利用光遗传学技术研究VTA内GABA能神经元在抑郁症发生中的作用

Major depression is a common mood disorder, and the underlying mechanism is not fully understood. Recent reports have shown that depression was associated with decreased activity of dopaminergic (DA) neurons in the ventral tegmental area (VTA). Moreover, there are abundant GABA neurons in the VTA, and their function is not determined. Previous studies indicated that stimulation of the GABA neurons in the VTA induced suppression of DA neurons, and led to behavioral aversion and reward ablation. However, the role of GABA neurons of the VTA in depression is still unknown. In the current project, the relationship of the activity of GABA neurons in the VTA with depression will be studied on a rat model of depression, by combination use of optogenetic, behavioral and electrophysiological tools. This study will discover the significance of GABA neurons of the VTA in depression, and provides new strategies for the treatment of depression.

抑郁症是一种常见的情感障碍疾病，目前其发生机制尚未明确。近年来一些研究表明，中脑奖赏环路腹侧被盖区（VTA）多巴胺能（DA）神经元兴奋性降低与抑郁症的发生密切相关。VTA内还有丰富的γ-氨基丁酸能（GABA）神经元，它们在抑郁症发生中的作用还未阐明。已有文献报道，兴奋VTA区GABA神经元可抑制VTA的DA神经元，使动物出现躲避、奖赏抑制等行为，但抑郁症中，是否由于VTA内GABA神经元兴奋而抑制DA神经元、引起抑郁样症状还有待研究。本课题拟在大鼠抑郁症模型上，研究VTA内GABA神经元的兴奋性变化；进一步利用光遗传学手段调控大鼠VTA区GABA神经元兴奋性，结合行为学和电生理技术，观察对大鼠抑郁样行为及VTA脑区DA神经元活动的影响，明确VTA内GABA神经元兴奋性变化在抑郁症发生中的意义，从新的角度阐明抑郁症的发病机制，并为抑郁症的治疗提供新策略和新方向。

抑郁症的发生与脑内单胺类神经递质5-羟色胺（5-HT）功能低下密切相关，然而5-HT功能低下引起抑郁症的神经环路机制还不清楚。外侧缰核（LHb）是一个与奖赏密切相关的脑区，它的兴奋引起奖赏躲避行为。已有报道5-HT神经元集中的脑区中缝背核（DRN）与LHb存在解剖和功能上的联系，而这一神经环路在抑郁症发生中的作用尚未明确。本研究利用大鼠慢性不可预知中度应激（CUMS）模型发现，模型鼠LHb脑区兴奋性升高。LHb接受来自DRN的5-HT能投射，该DRN-LHb投射通过突触前机制抑制LHb神经元的兴奋性。利用光遗传学技术兴奋DRN-LHb投射，可减轻CUMS模型鼠的抑郁样行为；而抑制DRN-LHb投射，则通过兴奋LHb脑区诱导大鼠抑郁样行为。本研究表明抑郁行为与DRN的5-HT能神经兴奋性降低、LHb兴奋性升高有关，而兴奋DRN-LHb投射可减轻抑郁行为，这为明确抑郁症相关的神经环路及开发可能的治疗靶标提供了依据。