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）： 该项目是为了确定突触粘附蛋白（SAPS），神经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。尽管某些抗抑郁药是治疗抑郁症的有效治疗方法，但这些治疗的功效仍有待改进。目前，只有三分之一的急性“纯”严重抑郁症患者在一线抗抑郁药单药治疗后可缓解。多达三分之二的严重抑郁症患者对第一种药物没有反应。更重要的是，抗抑郁药的有益作用通常不会在治疗的几周内发生。这使得治疗在最初的几周内的耐受性降低，许多患者停止治疗。然而，在过去30年的研究中，根据累积证据，SD立即改善了情绪，而不知道SD和抗抑郁药治疗之间影响的机制和差异。 我们假设恢复正常的前额叶皮质突触兴奋性和神经素之间的平衡 神经毒素在SD，Orexins和SSRI治疗的抑郁症状逆转中起着至关重要的作用。我们进一步假设，神经素1表达的抑制可能会消除SD和Orexins的直接抗抑郁作用以及慢性SSRI治疗的抗抑郁作用。 该提议的项目将以三个特定目标进行研究。 AIM 1将确定啮齿动物模型中SAPS的差异表达。我们发现，在新生儿暴露于氯米帕明引起的抑郁症模型中，神经素和神经毒素的改变不同。为了进一步定义SAPS在抑郁症病理中的潜在影响和抗抑郁作用的调节，我们建议检查具有不同遗传背景的大鼠模型和抑郁症小鼠模型中的SAP。 AIM 2将比较SD，Orexins和Fluoxetine处理中大鼠抑郁模型中SAPS的变化。我们将首先将SD通过温和处理与Orexin的SD和氟西汀的急性作用进行比较。其次，我们将比较氟西汀与奥雷敦蛋白对行为和SAPS的长期治疗的影响。我们将确定在抑郁模型中，神经素和神经毒素是否受到差异调节。 AIM 3将确定Neuroligin 1 siRNA对SD，Orexins和Fluoxetine诱导的抗抑郁作用的影响。我们将利用Neuroligin-1 siRNA改变前额叶皮层中神经素1的表达，并测量小鼠前额额皮层对抑制性病理学的抑郁行为和生物标志物在小鼠前额外SD和SD诱导的作用。 。