ONTOGENY OF DEPRESSIVE SUBSTRATES

描述（改编自申请人摘要）：长期目标

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.