NF-κB/SDF-1炎性应答系统在焦虑症形成中的作用与机制研究

It is evidenced that inflammatory response system are involved in the pathogenesis of anxiety disorder, as well as the disfunction of gamma-aminobutyric acid (GABA), a critical inhibitory neurotransmitter in the central nervous system. Stromal cell-derived factor (SDF-1), a CXC chemokine, has been reported taking part in the regulation of neurotransmitter release, however, the roles of SDF-1 in the mechanisms of anxiety development and neural networks are still unclear. Our data showed that two receptors of SDF-1, CXCR4 and CXCR7, were expressed in GABAergic neurons in basolateral amygdala; SDF-1 increased significantly in anxiety animal brain and was regulated by nuclear factor-κB (NF-κB). Perfusion of amygdala brain slice with SDF-1 antagonist, AMD3100, promoted the excitability of the GABAergic neurons, therefore enhanced the inhibitory neural transmission, implicating the inflammatory response of NF-κB/SDF-1 may take part in the development of anxiety by regulating neurotransmitter release and neural networks in amygdala. Therefore, we hypothesize that inflammatory response system of NF-κB/SDF-1 regulate GABAergic inhibitory neural transmission and precipitate anxiety development. In this study, we will combine techniques and methods including electrophysiology, molecular biology and behavior tests to investigate the relationship between the inflammatory response of NF-κB/SDF-1 and GABAergic inhibitory neurotransmission in anxiety development. To the end, this study will shed light on the ways and theory basis for anxiety pathological mechanisms and potential drug targets.

炎性应答系统参与焦虑症的发生，中枢抑制性神经递质GABA功能紊乱亦可致病。已证实基质细胞衍生因子（SDF-1）参与调节神经递质释放，但在焦虑症发病中的作用尚未明确。我们发现杏仁核基底外侧核GABA能抑制性神经元表达SDF-1受体CXCR4及CXCR7；焦虑动物脑内SDF-1表达升高，且受核转录因子NF-κB的调控。SDF-1拮抗剂AMD3100灌流杏仁核脑片，可显著增强GABA能神经元兴奋性，加强GABA受体介导的抑制性传递，提示NF-κB/SDF-1炎症应答通过调节杏仁核神经递质释放和神经网络功能参与焦虑症发病。本项目首次提出杏仁核NF-κB/SDF-1信号对GABA抑制性传递调节的异常参与焦虑症的发生，拟结合电生理、分子生物学和行为学研究方法，探讨杏仁核NF-κB/SDF-1与GABA能抑制性传递的关系。课题研究结果将为深入研究焦虑症的病理机制和发掘药物作用新靶点提供依据。

本项目结合电生理、分子生物学和行为学研究方法，旨在探究杏仁核NF-κB/SDF-1信号对GABA抑制性传递调节的异常参与焦虑症的发生。我们的研究证实，腹腔注射LPS可诱导小鼠焦虑样行为改变，同时，小鼠海马、杏仁核以及血浆中SDF-1急剧升高，脑内星型胶质细胞激活。体外实验证实，星型胶质细胞是LPS刺激下SDF-1生成的主要细胞来源。杏仁核BLA内立体定向注射SDF-1，可诱发动物焦虑样行为改变，预先给予受体CXCR4拮抗剂AMD3100，则能改善SDF-1和LPS诱发的动物焦虑样行为，但AMD3100不影响/降低LPS引起的血和脑内SDF-1含量的增加。给予AMD3100或shCXCR4，能够改善SDF-1诱发的小鼠筑巢行为受损。杏仁核基底外侧核GABA能抑制性神经元表达SDF-1受体CXCR4及CXCR7，电压钳模式下记录SDF-1灌流脑片，可显著增加由AMPA受体介导的sEPSC频率；然而，预先孵育AMD3100可逆转SDF-1诱导的增加的sEPSC频率。同时，无论SDF-1孵育或AMD3100预浴均不影响该sEPSC振幅。本研究结果表明，SDF-1通过其受体CXCR4增加的杏仁核锥体神经元兴奋性。更进一步，我们采用国际上公认的用于焦虑症研究的动物模型——SPS模型，即连续单一应激（SPS），发现SPS焦虑小鼠杏仁核NF-κB、SDF-1表达增高且SDF-1的表达受NF-κB的调节。本项目研究结果确定了杏仁核炎性应答系统NF-κB/SDF-1功能异常或对GABA抑制性递质调控作用的紊乱，参与了焦虑症的病理发生过程，探讨以NF-κB、SDF-1受体为药物作用位点，探索治疗焦虑症的新策略。课题研究结果将为深入研究焦虑症的病理机制和发掘药物作用新靶点提供依据。