ONTOGENY OF DEPRESSIVE SUBSTRATES

描述(改编自申请人的摘要)： 建议的工作是确定与发病机制有关的脑过程 内源性抑郁(ED)。在过去的工作中，调查人员发现，如果 用氯丙咪嗪(CLI)和其他抗抑郁药治疗新生大鼠 他们成年后出现了抑郁的迹象。这个 研究人员目前的工作涉及成年大鼠的大脑底物 抑郁症。本申请中建议的工作与流程有关 新生儿CLI给药与成人抑郁症之间的关系。这个 研究人员的问题是：CLI对成人的新生儿影响是什么 抑郁症?有证据表明，CLI(和其他方法)的新生儿RSD 抗抑郁药物)会导致成人抑郁。调查员已经 最近开发了第一个成功的技术来生产长期的， 器质性快速眼动睡眠剥夺(IRSD)使用这种技术，他的主要 目的是验证这样一种假设，即在大鼠中，新生RSD会导致成年 抑郁症(RSD假说)。对RSD假设的明确检验 要求对超过精确年龄的新生大鼠实施IRSD 对其他大鼠给予致抑CLI的时间(关键期)。 CLI管理的确切关键年龄段尚未达到 下定决心。因此，在IRSD研究的初步阶段，调查员的第一个 目的是确定抑郁症的确切新生儿临界年龄段。 CLI管理。此外，对RSD假设的明确测试需要 IRSD达到与新生儿CLI相同的RSD。CLI的RSD级别为 没有得到准确的确定。因此，在税务局进行研究前， 调查员的第二个目标是确定每日RSD的准确水平 由新生儿CLI在先前建立的精确危重期间产生 CLI管理期。使用这两个结果，他将管理 IRSD来检验RSD假设。几种成人行为和遥感测量方法 与抑郁症相关的将是结果衡量标准。虽然我们都知道 从短暂的(1-3小时)样本来看，RS时间在第一个出生后减少 月，人们对其他RS变量的个体发育和 它们发展变化的相互关系。调查员已经 最近开发了第一个成功的连续(24小时/ 一天)、长期(数周)多导睡眠图(PSG)记录睡眠/清醒 新生大鼠的状态。使用这种技术，调查员的初步研究 有证据表明，7个不同的RS变量是平行的 出生后2-4周的发育过程。确认这一点 初步发现可以：a)产生关于个体发育的第一个系统数据 几个不同的RS参数；b)识别 抑郁的CLI管理的关键时期；c)这些RS建议 标志物及其已知的神经生理学和神经化学可测试性 关于个体发育中涉及的潜在过程的假说 抑郁的性格。拟议工作的意义在于它 可能会揭示早期的发育过程，这些过程有助于后来 抑郁和压抑的气质。在这样做的过程中，拟议工作可 帮助寻找早期预防ED的方法，更准确地说 ED的靶向治疗。

DESCRIPTION (Adapted from applicant's abstract): The long-term goal of the proposed work is to determine brain processes involved in the pathogenesis of endogenous depression (ED). In past work investigator found that if neonatal rats were treated with clomipramine (CLI) and other antidepressant drugs they developed signs of depression when they became adults. The investigator's current work concerns the brain substrates of the adult rat depression. The work proposed in this application concerns the processes between neonatal CLI administration and the adult depression. The investigator's question is: what neonatal effect of CLI leads to the adult depression? Evidence suggests that neonatal RSD by CLI (and other antidepressant drugs) produces the adult depression. The investigator has recently developed the first successful technique to produce long-term, instrumental REM sleep deprivation (IRSD). Using this technique, his main aim is to test the hypothesis that in rats neonatal RSD causes adult depression (RSD hypothesis). An unambiguous test of the RSD hypothesis requires that IRSD be administered to neonatal rats over the precise age period (critical period) of depressogenic CLI administration to other rats. The precise critical age period of CLI administration has not been determined. Thus, preliminary to the IRSD study, the investigator's first aim is to determine the precise critical neonatal age period of depressive CLI administration. Also an unambiguous test of the RSD hypothesis requires that IRSD achieve the same RSD as neonatal CLI. The level of RSD by CLI has not been precisely determined. Thus, preliminary to the IRSD study, the investigator's second aim is to determine the precise level of daily RSD produced by neonatal CLI during the prior established precise critical period of CLI administration. Using these 2 results, he will administer IRSD to test the RSD hypothesis. Several adult behavior and RS measures related to depression will be the outcome measures. Although it is known from brief (1-3 hour) samples that RS time decreases in the first postnatal month, very little is known about the ontogeny of other RS variables and the interrelationships of their developmental changes. The investigator has recently developed the first successful technique for continuous (24 hour/ day), long-term (weeks) polysomnographic (PSG) recording of sleep/wake states in neonatal rats. With this technique the investigator's preliminary evidence suggests that 7 different RS variables follow parallel developmental courses over postnatal weeks 2-4. Confirmation of this preliminary finding can: a) yield the first systematic data on the ontogeny of several different RS parameters; b) identify the RS markers of the critical period of depressive CLI administration; c) suggest by these RS markers and their known neurophysiology and neurochemistry testable hypotheses about the underlying processes involved in the ontogeny of depressive disposition. The significance of the proposed work is that it may shed light on early developmental processes that contribute to later depression and depressive temperament. In doing so, the proposed work may help in the search for early prevention of ED, and in more precisely targeted treatments of ED.