Histamine regulates activities of neurons in the ventrolateral preoptic nucleus

The neurons responsible for the onset of sleep are thought to be located in the ventrolateral preoptic nucleus (VLPO), which receives a dense histaminergic innervation from the tuberomammillary nucleus (TMN). Yet, the role of histamine in the VLPO remains unclear. Here we report that microinjection of histamine into the VLPO increases the motor activity of rats. Moreover, a bath application of histamine to acute brain slices inhibits the majority of VLPO neurons, which are also inhibited by noradrenaline. Histamine hyperpolarizes the membrane potential and lowers the firing rate. These effects are associated with an increase in the frequency but not in the amplitude of spontaneous GABA_A receptor-mediated inhibitory postsynaptic currents, and are blocked by gabazine or tetrodotoxin, indicating an indirect action. Conversely, on the noradrenaline-excited VLPO neurons, histamine depolarizes the membrane potential and increases the firing rate via activation of H₁ and H₂ subtype histamine receptors. Moreover, histamine-induced depolarization persists in the presence of gabazine or tetrodotoxin, indicating a direct action. Based on these findings, we propose that in the VLPO, noradrenaline-inhibited neurons may normally be under the inhibitory control of noradrenaline-excited neurons. By facilitating the inhibitory control of the noradrenaline-excited neurons, histamine may inhibit the noradrenaline-inhibited neurons, resulting in excitation of histamine-releasing neurons in the TMN through disinhibition. This effect of histamine in the VLPO may contribute to the maintenance of wakefulness.The neurons responsible for the onset of sleep are known to be located in the ventrolateral preoptic nucleus (VLPO) situated in the region of the brain known as the hypothalamus. VLPO contains two types of neurons: the 'majority' and the 'minority' neurons, which are inhibited or excited by noradrenaline, respectively. VLPO receives a dense histaminergic innervation from the tuberomammillary nucleus, also situated in the hypothalamus. We show that when applied to VLPO of rats, histamine increases wakefulness. Moreover, histamine directly excites the 'minority' VLPO neurons, which results in inhibition of the 'majority' VLPO neurons. These results show that through this inhibition of the 'majority' VLPO neurons, histamine may excite the histamine-releasing neurons in the tuberomammillary nucleus through disinhibition. This effect of histamine in VLPO may contribute to the maintenance of wakefulness. This new knowledge on histamine regulation of VLPO neurons helps us better understand the regulation of wake-sleep cycles.