Control of wakefulness by lateral hypothalamic glutamatergic neurons in male mice

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 slow-wave 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.

Automated summary

The lateral hypothalamus (LH) plays a crucial role in maintaining and inducing wakefulness, with its glutamatergic neurons being essential for these processes while GABAergic neurons promote wakefulness. Through chemogenetic and optogenetic manipulations, the activity of LH glutamatergic neurons was shown to directly impact the duration and transitions of wakefulness, mediated by projections to the locus coeruleus/parabrachial nucleus and basal forebrain. This study offers new insights into the mechanisms of sleep-wake regulation and the specific role of LH in controlling wakefulness.