SMALL GRANT 3: EARLY-LIFE SLEEP; DEPRESSIVE FEATURES; RAT MODEL OF HUMAN MDD

小资助 3：早年睡眠；

• 批准号: 8360511
• 负责人: JAMES P SHAFFERY
• 金额: $ 3.21万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360511
• 关键词: Adolescence; Adolescent; Adult; Affect; Animals; Antidepressive Agents; Area; Autopsy; Autoreceptors; Biological; Biological Rhythm; Brain; Child; Circadian Rhythms; Clinical; Data; Depressed mood; Development; Drug Design; Electroencephalography; Etiology; Exhibits; Family history of; Female; Funding; Goals; Grant; Hippocampus (Brain); Homeostasis; Human; Impairment; Intervention; Life; Major Depressive Disorder; Measurable; Mental Depression; Mental Health; Modeling; National Center for Research Resources; Neurons; Neurosciences; Perinatal; Prefrontal Cortex; Principal Investigator; Proteins; Proxy; REM Sleep; Rattus; Regulation; Reporting; Research; Research Infrastructure; Resources; Risk; Serotonin; Sex Bias; Signaling Protein; Sleep; Sleep Deprivation; Sleep disturbances; Source; Symptoms; Synaptic plasticity; Time; United States National Institutes of Health; Woman; Work; base; cost; critical period; depressive symptoms; developmental plasticity; early adolescence; early onset; experience; high risk; improved; men; neurochemistry; non rapid eye movement; rapid eye movement; receptor; response; reuptake; serotonin receptor; serotonin transporter; sex; sleep abnormalities; therapy development

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Mental health is the expectable endpoint of brain maturation. Recent work shows that early-life rapid eye-movement sleep deprivation (ELRD) has long-lasting effects on synaptic plasticity mechanisms underlying CNS maturation, e.g., extending critical periods for brain development, in part, by altering expression of several neuronal signaling proteins. Other data implicate sleep in the etiology of major depressive disorder (MDD). The rhythmic organization of the sleep electroencelopgraph (EEG), slow-wave EEG activity (SWA), sleep homeostasis, rapid eye-movement (REM) sleep, and the circadian timing of the REM/non-REM (NREM) sleep cycle are all abnormal in early onset MDD. Similar findings have been reported for children at high risk for depression on the basis of maternal family history of MDD. These sleep abnormalities likely reflect an increased biological vulnerability to developing MDD in later adolescence. Moreover, there is now good evidence that such sleep abnormalities are sex-dependent, with greater biological rhythm disturbances in depressed women and greater sleep-homeostatic impairment in depressed men. In this project we will examine whether there are critical periods of brain development during which sleep disturbance impacts the risk for MDD. We will employ an established rat model, focusing on the permanence of ELRD effects upon brain maturation. We hypothesize that ELRD predisposes animals to exhibit measurable CNS signs as adults, which are proxies for the symptoms of MDD (1). A primary goal of this work is to determine whether there is a sex bias in the CNS consequences of ELRD. To uncover a likely biological basis for SWA and EEG alterations, we will investigate brain maturation in older adolescent rats after they have experienced ELRD at either of two points (early and late) during perinatal development, or at one (control) time-point during early adolescence. Once these rats reach late adolescence, we will determine functional changes in hippocampal synaptic plasticity as well as neurochemical changes in both hippocampus and prefrontal cortex. Changes in protein levels of serotonergic (5-HT) receptor subtype, 5-HT1A, and the serotonin transporter have been reported in postmortem studies of these same brain areas in depressed humans. It is notable that many antidepressant drugs, including those that reduce serotonin reuptake (SSRIs) also reduce REM sleep, and, when given during developmental periods, induce alterations in the serotonin transporter- and 5-HT1A autoreceptor-function, which are thought to be dysregulated in MDD. In addition, little is known about how ELRD affects developmental plasticity and serotonin receptor regulation in females. Results from the planned studies potentially offer direction in designing drug intervention strategies and development of treatment practices that may improve response to and clinical course of the illness.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 心理健康是大脑成熟的可预期终点。最近的工作表明，早期生活快速移动睡眠剥夺（ELRD）对中枢神经系统成熟的突触可塑性机制具有长期影响，例如，延长了脑发育的关键时期，部分通过改变了几种神经元信号蛋白的表达。其他数据暗示睡眠在主要抑郁症（MDD）的病因中。睡眠电唱片（EEG），慢波EEG活动（SWA），睡眠体内稳态，快速眼动（REM）睡眠以及REM/非REM/NON-REM（NREM）睡眠周期的昼夜节日的节奏组织都是异常的MDD。据报道，根据MDD的母亲家族史，针对抑郁症的儿童有类似的发现。这些睡眠异常可能反映出在青春期后期发展MDD的生物学脆弱性增加。此外，现在有充分的证据表明，这种睡眠异常是性别依赖性的，在抑郁症的女性中，生物节奏障碍更大，抑郁症患者的睡眠状态障碍更大。在这个项目中，我们将研究大脑发育是否存在关键时期，在此期间睡眠障碍会影响MDD的风险。 我们将采用既定的大鼠模型，重点介绍ELRD对脑成熟的影响。我们假设Elrd倾向于将动物作为成年人表现出可测量的中枢神经系统标志，这是MDD症状的代理（1）。这项工作的主要目标是确定ELRD的中枢神经系统后果是否存在性偏见。 为了揭示SWA和EEG改变的可能生物学基础，我们将在围产期发育期间在两个点（早期和晚期）中的任何一个（早期和晚期）或青春期早期的一个（对照）时间点进行ELRD之后，研究较老的青少年大鼠的大脑成熟。一旦这些大鼠达到青春期晚期，我们将确定海马突触可塑性的功能变化以及海马和额叶皮层的神经化学变化。在抑郁症人类的这些相同大脑区域的死后研究中，已经报道了血清素能（5-HT）受体亚型，5-HT1A和5-羟色胺转运蛋白的蛋白质水平的变化。值得注意的是，许多抗抑郁药，包括减少5-羟色胺再摄取（SSRIS）的药物，也可以减少REM睡眠，并且在发育期间给药时会诱导5-羟色胺转运蛋白转运蛋白和5-HT1A自感受体功能的改变，据认为这在MDD中被认为是失调的。此外，关于ELRD如何影响女性的发育可塑性和5-羟色胺受体调节的知之甚少。 计划研究的结果可能为设计药物干预策略和治疗方法的发展提供了方向，这些方法可能会改善对疾病的反应和临床过程。