Wake/Sleep Development and Depressive Substrates

觉醒/睡眠发展和抑郁基质

• 批准号: 6836101
• 负责人: PINGFU FENG
• 金额: $ 16.13万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-16 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6836101
• 关键词: REM sleep; acetylcholine; behavioral /social science research tag; biological signal transduction; depression; disease /disorder model; emotions; frontal lobe /cortex; growth /development; high performance liquid chromatography; imipramine; immunocytochemistry; laboratory rat; mitogen activated protein kinase; model design /development; muscarinic receptor; neuropsychology; neurotransmitter transport; newborn animals; orexin; psychopharmacology; serotonin; sleep; sleep deprivation; wakefulness; western blottings

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以及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。包括我们之前的研究在内的大量文献支持我们的假设，即新生儿快速眼动睡眠剥夺 (RSD) 会改变促醒后果的发展平衡，并创建一个影响行为和情绪的不受抑制的快速眼动生成系统。先前的研究结果表明，新生儿接触氯米帕明的大鼠成年后有更多的快速眼动睡眠，而我们最近的研究结果表明，氯米帕明的新生儿治疗会降低大脑中食欲素 B 的水平和/或延迟食欲素能神经元的发育，这些神经元被认为是唤醒促进神经元。这些数据支持了一个新观点，即新生儿 RSD 通过改变食欲素能和单胺能系统，然后通过额叶皮质中的 MAPK 信号转导途径发挥作用，从而产生行为后果。我们建议通过检查两个新生儿 RSD 模型中觉醒/快速眼动睡眠改变所发生的分子变化来检验这一假设。一种是通过快速眼动睡眠抑制剂氯米帕明治疗制成的，另一种是通过非药物 RSD 制成的。我们将检查成人的神经元和分子标记、唤醒相关分子对新生儿 RSD 的个体发生反应，以及逆转新生儿 RSD 影响的干预措施。我们还将通过药物或非药物方法调节唤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。结果表明，新生儿 RSD 对信号通路和单胺能功能慢性变化的影响与许多人类疾病有关，包括成人抑郁症和精神分裂症。识别成人行为改变的修饰因素可能有助于了解这些常见疾病的替代对策。目前的研究计划解决了开发抑郁症动物模型、睡眠对睡眠和情绪调节系统可塑性的影响以及了解药物干预机制的基本需求。该提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。