Depression: Synaptic mediation in sleep deprivation

描述（由申请人提供）： 本项目旨在确定突触粘附蛋白（SAP）、神经连接素和神经毒素是否介导睡眠剥夺（SD）和药物治疗的抗抑郁作用。虽然一些抗抑郁药物是治疗抑郁症的有效方法，但这些治疗方法的疗效仍有待提高。目前，只有三分之一的急性“纯”重性抑郁症患者在一线抗抑郁药单药治疗后获得缓解。多达三分之二的重度抑郁症患者对第一种药物没有反应。更重要的是，抗抑郁药的有益效果通常不会在治疗的几周内发生。这使得治疗在最初几周内耐受性较差，许多患者停止治疗。然而，根据过去30年的研究累积的证据，SD立即改善情绪，但不知道SD和抗抑郁治疗之间的作用机制和差异。 我们推测，恢复正常的前额叶皮层突触兴奋性和神经胶质之间的平衡， 而neurexins在SD、orexins和SSRI治疗逆转抑郁症状中起关键作用。我们进一步假设，神经连接素1表达的抑制可能会消除SD和食欲素的即时抗抑郁作用和慢性SSRI治疗的抗抑郁作用。 这项拟议的项目将在三个具体目标方面进行研究。目的1研究SAP在抑郁模型中的差异表达。我们已经发现，在新生儿暴露于氯丙咪嗪诱导的抑郁症大鼠模型中，神经连接素和neurexins的改变不同。为了进一步确定SAP在抑郁症的病理学和抗抑郁作用的调节中的潜在影响，我们建议在具有不同遗传背景的抑郁症大鼠模型和小鼠模型中检查SAP。目的2比较SD、食欲素和氟西汀对抑郁症模型大鼠SAP的影响。我们将首先比较通过温和处理的SD的短期效果与通过食欲素的SD的短期效果以及氟西汀的急性效果。其次，我们将比较氟西汀与食欲素长期治疗对行为和SAP的影响。我们将确定是否SAP，特别是，neuroligins和neurexins在抑郁症模型中的差异调节。目的3：研究神经连接素1 siRNA对SD、食欲素和氟西汀诱导的抗抑郁作用的影响。我们将利用neuroligin-1 siRNA来改变前额叶皮质中neuroligin 1的表达，并测量小鼠前额叶皮质中抑郁行为和抑郁病理学生物标志物，以观察食欲素和百忧解诱导的手动SD和SD的影响。治疗。

DESCRIPTION (provided by applicant): This project is to determine if synaptic adhesive proteins (SAPs), neuroligins and neurexins mediate the antidepressive effects of sleep-deprivation (SD) and drug treatments. Although some antidepressant drugs are effective treatments for depressive disorders, the efficacy of these treatments remains to be improved. Currently only one-third of patients with acute "pure" major depression achieve remission after the first-line antidepressant monotherapy. Up to two-thirds of patients with major depression do not respond to the first medication. More importantly, the beneficial effect of antidepressants usually does not occur within the few weeks of the treatment. This makes the treatment less tolerated during the first few weeks, and many patients discontinue treatment. However, SD improves mood immediately according to cumulative evidence in last 30 years of research without knowing the mechanisms and the difference for the effect between SD and antidepressant treatment. We hypothesize that restoration of normal prefrontal cortical synaptic excitability and the balance between neuroligins and neurexins plays a critical role in the reversal of depression symptoms by SD, orexins and SSRI treatment. We further hypothesize that the suppression of neuroligin 1 expression may eliminate the immediate antidepressive effect of SD and orexins and the antidepressive effect by chronic SSRI treatment. This proposed project will conduct studies in three specific aims. Aim 1 will determine the differential expression of SAPs in rodent models of depression. We have found that neuroligins and neurexins are altered differently in a rat model of depression induced by neonatal exposure to clomipramine. To further define the potential impact of SAPs in the pathology of depression and the regulation of antidepressive effects, we propose to examine SAPs in a rat model and mouse model of depression with different genetic background. Aim 2 will compare the alterations of SAPs in a rat model of depression among treatments with SD, orexins and fluoxetine. We will first compare the short-term effects of SD by gentle handling to that of SD by orexin and the acute effect of fluoxetine. Secondly, we will compare effects of long-term treatment with fluoxetine vs. orexin on behavior and SAPs. We will determine if SAPs, especially, neuroligins and neurexins are differentially regulated in depression models. Aim 3 will determine the effect of neuroligin 1 siRNA on SD, orexins and fluoxetine induced antidepressive effects. We will utilize neuroligin-1 siRNA to alter the expression of neuroligin 1 in the prefrontal cortex and to measure depressive behaviors and biomarkers of depressive pathology in the pre-frontal cortex in mice regarding the effects of manual SD and SD induced by orexins and fluoxetine treatment.