基于不同饲养环境下小鼠Kyn-AHR轴对内侧前额叶皮质突触可塑性的调控探讨“因于湿，首如裹”的病理机制

湿邪属中医外感六淫之一，其性重浊，致病后易出现头身困重、负面情绪等“首如裹”症状，极易兼夹他邪合而为病，导致病程缠绵难愈。但湿邪是如何导致抑郁样负面情绪的，其神经生物学机制仍缺乏深入研究。申请人既往研究发现，湿邪可导致肠道菌群代谢产物失衡，其差异代谢物显著富集于色氨酸代谢及突触功能相关通路，同时伴随内侧前额叶皮质（mPFC）Kyn-AHR信号轴、M1型小胶质细胞极化等明显改变。基于小胶质细胞对神经突触结构和功能可塑性的关键作用，我们推测：湿邪可下调色氨酸代谢产物Kyn水平，通过Kyn-AHR信号轴促进M1型小胶质细胞极化，导致mPFC突触可塑性障碍，进而造成湿邪致病“首如裹”的抑郁样行为。为验证该假说，本项目拟结合行为学、双光子在体成像等手段，研究湿邪通过Kyn及Kyn-AHR信号轴，对mPFC中M1型小胶质细胞极化、突触可塑性及抑郁样行为的调控机制，从而阐明“因于湿，首如裹”的病理机制。

In traditional Chinese medicine, damp evil is one of the six exogenous pathogens, which is heavy and turbid. Damp is the commonly-seen factor of gynecopathy and leads to drowsiness or negative emotions, like "head with binding sensation" symptoms. Damp is easy to clamp combine with other disease, leading to the course of the disease lingering and difficult to heal. However, how dampness causes depression-like neurological symptoms, the specific neurobiological mechanism is still unclear. According to the applicant's previous researches, we found that dampness can lead to the imbalance of metabolites of intestinal flora and the different metabolites are significantly enriched in the pathways related to tryptophan metabolism and synaptic function, accompanied by significant changes in the Kyn-AHR signal axis of the medial prefrontal cortex (mPFC) and the polarization of M1-type microglia. Microglia plays a key role in the structural and functional plasticity of synapses. On this basis, we speculated that dampness can down-regulate the expression of tryptophan metabolite Kyn and regulate the polarization of M1-type microglia mediated by the Kyn-AHR signaling axis, and then changed the synaptic plasticity of mPFC, leading to the depression-like behaviors of dampness. To test this hypothesis, the project combines with behavioral tests and two-photon in vivo imaging methods, so that we can research the damp environment regulates the polarization, synaptic plasticity and depression-like behaviors of M1-type microglia in mPFC through Kyn-AHR signal axis. Through the above experiments to clarify the pathological mechanism of "because of dampness, the head with binding sensation".