伏隔核Homer1a介导mGluR5信号调节慢性疼痛及相关抑郁样行为的研究

Chronic pain and depression always coexist in patients. But mechanism of this comorbidity is still unclear. Our previous research showed that AMPA receptors of synapse in the Nucleus Accumbens (NAc) can regulate chronic pain and chronic pain related depressive behaviors. Researches have showed that the short immediate-early gene (IEG) Homer1a can induce mGluR5 and mediate AMPA receptors to change neural exciting signaling transition. Our study showed that Homer1aKO made chronic pain related depressive behaviors worse. However, this chronic pain related depressive behaviors could be alleviated by Homer1a re-expression in NAc. Moreover, we found chronic pain related depressive behaviors changed expression of Homer1a in NAc. And Homer1a in NAc participated in mGluR5 signaling. According to previous study, we assume that Homer1a via mGluR5 regulating synaptic plasticity of AMPA receptors in NAc could modulate chronic pain related depressive behaviors in mice. Base on the model of chronic pain and related depressive behavior, behavior study, the molecular biology technology and IHC can be used to conform our hypothesis. Furthermore, with technology of gene regulation and neuro electrophysiology, we are going to explore the mechanism of Homer1a and mGluR5 is key to manipulate chronic pain and related depressive behaviors in NAc. This study can provide us a novel direction for clinical pain and related depression.

临床上疼痛和抑郁常常伴行, 但其发病机制仍不清楚。申请人前期研究发现伏隔核(NAc)突触AMPA受体有调节慢性疼痛及相关抑郁样行为的作用。鉴于即早基因（IEG）的表达产物Homer1a有介导mGluR5信号改变AMPA受体并进一步影响神经兴奋信号传导的作用，我们发现Homer1a基因敲除小鼠慢性疼痛相关抑郁样行为加剧，而在NAc重新表达Homer1a后该抑郁样行为明显缓解，进一步研究发现慢性疼痛及相关抑郁改变NAc内Homer1a的表达，且Homer1a密切参与mGluR5信号调节。综上所述，结合申请人前期实验结果，我们推测NAc内Homer1a通过mGluR5信号介导AMPA受体进行突触重塑是调节慢性疼痛相关抑郁样行为的分子机制。在成功构建慢性疼痛及相关抑郁模型的基础上，利用行为学、分子生物学、免疫组织化学、基因敲除和神经电生理技术验证该假说，为改善疼痛及相关抑郁提供新型治疗方向。

中文摘要：（背景）世界上约有四分之一的人口长期遭受慢性疼痛的折磨。长期疼痛的折磨使慢性疼痛患者常常出现情绪低落等抑郁症状。抑郁不仅会降低患者的治疗依从性，并对疼痛的预后也带来不良的影响，使慢性疼痛的治疗更具有复杂性和挑战性。谷氨酸被认为是中枢神经系统中最重要的兴奋性神经递质，其中。mGluR5是代谢性谷氨酸受体中重要的一种亚型，高度参与神经元兴奋性和突触传递。Homerla是一种短型Homer蛋白，即早基因（Immediately Early Gene, lEG）的表达产物，静息状态下表达相对较低而神经活动可诱导其快速而短暂的表达增加。Homer1a通过负反馈形式调节mGluR5信号改变进而影响神经元兴奋信号传导。（主要研究）发现：1.NAc中mGluR5信号的损伤是社会压力后行为适应性的突触特征。2. 分别恢复NAc壳区和核区的mGluR5信号表达可缓解CSDS诱导的抑郁样行为和痛觉过敏。3. 而NAc中mGluR5信号的的激活是通过内源性大麻素信号进行干预的。4. 在治疗层面，小剂量的艾司氯胺酮有缓解疼痛相关抑郁样行为的作用，但该剂量不影响机体的机械痛阈。5. 通过蛋白质组学定量技术体术，小剂量的艾司氯胺酮可以改变慢性疼痛大鼠PFC内mGluR5和Homer1a的表达。6.通过进一步验证，PFC内mGluR5和Homer1a的表达与小剂量艾司氯胺酮缓解疼痛相关抑郁样行为密切相关。（科学意义）mGluR5 及Homer1a分子信号通路在疼痛相关抑郁中的重要调节作用。并且在小剂量艾司氯胺酮的临床治疗方面提供了理论基础。为推动疼痛及抑郁相关治疗提供了可参考的分子基础。