Orexin/hypocretin modulation of the basal forebrain cholinergic system: Insights from in vivo microdialysis studies

Since its discovery less than a decade ago, interest in the hypothalamic orexin/hypocretin system has blossomed due to the diversity and importance of the roles played by these neuropeptides. Orexin neurons have widespread projections throughout the central nervous system and intense research has focused on elucidating the pathways and mechanisms by which orexins exert their diverse array of functions. Our group has recently focused on orexin inputs to the basal forebrain cholinergic system, which plays a crucial role in cognitive – particularly attentional – function. Orexin cells provide a robust input to cholinergic neurons in the basal forebrain and act here to modulate cortical acetylcholine release. Orexin A also increases local glutamate release within the basal forebrain, suggesting an additional, indirect effect of orexins on basal forebrain cholinergic activity. Orexin activation of the basal forebrain cholinergic system appears to be especially relevant in the context of homeostatic challenges, such as food deprivation. Thus, orexins can stimulate cortical cholinergic transmission which, in turn, may promote the detection and selection of stimuli related to physiological needs. In this manner, orexin interactions with the basal forebrain cholinergic system are likely to form a link between arousal and attention in support of the cognitive components of motivated behavior.