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Wake/Sleep Development and Depressive Substrates

觉醒/睡眠发展和抑郁基质

基本信息

批准号：
6991201
负责人：
PINGFU FENG
金额：
$ 15.75万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-16 至 2007-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to determine the role for neonatal rapid eye movement (REM) sleep in normal growth and development as well as in the determination of mood and sleep-wake behaviors in the adult. This is relevant to the neurobiologic and genetic mechanisms underlying depression. Extensive literature, including our previous studies, supports our hypothesis that neonatal REM sleep deprivation (RSD) alters the balance of development of wake promoting consequences and creates a disinhibited REM generation system that affects behavior and mood. Previous findings show that a rat with neonatal exposure to clomipramine has more REM sleep as an adult and our recent findings reveal that neonatal treatment with clomipramine reduce the brain levels of orexin B and/or delay the development of orexinergic neurons, which are identified as wake promotion neurons. This data supports a novel idea that neonatal RSD produces behavioral consequences by altering orexinergic as well as monoaminergic systems, then acting through MAPK signaltransduction pathways in the frontal cortex. We propose to test this hypothesis by examining the molecular changes occurring with wake/REM sleep alterations in two neonatal RSD models. One is made by treatment with REM sleep suppressant clomipramine and the other is made by non-pharmacological RSD. We will examine neuronal and molecular markers in the adult, the ontogenetic response of wake promoting related molecules to neonatal RSD, and interventions to reverse the effect of neonatal RSD. We will also examine the behavioral and molecular effect of the treatment by modulating wake regulation with either drug or non-drug methods and comparing with classic antidepressant. Results showing the impact of neonatal RSD on signaling pathways and on chronic changes in monoaminergic functions is relevant to a number of human illness, including depression and schizophrenia in the adult. Identifying modifiers of the adult behavioral alteration may provide insight into alternative countermeasures for these common illnesses. The present research plan addresses fundamental needs towards developing animal models of depression, the impact of sleep on the plasticity of systems regulating sleep and mood, and understanding the mechanisms of pharmacologic interventions. This proposal is also involved in a test of orexinergic effect on behavior and molecular alteration that may open a new scope toward the discovery of new antidepressant drugs.

描述（由申请人提供）：我们的长期目标是确定新生儿快速眼动（REM）睡眠在正常生长和发育中的作用，以及在成人情绪和睡眠-觉醒行为的确定中的作用。这与抑郁症的神经生物学和遗传机制有关。大量的文献，包括我们以前的研究，支持我们的假设，即新生儿REM睡眠剥夺（RSD）改变了唤醒促进后果的发展平衡，并创建了一个不受抑制的REM生成系统，影响行为和情绪。以前的研究结果表明，新生儿暴露于氯丙咪嗪的大鼠有更多的REM睡眠作为一个成年人，我们最近的研究结果表明，新生儿治疗氯丙咪嗪降低食欲素B的大脑水平和/或延迟食欲素能神经元，这被确定为唤醒促进神经元的发展。这些数据支持了一个新的想法，即新生儿RSD产生的行为后果，改变orexinergic以及单胺能系统，然后通过MAPK信号转导通路在额叶皮层。我们建议通过研究两个新生儿RSD模型中觉醒/REM睡眠改变发生的分子变化来验证这一假设。一种是通过快速眼动睡眠抑制剂氯丙咪嗪治疗，另一种是通过非药物RSD。我们将研究神经元和分子标记物在成人，个体发育反应的唤醒促进相关分子对新生儿RSD，干预措施，以扭转新生儿RSD的影响。我们还将通过药物或非药物方法调节觉醒调节并与经典抗抑郁药进行比较来检查治疗的行为和分子效应。结果显示，新生儿RSD信号通路和单胺能功能的慢性变化的影响是相关的一些人类疾病，包括抑郁症和精神分裂症的成年人。识别成人行为改变的修饰符可以为这些常见疾病的替代对策提供见解。目前的研究计划解决了开发抑郁症动物模型的基本需求，睡眠对调节睡眠和情绪的系统可塑性的影响，以及了解药物干预的机制。该方案还涉及食欲素对行为和分子改变的影响的测试，这可能为发现新的抗抑郁药物开辟新的范围。