Adult Neurogenesis: Regulation By Sleep

描述(由申请人提供)： 我们的实验室致力于了解睡眠促进大脑可塑性过程的机制。我们已经证明，持续的睡眠片断(SF)强烈抑制成年海马齿状回(DG)的神经发生，包括细胞增殖和成熟，这种抑制不是由于应激。我们现在建议研究睡眠促进神经发生作用的机制。拟开展的研究主要集中在DG-3-氨基丁酸(GABA)能神经元在睡眠中的激活，以此作为睡眠促进成人神经发生的机制。我们将检验以下一般性命题：持续睡眠强烈激活固有的DG-GABA能机制，从而促进海马神经发生，特别是提高有丝分裂后细胞的存活和成熟。运动对神经发生和随后的空间学习的影响依赖于持续睡眠期间GABA能的激活。我们将评估以下具体假设：1.在睡眠过程中，海马DG GABA能神经元被激活。通过操纵NREM和REM睡眠，我们将确定哪些睡眠属性和阶段与GABA能神经元激活最相关，以及SF是否会减少睡眠相关的DG GABA能神经元的激活。GABA能神经元的激活将通过神经元激活标志c-Fos蛋白和GABA神经元标志[谷氨酸脱羧酶(GAD)}]的双重标记来识别。我们开发了一种对SF进行良好控制的方法。2.在巩固睡眠过程中，DG GABA释放增加，睡眠碎片化会减少DG睡眠促进的GABA释放。采用体内微透析法测定DG-GABA释放量。我们将研究特定睡眠事件中GABA释放的变化，包括NREM睡眠相关的尖锐波(SPW)和REM相关的theta爆发。3.运动增加了随后睡眠中的GABA能过程。我们将确定运动对GABA释放的影响，以及NREM SPW和REM相关的theta爆发。睡眠碎片化会阻止运动引起的睡眠中GABA能的激活。4.运动增加了有丝分裂后细胞的存活和成熟，以及一种关键营养因子的表达，脑源性神经营养因子(BDNF)确定了BDNF、细胞存活(BrdU)和成熟(Doublecortin，DCX)的免疫组织化学标记。睡眠碎片化会阻碍锻炼的效果。5.运动对海马区依赖的认知能力和新奇抑制进食的有益影响依赖于持续的睡眠。运动后的海马区依赖功能将使用巴恩斯迷宫进行评估。失眠，特别是睡眠碎片，预示着随后的严重抑郁障碍(MDD)和缓解患者的MDD复发。在临床前研究中，抗抑郁药物治疗逐渐促进DG神经发生，并需要神经发生。抗抑郁药物的疗效可能取决于持续的睡眠。在人类中，最初的抗抑郁剂治疗效果很低。我们建议MDD治疗最好理解为一个多阶段的过程，需要持续的睡眠作为一个要素。运动促进神经发生，对动物和人类都有抗抑郁作用。我们将确定锻炼的这些效果是否依赖于持续的睡眠。 公共卫生相关性： 严重抑郁障碍(MDD)和抑郁症谱系障碍在退伍军人中很常见。许多其他神经病理障碍也与睡眠碎片有关。人类对MDD的初始药物治疗的反应不一致，但有证据表明，使用GABA激动剂辅助治疗MDD患者的失眠大大增强了抗抑郁治疗的反应。抗抑郁药物的治疗依赖于海马区的成年神经发生，而GABA激动剂促进了成年神经发生。对于睡眠障碍和MDD或其他障碍的同时治疗，没有特定的神经学理论基础。通过将抗抑郁治疗、持续睡眠和成人神经发生联系起来，拟议的工作可以为开发包括睡眠障碍管理在内的治疗方案提供特定的神经化学基础。

DESCRIPTION (provided by applicant): Our lab is focused on understanding mechanisms by which sleep enhances plastic processes in brain. We have shown that sustained sleep fragmentation (SF) strongly inhibits adult hippocampal dentate gyrus (DG) neurogenesis, including both cell proliferation and maturation, and that this inhibition is not due to stress. We now propose to study a mechanism underlying the pro-neurogenic effects of sleep. The proposed studies focus on DG 3-aminobutyric acid (GABA)-ergic neuronal activation during sleep as a mechanism by which sleep can promote adult neurogenesis. We will test the following general theses: Sustained sleep strongly activates intrinsic DG GABAergic mechanisms and thereby promotes hippocampal neurogenesis, particularly enhancing survival and maturation of post-mitotic cells. The effects of exercise on neurogenesis and subsequent spatial learning depend on GABAergic activation during sustained sleep. We will assess the following specific hypotheses: 1. Hippocampal DG GABAergic neurons are activated during sleep. By manipulating NREM and REM sleep, we will determine what properties and stages of sleep are maximally associated with GABAergic neuronal activation and if SF diminishes sleep-related DG GABAergic neuronal activation. GABAergic neuronal activation will be identified by double-labeling for c-Fos protein, a marker of neuronal activation, and a GABA neuronal marker [glutamic acid decarboxylase (GAD)}]. We developed a well-controlled method for SF. 2. DG GABA release is increased during consolidated sleep, and sleep fragmentation will reduce the sleep- enhanced release of GABA in DG. DG GABA release will be measured by in vivo microdialysis. We will examine changes in GABA release during specific sleep events, including NREM sleep-associated sharp waves (SPWs) and REM-associated theta bursts. 3. Exercise increases GABAergic processes during subsequent sleep. We will determine effects of exercise on GABA release, and NREM SPWs and REM-associated theta bursts. Sleep fragmentation will block the GABAergic activation during sleep resulting from exercise. 4. Exercise increases post-mitotic cell survival and maturation and expression of a critical trophic factor, Brain-Derived Neurotrophic Factor (BDNF) identified immunostaining for markers of BDNF, cell survival (bromo-deoxyuridine, BrdU) and maturation (doublecortin, DCX). Sleep fragmentation will block the effects of exercise. 5. The beneficial effects of exercise on hippocampal-dependent cognitive performance and novelty- suppressed feeding depend on sustained sleep. Hippocampal-dependent function following exercise will be assessed using the Barnes maze. Insomnia, particularly sleep fragmentation, predicts subsequent major depressive disorder (MDD) and recurrence of MDD in remitted patients. In preclinical studies, antidepressant treatments progressively facilitate DG neurogenesis and require neurogenesis. The efficacy of antidepressant treatment may depend on sustained sleep. In humans, initial antidepressant treatment has low efficacy. We propose that MDD treatment is best understood as a multi-stage process that requires sustained sleep as one element. Exercise facilitates neurogenesis and has antidepressant effects in animals and humans. We will determine if these effects of exercise depend on sustained sleep. PUBLIC HEALTH RELEVANCE: Major depressive disorder (MDD) and depression spectrum disorders are prevalent in veterans. Many other neuropathological disorders are also associated with sleep fragmentation. Response to initial drug treatment of MDD in humans is inconsistent, but there is evidence that adjunctive treatment of insomnia in MDD patients with a GABA agonist greatly enhances antidepressant treatment response. Antidepressant treatment can depend on hippocampal adult neurogenesis, and adult neurogenesis is facilitated by GABA agonists. There is no specific neurological rationale for coincident management of sleep disorders and MDD or other disorders. By linking antidepressant treatment, sustained sleep, and adult neurogenesis, proposed work could provide a specific neurochemical rationale for development of treatment protocols which include management of sleep disorders.