外侧下丘脑-PAG腹外侧区top-down神经环路调控慢性痛的作用机制研究

研究表明痛觉bottom-up上行传递系统的敏化和top-down下行抑制系统的失能协同加剧疼痛慢性化发展。近年来，尽管上行传递的敏化机制取得了长足进展，但下行抑制的调控环路和失能机制却尚未阐明。起自PAG的下行抑制通路介导痛觉调制的作用不言而喻，然而调控并驱动其慢性痛状态下功能下调的下行指令从何而来依然不清。我们最新预实验显示外侧下丘脑（LH）Parvalbumin神经元发出兴奋性投射至腹外侧PAG，激活或抑制该环路可缓解或诱致痛觉敏化。但是，其发挥下行痛觉调控的神经环路和介导慢性痛敏化的细胞分子机制尚不清楚。为此，本项目拟利用特异性Cre小鼠，结合嗜神经病毒标记、光遗传、钙成像、电生理及行为学等方法深入研究LH-PAG神经环路下行调控慢性痛的作用及机制，以期阐明其在top-down下行调控痛觉信息传递及慢性痛敏化中的功能意义，为研发针对外侧下丘脑的下行调控镇痛新策略提供重要的理论依据。

Accumulating evidence has shown that sensitization of bottom-up ascending pain pathways and impairment of top-down descending inhibitory pain system collectively contribute to the development of chronic pain. Despite major progress in the understanding of ascending pain sensitization, the exact neural circuits for descending inhibition and pathophysiological mechanisms for its deficiency in pathological states has remained elusive. Descending inhibitory pathways arising from periaqueductal (PAG) has been well known to be involved in pain modulation. However, which cortical or subcortical centers modulate descending pain inhibitory circuits derived from PAG and drove its abnormalities in chronic pain states has not been well understood. Our preliminary data demonstrated that parvalbumin-positive neurons in the lateral hypothalamus (LH) sends excitatory projections to ventrolateral PAG. Optogenetically stimulating PAG-projecting LH PV neurons eliminated pain hypersensitivity, and inhibiting these cells reversibly evoked pain sensitization. However, how individual LH PV neurons exert top-down control of pain modulation and by which underlying cellular and molecular basis is still an open question. To this end, by utilizing specific Cre mouse lines in combination with neurotropic virus-mediated tracing, optogenetics, calcium imaging, electrophysiology and behavioral surveys, the present study aims to explore how LH-PAG circuits exerts top-down modulation of chronic pain and its underlying mechanistic basis. Understanding the above questions may help to unravel the crucial role and functional significance of LH and its PV neurons in the top-down control of pain as well as pain chronicity. New insights derived from these advances are expected to expediate development of novel analgesic therapeutics acting at descending pain modulation system for the treatment of chronic pain.