慢性神经痛性失眠的神经生物学机制

Insomnia is a common problem for people with chronic neuropathic pain, and aggravate each other. However, there are no effective treatment ways because the mechanisms of sleep-wake regulation in chronic neuropathic pain are not clear. Therefore, the scientific question is what is the mechanism of insomnia with chronic neuropathic pain? It has been reported that anterior cingulate cortex (ACC) is closely involved in processing of pain, and has extensive connection with subcortical nuclei. Our preliminary study found that specific lesion of ACC pyramidal neurons partially decreased pain sensitivity, but completely abolished insomnia-induced by neuropathic pain. We hypothesize that ACC is a key brain region involved in insomnia with chronic neuropathic pain. In the present studies, we are going to explore the mechanisms of ACC on sleep-wake regulation under the conditions of physiological and chronic neuropathic pain using optogenetic and chemogenetic approaches, two-photo image, special anterograde and retrograde tracers, electrophysiological techniques, immunohistochemistry and automatic sleep bioassay systems. The expected results will clarify the key neurons in the ACC to regulate sleep-wake, and mechanisms of neural circuits and neural chemicals. The outcome of the proposal will shed light on the mechanisms for insomnia with chronic neuropathic pain, which in turn will aid in the development of novel treatment drugs.

失眠是慢性神经痛患者的常见并发症，失眠又加重疼痛感受。由于慢性神经痛性失眠的机制不明，临床缺乏有效对策。因此，揭示慢性神经痛性失眠的机制是重要的科学问题。前扣带回皮层（ACC）与疼痛密切相关，与皮层下许多核团存在广泛纤维联系。我们预实验发现特异性毁损ACC中锥体神经元，虽只部分减轻疼痛，但能完全消除慢性神经痛引起的失眠。因此，我们假说：ACC可能是调控慢性神经痛性失眠的重要脑区。本课题将采用光遗传学、化学遗传学、双光子成像、神经元损毁、特异性顺行和逆行神经纤维示踪、离体膜片钳和在体神经元放电记录、免疫组化等方法，结合睡眠记录解析平台，探索ACC在生理及慢性神经痛条件下对睡眠觉醒的调节机制。预期结果将揭示ACC调控睡眠觉醒的主要神经元类型、神经环路和神经递质等机制，对阐明慢性神经痛性失眠机制和开发其治疗新药具有重要价值。

前扣带回皮层（anterior cingulate cortex，ACC）与疼痛密切相关，与皮层下睡眠-觉醒核团存在广泛纤维联系，提示ACC可能是调控疼痛性失眠的重要脑区。采用坐骨神经部分结扎慢性神经痛模型鼠，利用光纤钙信号、光遗传学和化学遗传学、电生理膜片钳、特异性神经元示踪、脑电/肌电记录等方法，研究了ACC在生理及慢性神经痛条件下对睡眠觉醒的调节作用和机制。结果如下：（1）特异性激活ACC的GABA能中间神经元，增加小鼠脑电delta波功率并降低机械痛阈值；（2）特异性激活ACC锥体神经元促进觉醒；特异性毁损ACC锥体神经元增加睡眠量并升高痛阈；（3）ACC椎体神经元兴奋GABA能PV神经元，而PV神经元抑制ACC椎体神经元；（4）光遗传学激活ACC锥体神经元投射到背内侧纹状体（DMS）的末梢诱导觉醒；（5）抑制DMS D1R-MSNs可改善神经痛小鼠失眠症状，但不能缓解疼痛。（6）神经痛失眠小鼠降低ACC-DMS D1R-MSNs的突触功能。以上结果揭示了ACC调控睡眠觉醒的主要神经元类型和神经环路机制，可能为治疗疼痛性失眠提供新思路。