Hcrt And Waking

The hypocretins, also known as orexins, consist of two peptides (HCRT-1 and HCRT-2) that are synthesized solely in the lateral hypothalamus (LH) and adjacent regions. Despite their restricted origin, HCRT neurons extend a vast projection system that innervates virtually the entire neuroaxis. The widespread nature of the HCRT efferent projection system suggests multiple and varied actions of this neurotransmitter system in behavior. A comprehensive characterization of the actions of HCRT on cognition, affect/emotion and behavior remains to be elucidated. Nonetheless, a surprising amount of information exists regarding the behavioral actions of HCRT, given the short span of time since discovery of this peptide system.

Originally identified to enhance feeding26,81,92 extensive evidence now suggests the HCRT system modulates arousal and arousal-related processes. For example, HCRT-containing fibers and receptors are located within a variety of brainstem and basal forebrain structures associated with the regulation of behavioral state.25,65,72,77,81,93 Consistent with this, multiple observations indicate modulatory actions of the HCRT system on sleep and waking. For example, both clinical and animal studies demonstrate a dysregulation of HCRT neurotransmission is associated with the sleep/arousal disorder, narcolepsy.22,6174,94 Moreover, when administered intracerebroventricularly (ICV), HCRT-1 and HCRT-2 increase time spent awake and decrease time spent in slow-wave and REM sleep (Figure 1).11,35,36,42,48,78 HCRT-induced increases in time spent awake are associated with a variety of waking-related behaviors including eating, drinking, grooming, and locomotor activity.

A limited number of studies have begun to examine the neural circuitry associated with HCRT modulation of sleep-wake state. The locus coeruleus (LC) noradrenergic system exerts robust modulatory actions on behavioral state and state-dependent processes.3,7,12,13,16,39,45,76 Thus, it was of interest that the LC receives a prominent HCRT innervation.25,77 Moreover, HCRT application increases LC neuronal discharge in vitro and in vivo.17 4247 Consistent with these observations, infusion of HCRT into the LC region of the brainstem increases time spent awake.17

These observations raise the question of whether the LC is the primary site through which HCRT acts to impact behavioral state. To initially assess this issue, the wake-promoting effects of HCRT infused into the lateral ventricles were compared to those observed following HCRT infusions into the fourth ventricle, immediately adjacent to the LC. It was reasoned that if the LC were the primary site of action in HCRT-induced waking, more rapid and/or larger magnitude wake-promoting effects would be observed with fourth ventricular infusions. In contrast to this hypothesis, HCRT-1 infusion (0.07 nmol) into the fourth ventricle elicited less robust increases in time spent awake that

Figure 1. Effects of varying concentrations of HCRT-1 infused into the lateral ventricle on time spent awake (Total Waking) and in slow-wave sleep and REM sleep. Symbols represent mean (± SEM) time (sec) spent in the three different behavioral state categories per 30-min epoch. PRE1 and PRE2 represent pre-infusion epochs and POST1-POST3 represent post-infusion epochs. Vehicle-treated animals spent the majority of the testing period asleep. At 0.07 and 0.7 nmol, HCRT-1 significantly increased total waking and decreased slow-wave and REM sleep during POST-1 and POST-2. The 0.7-nmol dose significantly increased total waking and decreased slow-wave and REM sleep during POST-3. *P<0.01 significantly different from vehicle-treated animals. Modified from35.

Figure 1. Effects of varying concentrations of HCRT-1 infused into the lateral ventricle on time spent awake (Total Waking) and in slow-wave sleep and REM sleep. Symbols represent mean (± SEM) time (sec) spent in the three different behavioral state categories per 30-min epoch. PRE1 and PRE2 represent pre-infusion epochs and POST1-POST3 represent post-infusion epochs. Vehicle-treated animals spent the majority of the testing period asleep. At 0.07 and 0.7 nmol, HCRT-1 significantly increased total waking and decreased slow-wave and REM sleep during POST-1 and POST-2. The 0.7-nmol dose significantly increased total waking and decreased slow-wave and REM sleep during POST-3. *P<0.01 significantly different from vehicle-treated animals. Modified from35.

occurred with a longer latency than that observed following lateral ventricular infusions (Figure 2). These observations suggest that the LC is not the sole site wherein HCRT acts to elicit waking and that one or more sites anterior to LC participate in the behavioral state-modulatory actions of HCRT.

