Abstract
Cognitive function represents a key determinative factor for independent functioning among the elderly, especially among those with age-related cognitive disorders. However; existing pharmacotherapeutic tactics for treating these disorders provide only modest benefits on cognition. The hypothalamic orexin (hypocretin) system is uniquely positioned, anatomically and functionally, to integrate physiological functions that support proper cognition. The ongoing paucity of orexin receptor agonists has mired the ability to study their potential as cognitive enhancers. Fortunately, intranasal administration of native orexin peptides circumvents this issue and others concerning peptide transport into the central nervous system (CNS). To investigate the ability of intranasal orexin-A (OxA) administration to improve the anatomical, neurochemical, and behavioral substrates of age-related cognitive dysfunction, these studies utilized a rodent model of aging combined with acute intranasal administration of saline or OxA. Here, intranasal OxA increases c-Fos expression in several telencephalic brain regions that mediate important cognitive functions, increases prefrontal cortical acetylcholine efflux, and alters set-shifting-mediated attentional function in rats. Ultimately, these studies provide a framework for the possible mechanisms and therapeutic potential of intranasal OxA in treating age-related cognitive dysfunction.
Highlights
Increased attention is being paid to how physiological and homeostatic alterations, including altered sleep patterns and unexplained weight loss, may be early indicators of subsequent cognitive decline in the elderly (Buchman et al, 2005; Grundman, 2005; Johnson et al, 2006; Cova et al, 2016)
Intranasal OxA did not globally excite all brain regions as there were no significant changes in c-Fos expression within the piriform cortex, ventral orbital cortex, nucleus accumbens shell, retrosplenial cortex, and regions CA3 and CA1 of the hippocampus
There was a strong trend for decreased c-Fos expression in the infralimbic cortex (t14 = 1.91, p = 0.0769) after intranasal OxA administration
Summary
Increased attention is being paid to how physiological and homeostatic alterations, including altered sleep patterns and unexplained weight loss, may be early indicators of subsequent cognitive decline in the elderly (Buchman et al, 2005; Grundman, 2005; Johnson et al, 2006; Cova et al, 2016). The hypothalamus, the primary central node for integration of peripheral cues indicative of physiological status, contains cell populations comprising numerous neurochemical and neuropeptide signaling molecules, including orexins (hypocretins), that regulate the endocrine, autonomic, and behavioral responses that arise from homeostatic challenges (Li et al, 2014). Reciprocal innervation, arising primarily from limbic structures, provides feedback to orexin neurons (Sakurai et al, 2005; Yoshida et al, 2006). These wide-ranging projections place orexin neurons in a unique anatomical and functional position to integrate the physiological and cognitive responses that maintain proper homeostasis (Li et al, 2014). The studies described here center around interactions between the orexin system and acetylcholine, glutamate, and GABA neurotransmission
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