蓝斑-前边缘皮层环路在扩散性神经病理性疼痛与情绪障碍共病中的作用及机制研究

神经病理性疼痛（Neuropathic pain, NeuP）常引起情绪障碍共病，现有的药物治疗效果不佳，亟待寻找新的药物作用靶点和治疗策略。脑内蓝斑（locus coeruleus, LC）-去甲肾上腺素（norepinephrine, NE）系统密切参与痛觉和情绪调节，但其在NeuP-情绪障碍共病中的作用和环路机制尚不清楚。申请人前期建立了稳定的扩散性NeuP-情绪障碍共病的小鼠模型，发现模型小鼠LC神经元和接受LC-NE支配的前边缘皮层（prelimbic cortex, PrL）锥体神经元的兴奋性发生了改变，可能参与了NeuP-情绪障碍共病。本研究拟采用光遗传学和化学遗传学方法特异性追踪和调控LC-PrL环路，结合电生理学和药理学手段，阐明该环路中LC神经元和PrL锥体神经元在NeuP-情绪障碍共病中的作用和受体机制，为发现潜在的药物作用靶点和开发特异性治疗药物提供重要实验依据。

Neuropathic pain (NeuP) often leads to mood disorder or anxio-depression comorbidity, which is positively correlated with the pain severity and distribution. Pain abnormality and anxio-depression can enhance each other and the efficacy of pharmacological treatment is far from optimistic, thus decrease the life quality of patients dramatically. New targets for therapeutic approaches and strategy are urgently needed. Norepinephrine (NE) in the central nervous system is closely involved in the modulation of pain and mood. It is known that NE-ergic neurons are mainly located in the locus coeruleus (LC) and project to a wide array of brain regions. Previous studies revealed complicated changes in NE-ergic neurons in the LC after nerve injury, while their contribution to and related neural circuits in NeuP and anxio-depression comorbidity remain unknown. The applicant has been dedicated to the study of the pathogenesis and treatment of NeuP. The research group has established a reliable mouse model of NeuP and anxio-depression comorbidity, which is induced by partial infraorbital nerve transection (p-IONX). We preliminarily found that LC neurons and pyramidal neurons in the prelimbic cortex (PrL) changes their excitability after p-IONX. We also found that regulation of neuronal excitability of layer 2/3 pyramidal neurons in the PrL affected anxio-depressive behaviors in mice. Since PrL receives abundant NE-ergic projections from LC, we hypothesize that LC- PrL circuit may play a role in NeuP and anxio-depression comorbidity. The present proposal aims to elucidate systemically the activity changes of neurons involved in the LC- PrL circuit and their roles in NeuP and anxio-depression comorbidity, taking advantage of optogenetic and chemogenetic approaches to trace and modulate this circuit as well as electrophysiological and pharmacological techniques. Moreover, the contribution of different types of adrenoceptors will be also investigated in order to find potential therapeutic target (s) for the development of specific treatment in the future.