促进突触可塑性来实现的。本研究拟采用正常和抑郁模型大鼠，在整体水平上通过动物行为学方法验证DBS的抗抑郁作用；在器官水平上通过在体多通道记录明确DBS对γ振荡的调节作用；在细胞水平上通过分子生物学方法观察DBS对突触功能的影响。并进一步通过增加情绪相关脑区γ振荡（光遗传技术）或者阻断γ振荡（γ-氨基丁酸受体拮抗剂）的方式明确γ振荡在DBS治疗中的作用，探讨DBS的作用机制。本研究为DBS的作用靶点提供新视角，为DBS的临床应用提供客观依据。

大约四分之一的抑郁症患者抗抑郁药治疗无效，是临床工作中亟待解决的问题。我们前期的研究结果提示深部脑刺激（deep brain stimulation, DBS）能显著改善抑郁模型动物的抑郁样行为，但机制不清。海马和腹内侧前额叶皮层（vmPFC）之间的神经元γ频率同步化活动（γ振荡）调控的突触传递可能在与抑郁相关的情绪过程中起重要作用。本项目通过在慢性不可预知应激（CUS）抑郁大鼠中记录DBS刺激前后不同时间内vmPFC-海马通路神经元电活动探索DBS抗抑郁的作用机制。我们发现4周的DBS刺激具有显著的抗抑郁作用，且能改善抑郁模型大鼠的学习和记忆能力。对局部场电位（LFP）震荡结果的分析表明，模型大鼠的vmPFC和海马中γ振荡显著低于正常大鼠，急性（1小时）的DBS刺激能瞬时显著增加γ振荡，加强神经元的同步化活动。γ-氨基丁酸受体拮抗剂抑制γ振荡后，DBS的抗抑郁作用减弱，这证明了vmPFVC-海马通路的γ振荡是DBS抗抑郁的重要机制。4周的DBS刺激能改善抑郁模型大鼠海马中的兴奋-抑制失衡，降低谷氨酸并增加γ-氨基丁酸的含量，改善突触损伤，增加突触数目。但DBS对vmPFC和海马中的γ振荡增加作用持续时间有限，在DBS停止24小时后无显著的增加作用，这提示DBS抗抑郁及突触改善作用可能存在其它的机制。为此，本项目进一步分析DBS是否通过mTORC信号通路发挥作用。结果显示，4周DBS治疗显著增加了模型大鼠海马中BDNF/Akt/mTOR信号通路的表达。这些结果提示vmPFC-海马通路的γ振荡以及BDNF/Akt/mTOR信号通路是DBS的抗抑郁及改善认知的重要机制，可能在DBS的急性以及长期抗抑郁中发挥作用。这为DBS对瞬时神经元活动的调节乃至信号通路的长期变化提供了理论依据。

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