Activation of Ventrolateral Preoptic Neurons During Sleep

Harvard University, Cambridge, Massachusetts, United States
Science (Impact Factor: 33.61). 02/1996; 271(5246):216-9. DOI: 10.1126/science.271.5246.216
Source: PubMed

ABSTRACT The rostral hypothalamus and adjacent basal forebrain participate in the generation of sleep, but the neuronal circuitry involved
in this process remains poorly characterized. Immunocytochemistry was used to identify the FOS protein, an immediate-early
gene product, in a group of ventrolateral preoptic neurons that is specifically activated during sleep. The retrograde tracer
cholera toxin B, in combination with FOS immunocytochemistry, was used to show that sleep-activated ventrolateral preoptic
neurons innervate the tuberomammillary nucleus, a posterior hypothalamic cell group thought to participate in the modulation
of arousal. This monosynaptic pathway in the hypothalamus may play a key role in determining sleep-wake states.

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Available from: Priyattam J Shiromani, Nov 05, 2014
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    • "In order to assess the neuronal activation after pharmacological treatment, we chose to use the c-FOS method. Indeed, although c-FOS is not a perfect marker of neuronal activation as its expression does not strictly correlate with neuronal discharge [18], [24], it has been extensively used to map the neuronal circuitry controlling the sleep-wake cycle [11], [25]–[30] as well as the activation of TH+, 5-HT+, ChAT+, HCRT+ and HDC+ neurons following diverse experimental paradigms [31]–[41]. C-FOS labelling was not performed after clonidine injection since we believe that the decrease of PS obtained was not strong enough to induce c-FOS expression in the neurons inhibiting PS. "
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    ABSTRACT: GABAergic neurons specifically active during paradoxical sleep (PS) localized in the dorsal paragigantocellular reticular nucleus (DPGi) are known to be responsible for the cessation of activity of the noradrenergic neurons of the locus coeruleus during PS. In the present study, we therefore sought to determine the role of the DPGi in PS onset and maintenance and in the inhibition of the LC noradrenergic neurons during this state. The effect of the inactivation of DPGi neurons on the sleep-waking cycle was examined in rats by microinjection of muscimol, a GABAA agonist, or clonidine, an alpha-2 adrenergic receptor agonist. Combining immunostaining of the different populations of wake-inducing neurons with that of c-FOS, we then determined whether muscimol inhibition of the DPGi specifically induces the activation of the noradrenergic neurons of the LC. Slow wave sleep and PS were abolished during 3 and 5 h after muscimol injection in the DPGi, respectively. The application of clonidine in the DPGi specifically induced a significant decrease in PS quantities and delayed PS appearance compared to NaCl. We further surprisingly found out that more than 75% of the noradrenergic and adrenergic neurons of all adrenergic and noradrenergic cell groups are activated after muscimol treatment in contrast to the other wake active systems significantly less activated. These results suggest that, in addition to its already know inhibition of LC noradrenergic neurons during PS, the DPGi might inhibit the activity of noradrenergic and adrenergic neurons from all groups during PS, but also to a minor extent during SWS and waking.
    PLoS ONE 05/2014; 9(5):e96851. DOI:10.1371/journal.pone.0096851 · 3.23 Impact Factor
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    • "We hypothesize that inhibition of the ventrolateral preoptic nucleus (VLPO) may be a mechanism for mediating the arousal-promoting effects of armodafinil. Neurons of the VLPO are sleep-active and cell-body specific lesions of the VLPO result in profound insomnia in rats.9–11 During the waking period, sleep-active VLPO neurons are inhibited by inputs from brainstem monoaminergic arousal systems, including both dopaminergic and noradrenergic systems.12 "
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    ABSTRACT: Armodafinil is the pharmacologically active R-enantiomer of modafinil, a widely prescribed wake-promoting agent used to treat several sleep-related disorders including excessive daytime sleepiness associated with narcolepsy, shift work sleep disorder, and obstructive sleep apnea/hypopnea syndrome. Remarkably, however, the neuronal circuitry through which modafinil exerts its wake-promoting effects remains unresolved. In the present study, we sought to determine if the wake-promoting effects of armodafinil are mediated, at least in part, by inhibiting the sleep-promoting neurons of the ventrolateral preoptic (VLPO) nucleus. To do so, we measured changes in waking following intraperitoneal administration of armodafinil (200 mg/kg) or the psychostimulant methamphetamine (1 mg/kg) in rats with cell-body specific lesion of the VLPO. Rats with histologically confirmed lesions of the VLPO demonstrated a sustained increase in wakefulness at baseline, but the increase in wakefulness following administration of both armodafinil and methamphetamine was similar to that of intact animals. These data suggest that armodafinil increases wakefulness by mechanisms that extend beyond inhibition of VLPO neurons.
    Nature and Science of Sleep 05/2014; 6:57-63. DOI:10.2147/NSS.S53132
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    • "Extracellular recording studies have identified sleep-active neurons in a region extending from the medial through the lateral POA (Kaitin, 1984; Koyama and Hayaishi, 1994), while it was reported that neurons in the rat ventrolateral preoptic area (VLPO) and median preoptic nucleus (MnPN) exhibited Fos expression following consolidated sleep (Gong et al., 2000). The POA was shown to send GABAergic inhibitory projections to monoaminergic regions, including the locus coeruleus (LC), dorsal raphe nucleus (DRN), and tuberomammilary nucleus (TMN) (Sherin et al., 1996, 1998; Steininger et al., 2001; Uschakov et al., 2007). Consistently, firing patterns of monoaminergic neurons in these nuclei across the sleep-waking cycle are the reciprocal of those observed in POA sleep-active neurons. "
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    ABSTRACT: Populations of neurons in the hypothalamic preoptic area (POA) fire rapidly during sleep, exhibiting sleep/waking state-dependent firing patterns that are the reciprocal of those observed in the arousal system. The majority of these preoptic "sleep-active" neurons contain the inhibitory neurotransmitter GABA. On the other hand, a population of neurons in the lateral hypothalamic area (LHA) contains orexins, which play an important role in the maintenance of wakefulness, and exhibit an excitatory influence on arousal-related neurons. It is important to know the anatomical and functional interactions between the POA sleep-active neurons and orexin neurons, both of which play important, but opposite roles in regulation of sleep/wakefulness states. In this study, we confirmed that specific pharmacogenetic stimulation of GABAergic neurons in the POA leads to an increase in the amount of non-rapid eye movement (NREM) sleep. We next examined direct connectivity between POA GABAergic neurons and orexin neurons using channelrhodopsin 2 (ChR2) as an anterograde tracer as well as an optogenetic tool. We expressed ChR2-eYFP selectively in GABAergic neurons in the POA by AAV-mediated gene transfer, and examined the projection sites of ChR2-eYFP-expressing axons, and the effect of optogenetic stimulation of ChR2-eYFP on the activity of orexin neurons. We found that these neurons send widespread projections to wakefulness-related areas in the hypothalamus and brain stem, including the LHA where these fibers make close appositions to orexin neurons. Optogenetic stimulation of these fibers resulted in rapid inhibition of orexin neurons. These observations suggest direct connectivity between POA GABAergic neurons and orexin neurons.
    Frontiers in Neural Circuits 12/2013; 7:192. DOI:10.3389/fncir.2013.00192 · 3.60 Impact Factor
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