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Item ACUTE EXERCISE INDUCED MICROSTRUCTURAL AND FUNCTIONAL CHANGES IN THE HIPPOCAMPUS OF OLDER ADULTS(2023) Callow, Daniel; Carson, Jerome J; Neuroscience and Cognitive Science; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Declining memory function is a common complaint of aging adults and a primary symptom of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). The hippocampus is often the first brain area to exhibit noticeable deficits in age and pathologically-related cognitive decline and is a necessary structure for proper memory function. More specifically, the dentate gyrus (DG) and the third cornu ammonis area (CA3) of the hippocampus directly support mnemonic discrimination (MD), which is the process of reducing interference among new representations and distinctly encoding them as independent memories. Poor MD is associated with age and is a presymptomatic biomarker of cognitive decline and is believed to result from reduced neurogenesis, angiogenesis, and synaptogenesis within the DG/CA3 subregion of the hippocampus. While causes and treatments for memory decline remain elusive, lifestyle interventions, especially physical activity, have received attention as cost-effective and safe means of ameliorating and potentially preventing cognitive decline in a growing aging population. Animal and human studies suggest exercise benefits the hippocampal structure, preserving neurogenesis and angiogenesis in aging rodents and macrostructure and memory in older adults. However, the mechanisms by which exercise affects the human hippocampus remains a significant knowledge gap in the field and is a critical aspect in understanding the long-term impact exercise has on the aging hippocampus. To better address this gap, researchers have begun implementing acute exercise studies, which allow for greater control of non-exercise-related factors, are cheaper and more time efficient to conduct than training studies, and can predict and inform training-related adaptations. Unfortunately, limitations in the study designs, population tested, specificity of cognitive tasks, and spatial resolution of human imaging techniques have posed significant barriers to our understanding of how acute exercise relates to healthy brain aging at the functional and microstructural levels. Therefore, the objective of this dissertation was to expand our understanding of how acute aerobic exercise alters the function and microstructure of the aging hippocampus. Three within-subject studies were conducted comparing the relationship between a 30-minute bout of moderate to vigorous intensity aerobic exercise vs seated rest on MD performance, hippocampal microstructure, and high-resolution hippocampal-subfield microstructure and functional activity in healthy older adults. In study one, acute exercise preserved MD performance compared to decrements exhibited after seated rest in a pre and post-condition study design. In study two, a post-condition-only study design, acute exercise elevated microstructural diffusion within the hippocampus, indicative of a hippocampal neuroinflammatory response and upregulation of neurotrophic factors. Finally, in study three, a post-condition-only study design, we found that acute exercise resulted in lower MD, suppressed MD-related DG/CA3 network hyperactivity (indicative of healthier network function), and led to higher DG/CA3 extracellular diffusion. However, these neuroimaging-based correlates of hippocampal neuroplasticity and network function were not associated with differences in MD performance. These findings suggest that higher-intensity acute exercise can alter memory performance and stimulate neuroplasticity and neurotrophic cascades within the hippocampus and the DG/CA3 subfield, potentially via different mechanisms. Furthermore these results give insight into the immediate neurotrophic and behavioral effects of acute moderate to vigorous intensity aerobic exercise in older adults and provide new methods and tools for better understanding if and how exercise promotes healthy brain aging. Finally, these initial findings lay a foundation for optimizing exercise prescription and identifying future effective exercise treatments.Item SYSTEMS IMMUNOLOGY OF IMMUNE IMPRINTS INDUCED BY ACUTE VIRAL INFECTIONS(2023) Liu, Can; Johnson, Philip L.F.; Tsang, John S.; Biology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Upon encountering perturbations such as viral infections, the immune system initiates a cascade of molecular and cellular responses. These alterations may persist even after recovery, resulting in enhanced or diminished response to subsequent stimuli compared to the naïve state. Such persistent changes, referred to as immune imprints or long-term non-specific memory, indicate an incomplete resolution from immunological perturbations. The primary focus of this dissertation is to systemically investigate the immune imprints resulting from acute infections and how they shape the baseline immune status to future heterologous challenges.First, we employed cutting-edge single-cell multi-omics and computational approaches to assess the immune response during the COVID-19 disease course and severity correlates at an unprecedented resolution. We identified gene expression profiles – apoptosis in plasmacytoid dendritic cells and IL-15-linked increase of fatty acid (FA) metabolism in CD56dimCD16hi NK cells – as primary correlates of disease severity. This increase of FA signature with disease severity was also concomitant with an attenuated inflammation, indicating a dysfunctional or exhaustion-like state of these NK cells. While the depressed inflammation signature in severe patients was also found in different cell types near hospitalization, it increased temporally at later time points, indicating a critical late-stage juncture in the disease course. Next, we took the opportunity of the period following the first wave of COVID-19 pandemic to study immune imprints in human cohorts who had recovered from COVID-19 before widespread vaccination and reinfection occurred. We demonstrated that individuals who recovered from mild COVID-19, exhibit distinct immune signatures through single-cell transcriptomic profiling. Male recoverees also showed heightened responses to the seasonal influenza vaccine compared to healthy individuals without a history of COVID-19 and female recoverees. These sex dimorphic imprints highlight the interplay between intrinsic factors like sex and non-intrinsic factors such as prior SARS-CoV-2 infection, in shaping an individual's immune system over time. Lastly, we also investigated the immune imprints after acute viral infection using a controlled experimental mouse model of influenza infection. After examining cellular and gene expression profiles in various organs after the infection, we found persistent changes in both adaptive and innate immune components across multiple organs. Moreover, these changes affected subsequent local IL-17 inflammatory response and secondary heterologous vaccinations in anatomically distinct organs. Together, both human and mouse studies here are important pieces toward an improved understanding of long-term immune imprints after perturbations, which can be leveraged to develop more effective and personalized vaccines and disease treatments.Item Memory-related cognitive modulation of human auditory cortex: Magnetoencephalography-based validation of a computational model(2008-04-09) Rong, Feng; Contreras-Vidal, José L; Neuroscience and Cognitive Science; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)It is well known that cognitive functions exert task-specific modulation of the response properties of human auditory cortex. However, the underlying neuronal mechanisms are not well understood yet. In this dissertation I present a novel approach for integrating 'bottom-up' (neural network modeling) and 'top-down' (experiment) methods to study the dynamics of cortical circuits correlated to shortterm memory (STM) processing that underlie the task-specific modulation of human auditory perception during performance of the delayed-match-to-sample (DMS) task. The experimental approach measures high-density magnetoencephalography (MEG) signals from human participants to investigate the modulation of human auditory evoked responses (AER) induced by the overt processing of auditory STM during task performance. To accomplish this goal, a new signal processing method based on independent component analysis (ICA) was developed for removing artifact contamination in the MEG recordings and investigating the functional neural circuits underlying the task-specific modulation of human AER. The computational approach uses a large-scale neural network model based on the electrophysiological knowledge of the involved brain regions to simulate system-level neural dynamics related to auditory object processing and performance of the corresponding tasks. Moreover, synthetic MEG and functional magnetic resonance imaging (fMRI) signals were simulated with forward models and compared to current and previous experimental findings. Consistently, both simulation and experimental results demonstrate a DMSspecific suppressive modulation of the AER and corresponding increased connectivity between the temporal auditory and frontal cognitive regions. Overall, the integrated approach illustrates how biologically-plausible neural network models of the brain can increase our understanding of brain mechanisms and their computations at multiple levels from sensory input to behavioral output with the intermediate steps defined.