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.
|Advisor:||Fadel, James R.|
|Commitee:||Goodwin, Richard, Moss, Melissa, Reagan, Lawrence P., Wilson, Marlene A.|
|School:||University of South Carolina|
|School Location:||United States -- South Carolina|
|Source:||DAI-B 69/11, Dissertation Abstracts International|
|Keywords:||Acetylcholine, Aging, Basal forebrain, Cholinergic decline, Homeostasis, Hypothalamus, Orexin|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be