Depression: Synaptic mediation in sleep deprivation

抑郁症：睡眠剥夺中的突触介导

• 批准号: 8974290
• 负责人: PINGFU FENG
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974290
• 关键词: Acute; Adhesives; Affect; Animal Model; Antidepressive Agents; Behavior; Biological Markers; Brain; Caring; Chronic; Clinic; Clomipramine; Depressive disorder; Developed Countries; Developing Countries; Disease remission; Dose; Equilibrium; Exposure to; Fluoxetine; General Population; Genetic; Goals; Health; Healthcare; Human; Long-Term Effects; Major Depressive Disorder; Manuals; Measures; Mediating; Mediation; Mental Depression; Mental disorders; Modeling; Molecular; Mood Disorders; Moods; Mus; Pathogenesis; Pathology; Patients; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Play; Prefrontal Cortex; Prevalence; Proteins; Publications; Rattus; Regulation; Relapse; Reporting; Research; Rodent Model; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Single Nucleotide Polymorphism; Sleep; Sleep Deprivation; Small Interfering RNA; Symptoms; Synapses; Time; Treatment Efficacy; antidepressant effect; depression model; depressive behavior; depressive symptoms; differential expression; effective therapy; frontal lobe; genome wide association study; hypocretin; improved; inhibitor/antagonist; insight; mouse model; neonatal exposure; neuroligin 1; neuromechanism; patient population; prevent; restoration; reuptake; synaptic depression

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.

描述(由申请人提供)： 该项目旨在确定突触黏附蛋白(SAP)、神经连接蛋白和Neurexins是否介导睡眠剥夺(SD)和药物治疗的抗抑郁效应。虽然一些抗抑郁药物是治疗抑郁障碍的有效药物，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”重度抑郁症患者在一线抗抑郁药单一治疗后获得缓解。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，抗抑郁药物的有益效果通常不会在治疗后的几周内出现。这使得在最初的几周内对治疗的耐受性较差，许多患者停止治疗。然而，根据最近30年的研究积累的证据，SD可以立即改善情绪，但对SD和抗抑郁药物治疗的作用机制和差异尚不清楚。我们假设，正常前额叶皮质突触兴奋性的恢复和神经连接素之间的平衡 而Neurexins在SD、食欲素和SSRI治疗逆转抑郁症状中起着关键作用。我们进一步假设，抑制神经连接蛋白1的表达可能会消除SD和食欲素的即刻抗抑郁作用和慢性SSRI治疗的抗抑郁作用。这个拟议的项目将进行三个具体目标的研究。目的1确定SAPS在抑郁症啮齿动物模型中的差异表达。我们发现，在新生儿暴露于氯丙咪嗪所致抑郁的大鼠模型中，神经连接素和纽瑞辛的变化是不同的。为了进一步明确SAPS在抑郁症病理中的潜在影响和抗抑郁作用的调节，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测SAPS。目的2将比较SD、食欲素和氟西汀治疗大鼠抑郁模型后SAP的变化。我们将首先比较温和处理SD与食欲素治疗SD的短期疗效以及氟西汀的急性疗效。其次，我们将比较长期服用氟西汀和食欲素对行为和SAPS的影响。我们将确定SAP，特别是神经连接蛋白和神经毒素在抑郁症模型中是否受到不同的调节。目的3研究神经连接素1siRNA对SD、食欲素和氟西汀抗抑郁作用的影响。我们将利用神经连接蛋白-1 siRNA改变神经连接蛋白1在前额叶皮质的表达，并检测小鼠前额叶皮质的抑郁行为和抑郁病理的生物标志物，以了解手动SD和食欲素和氟西汀治疗诱发的SD的影响。