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，以及确定成年人的情绪和睡眠效果行为。这与抑郁症的神经生物学和遗传机制有关。广泛的文献，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的平衡，并创造了影响行为和情绪的Dias抑制REM生成系统。先前的发现表明，与新生儿接触氯米帕明的大鼠成年后有更多的REM睡眠，而我们最近的发现表明，新生儿治疗氯米帕明的治疗降低了Orexin B的大脑水平，并且/或延迟了Orecinagon神经元的发展，这些神经元被鉴定为助攻神经元。该数据支持一个新颖的想法，即新生儿RSD通过改变甲状腺素能和单胺能系统而产生行为后果，然后通过额叶皮质中的MAPK Signal Transduction途径作用。我们建议通过检查两个新生儿RSD模型中的唤醒/REM睡眠改变发生的分子变化来检验这一假设。一种是用REM睡眠抑制氯米帕明治疗制成的，另一种是由非药理学RSD制成的。我们将检查成人的神经元和分子标记，促进唤醒分子对新生儿RSD的个体发生反应以及扭转新生儿RSD影响的干预措施。我们还将通过使用药物或非药物方法调节唤醒调节并与经典抗抑郁药进行调节，以检查处理的行为和分子效应。结果表明新生儿RSD对信号通路和单胺能功能的慢性变化的影响与许多人类疾病有关，包括抑郁症和精神分裂症。识别成人行为改变的修饰符可能会深入了解这些常见疾病的替代对策。本研究计划解决了发展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理学干预的机制。该提案还参与了对行为和分子改变的甲素能作用的测试，这可能为发现新的抗抑郁药的新范围开辟了新的范围。