Sleep deprivation-induced pre- and postsynaptic modulation of orexin neurons.

Abstract Sleep/wake states are controlled by sleep- and wake-promoting systems, and transitions between states are thought to be regulated by their reciprocal inhibition and homeostatic sleep need. Orexin neurons are known to promote wake maintenance and stabilize the sleep/wake switch. Thus, we asked whether orexin neurons are modulated by homeostatic sleep need. Rats were sleep deprived or left undisturbed to rest for 6 h, then acute brain slices were generated for patch clamp recordings. We found that sleep deprivation increased firing and reduced spike frequency adaptation in response to excitatory drive in orexin neurons. These changes were specific to D-type orexin neurons which, unlike H-type orexin neurons, lack A-type current. In D-type orexin neurons, sleep deprivation decreased afterhyperpolarizing potential, which was associated with increased gain, measured as the slope of the input-output relationship. These effects were mimicked by inhibition of SK channels. Furthermore, sleep deprivation resulted in presynaptic inhibition of excitatory inputs to both D-type and H-type orexin neurons, which preferentially affected sparse synaptic inputs while sparing high frequency synaptic activities. Taken together, our results indicate that sleep deprivation modulates the gain control and synaptic gating in orexin neurons. These pre-and postsynaptic changes would tune orexin neurons to strong wake-promoting excitatory signals, while dampening weak synaptic inputs to allow transition to sleep in the absence of such strong signals. These mechanisms are consistent with a role of orexin neurons not only as a key state stabilizer, but also as a homeostatic wake integrator in the sleep/wake switch. This article is part of the Special Issue entitled ‘Hypothalamic Control of Homeostasis’.