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

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 心理健康是大脑成熟的预期终点。最近的研究表明，早期快速眼动睡眠剥夺（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，延长大脑发育的关键期，部分是通过改变几种神经元信号蛋白的表达。其他数据暗示睡眠是重度抑郁症（MDD）的病因。早发性MDD患者的睡眠脑电图（EEG）节律性结构、慢波EEG活动（SWA）、睡眠稳态、快速眼动（REM）睡眠以及REM/非REM（NREM）睡眠周期的昼夜节律均异常。类似的研究结果也报告了儿童在高风险的抑郁症的基础上，母亲的家族病史的MDD。这些睡眠异常可能反映了在青春期后期发展MDD的生物脆弱性增加。此外，现在有充分的证据表明，这种睡眠异常是依赖于性别的，抑郁症女性的生物节律紊乱更严重，抑郁症男性的睡眠稳态损害更严重。在这个项目中，我们将研究是否有大脑发育的关键时期，在此期间，睡眠障碍会影响MDD的风险。 我们将采用一个已建立的大鼠模型，重点是持久的ELRD影响后，大脑成熟。我们假设ELRD使动物在成年后表现出可测量的CNS体征，这是MDD症状的代表（1）。这项工作的主要目标是确定ELRD的CNS后果是否存在性别偏见。 为了揭示SWA和EEG改变的可能生物学基础，我们将研究在围产期发育期间的两个点（早期和晚期）或青春期早期的一个（对照）时间点经历ELRD后，老年青春期大鼠的大脑成熟。一旦这些大鼠进入青春期后期，我们将确定海马突触可塑性的功能变化以及海马和前额皮质的神经化学变化。在对抑郁症患者相同脑区的尸检研究中，已经报道了多巴胺能（5-HT）受体亚型、5-HT 1A和5-羟色胺转运蛋白的蛋白水平变化。值得注意的是，许多抗抑郁药物，包括那些减少5-羟色胺再摄取（SSRIs）也减少REM睡眠，并且当在发育期间给予时，诱导5-羟色胺转运蛋白和5-HT 1A自身受体功能的改变，这被认为是MDD中的失调。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，我们知之甚少。 计划中的研究结果可能为设计药物干预策略和开发治疗实践提供方向，这些策略和治疗实践可能会改善对疾病的反应和临床病程。

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.