Modulation of thalamic neuron excitability by orexins.

Orexins (hypocretins) are peptides of hypothalamic origin that play an important role in maintaining wakefulness. Reduced orexin levels have been associated with an increased incidence of narcolepsy. Considering thalamic nuclei are interconnected with virtually all neocortical regions and the thalamus has been found to produce distinct activities related to different levels of arousal, we have examined the actions of orexins on thalamic neurons using an in vitro thalamic slice preparation. The orexins (orexin-A and orexin-B) produced distinct actions within different intralaminar nuclei. Orexin-B strongly depolarized the majority of centrolateral nucleus (CL) neurons (71%), but depolarized a significantly smaller population of parafascicular nuclei (Pf) neurons (10%). In the mediodorsal thalamic nucleus (MD), orexin-B depolarized 21% of the neurons tested. Overall, orexin-B was found to be more potent than Orexin-A. Orexin-A depolarized a significantly smaller population of CL neurons (23%), but had no effect on Pf neurons. In addition, orexin-A produced a small depolarization in 28% of neurons in the thalamic reticular nucleus (TRN). Both orexin-A and orexin-B had no effect on neurons in the lateral posterior (LP), lateralodorsal (LD), posterior thalamic (Po), ventrobasal (VB) nucleus and lateral geniculate nucleus (LGN). The depolarizing actions of orexins were sufficient to alter the firing mode of these neurons from a burst- to tonic-firing mode. The excitatory actions of orexin-B result from a decrease in the apparent leak potassium current (Kleak). The orexin-B mediated excitation was also attenuated by bupivacaine suggesting the involvement of Kleak current. Further, the actions of orexin-B were occluded by the classical neurotransmitter dopamine, indicating the orexins may share similar ionic mechanisms. Thus, the depolarizing actions of orexins may play a key role in altering the firing mode of thalamic neurons associated with different states of consciousness.