脑干NE能和5-HT能神经元对急慢性痒的下行调控

Itch (pruritus) is a known complication in chronic dermatitis, diseases of the liver and kidneys, and also in certain neurological and psychiatric disorders. Itch,and chronic itch in particular, is a poorly treated medical condition that greatly affects the quality of life, thus emphasizing the importecne of the ongoing investigation into the mechanism of itch. Recent literatures have demonstrated that sensation of pain and itch are experienced through different molecular mechanisms and transmission pathways at the spinal cord level. Locus coeruleus and rostral ventromedial medulla of brainstem, rich in norepinephrine and serotonergic neurons, has been shown to be an essential center for the descending modulation of pain, but its modulating effects on itch are still unclear. In our study, the Cre-inducible recombinant AAV vectors carrying optogenetic transgenes will be microinjected into conditional knock out mice to specifically control norepinephrine and serotonergic neurons. Combined with the methods of electrophsciology, immunohistrochemistry, pharmacology and behaviorology ,the descending modulating effects of these two neurons along with the neuronal and molecular mechanisms that they have on acute and chronic itch will be investigated.

痒是临床慢性皮肤病、肝肾疾病，神经和精神疾病非常常见的并发症，因缺乏有效的治疗手段，痒尤其是慢性痒严重影响了患者的身心健康。因此对痒觉机制的深入研究尤为重要。近年采用基因敲除等方法已在脊髓水平证明痒和痛由不同的神经机制介导。脑干的蓝斑和延髓头端腹内侧部是调控疼痛的重要脊髓上中枢，但是脑干是否对痒具有调控作用目前还一无所知。已知蓝斑和延髓头端腹内侧部是去甲肾上腺素（NE）能和5羟色胺（5-HT）能神经元汇聚的脑区，能特异地操控这两类神经元的活动、研究他们对痒觉的调控作用，对于揭示痒觉的神经机制具有重要意义。本项目拟采用光遗传学技术将光敏感通道特异地标记在NE能和5-HT能神经元内、并以相应波长的激光兴奋或抑制这两类神经元，结合传统的研究方法，研究脑干NE能和5-HT能神经元对急慢性痒的下行调控及其作用机制。该研究不仅有助于揭示痒的脊髓上神经机制，还将为临床治疗痒提供新的思路和手段。

痒是临床常见的症状，严重影响人们的身体健康和生活质量。虽然近年来痒的神经机制的研究具有突破性的进展，但是对于脊髓以及脊髓以上的机制了解甚少。而脑干对痒的下行调控还未见报道。我们用行为学、形态学、电生理学和光遗传学的手段研究了急慢性痒的脊髓分子机制，证明脊髓背角ERK的磷酸化参与组胺诱发的急性痒和DNFB诱发的慢性痒。同时我们成功操控了脑干蓝斑核的去甲肾上腺素神经元，并对脊髓急慢性痛和痒的下行调控进行研究。实验结果显示兴奋蓝斑去甲肾上腺素能神经元对热痛具有双向调节作用，而对于组胺依赖的痒具有显著增强作用。而这种增强作用与去甲肾上腺素a2受体有关。我们目前已经建立结合光遗传的多通道神经元电活动记录系统，接下来将对痛和痒下行调控的神经网络进行研究。