Physiological roles of the regulatory system of orexin-producing neurons

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We studied the physiological roles of the regulatory system of orexin-producing neurons. We examined the involvement of GABA_B receptors in the regulation of orexin neurons, by utilizing mice with a conditional deletion of the GABA_<B1> subunit in these neurons. The frequency of spontaneous fast TPSCs mediated by GABA_A receptors was markedly increased to compensate for an increase in orexin receptor-1 mediated excitation of local GABAergic interneurons. Sleep state analysis of the conditional GABA_<B1> knockout mice revealed that these mice displayed a robust fragmentation of the sleep/waking states. These observations suggest that pre- and postsynaptic GABA_B receptors in orexin neurons are essential for the normal regulation of orexin neuronal activity, and regulation of sleep/wakefulness states in vivo. We also revealed the involvement of BRS-3 in the regulation of orexin neuron. We also found that orexin-overexpresisng mice exhibit fragmentation of NREM sleep, suggesting the importance of inhibitory mechanisms of orexin neurons in maintenance of normal sleep.