SMALL GRANT 3: EARLY-LIFE SLEEP; DEPRESSIVE FEATURES; RAT MODEL OF HUMAN MDD

小资助 3：早年睡眠；

基本信息

批准号：
8360511
负责人：
JAMES P SHAFFERY
金额：
$ 3.21万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8360511
关键词：
Adolescence Adolescent Adult Affect Animals Antidepressive Agents Area Autopsy Autoreceptors Biological Biological Rhythm Brain Child Circadian Rhythms Clinical Data Depressed mood Development Drug Design Electroencephalography Etiology Exhibits Family history of Female Funding Goals Grant Hippocampus (Brain)Homeostasis Human Impairment Intervention Life Major Depressive Disorder Measurable Mental Depression Mental Health Modeling National Center for Research Resources Neurons Neurosciences Perinatal Prefrontal Cortex Principal Investigator Proteins Proxy REM Sleep Rattus Regulation Reporting Research Research Infrastructure Resources Risk Serotonin Sex Bias Signaling Protein Sleep Sleep Deprivation Sleep disturbances Source Symptoms Synaptic plasticity Time United States National Institutes of Health Woman Work base cost critical period depressive symptoms developmental plasticity early adolescence early onset experience high risk improved men neurochemistry non rapid eye movement rapid eye movement receptor response reuptake serotonin receptor serotonin transporter sex sleep abnormalities therapy development

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Mental health is the expectable endpoint of brain maturation. Recent work shows that early-life rapid eye-movement sleep deprivation (ELRD) has long-lasting effects on synaptic plasticity mechanisms underlying CNS maturation, e.g., extending critical periods for brain development, in part, by altering expression of several neuronal signaling proteins. Other data implicate sleep in the etiology of major depressive disorder (MDD). The rhythmic organization of the sleep electroencelopgraph (EEG), slow-wave EEG activity (SWA), sleep homeostasis, rapid eye-movement (REM) sleep, and the circadian timing of the REM/non-REM (NREM) sleep cycle are all abnormal in early onset MDD. Similar findings have been reported for children at high risk for depression on the basis of maternal family history of MDD. These sleep abnormalities likely reflect an increased biological vulnerability to developing MDD in later adolescence. Moreover, there is now good evidence that such sleep abnormalities are sex-dependent, with greater biological rhythm disturbances in depressed women and greater sleep-homeostatic impairment in depressed men. In this project we will examine whether there are critical periods of brain development during which sleep disturbance impacts the risk for MDD. We will employ an established rat model, focusing on the permanence of ELRD effects upon brain maturation. We hypothesize that ELRD predisposes animals to exhibit measurable CNS signs as adults, which are proxies for the symptoms of MDD (1). A primary goal of this work is to determine whether there is a sex bias in the CNS consequences of ELRD. To uncover a likely biological basis for SWA and EEG alterations, we will investigate brain maturation in older adolescent rats after they have experienced ELRD at either of two points (early and late) during perinatal development, or at one (control) time-point during early adolescence. Once these rats reach late adolescence, we will determine functional changes in hippocampal synaptic plasticity as well as neurochemical changes in both hippocampus and prefrontal cortex. Changes in protein levels of serotonergic (5-HT) receptor subtype, 5-HT1A, and the serotonin transporter have been reported in postmortem studies of these same brain areas in depressed humans. It is notable that many antidepressant drugs, including those that reduce serotonin reuptake (SSRIs) also reduce REM sleep, and, when given during developmental periods, induce alterations in the serotonin transporter- and 5-HT1A autoreceptor-function, which are thought to be dysregulated in MDD. In addition, little is known about how ELRD affects developmental plasticity and serotonin receptor regulation in females. Results from the planned studies potentially offer direction in designing drug intervention strategies and development of treatment practices that may improve response to and clinical course of the illness.