This research program was initiated in 1999 in response to RFA HL99001. The goal of the RFA was to stimulate improved molecular, cellular, and systems approaches to investigate sleep in mice. Every human gene has a mouse homologue. This remarkable homology means that the mouse genome may provide unique insights into human disease. Advances in sequencing the mouse genome now require complimentary data regarding normal and abnormal phenotypes. In accord with consensus statements published by The Jackson Laboratory, this application focuses on the C57BL/6J (B6) mouse strain. The long-term objectives are to advance scientific knowledge by providing data not presently available concerning molecules that regulate ACh release and alter electroencephalographic (EEG) excitability, sleep, and breathing.
Aim 1 will test the hypothesis that microinjecting neostigmine into the pontine reticular formation of B6 mouse causes a REM sleep-like state and changes in breathing that are concentration-dependent, site-specific within the pons, and blocked by atropine.
Aim 2 will use in vivo microdialysis and high performance liquid chromatography (HPLC) to test the hypothesis that dialysis delivery of an adenosine A1 receptor agonist into the prefrontal cortex of B6 mouse will decrease cortical ACh release and EEG power, and delay wake-up time from anesthesia.
Aim 3 will use combined microdialysis and microinjection to test the hypothesis that ACh release in the pontine reticular formation of B6 mouse is altered by nitric oxide donors and by inhibitors of nitric oxide synthase.
Aim 4 will use a quantitative Western assay to test the hypothesis that brain expression of M2 muscarinic receptor protein varies significantly as a function of mouse strain and brain region.
These aims will take this research program in new directions by developing a pharmacological model of rapid eye movement sleep in mouse (Aim 1), quantifying the effects of endogenous neuromodulators on ACh release (Aims 2 and 3), and initiating strain comparisons of muscarinic receptor protein expression (Aim 4). The unifying conceptual scheme of this proposal is that higher level phenotypes such as sleep and breathing (Aim 1) emerge from the expression of lower level phenotypes such as ACh (Aims 2 and 3) and muscarinic cholinergic receptors (Aim 4).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065272-08
Application #
7114843
Study Section
Respiratory Physiology Study Section (RESP)
Program Officer
Twery, Michael
Project Start
1999-09-30
Project End
2008-02-28
Budget Start
2006-09-01
Budget End
2008-02-28
Support Year
8
Fiscal Year
2006
Total Cost
$255,838
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Angel, Chelsea; Glovak, Zachary T; Alami, Wateen et al. (2018) Buprenorphine Depresses Respiratory Variability in Obese Mice with Altered Leptin Signaling. Anesthesiology 128:984-991
Glovak, Zachary; Mihalko, Sara; Baghdoyan, Helen A et al. (2017) Leptin status alters buprenorphine-induced antinociception in obese mice with dysfunctional leptin receptors. Neurosci Lett 660:29-33
Zhang, Hao; Wheat, Heather; Wang, Peter et al. (2016) RGS Proteins and G?i2 Modulate Sleep, Wakefulness, and Disruption of Sleep/ Wake States after Isoflurane and Sevoflurane Anesthesia. Sleep 39:393-404
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Filbey, William A; Sanford, David T; Baghdoyan, Helen A et al. (2014) Eszopiclone and dexmedetomidine depress ventilation in obese rats with features of metabolic syndrome. Sleep 37:871-80
Vanini, Giancarlo; Nemanis, Kriste; Baghdoyan, Helen A et al. (2014) GABAergic transmission in rat pontine reticular formation regulates the induction phase of anesthesia and modulates hyperalgesia caused by sleep deprivation. Eur J Neurosci 40:2264-73
Watson, S L; Watson, C J; Baghdoyan, H A et al. (2014) Adenosine A? receptors in mouse pontine reticular formation modulate nociception only in the presence of systemic leptin. Neuroscience 275:531-9
Hambrecht-Wiedbusch, Viviane S; Mitchell, Melinda F; Firn, Kelsie A et al. (2014) Benzodiazepine site agonists differentially alter acetylcholine release in rat amygdala. Anesth Analg 118:1293-300
Gettys, George C; Liu, Fang; Kimlin, Ed et al. (2013) Adenosine A(1) receptors in mouse pontine reticular formation depress breathing, increase anesthesia recovery time, and decrease acetylcholine release. Anesthesiology 118:327-36

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