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Dissertation/Thesis Abstract

Age-related loss of orexin innervation contributes to cortical cholinergic decline
by Frederick-Duus, Danielle, Ph.D., University of South Carolina, 2008, 148; 3336706
Abstract (Summary)

A growing body of data suggests homeostatic disturbances, including unexplained weight loss, precede and predict the onset of cognitive decline in certain elderly populations. An intriguing possibility is that these phenomena may be mechanistically linked; that is, brain regions important for homeostatic regulation may inappropriately activate neural pathways that mediate higher cognitive functions. Orexin/hypocretin neurons of the lateral hypothalamus and perifornical area are "physiological integrators" involved in several aspects of homeostatic regulation, including modulation of state-dependent behavior, arousal, reward and feeding. Orexin neurons project robustly to the basal forebrain where they excite cholinergic neurons, increasing cortical acetylcholine release. Our lab has reported that aged animals display diminished orexin innervation and appositional contact with choline acetyltransferase positive neurons, a phenomenon associated with attenuated cholinergic responses upon presentation of food-paired stimuli.

Given the role of cortical cholinergic transmission in cognition, we hypothesize that orexin inputs to the basal forebrain form an anatomical substrate for biasing allocation of attentional resources toward stimuli related to underlying homeostatic challenges. Here, we used in vivo microdialysis, pharmacological and behavioral methods, immunohistochemistry and virus mediated gene transfer to examine the role of orexin inputs to the basal forebrain on cortical cholinergic transmission and age-related deficits in cortical ACh release.

Young rats were studied employing lesioning and orexin antagonist techniques, resulting in a phenotypic model of an aged animal; thereby suggesting a role for orexin in age-related deficits. Subsequently, orexin peptides were administered into the cerebral cortex or the basal forebrain, restoring food-paired cholinergic and behavioral responses in aged rats comparable to young animals. This result suggested that post-synaptic orexin receptor expression and intracellular signaling cascades were intact and responsive in aged animals. Furthering this investigation, we utilized lenti-virus-mediated gene transfer expressing prepro-orexin sense, antisense and EGFP and delivered it to the lateral hypothalamus. These experiments will determine if orexin expression can be functionally restored in an animal model of aging and ameliorate homeostatic age-related cholinergic dysfunction.

Indexing (document details)
Advisor: Fadel, James R.
Commitee: Goodwin, Richard, Moss, Melissa, Reagan, Lawrence P., Wilson, Marlene A.
School: University of South Carolina
Department: Biomedical Science
School Location: United States -- South Carolina
Source: DAI-B 69/11, Dissertation Abstracts International
Subjects: Neurosciences
Keywords: Acetylcholine, Aging, Basal forebrain, Cholinergic decline, Homeostasis, Hypothalamus, Orexin
Publication Number: 3336706
ISBN: 978-0-549-90434-2
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