神经肽VGF作为新型抗抑郁调节因子在抑郁症中的调节作用及机制研究

Depression is a common mental disorders.With the research in depression shifting from monoamine hypothesis to the realm of neurotrophic hypothesis, neural plasticity hypothesis and enhancing neurogenesis as an antidepressant-like agent, an emerging research that may bring crucial insights to find novel mediator of antidepressant activity. We have demonstrated that cAMP signaling regulated neuropeptide VGF,brain-derived neurotrophic factor (BDNF)and neurogenesis playing anti-depressive effect. Our preliminary data also showed that therapeutic actions of antidepressant have been related to increases the expression of BDNF and VGF, and these increases are also thought to be involved in the regulation of depression. VGF as the common target of cAMP signaling and antidepressant may be the candidate mediator of antidepressant activity. However, the regulation of VGF on BDNF,synaptic activity,neurogenesis are not known. There also need to be more detailed under of VGF expression during the course of prototypical antidepressant and depression. We propose to conduct animal studies designed including stressed paradigms, transgenetic animals and VGF knock out mouse in vivo and NPCs, primary hippocampal neurons in vitro to understand the regulation of VGF on depression.Our results may contribute to clarify the regulation of VGF on depression and to bring new insights to find new strategies in antidepressant development.

抑郁症作是一种常见精神障碍疾病。伴随对该病发病机制由单胺递质假说向神经营养、神经可塑性及神经发生假说的转变，为发现新型抗抑郁治疗手段带来机遇。我们研究发现cAMP信号通路通过调节脑源性神经营养因子（BDNF），神经肽VGF（非缩写形式）及神经发生功能发挥抗抑郁作用，且抗抑郁药物上调了VGF及BDNF的表达。VGF作为cAMP信号通路及抗抑郁药物的共同作用靶标有望成为新型抗抑郁调节因子。但VGF对BDNF、突触活动、神经发生及在抗抑郁中的调节机制尚不清楚，且有必要进一步明确VGF在抑郁中的调节作用。本项目将采用应激动物模型、转基因动物及基因敲除动物作为整体动物模型明确VGF在抗抑郁中的作用,并采用神经前体细胞系及原代海马神经元作为离体模型进一步阐明VGF在抑郁症中的调节机制。本项目将为明确VGF在抑郁中的调节作用及探索新型抗抑郁策略带来希望。

神经肽VGF作为一种新型抗抑郁调节因子在抑郁样行为，海马突触可塑性及神经发育中发挥重要调控作用。但是，有必要对VGF的作用分子标靶及其介导的下游分子信号通路参与抗抑郁的分子机制进一步明确。首先，我们证实了神经肽VGF基因敲除显著下调了小鼠海马神经发育并伴随认知功能障碍及抑郁样行为。有趣的是VGF敲除显著阻断了抗抑郁剂（Fluoxetine及Ketameine）的抗抑郁作用；其次，我们证实神经肽VGF C-末端衍生肽TLQP-62（用N末端四位氨基酸残基的长度命名）通过调控BDNF/TrkB/CREB信号通路在抗抑郁中发挥作用，表明神经肽VGF的抗抑郁作用可能依赖于BDNF介导的信号转导通路；再次，我们首次报道了神经肽VGF及PI3K/AKT/mTORC1信号转导通路参与GLYX-13快速抗抑郁作用。尤其值得关注的是，β-淀粉样蛋白1-42 （Aβ1-42）、慢性应激（CUS）、脂多糖(lipopolysaccharide,LPS)及Vgf-shRNA均可以显著诱导海马内神经肽VGF表达的下调从而诱导认知功能障碍及抑郁样行为。而上调VGF的表达可有效逆转动物的认知缺陷及抑郁样行为，表明VGF可能是认知功能与抑郁行为的共同调控因子。最后，我们对PI3K/AKT/BDNF/VGF信号通路参与乙酰基肉碱(acetyl-L-carnitine, ALC)抗抑郁作用以及cAMP(cGMP)/CREB/BDNF/VGF信号通路参与磷酸二酯酶抑制剂在认知功能障碍，抑郁样行为中的调控作用及机制进行了研究。总之，我们的研究不仅仅证明了调控VGF的上游分子靶标，而且对VGF下游信号通路进行了率先研究，为发现以VGF为靶标的新型抗抑郁及认知障碍的干预策略提供了新的思路。