The broad purpose of this series of studies is to use work in animals to understand the physiological and pharmacological mechanism controlling sleep, and thereby provide a sound baiss for the understanding and treatment of human sleep disorders, both primary and secondard to medical and physchiatric conditions. Previous work has greatly advanced our knowledge of brainstem mechanisms controlling the rapid eye movement (REM) phase of sleep, suggesting that brainstem neurons using acetylcholine as a neurotransmitter (cholinergic neurons) promote this phase of sleep. This application builds on, and extends this work. The key techniques to be used are a novel combination of microdialysis and extramcellular unit recording in freely moving cats, intracellular recordings in naturally sleeping cats and the rat in vitro slice preparation. Hypotheses to be investigated include whether increases in adenosine following prolonged wakefulness (and increased etabolic activity) act as a factor reducing wakefulness (W) and increasing the Slow Wave Sleep (SWS or nonREM) phase of sleep. We hypothesize adenosine increases act most strongly on cholinergic neurons in the basal forebrain and the mesopontine area that promote W and an activated electroencephalogram (EEG). New data suggest strong adenosine state-altering effects on the dorsal raphe nucleus (DRN) also. Microdialysis measurements of extracellular adenosine and delivery of adenosine transport inhibitors and concomitant unit recordings will be used for in vivo tests, while in vitro studies will examine mechanisms of action. The hypothesis that serotonin-containing DRN neurons disinhibit cholinergic neurons and allow REM sleep to occur when these DRN neurons slow discharge during SWS and REM will also be evaluated; in vivo and in vitro techniques will examine the degree to which each of four factors may control the slowing of DRN discharge: GABA, 5HT collateral feedback, adenosine, and presynaptic disfacilitation of adrenergic input. We will use intracellular in vivo recording and double labeling to determine if the REM-on neurons (=discharge activity selective for REM sleep, and possibly controlling this state) and the Waking- and REM-on neurons (W/R-on, possibly controlling EEG activation in both W and REM) recorded in the mesopontine cholinergic zone can be positively identified as cholinergic. Using microdialysis and unit recording we will test the hypothesis that the REM-on neurons of this cholinergic zone differ from W/R-on neurons by their inhibtability by DRN input acting on 5HT1A receptors. Finally we will examine the Ventrolateral preoptic Area (VLPOA) of hypothalamus, where earlier work with cFos protein indicated a selective activation of a population of neurons during SWS. Using microdialysis (MD) we will evaluate whether spontaneous extracellular GABA levels decrease during SWS, suggesting disinhibition, and whether MD-perfused bicuculline promotes SWS, as it did in preliminary data. We will also evaluate the extent of cholinergic control (from basal forebrain) and of histaminergic control (from the tuberomammillary nucleus). In vitro work will examine the post- and pre-synaptic effects of these and other neurotransmitters on VLPOA neurons identified with biocytin and GAD immunohistochemical labeling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH039683-15
Application #
2674831
Study Section
Psychobiology, Behavior, and Neuroscience Review Committee (PBN)
Project Start
1984-09-30
Project End
2002-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
15
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Harvard University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Cordeira, Joshua; Kolluru, Sai Saroja; Rosenblatt, Heather et al. (2018) Learning and memory are impaired in the object recognition task during metestrus/diestrus and after sleep deprivation. Behav Brain Res 339:124-129
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Kim, Youngsoo; Chen, Lichao; McCarley, Robert W et al. (2013) Sleep allostasis in chronic sleep restriction: the role of the norepinephrine system. Brain Res 1531:9-16

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