伏隔核介导慢性疼痛-睡眠障碍共病的神经环路机制研究

慢性疼痛患者常伴有睡眠障碍，睡眠障碍患者往往也遭受着慢性疼痛折磨，共病严重损害人类健康。有研究表明伏隔核不仅介导疼痛还参与睡眠/觉醒调控，但是伏隔核是否介导慢性疼痛-睡眠障碍共病？其机制还不清楚。合作团队前期研究发现，腹侧被盖区至伏隔核通路介导疼痛。预实验发现伏隔核疼痛神经元在觉醒时异常兴奋，激活这些神经元促进觉醒，提示这些疼痛神经元也是促觉醒神经元。神经示踪发现这些疼痛-觉醒神经元投射至控制睡眠的关键脑区-视前区。我们推测：当发生慢性疼痛或睡眠障碍时，来自腹侧被盖区传入通路过度兴奋伏隔核疼痛-觉醒神经元，这些过度激活的GABA能神经元进而过度抑制视前区睡眠神经元，导致慢性疼痛-睡眠障碍恶性循环。我们将利用c-fos-tTA转基因小鼠，结合在体多通道光电极记录、光/化学遗传学及动物行为学，研究伏隔核介导慢性疼痛-睡眠障碍共病的环路机制，为慢性疼痛-睡眠障碍的临床治疗和药物研发提供科学依据。

Patients with chronic pain often complain of significant sleep disturbance, and those with sleep disorders often suffer from chronic pain. The comorbidity of chronic pain and sleep disorders seriously threaten human health. However, the underlying mechanisms are largely unknown. Studies have shown that the nucleus accumbens (NAc) not only mediates pain but also participates in sleep-wake regulation. However, whether the NAc is involved in the comorbidity of chronic pain and sleep disorders and the underlying neural circuits remains to be elucidated. Our previous studies indicate that the ventral tegmental area (VTA) to NAc pathway has been implicated in chronic pain. Our preliminary data show that the pain neurons in NAc exhibite extremely higher activities preferentially during wakefulness. Optogenetic activation of these neurons induces immediate transitions from non-rapid eye movement sleep to wakefulness. Collectively, these data indicate that these pain neurons are typical wake-active neurons. Moreover, these pain-wake neurons directly project to the preoptic area, which is a hub region for controlling sleep. Based on these, we hypothesize that, when chronic pain or sleep disturbance occurs, the pain-wake neurons in NAc are over-activated through VTA-NAc projection, subsequently inhibit sleep neurons in POA by the inhibitory projection from NAc to POA, leading to a vicious cycle of chronic pain and sleep disorders. In the present study, by taking advantage of c-fos-tTA transgenic mice, we will systematically investigate the precise role of NAc and the neural circuits in the comorbidity of chronic pain and sleep disorders by using in vivo optrode recordings, optogenetics, chemogenetics and animal behavioral tests. Together, these studies will help understand the neural substrates of the comorbidity of chronic pain and sleep disorders. The findings will provide a scientific basis for new medicine discovery and clinical therapies for patients with chronic pain and sleep disorders.