Neuronal ensembles sufficient for recovery sleep and the sedative actions of α2 adrenergic agonists

Abstract

Do sedatives engage natural sleep pathways? It is usually assumed that anesthetic-induced sedation and loss-of-righting-reflex (LORR) arise by influencing the same circuitry to lesser or greater extents. For the α2 adrenergic receptor agonist dexmedetomidine, we find that sedation and LORR are in fact distinct states, requiring different brain areas, the preoptic hypothalamic area and locus coeruleus (LC) respectively. Selective knockdown of α2A adrenergic receptors from the LC abolished dexmedetomidine-induced LORR, but not sedation. Instead, we found that dexmedetomidine-induced sedation resembles the deep recovery sleep that follows sleep deprivation. We used TetTag-pharmacogenetics in mice to functionally mark neurons activated in the preoptic hypothalamus during dexmedetomidine-induced sedation or recovery sleep. The neuronal ensembles could then be selectively reactivated. In both cases NREM sleep, with the accompanying drop in body temperature, was recapitulated. Thus α2 adrenergic receptor-induced sedation and recovery sleep share hypothalamic circuitry sufficient for producing these behavioral states.

Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons

“…We have previously suggested that sedatives produce sleep by interacting with the NREM sleep-inducing circuitry, changing activity in the hypothalamic and brainstem circuits that globally govern arousal (Nelson et al, 2002;Lu et al, 2008;Zhang et al, 2015). We show here that this seems to be the case for zolpidem, too.…”

“…Natural NREM sleep is hypothesized to start when GABA neurons in the preoptic hypothalamus increase their activity onto, among other targets, the wake-promoting histaminergic neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus (Nitz and Siegel, 1996;Sherin et al, 1996Sherin et al, , 1998Zhang et al, 2015). Infusing the GABA A agonist muscimol into this area induces sleep (Lin et al, 1989;Nitz and Siegel, 1996); conversely, injecting GABA A receptor antagonists there decreases the potency of GABAergic anesthetics (Nelson et al, 2002).…”

α2-Adrenergic Receptor and Isoflurane Modulation of Presynaptic Ca2+ Influx and Exocytosis in Hippocampal Neurons

“…9 In another study in vivo, acute knockdown of α 2A -AR expression in the locus coeruleus failed to affect DEX induced sedation. 46 These findings suggest that α 2A -ARs on non-adrenergic neurons mediate their sedative effects. Furthermore, dopamine-β-hydroxylase knockout mice that have no synaptic norepinephrine release show enhanced sensitivity to and delayed emergence from DEX-induced hypnosis compared to wild-type mice.…”

“…45 However, more recent studies have implicated effects of α 2 -AR agonists on non-adrenergic neurons in these actions. 9,46,47 Genetically engineered mice that express α 2A -ARs only in noradrenergic terminals show minimal neurological effects of the α 2 -AR agonist medetomidine, including loss of righting reflex and anesthetic-sparing, in contrast to a strong hypnotic effect in wild-type littermates. 9 In another study in vivo, acute knockdown of α 2A -AR expression in the locus coeruleus failed to affect DEX induced sedation.…”

“…45,48 While indirect neurophysiological studies in vivo continue to invoke this mechanism, 49 genetic studies provide strong evidence that non-adrenergic, not noradrenergic, α 2A -ARs mediate the sedative, hypnotic and anesthetic-sparing actions of α 2 -AR agonists. 9,10,46,47 Plausible targets for the hypnotic and anesthetic-sparing effects of α 2 -AR agonists include direct suppression of synaptic transmission in cortico-cortical 3 and thalamo-cortical networks. 48,49 A recent study in vivo using the TetTag-hM 3 D q system to record and reactivate neuronal groups activated by DEX implicates the preoptic hypothalamus and neighboring dorsal structures in DEX-induced sedation.…”