| The hypocretins are a recently identified peptide family consisting of two peptides (hypocretin-1 and hypocretin-2) that are synthesized solely in the lateral hypothalamus and adjacent regions. Although originally identified to elicit feeding, extensive evidence now suggests the hypocretins modulate arousal via actions across multiple terminal fields. For example, hypocretin fibers and receptors are located within a variety of regions associated with the regulation of arousal. Additionally, hypocretin administration within the lateral ventricle or within the locus coeruleus region elicits increased waking. Further, limited observations suggest that hypocretin neurotransmission may vary across the circadian cycle. Finally, both animal and clinical studies suggest a dysregulation of hypocretin neurotransmission in the arousal/sleep disorder, narcolepsy. Combined, these observations suggest that hypocretin exerts wake-promoting actions that may be important for normal waking. Until recently, much remained unknown regarding the neurobiology of hypocretin-induced arousal. The present thesis was designed to provide basic information concerning the extent to which these peptides modulate arousal and the neural mechanisms that underlie these actions. These studies have demonstrated that hypocretin-1 and/or hypocretin-2 administration exerts wake-promoting and sleep-suppressing actions when infused into the lateral ventricle or within select basal forebrain regions. Additional studies suggest that the ability of hypocretin to increase feeding may reflect a general behavioral activation associated with waking and not direct actions on feeding. Further studies, conducted to characterize the relationship between hypocretin neuronal activity and behavioral state, demonstrated that waking per se, was not associated with elevated levels of hypocretin neuronal activity, as measured by Fos-immunoreactivity. Thus, waking during the day was not associated with increased hypocretin neuronal activity. Additionally, although waking during the night was associated with a slight increase in pre-synaptic hypocretin neuronal activity, only stress was associated with increases in both pre-synaptic and post-synaptic neuronal activity. Finally, experiments utilizing retrograde labeling techniques demonstrated collateral projections of single hypocretin neurons to multiple arousal-related structures and suggest a mechanism whereby subsets of hypocretin neurons might exert a coordinated influence on multiple terminal structures to regulate arousal. |
