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


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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    • "Brain state transitions between sleep and wakefulness produce robust changes in the spike rate and pattern of distinct classes of neurons across the brain. Neurons in the brainstem, midbrain and basal forebrain are particularly responsive to brain state changes, tuning their activity to produce a homeostatic balance in the sleep-wake cycle (Aston-Jones and Bloom, 1981; Fornal et al., 1985; Steriade et al., 1991; Sherin et al., 1996; Szymusiak et al., 1998; Steininger et al., 1999; Lee et al., 2005). "
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    ABSTRACT: Cholinergic neurons of the pedunculopontine nucleus (PPN) are most active during the waking state. Their activation is deemed to cause a switch in the global brain activity from sleep to wakefulness, while their sustained discharge may contribute to upholding the waking state and enhancing arousal. Similarly, non-cholinergic PPN neurons are responsive to brain state transitions and their activation may influence some of the same targets of cholinergic neurons, suggesting that they operate in coordination. Yet, it is not clear how the discharge of distinct classes of PPN neurons organize during brain states. Here, we monitored the in vivo network activity of PPN neurons in the anesthetized rat across two distinct levels of cortical dynamics and their transitions. We identified a highly structured configuration in PPN network activity during slow-wave activity that was replaced by decorrelated activity during the activated state (AS). During the transition, neurons were predominantly excited (phasically or tonically), but some were inhibited. Identified cholinergic neurons displayed phasic and short latency responses to sensory stimulation, whereas the majority of non-cholinergic showed tonic responses and remained at high discharge rates beyond the state transition. In vitro recordings demonstrate that cholinergic neurons exhibit fast adaptation that prevents them from discharging at high rates over prolonged time periods. Our data shows that PPN neurons have distinct but complementary roles during brain state transitions, where cholinergic neurons provide a fast and transient response to sensory events that drive state transitions, whereas non-cholinergic neurons maintain an elevated firing rate during global activation.
    Full-text · Article · Aug 2015 · Frontiers in Neural Circuits
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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.
    Full-text · Article · May 2014 · PLoS ONE
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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.
    Full-text · Article · May 2014 · Nature and Science of Sleep
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