Modulators of the human hippocampal memory system
Nauer Wehr, Rachel
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Given the importance of the hippocampus in episodic memory and its particular vulnerability during aging, considerable attention has gone into identifying modulators of hippocampal neuroplasticity. In rodents, aerobic exercise counteracts hippocampal age-effects and enhances performance on pattern separation, which entails the orthogonalization of overlapping inputs into distinct memory representations during encoding. Performance on mnemonic discrimination tasks requires pattern separation and these tasks are a promising metric of putative hippocampal neuroplasticity. To date, studies in humans have focused on utilizing exercise as a tool to manipulate hippocampal neuroplasticity in older adult populations, largely ignoring the younger and middle-aged groups. The goals of this dissertation were to investigate the relationship between aerobic exercise, cardiorespiratory fitness (CRF) and hippocampal subfield structure and function in young adults, and to examine how CRF may mitigate age-related decline in mnemonic discrimination across adulthood. A series of three experiments tested the central hypothesis that CRF is linked to hippocampal plasticity and is a modulating factor of behavioral performance in mnemonic discrimination tasks. Data from Experiments 1 and 2 were acquired from a longitudinal randomized controlled trial (RCT) in healthy young adults (ages 18-35 years). Experiment 1 (N = 50) focused on baseline data from the RCT, and Experiment 2 (N = 38) elucidated longitudinal changes following a twelve-week exercise intervention program. In a separate, cross-sectional design, Experiment 3 elucidated the relationships between CRF and behavioral performance across the adult lifespan (ages 18-83 years, N = 80). Experiment 1 used high-resolution fMRI and a mnemonic discrimination task with manipulations of stimulus similarity to examine task-related functional activation within the hippocampal subfields in healthy, but sedentary, young adults. Objectives were to test the predictions that the hippocampal subfields, particularly the DG/CA2/3, support successful encoding and retrieval of overlapping information, and that this activity is modulated by stimulus similarity. An additional hypothesis was that higher CRF is associated with better behavioral performance and greater hippocampal activity during mnemonic discrimination. Findings demonstrated greater activity in the DG/CA2/3 associated with better task performance during retrieval on trials in which stimuli shared the highest similarity. Behaviorally, higher-fit individuals performed better than lower-fit individuals, particularly when stimulus similarity was low. However, the baseline levels of CRF in sedentary adults did not modulate hippocampal subfield activity during the task. Experiment 2 investigated the relationship between changes in CRF following a twelve-week exercise intervention, changes in hippocampally-dependent mnemonic discrimination, and hippocampal subfield volume change. The primary hypotheses were that enhanced CRF would predict an increase in hippocampal volume, specifically in the DG/CA3 subregion within the hippocampal head, and that improved CRF would relate to enhanced mnemonic discrimination performance. Consistent with these predictions, improvement in CRF was linked to an increased volume specific to the hippocampal head of the left DG/CA3 subregion. In addition, there was a positive relationship between change in CRF and mnemonic discrimination for highly similar stimuli, particularly for individuals who were initially lower-fit. Experiment 3 tested the hypothesis that higher CRF attenuates age-related impairments on mnemonic discrimination performance in both the non-spatial and spatial domains across the adult lifespan. In addition to robust deleterious age-effects across both domains, results demonstrated that higher CRF enhanced performance on non-spatial mnemonic discrimination for the youngest adults only. In contrast, higher CRF partially attenuated age-related deficits for spatial contextual discrimination. Together, these results provide evidence for a relationship between CRF and exercise and hippocampal neuroplasticity across adulthood. Building on work done in animal models and extending previous work in older adult humans, these results provide evidence for a positive relationship between CRF and exercise with hippocampal subfield structure and function in healthy young adults. The data further suggest that higher CRF is associated with enhanced mnemonic discrimination and partially mitigates age-related effects in a spatial contextual discrimination task. This has potential implications for a therapeutic value of aerobic exercise to promote brain health and enhance cognition across the adult lifespan, as well as to counteract deleterious effects of aging.