UNRAVELING NOREPINEPHRINE RELEASE DYSREGULATION IN AGING BRAIN: FROM MOLECULAR MECHANISMS TO PHARMACOLOGICAL RESTORATIONS OF NEUROPLASTICITY AND COGNITION

Abstract

Understanding the neuronal changes of the aging brain, even in the absence of disease, is an essential step toward revealing neurofunctional alterations in the brain that could correlate with the decline in higher-order cognition. While the aging process is biologically complex, a complete understanding of altered neuronal communications is an unmet need for potential pharmacotherapy for cognitive decline. Herein, I examined age-related changes in noradrenergic signaling in aged F-344 rats, an established animal model for neurocognitive aging. Specifically, I demonstrate age-related vulnerabilities in NMDA-mediated glutamate-stimulated noradrenaline (NE) release in the cerebral cortex and hippocampus that are rescued pharmacologically with CNS stimulants (amphetamine & methylphenidate) and drugs that target central α-2 adrenoreceptors. With their potential to guide future pharmacotherapy research, these findings were further explored through radioligand, electrophysiological, and behavioral studies indicating that the age-dependent glutamate (Glu)-stimulated NE release pathway determines a neuronal vulnerability underlying cognitive decline during aging. In fact, the drugs that rescue the aforementioned noradrenergic signaling pathways further go on to rescue cognitive deficits in working memory, which I have demonstrated using the Novel Object Recognition (NOR) and the Y-maze tasks. The second part of my thesis focuses on examining how aging impacts preterminal release regulating NMDA receptors at NE terminals and their pharmacological and structural profiles, including functional regulation and protein expression, to understand the neurobiological underpinnings of selective NMDA receptor-mediated pathways that hypofunction during senescence. This research paves the way for future studies in neuroscience and pharmacology.