Various basal forebrain regions have been implicated in the regulation of behavioral state, including the general region of the medial septal area (MS), the general region of the medial preoptic area (MPOA), and the substantia innominata (SI).13,15,18,39,45,57,64,71 Importantly, HCRT fibers and receptors are located within each of these structures.8 24,25,41,44,65,72,77,81,91 93 Microinfusion of HCRT-1 (0.01 - 0.07 nmol) into MS, MPOA or SI elicited dose-dependent increases in time spent awake and decreases in slow-wave and REM sleep.35 The largest increases in waking were observed following infusions within MPOA (see Figure 3). Infusions placed immediately outside these regions did not modulate sleep-wake state.

Two observations made in these studies are worth emphasizing. First, the latency to waking following ICV infusions of HCRT was extremely short (e.g. within 30 seconds of the start of the infusion). In contrast, for fourth ventricular and all intra-tissue infusions latency to waking was in the range of 3-8 minutes.35 Second, a largely comparable dose range for HCRT-1-induced waking was observed with both ICV and intratissue infusion. Combined, these observations suggest that HCRT acts within multiple terminal fields to modulate behavioral state and/or state-dependent processes. Moreover, the extremely short latency to waking following lateral ventricular infusions of HCRT suggests that

Figure 2. Effects of 0.07 nmol HCRT-1 infusions into the lateral and fourth ventricles on time spent awake (Total Waking), slow-wave sleep and REM sleep. Symbols represent mean (± SEM) time (sec) spent in the three different behavioral state categories per 30-min. PRE1 and PRE2 represent pre-infusion epochs and POST1-POST3 represent post-infusion epochs. HCRT-1 administered into the fourth ventricle increased total waking and decreased slow-wave and REM sleep. However, these effects were of a smaller magnitude than that observed following infusion into the lateral ventricles. Latency to waking following fourth ventricular infusion of HCRT (mean = 320 ± 40 sec from start of infusion; Range = 216-416 sec) was substantially longer than that observed following infusions into the lateral ventricles (mean = 191 ± 48 sec from the start of the infusion; Range = 123-375 sec; see results). *P<0.01 significantly different from fourth ventricle infusion values. Modified from.35

Figure 2. Effects of 0.07 nmol HCRT-1 infusions into the lateral and fourth ventricles on time spent awake (Total Waking), slow-wave sleep and REM sleep. Symbols represent mean (± SEM) time (sec) spent in the three different behavioral state categories per 30-min. PRE1 and PRE2 represent pre-infusion epochs and POST1-POST3 represent post-infusion epochs. HCRT-1 administered into the fourth ventricle increased total waking and decreased slow-wave and REM sleep. However, these effects were of a smaller magnitude than that observed following infusion into the lateral ventricles. Latency to waking following fourth ventricular infusion of HCRT (mean = 320 ± 40 sec from start of infusion; Range = 216-416 sec) was substantially longer than that observed following infusions into the lateral ventricles (mean = 191 ± 48 sec from the start of the infusion; Range = 123-375 sec; see results). *P<0.01 significantly different from fourth ventricle infusion values. Modified from.35

HCRT may act at a site within or extremely close to the ventricular wall. It has been posited previously select peptides may act within circumventricular sites (e.g. organum vasculosum) and that the ventricular system provides a mode of peptide transport to these sites.33,46,60 Consistent with this idea, in immunohistochemical studies conducted in our laboratory, we observed occasional HCRT-ir fibers adjacent to, and in some cases, projecting directly into the lateral and third ventricles.

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