Huntington's disease (HD) is associated with sleep and circadian disturbances in addition to hallmark motor and cognitive impairments. Electrophysiological studies on HD mouse models have revealed an aberrant oscillatory activity at the beta frequency, during sleep, that is associated with HD pathology. Moreover, HD animal models display an abnormal sleep-wake cycle and sleep fragmentation. In this study, we investigated a potential involvement of the orexinergic system dysfunctioning in sleep-wake and circadian disturbances and abnormal network (i.e., beta) activity in the R6/1 mouse model. We found that the age at which orexin activity starts to deviate from normal activity pattern coincides with that of sleep disturbances as well as the beta activity. We also found that acute administration of Suvorexant, an orexin 1 and orexin 2 receptor antagonist, was sufficient to decrease the beta power significantly and to improve sleep in R6/1 mice. In addition, a 5-day treatment paradigm alleviated cognitive deficits and induced a gain of body weight in female HD mice. These results suggest that restoring normal activity of the orexinergic system could be an efficient therapeutic solution for sleep and behavioral disturbances in HD.

The expression of motivated behaviors depends on both external and internally-arising neural stimuli, yet the intrinsic releasing mechanisms for such variably occurring behaviors remain elusive. In isolated nervous system preparations of Aplysia, we have found that irregularly expressed cycles of motor output underlying food-seeking behavior arise from regular membrane potential oscillations of varying magnitude in an identified pair of interneurons (B63) in the bilateral buccal ganglia. This rhythmic signal, which is specific to the B63 cells, is generated by organelle-derived intracellular calcium fluxes that activate voltage-independent plasma membrane channels. The resulting voltage oscillation spreads throughout a subset of gap junction-coupled buccal network neurons and by triggering plateau potential-mediated bursts in B63, can initiate motor output driving food-seeking action. Thus, an atypical neuronal pacemaker mechanism, based on rhythmic intracellular calcium store release and intercellular propagation, can act as an autonomous intrinsic releaser for the occurrence of a motivated behavior.

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The expression of motivated behaviors depends on both external and internally-arising neural stimuli, yet the intrinsic releasing mechanisms for such variably occurring behaviors remain elusive. In isolated nervous system preparations of Aplysia, we have found that irregularly expressed cycles of motor output underlying food-seeking behavior arise from regular membrane potential oscillations of varying magnitude in an identified pair of interneurons (B63) in the bilateral buccal ganglia. This rhythmic signal, which is endogenous and specific to the B63 cells, is generated by organelle-derived intracellular calcium fluxes that activate voltage-independent plasma membrane channels. The resulting voltage oscillation spreads throughout a subset of gap junction-coupled buccal network neurons and by triggering plateau potential-mediated bursts in B63, can initiate motor output driving food-seeking action. Thus, an atypical neuronal pacemaker mechanism, based on rhythmic intracellular calcium store release and intercellular propagation, can act as an autonomous intrinsic releaser for the occurrence of a motivated behavior.