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Physiology of the mesopontine cholinergic/nitric oxide system : mechanisms of behavioral state control

University of British Columbia

Historically, research on questions which address the neurobiological mechanisms of behavioral state control has focused upon identifying neuronal candidates for the ascending reticular activating system. Several lines of evidence now suggest that mesopontine cholinergic neurons indeed play a key role in EEG desynchronized states as well as in the triggering of rapid eye movement (REM) sleep. Using in vitro patch clamp and in vivo microdialysis techniques combined with histochemical and immunocytochemical staining, some of the intrinsic biophysical, pharmacological, and behavioral properties of mesopontine cholinergic/nitrergic neurons were characterized. Several lines of evidence had suggested that inhibition of brainstem cholinergic neurons by noradrenergic neurons of the locus ceruleus is a key mechanism of behavioral state control; however, this effect had never been directly demonstrated. The whole-cell patch clamp technique was used to investigate the effects of noradrenaline (NA) on mesopontine cholinergic neurons in vitro. The majority of identified cholinergic neurons hyperpolarized in response to NA, an effect mediated by an α₂receptor via activation of an outward potassium current. In addition, cholinergic neurons expressed intrinsic ionic currents which predisposed them to burst-firing activity, a feature which may underly PGO activity. To test the hypothesis that these cells would be selectively active during REM sleep, in vivo microdialysis was used to monitor acetylcholine (ACh) release across behavioral state in the rat thalamus, a major projection site of mesopontine cholinergic neurons. ACh was released at equal rates during wake and REM sleep, and significantly less during slow-wave sleep (SWS). Retrograde tracing combined with ChAT immunohistochemistry verified that the majority of cholinergic projections in the vicinity of the dialysis probe originated in the mesopontine tegmentum. Finally, a feature of mesopontine cholinergic neurons which has been addressed to a limited extent is the role of nitric oxide (NO) synthase, which is known to co-localize in these cells. Using the hemoglobin-trapping technique coupled with in vivo microdialysis, NO production in the thalamus was measured across the sleep-wake cycle. NO concentrations were high during wake and REM sleep as compared to SWS. Taken together, these data provide a broad profile of some of the properties of the mesopontine cholinergic/nitric oxide system.

Thesis/Dissertation

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2009-04-06

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http://hdl.handle.net/2429/6836

Neuroscience

University of British Columbia

UBCV

DSpace