Control of wakefulness by lateral hypothalamic glutamatergic neurons in male mice

Abstract

The lateral hypothalamus (LH) plays a key role in the maintenance of cortical activation and wakefulness. In the LH, the two main neuronal cell populations consist of excitatory glutamatergic neurons and inhibitory GABAergic neurons. Recent studies have shown that inhibitory LH GABAergic neurons are wake-promoting. However, the mechanism by which excitatory LH glutamatergic neurons contribute to sleep-wake regulation remains unclear. Using fiber photometry in male mice, we demonstrated that LH glutamatergic neurons exhibited high activities during both wakefulness and rapid eye movement sleep. Chemogenetic activation of LH glutamatergic neurons induced an increase in wakefulness that lasted for 6 hr, whereas suppression of LH glutamatergic neuronal activity caused a reduction in wakefulness. Brief optogenetic activation of LH glutamatergic neurons induced an immediate transition from slowwave sleep to wakefulness, and long-lasting optogenetic stimulation of these neurons maintained wakefulness. Moreover, we found that LH-locus coeruleus/parabrachial nucleus and LH-basal forebrain projections mediated the wake-promoting effects of LH glutamatergic neurons. Taken together, our data indicate that LH glutamatergic neurons are essential for the induction and maintenance of wakefulness. The results presented here may advance our understanding of the role of LH in the control of wakefulness.

Parabrachial nucleus astrocytes regulate wakefulness and isoflurane anesthesia in mice

“…For example, optogenetic stimulation of VTA dopaminergic neurons generates long-time wakefulness in mice and restores the righting reflex after isoflurane-induced general anesthesia (Taylor et al, 2016). Activation of the glutamatergic neurons in the lateral hypothalamus induces instant wakefulness from sleep, lengthens the general anesthesia induction time and accelerates emergence from general anesthesia (Wang et al, 2021;Zhao et al, 2021). Additionally, the activation of noradrenergic neurons in the locus coeruleus induces instant arousal and markedly facilitates behavioral emergence from general anesthesia (Vazey and Aston-Jones, 2014).…”

Hypothalamic supramammillary neurons that project to the medial septum control wakefulness

“…Thus, wake-active SuM MS projecting neurons identified here are likely to be glutamatergic and innervate MS Vglut2 neurons, which are known to control wakefulness by activating lateral hypothalamus glutamatergic neurons (An et al, 2021;Wang et al, 2021).…”

“…In particular, SuM MS projecting neurons are well-established to be primarily glutamatergic (Kesner et al, 2021), and SuM Vglut2 neurons can monosynaptically innervate MS Vglut2 neurons by releasing glutamate (Kesner et al, 2021). Thus, wake-active SuM MS projecting neurons identified here are likely to be glutamatergic and innervate MS Vglut2 neurons, which are known to control wakefulness by activating lateral hypothalamus glutamatergic neurons (An et al, 2021; Wang et al, 2021).…”

GABAergic neurons in the rostromedial tegmental nucleus are essential for rapid eye movement sleep suppression

“…In addition to GABAergic neurons, the LH also contains a large number of glutamatergic neurons that are active during REM sleep and wakefulness. Activation of these neurons induces and maintains arousal 56 . In the LH, neuropeptidergic neurons expressing the neuropeptides MCH and orexin, each of which only comprises a small population of LH neurons 49 , have been shown to promote REM sleep 57 and prolong REM sleep episodes 58 , respectively.…”