The aging U.S. population has resulted in substantial increases in resources allocated to the prevention and treatment of age-related neurodegenerative conditions. Normal cognitive and homeostatic functions are major determinants of the capacity for independence and quality of life in the elderly. A growing body of data suggests that changes in homeostatic function, such as unexplained weight loss late in life, frequently precedes and may predict subsequent development of mild cognitive impairment or Alzheimer's disease. An intriguing hypothesis - based in part on the heuristic observation that proper behavioral responses to homeostatic challenges, such as food or water deprivation, entail a cognitive component - is that age-related changes in homeostatic function and cognitive decline may be mechanistically linked. This hypothesis is supported by studies showing clear anatomical connections between certain hypothalamic regions classically associated with homeostatic function and rostral brain regions, such as the basal forebrain cholinergic system (BFCS), that play crucial roles in cognition. Impairment of cognitive abilities dependent on the integrity of the cholinergic system is an early and consistent feature of age-related dementias, even in the absence of frank loss of cholinergic neurons, suggesting that changes in the afferent regulation of the BFCS may underlie some types of age-related cognitive decline. We have recently described a dense innervation of the BFCS by hypothalamic orexin/hypocretin neurons and shown that this input is dramatically reduced in aged animals. Orexins play prominent roles in multiple aspects of homeostasis but the conditions that activate orexin inputs to the basal forebrain and the functional implications of these interactions are largely unknown. Here, we propose a multi-level (neurochemical, anatomical, behavioral, genetic) approach to elucidate the role of orexin-cholinergic interactions in responses to homeostatic challenges and age-related cognitive decline.
Aim 1 will combine lesion and pharmacological approaches to determine the role of orexin peptides in cortical acetylcholine release.
Aim 2 will examine the role of orexin-ACh interactions in age-related deficits in activation of the BFCS as well as the ability of ectopic administration of orexins via direct intracranial administration or by lentiviral- mediated gene transfer to restore normal cholinergic function.
Aim 3 will determine age-related effects of intra-basalis administration of orexins on attentional function. Collectively, these experiments will comprise a systematic description of the importance of orexin-acetylcholine interactions in arousal and how alterations in these interactions may contribute to age-related deficits in cognitive function and motivated behavior. The results of these studies will have important implications for understanding the basis of age- related cognitive decline and may suggest novel therapeutic targets for the treatment of these disorders.

Public Health Relevance

Compelling clinical data now indicate that Alzheimer's disease and other age-related dementias are often preceded by metabolic disturbances, including unexplained weight loss, years prior to diagnosis of frank dementia. Our novel hypothesis is that some aspects of homeostatic changes and cognitive decline may be mechanistically linked at the neural systems level. Accordingly, these studies are designed to investigate how the hypothalamus regulates the basal forebrain cholinergic system and how these interactions change with aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG030646-04
Application #
8113318
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Wagster, Molly V
Project Start
2008-08-15
Project End
2014-07-31
Budget Start
2011-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$275,530
Indirect Cost
Name
University of South Carolina at Columbia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
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Fadel, Jim R; Reagan, Lawrence P (2016) Stop signs in hippocampal insulin signaling: the role of insulin resistance in structural, functional and behavioral deficits. Curr Opin Behav Sci 9:47-54
Zajo, Kristin N; Fadel, Jim R; Burk, Joshua A (2016) Orexin A-induced enhancement of attentional processing in rats: role of basal forebrain neurons. Psychopharmacology (Berl) 233:639-47
Hirsh, Adam H; Burk, Joshua A (2013) Repeated visual distracter exposure enhances new discrimination learning and sustained attention task performance in rats. Behav Processes 92:147-51
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Fadel, Jim R; Jolivalt, Corinne G; Reagan, Lawrence P (2013) Food for thought: the role of appetitive peptides in age-related cognitive decline. Ageing Res Rev 12:764-76
Robinson, Andrea M; Mangini, David F; Burk, Joshua A (2012) Task demands dissociate the effects of muscarinic M1 receptor blockade and protein kinase C inhibition on attentional performance in rats. J Psychopharmacol 26:1143-50
Stanley, Emily M; Wilson, Marlene A; Fadel, Jim R (2012) Hippocampal neurotransmitter efflux during one-trial novel object recognition in rats. Neurosci Lett 511:38-42
Stanley, Emily M; Fadel, Jim (2012) Aging-related deficits in orexin/hypocretin modulation of the septohippocampal cholinergic system. Synapse 66:445-52
Kessler, B A; Stanley, E M; Frederick-Duus, D et al. (2011) Age-related loss of orexin/hypocretin neurons. Neuroscience 178:82-8

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