Adult Neurogenesis: Regulation By Sleep

成人神经发生:睡眠调节

基本信息

项目摘要

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): 我们的实验室专注于理解睡眠增强大脑塑料过程的机制。我们已经表明,持续的睡眠碎片(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。现在,我们建议研究睡眠促促性神经作用的基础机制。拟议的研究集中于DG 3-氨基丁酸(GABA)在睡眠期间的神经元激活作为睡眠可以促进成人神经发生的机制。我们将测试以下一般论文: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,尤其是增强了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的GABA能激活。我们将评估以下特定假设:1。在睡眠期间激活海马DG GABA能神经元。通过操纵NREM和REM睡眠,我们将确定什么特性和睡眠阶段与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。通过双标记蛋白,神经元激活的标记和GABA神经元标记[谷氨酸脱羧酶(GAD)}],将通过双标记蛋白的双标记来鉴定GABA能神经元激活。我们为SF开发了一种良好的控制方法。 2。DGGABA释放在整合睡眠期间增加,睡眠碎片化将减少DG中GABA的睡眠增强。 DG GABA释放将通过体内微透析测量。我们将检查在特定睡眠事件期间GABA释放的变化,包括NREM睡眠相关的锋利波(SPW)和REM相关的theta爆发。 3。运动在随后的睡眠期间增加了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。睡眠碎裂将阻止运动过程中的GABA能激活。 4。运动增加了临界营养因子,脑源性神经营养因子(BDNF)的成熟和表达,这些因素(BDNF)鉴定出用于BDNF标志物,细胞存活(Bromo-脱氧尿苷,BRDU)和成熟(DCORTIN,DCX)的免疫染色。睡眠破碎将阻止运动的影响。 5。运动对海马依赖性认知表现和抑制新颖的喂养的有益影响取决于持续的睡眠。运动后的海马依赖性功能将使用巴恩斯迷宫进行评估。 失眠症,尤其是睡眠破碎化,预测随后的主要抑郁症(MDD)和MDD的复发。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。抗抑郁治疗的功效可能取决于持续的睡眠。在人类中,初始抗抑郁药的功效低。我们建议最好将MDD治疗理解为一个多阶段的过程,需要持续睡眠作为一个元素。运动促进神经发生,并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。

项目成果

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DENNIS J MCGINTY其他文献

DENNIS J MCGINTY的其他文献

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{{ truncateString('DENNIS J MCGINTY', 18)}}的其他基金

Adult Neurogenesis: Regulation By Sleep
成人神经发生:睡眠调节
  • 批准号:
    8048035
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Adult Neurogenesis: Regulation By Sleep
成人神经发生:睡眠调节
  • 批准号:
    8242618
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Adult Neurogenesis: Regulation By Sleep
成人神经发生:睡眠调节
  • 批准号:
    8597376
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Effects of Sleep Fragmentation on Adult Neurogenesis
睡眠碎片化对成人神经发生的影响
  • 批准号:
    7749990
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
Effects of Sleep Fragmentation on Adult Neurogenesis
睡眠碎片化对成人神经发生的影响
  • 批准号:
    7332214
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
Effects of Sleep Fragmentation on Adult Neurogenesis
睡眠碎片化对成人神经发生的影响
  • 批准号:
    7194734
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
Effects of Sleep Fragmentation on Adult Neurogenesis
睡眠碎片化对成人神经发生的影响
  • 批准号:
    7676371
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
Effects of Sleep Fragmentation on Adult Neurogenesis
睡眠碎片化对成人神经发生的影响
  • 批准号:
    7531027
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
Regulation of Adult Neurogenesis During Intermittent Hypoxia
间歇性缺氧期间成人神经发生的调节
  • 批准号:
    6741108
  • 财政年份:
    2003
  • 资助金额:
    --
  • 项目类别:
HYPOTHALAMIC REGULATION OF RESPIRATION DURING SLEEP
睡眠期间下丘脑的呼吸调节
  • 批准号:
    6505105
  • 财政年份:
    2001
  • 资助金额:
    --
  • 项目类别:

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