Wake/Sleep Development and Depressive Substrates

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）睡眠在正常生长发育中的作用，以及在成年人情绪和睡眠-觉醒行为的决定中所起的作用。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）改变了促进觉醒后果的发展平衡，并创造了一个影响行为和情绪的非抑制快速眼动生成系统。先前的研究结果表明，新生儿暴露于氯丙帕明的大鼠成年后有更多的快速眼动睡眠，我们最近的研究结果表明，氯丙帕明治疗新生儿会降低大脑中食欲素B的水平和/或延迟食欲能神经元的发育，这些神经元被认为是促进觉醒的神经元。这一数据支持了一种新颖的观点，即新生儿RSD通过改变食欲能和单胺能系统，然后通过额叶皮层的MAPK信号转导途径产生行为后果。我们建议通过检查两种新生儿RSD模型中觉醒/快速眼动睡眠改变时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治疗。我们将研究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尾流调节，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对信号通路和单胺功能慢性变化的影响与许多人类疾病有关，包括成人的抑郁症和精神分裂症。识别成人行为改变的修饰因子可能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。这一建议也涉及到对食欲能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领域。

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.