Date of Award

Fall 2023

Document Type

Open Access Thesis

Department

Biomedical Science

First Advisor

Joseph McQuail

Abstract

As the aging demographic of the United States expands, the convergence of age-related cognitive decline and stress-related dysregulation emerges as a substantial concern, impacting not only the lifespan but also the overall well-being of American citizens. In the realm of research, there has been a pronounced focus on Alzheimer's Disease, leading to an imbalanced allocation of resources compared to the study of normal aging. It is widely acknowledged that executive function deteriorates as individuals age, a concept substantiated by numerous investigations conducted in labs dedicated to the study of normal aging. Significantly, even among individuals afflicted with neurodegenerative disorders affecting distinct brain regions, there remains evidence of cognitive decline typical of normal aging, especially in the prefrontal cortex. While it is well-established that mild cognitive impairment and eventual decline in executive functions are associated with advancing age, the extent to which different cognitive domains deteriorate in response to various modifiable risk factors remains uncertain. One such factor under scrutiny is psychogenic stress, which, when endured over extended periods, has been demonstrated to induce structural changes in the apical dendritic morphology of neuronal populations in the prefrontal cortex. Furthermore, research has indicated that stress exposure can influence prefrontal cortex activity in a manner that diminishes behavioral performance, a consequence of excessive activation of pyramidal neurons in this brain region. The imperative, therefore, is to delve into the ramifications of normal aging within the context of stress on a behaviorally relevant evaluation of working memory. The absence of such an investigation would mean that the most vulnerable members of the American population, as they traverse the realm of cognitive decline, could be subjected to exacerbated executive function impairments due to prolonged stress exposure. Consequently, our hypothesis posits that chronic stress exacerbates the age-related decline in working memory. To test this, we procured young, middle-aged, and aged F344 rats from the National Institutes of Health (NIH) and trained them in the delayed match-to-sample task (DMTS) as a measure of working memory. Once we established their baseline working memory performance, we evenly distributed them into unstressed (UNS) and chronic variable stress (CVS) groups. The CVS group was subjected to a randomized regimen of twice-daily stressors for a period of 21 days, including two forced swims at varying temperatures, cage flooding, restraint stress, and exposure to predator urine (coyote and bobcat). Interestingly, the influence of stress on working memory was found to be contingent on age and sex. In young males, stress attenuated working memory performance, whereas in aged males, it improved it. Importantly, stress did not impair or enhance working memory performance across all groups. Moreover, body weight decreased, and adrenal weights increased in response to stress. To further explore the unexpected findings in stressed aged males, we conducted a subsequent study involving corticoid steroid modulation. Employing the same experimental design as the initial study, we administered pretreatments of either a vehicle, Mifepristone (a glucocorticoid receptor antagonist), or Spironolactone (a mineralocorticoid receptor antagonist) to rats after they completed the DMTS task and 30 minutes before the CVS regimen. As anticipated, corticoid steroid receptor antagonists attenuated working memory performance, and they were also associated with increased adrenal gland weight and elevated corticosterone concentrations. Collectively, these two studies provide insights into the intricate relationship between working memory, stress, age, sex, and corticoid steroid receptor signaling. The knowledge gleaned from these investigations holds significant potential for translational and clinically pertinent discoveries, offering avenues to harness the signaling pathways of the hypothalamic-pituitary-adrenal axis for the enhancement of working memory in the context of advanced age.

Rights

© 2024, Tyler Jamison Cox

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