dmPFC-vlPAG神经通路对慢性痛及其负性情绪的下行调控机制

Dorsal medial prefrontal cortex (dmPFC) including rostral anterior cingulate cortex (rACC) and prelimbic cortex (PL) is the nucleus involved into the pain related negative emotion. A few studies also suggest that dmPFC was related to the pain perception. However, the exact neural pathway coming from the dmPFC involved into the descending pain modulation has not been reported. The periaqueductal gray (PAG) is one of the most important nucleus involved into the descending pain modulation. Is there the possibility that dmPFC projecting to ventrolateral PAG (vlPAG) participates into the descending pain modulation, which is the most related division to pain in the PAG? Our morphological data has shown that the pyramidal neurons in the dmPFC projected to the vlPAG and made synapse with the neurons containing glutamate in the vlPAG. Moreover, specifically activating the dmPFC-vlPAG neural pathway produced obvious analgesic effects. Thus, our project will further confirm the neural pathway dmPFC-vlPAG and investigate the neurochemical properties of this pathway by using various kinds of morphological approaches. The local circuits and descending pathway in the vlPAG will also be revealed, which participate into pain modulation and negative emotion as a relay to dmPFC-vlPAG pathway. The synaptic plasticity of neurons projecting to the vlPAG and related molecular mechanisms in the dmPFC will also be investigated. At last, we would like to show that the dmPFC be the central nucleus involved into ‘chronic pain recycle’. Activation of dmPFC-vlPAG neural pathway might be a straight and useful therapeutic method to both alleviate chronic pain and rescue the anxiety/depression behaviors at chronic pain condition.

背内侧前额叶皮层（dmPFC）包括吻侧前扣带回皮层（rACC）和缘前皮层（PL），为产生疼痛相关负性情绪的重要脑区。既往报道其与疼痛的感知相关，但对于dmPFC参与疼痛下行调控神经通路的研究尚无报道。中脑导水管周围灰质（PAG）为内源性痛觉调控系统的中枢，其中PAG的腹外侧区（vlPAG）与痛觉的下行调控关系更加密切。我们的形态学研究已证实dmPFC内锥体神经元下行投射到vlPAG并与其内谷氨酸能神经元形成突触，功能学研究证实兴奋dmPFC-vlPAG通路可产生镇痛作用。本课题以dmPFC-vlPAG神经通路为研究对象，拟综合应用现代神经科学研究方法，探讨该通路的形态学特点和神经元基础，研究该通路在vlPAG内发挥镇痛作用的局部环路和下行通路，揭示dmPFC内向vlPAG投射神经元参与慢性痛的突触可塑性改变及其相关的分子机制。以期为慢性痛及其负性情绪的临床共治提供理论依据和作用靶标。

慢性痛对机体的危害不仅是持续的疼痛感受，还可导致情绪低落和认知功能的下降，而后负性情绪和认知下降又会进一步的加剧慢性疼痛，形成疼痛-负性情绪和认知下降-疼痛的恶性循环。目前，关于此“慢性痛后的恶性循环”的潜在神经机制仍不明确，而解决这一问题的关键是找到一个同时参与了疼痛的调控、负性情绪的形成和认知功能维持的神经核团。背内侧前额叶皮层（dmPFC）已经被证实广泛参与了焦虑抑郁负性情绪和认知功能障碍的产生，那么作为产生疼痛相关负性情绪和认知下降的dmPFC是否又是内源性易化疼痛的神经中枢，而参与了“慢性痛后的恶性循环”呢？本研究课题综合运用多种形态学方法证明dmPFC内含VGLUT1的兴奋性锥体神经元投射到腹外侧中脑导水管周围灰质（vlPAG）内的VGLUT2阳性神经元形成兴奋性的神经通路，这一通路可以通过从vlPAG发出的VGLUT2阳性的纤维终末正向调控延髓吻端腹内侧结构（RVM）内的5-HT神经元，从而形成从皮层到脊髓Top-Down的下行调控神经通路。运用光遗传学方法特异性地激活dmPFC-vlPAG神经通路产生镇痛和抗焦虑样作用。化学毁损双侧dmPFC或化学遗传学方法特异性兴奋dmPFC内的抑制性神经元间接沉默dmPFC-vlPAG神经通路，可降低动物正常时和慢性痛时的机械性痛阈值，增加动物对机械性刺激的反应，导致动物焦虑样负性情绪的产生，兴奋dmPFC内的抑制性神经元还可恶化慢性痛所致的负性情绪。慢性痛时dmPFC内GABAAR和mGluR1表达的上调能够抑制dmPFC-vlPAG下行镇痛通路，参与了慢性痛的发生、发展及负性情绪的形成。综上，作为感受慢性痛后负性情绪和认知下降的高级神经中枢dmPFC下行镇痛作用的减弱从而形成了“慢性痛后的恶性循环”。本研究对于揭示慢性痛难治不愈，提高疼痛患者的生活质量，指导慢性痛及其负性情绪的临床共治提供重要的理论和实验依据。