Paradoxical function of orexin/hypocretin circuits in a mouse model of Huntington's disease

Huntington's disease (HD) is a neurodegenerative disorder involving progressive motor disturbances, cognitive decline, and desynchronized sleep-wake rhythms. Recent studies revealed that restoring normal sleep-wake cycles can improve cognitive function in HD mice, suggesting that some sleep/wake systems remain operational and thus represent potential therapeutic targets for HD. Hypothalamic neurons expressing orexins/hypocretins (orexin neurons) are fundamental orchestrators of arousal in mammals, but it is unclear whether orexin circuits operate normally in HD. Here we analyzed the electrophysiology, histology, and gene expression of orexin circuits in brain slices from R6/2 mice, a transgenic model of HD with a progressive neurological phenotype. We report that in R6/2 mice, the size of an electrically distinct subpopulation of orexin neurons is reduced, as is the number of orexin-immunopositive cells in some hypothalamic regions. R6/2 orexin cells display altered glutamatergic inputs, and have an abnormal circadian profile of activity, despite normal circadian rhythmicity of the suprachiasmatic nucleus (SCN), the "master clock" of the brain. Nevertheless, even at advanced stages of HD, intrinsic firing properties of orexin cells remain normal and suppressible by serotonin, noradrenaline, and glucose. Furthermore, histaminergic neurons (key cells required for the propagation of orexin-induced arousal) also display normal responses to orexin. Together, these data suggest that the orexin system remains functional and modifiable in HD mice, although its circadian activity profile is disrupted and no longer follows that of the SCN.