Adult Neurogenesis: Regulation By Sleep

成人神经发生：睡眠调节

• 批准号: 8391598
• 负责人: DENNIS J MCGINTY
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391598
• 关键词: 3-aminobutyric acid; Adult; Animals; Antidepressive Agents; Behavioral; Brain; Brain-Derived Neurotrophic Factor; Cell Maturation; Cell Proliferation; Cell Survival; Cells; Cognition; Cognitive; Data; Deoxyuridine; Development; Disease; Elements; Etiology; Event; Exercise; FOS Protein; GABA Agonists; Glutamate Decarboxylase; Hippocampus (Brain); Human; Label; Lead; Learning; Link; Major Depressive Disorder; Measures; Mental Depression; Methods; Microdialysis; Mitotic; Neocortex; Neurologic; Neurons; Newborn Infant; Patients; Performance; Pharmaceutical Preparations; Plastics; Process; Proliferating; Property; REM Sleep; Recurrence; Regulation; Rodent; Role; Running; Selective Serotonin Reuptake Inhibitor; Sleep; Sleep Disorders; Sleep Fragmentations; Sleep Stages; Sleeplessness; Staging; Stress; Testing; Treatment Protocols; Veterans; Work; adult neurogenesis; cognitive function; critical period; dentate gyrus; effective therapy; feeding; gamma-Aminobutyric Acid; improved; in vivo; nervous system disorder; neurochemistry; neurogenesis; novel therapeutics; preclinical study; prevent; public health relevance; response; treatment response

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.

描述（由申请人提供）： 我们的实验室致力于了解睡眠增强大脑可塑性过程的机制。我们已经证明，持续的睡眠碎片化（SF）强烈抑制成人海马齿状回（DG）神经发生，包括细胞增殖和成熟，并且这种抑制不是由于压力造成的。我们现在建议研究睡眠促神经原性作用的潜在机制。拟议的研究重点关注睡眠期间 DG 3-氨基丁酸 (GABA) 能神经元的激活，作为睡眠促进成人神经发生的机制。我们将测试以下一般论点：持续的睡眠强烈激活内在的 DG GABA 能机制，从而促进海马神经发生，特别是增强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取决于持续睡眠期间 GABA 能的激活。我们将评估以下具体假设： 1. 海马 DG GABA 能神经元在睡眠期间被激活。通过操纵 NREM 和 REM 睡眠，我们将确定睡眠的哪些属性和阶段与 GABA 能神经元激活最大相关，以及 SF 是否会减少与睡眠相关的 DG GABA 能神经元激活。 GABA 能神经元激活将通过 c-Fos 蛋白（神经元激活标记物）和 GABA 神经元标记物 [谷氨酸脱羧酶 (GAD)}] 的双标记来鉴定。我们开发了一种控制良好的 SF 方法。 2、巩固睡眠期间DG GABA释放增加，碎片化睡眠会减少DG中睡眠增强的GABA释放。 DG GABA 释放将通过体内微透析测量。我们将检查特定睡眠事件期间 GABA 释放的变化，包括 NREM 睡眠相关的尖波 (SPW) 和 REM 相关的 θ 爆发。 3. 运动会增加随后睡眠期间的 GABA 能过程。我们将确定运动对 GABA 释放、NREM SPW 和 REM 相关 θ 爆发的影响。睡眠碎片化会阻碍睡眠期间运动引起的 GABA 激活。 4. 运动可增加有丝分裂后细胞的存活和成熟以及关键营养因子脑源性神经营养因子 (BDNF) 的表达，通过免疫染色鉴定 BDNF 标记物、细胞存活（溴脱氧尿苷，BrdU）和成熟（双皮质素，DCX）。睡眠碎片化会阻碍锻炼的效果。 5. 运动对海马依赖性认知能力和新奇抑制进食的有益影响取决于持续的睡眠。运动后海马依赖性功能将使用巴恩斯迷宫进行评估。 失眠，尤其是睡眠碎片化，可以预测随后的重度抑郁症 (MDD) 以及缓解后患者的 MDD 复发。在临床前研究中，抗抑郁治疗逐渐促进 DG 神经发生并需要神经发生。抗抑郁治疗的疗效可能取决于持续的睡眠。对于人类来说，初始抗抑郁治疗的疗效较低。我们建议，MDD 治疗最好理解为一个多阶段过程，需要持续睡眠作为其中一个要素。运动促进神经发生，对动物和人类具有抗抑郁作用。我们将确定运动的这些影响是否取决于持续的睡眠。