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Associate Professor, Psychiatry and Human BehaviorSmall Grant Principal InvestigatorAssistant Professor, Pharmacology and ToxicologyPhone: (601) 984-6684
The rapid eye-movement (REM) sleep state appears to be necessary for proper brain maturation. Research in the Animal Sleep Laboratory is currently aimed at working out the neurophysiological and biochemical mechanisms which allow the REM sleep state to affect maturation of the central nervous system.
Title: Effects of Early-Life Sleep Abnormalities in the Production of Depressive-Like Features in a Rat Model of Human Major Depressive Disorder (MMOD)
Mental health is the normal, 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 neural signaling proteins. Other data implicate sleep in the etiology of major depressive disorder (MDD). Sleep electroencelopgraph (EEG) rhythmicity, sleep homeostasis as measured by slow-wave activity (SWA) in non-REM (NREM) sleep, rapid eye-movement (REM) sleep, as well as REM/NREM stage-cycle circadian timing are all abnormal when assessed at the time of early onset MDD. Similar abnormalities have been reported in children deemed at high risk for depression on the basis of maternal family history of MDD and likely reflect increased biological vulnerability to development of MDD in adolescence.
Moreover, there is now good evidence that such sleep abnormalities are sex-dependent, namely greater biological rhythm disturbance in depressed women but less SWA in depressed men. Further, mild sleep deprivation provokes a very large SWA response in MDD women and a blunted response in MDD men, compared to healthy controls. These data point to impairments in sleep homeostasis at the core of sleep complaints in MDD. More generally, these findings have been interpreted to reflect greater neural plasticity in females than in males. In this project we plan to examine whether sleep deprivation increases the risk for MDD-like behaviors in particular critical periods of brain development and whether gender also impacts this risk. We will use an established rat model and focus on the relative permanence of ELRD effects upon brain maturation. We hypothesize that early ELRD predisposes developing brains to exhibit measurable, abnormal CNS signs in early adulthood that are proxies for CNS signs of MDD in people
Another goal of this work is to determine whether a sex bias prevails in the CNS consequences of ELRD in rodents as it does in humans in terms of incidence of MDD. One major modification to the rat model is a focus on sleep homeostasis as measured by the SWA response to sleep deprivation. We raise the possibility that it is the effects of ELRD on sleep homeostasis and the recovery function of sleep that that confers greatest risk for MDD.
We will investigate in late-adolescent rats the effects of ELRD at two points during early and late perinatal development on subsequent brain maturation, sleep regulation and behavior compared to control animals exposed to REM deprivation (ELRD) in early adolescence, outside of the critical period. In addition, we will also compare sleep homeostasis and SWA response to sleep deprivation between both experimental groups and controls. Potential group differences in hippocampal synaptic plasticity, behavior and neurochemical changes in both hippocampus and prefrontal cortex will be contrasted between groups.
In future (translational) work, we also will determine whether SWA homeostasis and sleep EEG regulation in adolescent ELRD rats conform to the patterns seen in children at high risk for MDD (e.g., NIH R01). Further, results from the planned studies potentially offer direction in the design of drug intervention and other treatments that selectively target sex differences in sleep regulation to improve depression.
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