Age-Related Alterations in Orexin Modulation of Septo-Hippocampal Neurotransmission

Hypothalamic orexin/hypocretin neurons project widely to telencephalic regions influential in learning and memory, such as the hippocampus and the medial septum (MS) of the basal forebrain. Within the MS, orexin innervates cholinergic and GABAergic parvalbumin (PV) containing neurons that project to the hippocampus via the septo-hippocampal pathway. This anatomy suggests that orexin exerts transsynaptic control of cholinergic and GABAergic efflux in the hippocampus by way of the MS, as well as direct hippocampal modulation via hypothalamic afferents. However, the precise role of orexin inputs to the hippocampus, both direct and transsynaptic, on the modulation of hippocampal transmission has not been defined. Moreover, the hypothalamus, hippocampus and basal forebrain undergo a significant aging-induced neurodegeneration, which could alter orexin modulation of hippocampal neurochemistry. Using young (4 mo) and aged (27-29 mo) rats, immunohistochemistry, in vivo microdialysis, and field potential electrophysiology were used to assess the anatomical, neurochemical, and physiological profiles of the hippocampus. Aging significantly reduced the number of PV projection cells and hippocampal interneurons, resulting in a decrease in GABA release and reduced inhibition. Furthermore, orexin innervation to both the hippocampus and MS was reduced as a function of age. To define the role of orexin on hippocampal neurotransmission, orexin A (OxA) was infused into the MS or hippocampus, and hippocampal acetylcholine (ACh), GABA and glutamate efflux were analyzed. OxA increased ACh in young but not aged rats at both MS and hippocampal infusion sites. GABA and glutamate were increased following hippocampal infusion of OxA at both ages, while MS administration of OxA increased GABA and glutamate efflux as a function of age. These data indicate that orexin can directly and transsynaptically modulate hippocampal neurotransmission, which is altered over the course of normal aging. Importantly, the age-related alterations in orexin-hippocampus connectivity may underlie aging-induced cognitive decline, and could provide a potential avenue for therapeutic intervention