腺苷酸环化酶3介导痛厌恶情绪反应的非突触机制

Long ignored as traditional organelles, primary cilia have gradually attracted the attention of researchers due to its non-synaptic modulation in recent years. Ciliary dysfunction can results in numerous human diseases. The type 3 adenylyl cyclase (AC3), widely known as a key enzyme, is highly and specifically expressed in cilia throughout the brain. Combined studies of human Genome-wide association study (GWAS) and transgenic mice have implying that AC3 is strongly related with negative emotion. Our previous studies have demonstrated that, AC-cAMP/PKA signaling pathway in the rACC is necessary for pain-related aversion. Whether AC3 in primary cilia mediates cAMP signaling, thereby contributes to pain emotion is unknown. In this project, using molecular biological assays, morphological stainings, electrophysiological recordings, as well as behavioral surveys, we will uncover the possible non-synaptic mechanisms underlying pain-related aversion modulated by AC3 and elucidate the molecular players that are involved in AC3 function. Our proposed study will provide new insights of non-synaptic mechanisms in CNS and a potential drug target site to combat chronic pain.

神经细胞初级纤毛是一种长期被忽视的细胞器。近年来，对它的非突触调控引起了研究者的关注。越来越多的证据表明神经细胞初级纤毛的异常与很多疾病密切相关。腺苷酸环化酶3（AC3）是一种特异性表达在初级纤毛中的激酶,来自人类全基因组关联研究、动物遗传学的实验表明AC3与焦虑/抑郁等负性情绪密切相关。我们前期的系列研究证明前扣带皮层中AC-cAMP/PKA信号通路参与痛厌恶情绪的形成。那么，初级纤毛中的AC3是否介导cAMP信号通路、进而介导痛厌恶情绪反应？为此，本项目拟利用AC3flox/flox小鼠，结合动物行为学、分子生物学、形态学以及电生理学等实验手段，揭示AC3介导痛厌恶情绪形成的非突触机制，明确纤毛内参与调控AC3的相关受体和递质/调质等。通过本课题研究，我们将启动对神经系统非突触机制的重新认识和全面解析，同时，也将为慢性痛的综合治疗提供新的靶点和理论依据。

神经细胞初级纤毛是一种长期被忽视的细胞器。近年来，对它的非突触调控引起了研究者的关注。越来越多的证据表明神经细胞初级纤毛的异常与很多疾病密切相关。腺苷酸环化酶3（AC3）是一种特异性表达在初级纤毛中的激酶,来自人类全基因组关联研究、动物遗传学的实验表明AC3与焦虑/抑郁等负性情绪密切相关。本课题利用AC3flox/flox小鼠，结合动物行为学、分子生物学、形态学等实验手段，揭示了AC3介导痛相关负性情绪的非突触机制，明确纤毛内参与调控AC3的相关受体和递质/调质。我们的研究结果表明：AC3广泛表达在小鼠内侧前额叶皮层 (mPFC) 和前扣带皮层吻侧部 (rACC) 各种类型神经元的初级纤毛中；特异性敲除CaMK2α阳性的兴奋性神经元、SST阳性的中间神经元而非PV阳性的中间神经元中的AC3，小鼠表现出明显的焦虑/抑郁样行为；mPFC而非rACC中AC3介导了小鼠焦虑/抑郁样行为；5-HT6受体与AC3 共存于小鼠mPFC中，并调控AC3的表达；三叉神经慢性压迫（CION）模型小鼠2周后继发焦虑/抑郁样行为，同时mPFC中5-HT6受体表达下调；mPFC中给予5-HT6受体激动剂可以剂量依赖地缓解CION引起的焦虑/抑郁样行为；AC3是5-HT6R发挥缓解痛相关焦虑/抑郁样行为的关键下游分子。综上所述，内侧前额叶皮层神经元初级纤毛中5-HT6R-AC3信号通路是调控痛相关焦虑/抑郁样行为的重要非突触机制，该研究为揭示痛相关负性情绪的神经机制提供新的理论，同时也为慢性痛的综合治疗提供新的视角和可能靶点。.