mPFC脑区OAT1膜蛋白参与调控抑郁症睡眠障碍的作用与机制的研究

抑郁症发病率较高，严重者导致功能性残疾或死亡。但我们对抑郁症尚未完全认识，影响了对其有效治疗。研究证实睡眠障碍在抑郁症中占据核心地位，从睡眠障碍来研究抑郁症发病机制提供了新的角度。我们前期工作证实了内侧前额叶皮质mPFC在生理睡眠觉醒及药理麻醉苏醒中发挥重要作用，提示mPFC在病理抑郁症睡眠障碍中也可能发挥作用。我们进一步工作发现在抑郁症睡眠障碍中mPFC内的应激激素调控膜蛋白OAT1的表达明显降低，并与抑郁症睡眠障碍症状之间存在相关性，但其在疾病发生发展中的具体作用和机制还不清楚。我们拟综合应用形态、分子、电生理和化学遗传学等方法，详细描述OAT1在mPFC的表达以及在应激压力下的表达变化，阐述OAT1表达变化对抑郁症睡眠障碍和情绪障碍的影响，研究OAT1对mPFC神经元形态和相关环路功能的调节作用，探讨OAT1发挥行为调控作用的分子神经机制。本课题将为抑郁症的诊治提供新靶点和新证据。

The incidence of depression is high, with severe cases leading to functional disability or death. Our absence of fully understanding of depression affects the effective treatment. It has been confirmed that sleep disturbances play a central role in depression, which inspires us to study the pathogenesis of depression from sleep disturbances. Our previous work has proved that medial prefrontal cortex (mPFC) plays important roles in physiological sleep-wake behavior and arousal from pharmacological general anesthesia, which suggests that mPFC may also play a role in pathological sleep disturbances during depression. Our further work found that the expression of the stress hormone-regulating membrane protein OAT1 in mPFC significantly decreased in sleep disturbances during depression and was correlated with sleep disorder symptoms. However, the specific role and regulating mechanism of OAT1 in the development of the disease was still unclear. We will apply integrated methods of morphology, molecular biology, electrophysiology and the chemical genetics, to detail OAT1 expression in mPFC and the changes of OAT1 expression while facing stresses, to illustrate the effects of OAT1 expression changes on sleep disturbances and mood disorders, to study the role of OAT1 in regulating the morphological changes of mPFC neurons and the function of mPFC-related neural circuits, to explore the molecular neural mechanisms of OAT1 in regulating behaviors. This study will provide new targets and new evidence for the diagnosis and treatment of depression.