Circadian and dark pulse regulation of orexin cellular activation. (A) Mid-subjective day: inhibitory output (broken red lines) from the SCN is high, with cells in the medial (mTH) and lateral tuberal hypothalamus (lTH), including orexin neurons, minimally active with little/no excitatory outputs (green arrows) to the IGL and median raphe (MR) whose cellular activity/output is also low. Orexin efferents may (?) act via the PeriSCN to suppress SCN activity . (B) Late subjective day: SCN inhibitory output reduced, orexin cells submaximally activated, with increased excitatory output to the PeriSCN, IGL, and MR. (C) Mid-subjective night: SCN inhibitory output minimal, orexin cellular activation maximal. Increased excitatory input to the PeriSCN, IGL and MR increases inhibitory outputs to the SCN. (D) Dark pulse at mid-subjective day interrupts retinal input, reducing SCN activity and its inhibition of the mTH and lTH. Disinhibited orexin cells excite PeriSCN, IGL and MR neurons whose outputs suppress the SCN. (E) Circadian variation in SCN (blue line) and orexin (green line) activation and the effects of a daytime dark pulse (timing and duration indicated by filled horizontal box) on this activation (broken lines). In (A-D), the width of the lines indicates the level of excitatory or inhibitory signal. NPY = neuropeptide Y; 5-HT = serotonin; GABA = γ-aminobutyric acid.