Orcadianindependent Actions Of Hcrt

The wake-promoting actions of HCRT suggest a potential role of HCRT in circadian-dependent alterations in sleep and waking. In studies that have examined rates of HCRT release as assessed by in vivo microdialysis, HCRT levels increase slowly over the active period and decreases during the sleep period.100 Similarly, when measured within cisternal cerebrospinal fluid, highest levels of HCRT-1 are observed during the latter third of the active period and lowest levels at the end of the sleep period.102

Although the temporal resolution of these measures is limited, these observations suggest that HCRT release is not initiating waking per se, but instead may be important in

MPOA MS

MPOA MS

¡PRE1 PRE2 POST1 PQST2 POST3

Time

Figure 3. Effects of bilateral HCRT-1 infusions into MPOA, MS and SI on time spent awake (Total Waking). Symbols represent mean (± SEM) time (sec) spent awake per 30-min epoch. PRE1 and PRE2 represent pre-infusion epochs and POST1-POST3 represent post-infusion epochs. For MPOA, total time spent awake was significantly increased during POST1 in both the 0.07 nmol and 0.01 nmol groups and during POST2 and POST3 for the 0.07 nmol group. Less robust increases in waking were observed following infusions of HCRT within MS and SI. *P<0.01 significantly different from vehicle-treated animals. Modified from35.

¡PRE1 PRE2 POST1 PQST2 POST3

Time

Figure 3. Effects of bilateral HCRT-1 infusions into MPOA, MS and SI on time spent awake (Total Waking). Symbols represent mean (± SEM) time (sec) spent awake per 30-min epoch. PRE1 and PRE2 represent pre-infusion epochs and POST1-POST3 represent post-infusion epochs. For MPOA, total time spent awake was significantly increased during POST1 in both the 0.07 nmol and 0.01 nmol groups and during POST2 and POST3 for the 0.07 nmol group. Less robust increases in waking were observed following infusions of HCRT within MS and SI. *P<0.01 significantly different from vehicle-treated animals. Modified from35.

maintaining sustained waking, particularly toward the end of the activity portion of the circadian cycle (diurnal for monkeys, nocturnal for rats).

These observations are consistent with studies that have assessed neuronal/genomic activity within HCRT neurons using immunohistochemical measures of the protein product (Fos) of the immediate-early gene, c-fos, across various behavioral states. In these studies, waking per se was not associated with an increase in Fos immunoreactivity (Fos-ir)37 within HCRT-synthesizing neurons (prepro-HCRT-ir neurons). Thus, as shown in Figure 4, low levels of Fos-ir are observed in HCRT-synthesizing neurons in rats that are spontaneously awake diurnally or nocturnally. Similar results were observed for HCRT-receptor-expressing (HCRT-r1) neurons within basal forebrain regions (MS, MPOA, SI) and LC (Figure 4).37 Interestingly, correlation analyses indicated that the relatively small amount of Fos-ir observed in HCRT-synthesizing ne.37

Additional studies have examined the degree to which the behavioral actions of HCRT are circadian-dependent. In these studies, both circadian-dependent and circadian-independent behavioral actions of HCRT-1 have been observed. Thus, ICV HCRT-1 administration elicits comparable increases in time spent awake when administered during the sleep- and activity-periods.35-37,42 During both nocturnal and diurnal periods, HCRT-1-induced waking was accompanied by significant increases in time spent grooming, chewing of inedible material (e.g., bedding) and locomotor activity as measured by quadrant entries and rears. In contrast to these largely circadian-independent actions of HCRT-1, when administered during the activity-period, HCRT-1

Figure 4. Effects of varying behavioral state/environmental condition on the percentage of Fos-ir nuclei within hypocretin-synthesizing (prepro-HCRT-ir) and hypocretin-1 receptor-expressing (HCRTr1-ir) neurons. Shown are diurnal sleeping (SLP), diurnal spontaneous waking (DSW), nocturnal spontaneous waking (NSW) and high-arousal waking (HAW). Neither diurnal sleeping nor diurnal spontaneous waking was associated with an increase in the percentage of Fos-ir within prepro-HCRT-ir neurons in LH. Relative to diurnal sleeping, nocturnal spontaneous waking was associated with a slight, yet significant, increase in the percentage of Fos-ir within prepro-HCRT-ir neurons. In contrast, high-arousal waking was associated with a significantly higher percentage of Fos-ir within prepro-HCRT-ir relative to diurnal sleeping, diurnal spontaneous waking and nocturnal spontaneous waking. Within HCRTr1-ir neurons across varying regions, only high-arousal waking was associated with increased levels of Fos. +P < 0.05; ^P < 0.01 significantly different from diurnal sleeping. **P < 0.01 significantly different from group indicated by brackets. Modified from37.

Figure 4. Effects of varying behavioral state/environmental condition on the percentage of Fos-ir nuclei within hypocretin-synthesizing (prepro-HCRT-ir) and hypocretin-1 receptor-expressing (HCRTr1-ir) neurons. Shown are diurnal sleeping (SLP), diurnal spontaneous waking (DSW), nocturnal spontaneous waking (NSW) and high-arousal waking (HAW). Neither diurnal sleeping nor diurnal spontaneous waking was associated with an increase in the percentage of Fos-ir within prepro-HCRT-ir neurons in LH. Relative to diurnal sleeping, nocturnal spontaneous waking was associated with a slight, yet significant, increase in the percentage of Fos-ir within prepro-HCRT-ir neurons. In contrast, high-arousal waking was associated with a significantly higher percentage of Fos-ir within prepro-HCRT-ir relative to diurnal sleeping, diurnal spontaneous waking and nocturnal spontaneous waking. Within HCRTr1-ir neurons across varying regions, only high-arousal waking was associated with increased levels of Fos. +P < 0.05; ^P < 0.01 significantly different from diurnal sleeping. **P < 0.01 significantly different from group indicated by brackets. Modified from37.

had only minimal effects on eating and drinking. These observations demonstrate a robust circadian dependence of HCRT-1-induced alterations in feeding and drinking but not chewing or locomotor activity.

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