蓝斑核糖皮质激素受体GR和腹外侧视前核GABA能系统参与慢性高皮质酮水平诱导抑郁形成机制研究

The etiology of depression is not fully understood. Sleep disorders may play an important role in the development of depression. And that depression can aggravate the sleep disorder symptoms. Improvement of sleep quality may alleviate symptoms of depression, promote rehabilitation and it is of great importance to prevent recurrence. Therefore, the study of the relationship between sleep disorders and depression not only is helpful to find the new treatment of depression, but also conducive to find effective precautionary measures. In recent study, we found rats revealed significant sleep disturbance and depression trend after 7 days treatment of corticosterone( CORT), meanwhile, the glucocorticoid receptor (GR) level was notably lowered in locus coeruleus (LC). We further discovered the activation of noradrenergic neuron in LC, the suppression of GABAergic neuron in ventrolateral preoptic area (VLPO). Microinjection of GR antagonist RU486 into LC reversed the CORT-induced sleep changes. These results suggest that GR in LC and GABAnergic in VLPO may play the key roles in stress-related sleep disorders. We also observed that after 21 days administration of CORT that mimicked the chronic stress caused high CORT level, induced depression and co-morbid with sleep disorders. These results suggested that the LC-GR and VLPO-GABAnergic system may participated in the chronic high CORT level induced depression. Therefore, we focused on the LC-GR and VLPO-GABA circuit, to investigate the novel etiological mechanism from a new perspective and to find a new way for the treatment of depression co-morbid with sleep disorders.

抑郁形成机制，目前尚不十分清楚。睡眠障碍在抑郁症形成过程中起重要作用。睡眠质量的改善对缓解抑郁症状，促进康复，防止复发具有重要的意义。本课题组前期发现，在连续7天给与皮质酮（CORT）所致睡眠障碍和抑郁形成趋势，与蓝斑核（LC）中糖皮质激素受体（GR）下调以及腹外侧视前核（VLPO）γ-氨基丁酸 (GABA) 能系统活性下降相关。在LC中定位注射GR拮抗剂，可逆转睡眠障碍和抑郁形成趋势。而连续给与CORT 21天，模拟慢性应激所致高皮质酮水平状态，可诱导形成抑郁伴发睡眠障碍模型。提示，LC-GR及VLPO-GABA能系统，有可能参与了慢性高皮质酮水平诱导的伴发睡眠障碍的抑郁形成过程。本课题将以LC-GR及VLPO-GABA能系统为切入点，探索伴发睡眠障碍的抑郁形成机制网络，为发现新的治疗抑郁途径和方法，提供科学实验证据。

抑郁形成机制，目前尚不十分清楚。睡眠障碍在抑郁症形成过程中起重要作用。睡眠质量的改善对缓解抑郁症状，促进康复，防止复发具有重要的意义。本课题组前期发现，在连续7天给与皮质酮（CORT）所致睡眠障碍和抑郁形成趋势，与蓝斑核（LC）中糖皮质激素受体（GR）下调以及腹外侧视前核（VLPO）γ-氨基丁酸 (GABA) 能系统活性下降相关。在LC中定位注射GR拮抗剂，可逆转睡眠障碍和抑郁形成趋势。而连续给与CORT 21天，模拟慢性应激所致高皮质酮水平状态，可诱导形成抑郁伴发睡眠障碍模型。提示，LC-GR及VLPO-GABA能系统，有可能参与了慢性高皮质酮水平诱导的伴发睡眠障碍的抑郁形成过程。本课题以LC-GR及VLPO-GABA能系统为切入点，探索了伴发睡眠障碍的抑郁形成机制。研究发现：1）反复注射皮质酮(CORT)确实会使啮齿动物产生抑郁样行为；2）长期饮用皮质酮引起的抑郁样行为依赖于时间的改变而变化；3）与抑郁相关5-HT能中缝背核Ca2+通过内源性睡眠-觉醒调节通路促进大鼠觉醒；4）安神中药远志有效成分远志皂苷改善睡眠障碍机制与LC-VLPO通路相关；5）天然抗抑郁剂粉防己碱（tetrandrine, TET）改善SHR大鼠睡眠障碍的机制与LC-VLPO-下丘脑通路相关；6）散发型AD模型鼠睡眠障碍与抑郁行为与LC无关，而与VLPO、臂旁核、侧颜区GABA能系统相关；7) LC中的黑色素聚集激素受体R1（Melanin-Concentrating Hormone，MCH) 可能参与了抑郁行为的形成；8) 天然抗抑郁剂人参皂苷Rg1促眠作用可能与LC-NE及DRN-5-HT能系统相关；9) DRN及VLPO中的5-HT能系统可能参与了SHR大鼠睡眠障碍的形成过程。研究为发现新的治疗抑郁途径和方法，提供了科学实验证据。