Wake/Sleep Development and Depressive Substrates

描述(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，以及在决定成年人的情绪和睡眠-觉醒行为方面的作用。这与抑郁症的神经生物学和遗传机制有关。大量文献，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)改变了促进觉醒的结果的发育平衡，并创建了一个影响行为和情绪的非抑制REM生成系统。以前的研究结果表明，新生大鼠暴露于氯丙咪嗪后，成年后有更多的REM睡眠，我们最近的发现表明，新生儿用氯丙咪嗪治疗会降低大脑中食欲素B的水平和/或延缓食欲素能神经元的发育，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的观点，即新生儿RSD通过改变食欲素能和单胺能系统，然后通过额叶皮质的MAPK信号转导通路来产生行为后果。我们建议通过检测两个新生儿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。一种是用快速眼动睡眠抑制剂氯丙咪嗪治疗，另一种是由非药物RSD制成。我们将检测成人的神经元和分子标志物，觉醒促进相关分子对新生儿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觉醒，并与经典的抗抑郁药物进行比较，来检验治疗的行为和分子效应。结果显示，新生儿RSD对信号通路和单胺能功能的慢性变化的影响与许多人类疾病有关，包括成年人的抑郁症和精神分裂症。识别成人行为改变的修饰者可能会为这些常见疾病提供替代对策。目前的研究计划涉及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，以及了解药物干预的机制。这一建议还涉及食欲素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一个新的领域。

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.