抑郁症患者常伴有维生素D（VitD）缺乏，而较低的VitD水平与抑郁症发病是否有关仍存在争议。前期我们首次在抑郁大鼠模型脑内发现VitD通路紊乱，并进一步证实VitD缺乏加剧了应激引起的抑郁样行为，但其作用机制仍亟待阐明。BDNF/NGF与抑郁症发病密切相关，而它们只有通过tPA酶解成熟才能起到神经营养作用。VitD不仅会诱导BDNF/NGF生成，同时能调控PAI-1/tPA的活性与表达。因此，我们推测VitD的抗抑郁活性可能与其对PAI-1/tPA和BDNF/NGF的网络调控有关。为验证该假设，我们拟通过补充或耗竭大鼠体内VitD，随后给予应激造模，分析VitD水平和抑郁样行为之间的相关性，并在整体和细胞水平考查VitD对神经营养因子网络的调控作用，最后通过阻断相应受体，确证VitD的抗抑郁机制。本课题旨在进一步阐明VitD神经活性的同时，也为探索抑郁症的病理机制及防治策略提供新的思路。

Depressive patients are prone to have suboptimal vitamin D (VitD) status, whereas the association between the insufficient VitD status and the development of depression is still controversial. Recently, we firstly found the altered VitD signaling in the brain of the animal models of depression, and further showed that VitD deficiency exacerbates the stress-induced depression-like behaviors in rats. However, the underlying mechanisms remain elusive. There is accumulating evidence that neural atrophy in the limbic brain areas regulated by BDNF and NGF are closely linked to the onset of depression. However, BDNF/NGF can exert their neurotrophic effects only after cleaved by tPA. Interestingly, VitD not only can induce BDNF/NGF expression, but also can modulate PAI-1/tPA system. Thus, there is a great possibility that the antidepressant properties of VitD might be mediated by its modulating effects on the neurotrophic PAI-1/tPA and BDNF/NGF system. To test this hypothesis, we plan to give rats VitD deficient or VitD sufficient diet, after which the rats will be exposed to the stress paradigm, and the association between VitD status and behavioral changes will be analyzed. We decide to further investigate the regulatory effects of VitD on the neurotrphic network both in vivo and in vitro, and through blocking the relative receptors, the mechanisms underlying the neuroprotective and antidepressant properties of VitD would be confirmed. This project will further illuminate the neural activities of VitD, and provide novel insight into the pathological mechanisms and preventive strategies for depression.