Aging-related deficits in orexin/hypocretin modulation of the septohippocampal cholinergic system

The medial septum (MS) of the basal forebrain contains cholinergic neurons that project to the hippocampus, support cognitive function, and are implicated in age-related cognitive decline. Hypothalamic orexin/hypocretin neurons innervate and modulate basal forebrain cholinergic neurons and provide direct inputs to the hippocampus. However, the precise role of orexin in modulating hippocampal cholinergic transmission--and how these interactions are altered in aging--is unknown. Here, orexin A was administered to CA1 and the MS of young (3-4 months) and aged (27-29 months) Fisher 344/Brown Norway rats, and hippocampal acetylcholine efflux was analyzed by in vivo microdialysis. At both infusion sites, orexin A dose-dependently increased hippocampal acetylcholine in young, but not aged rats. Moreover, immunohistochemical characterization of the MS revealed no change in cholinergic cell bodies in aged animals, but a significant decrease in orexin fiber innervation to cholinergic cells. These findings indicate that: (1) Orexin A modulates hippocampal cholinergic neurotransmission directly and transsynaptically in young animals, (2) Aged animals are unresponsive to orexin A, and (3) Aged animals undergo an intrinsic reduction in orexin innervation to cholinergic cells within the MS. Alterations in orexin regulation of septohippocampal cholinergic activity may contribute to age-related dysfunctions in arousal, learning, and memory.