Sleep-active neurons

Studies of sleep-active neuronal discharge across the sleep-wake cycle in freely moving animals provide important information about the hypnogenic process (see below) but, because of sampling limitations, are not suitable for systematic mapping of the exact locations of putative hypnogenic neurons. The application of the c-Fos immunoreactivity (IR) method to map sleep-active neurons has stimulated several advances. C-Fos IR is a marker of neuronal activation in most brain sites immunohistochemically labeled neurons can be mapped systematically. The localization of c-Fos IR following sustained sleep, but not... 

Some arousal-related neurotransmitters, including noradrenaline, serotonin, and acetylcholine, feed back to inhibit POA sleep-active neurons. This aspect of the system has been reviewed previously (McGinty Szymusiak, 2000 Saper et al., 2001). Therefore, once sleep-active neurons are activated, arousal-related neurons are inhibited, and inhibitory control of sleep-active neurons by arousal systems is reduced. In this way, sleep onset is facilitated. That is, the mutually inhibitory systems can switch more quickly from wake to sleep, and back. These mutually inhibitory interactions also promote stability of both waking and sleep. 

Sleep-related VLPO neurons exhibit increased discharge within NREM during recovery sleep after deprivation, and their discharge rates were correlated with the amount of SWA within sleep episodes (Szymusiak et al., 1998). Thus, VLPO-type sleep-active neurons may directly control the SW content of the NREM EEG, presumably by suppressing arousal systems. 

A fundamental question concerns the neurochemical mechanisms that regulate the activity of POA sleep-active neurons. Currently, this problem has been approached through studies of putative sleep factors , endogenous... 

IL-ip is a well documented sleep factor (reviewed by Obal Krueger, 2003). Its administration increases sleep, its blockade decreases sleep and sleep rebound, and its transcription increases during waking. IL-1 receptor knock-out mice sleep less. Local application of IL-1 p in POA also stimulates NREM sleep. We examined the effects of local administration of IL-1 p and an antagonist through microdialytic application adjacent to lateral POA neurons (Alam et at, 2004). Neuronal activity is recorded within 0.5-1.0 mm of a microdialysis membrane in unrestrained rats. IL-ip potently inhibited the activity of 79% of wake-active neurons. The inhibitory response to IL-ip of wake-active neurons could be blocked by pre-treatment with IL-lra, an IL-ip antagonist. IL-ip application also excited some sleep-active neurons, but this response was inconsistent. 

Most hypnotic drugs act on GABA receptors. It is reasonable to hypothesize that hypnotic actions are mediated by the GABA receptors on wake-promoting neurons innervated by POA sleep-active neurons, but there is little study of this problem. However, there is evidence that GABAergic anesthetics induce c-Fos IR in the VLPO and suppress c-Fos IR in histaminergic neurons (Nelson et al, 2002). 

Figure 2.4 Flip-flop switch model of wake and slow wave sleep active systems. Mutually inhibitory connections exist between GABAergic/Galaninergic slow wave sleep active neurons in the ventrolateral preoptic area (VLPO) of the anterior hypothalamus and aminergic neurons in the hypothalamus (histamine (HA) neurons in the tuberomammillary nucleus (TMN)) and brainstem (serotonin (5-HT) neurons in the dorsal raphe (DR) and noradrenaline (NA) neurons in the locus coeruleus (LC)). Orexinergic neurons in the perifornical hypothalamus (PFH) stabilize the waking state via excitation of the waking side of the flip-flop switch (aminergic neurons).

Sleep-active neurons have been identified in the ventrolateral and medial preoptic areas. These neurons exhibit increased discharge during SWS and REMS rather than W. Sleep-active neurons colocalize GABA and are excited by adenosine and prostaglandin D2 (McGinty Szymusiak, 2001) (Table 9.3). 

Morairty, S., Rainnie, D., McCarley, R. Greene, R. (2004). Disinhibition of ventrolateral preoptic area sleep-active neurons by adenosine a new mechanism for sleep promotion. Neuroscience 123 (2), 451-7. 

An unanswered question about adenosine is how this inhibitory neurotransmitter activates the ventrolateral preoptic area of the hypothalamus (VLPO), which contains a population of sleep-active neurons and is hypothesized to be... 

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