Narcoleptic patients suffer from excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep attacks. Other identifying feature of narcolepsy is the entry into REM sleep directly from wakefulness. The disease appears to be a disorder of mechanisms controlling REM sleep because some narcoleptic symptoms, such as cataplexy and hypnagogic hallucinations are components of REM sleep, and in narcolepsy these components inexplicably encroach into the waking state.There is considerable evidence that acetylcholine plays important role in triggering REM sleep, and we have contributed some of this data. Specifically, it is now clear that a group of cholinergic neurons in the lateral dorsal tegmental and pedunculopontine tegmental Pffl nuclei are important for REM sleep onset. We now have data that a subset of these cholinergic neurons show immediate- early gene expression, as assessed by the presence of the c-fos protein, Fos, in conjunction with cholinergically-induced REM sleep. The function of c-fos expression in these neurons is unclear at this time but, among various possibilities, such cascades, in pools of REM sleep related neurons, might reset the """"""""need"""""""" for REM sleep. For instance, narcoleptics are urged to take periodic naps and this is extremely effective in alleviating their excessive sleepiness and cataplectic attacks. The first series of experiments will determine where immediate early gene expression occurs and under what circumstances. This is necessary in order to accomplish the long-term goal of determining what is being coded during sleep and REM sleep. Fos-like immunoreactivity (Fos-LI) will be examined in response to pharmacological manipulations of REM sleep. Microinjections of cholinergic drugs and the noradrenergic alpha- I antagonist, idazoxan, will be made into the medial pontine reticular formation (mPRF), an area which interacts with the LDT-PFT cholinergic neurons to produce REM sleep. Fos-L1 will be examined in neurotransmitter specific neurons. In another study, the role of NMDA and non-NMDA receptors in the LDTP~ will be assessed by examining changes in REM sleep and Fos-LI in neurotransmitter specific neurons. The second series of experiments will examine the age-related development of muscarinic receptors and choline acetyltransferase, the acetylcholine synthesizing enzyme, in a line of rats bred for increased cholinergic function. The changes in cholinergic markers will be correlated with development of REM sleep. Cur studies, in the adult rats, have shown that compared to age-matched controls, the cholinergic rats show 35% more REM sleep, 22% more LDT-P~ cholinergic soma, and II more pontine muscarinic receptors.Collectively, these studies are a logical next step in our efforts to understand how changes in the cholinergic system influence REM sleep.
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