ORCID ID

0000-0002-6209-4386

Graduation Date

Spring 5-8-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Neuroscience

First Advisor

Tony W. Wilson

Abstract

Despite effective regimens of combination antiretroviral therapy, individuals with HIV are still at higher risk for developing forms of cognitive impairment, with one of the most common behavioral abnormalities to manifest being motor dysfunction. This is an important consideration, as deficits in motor control likely contribute to higher-order cognitive impairments, which together, lead to functional dependencies in the ever-growing aging population of HIV-infected adults. While the neuroanatomical bases of motor dysfunction have recently been illuminated in people living with HIV (PLWH), there remains an open question regarding the molecular processes supporting the circuit-level neuronal dynamics that potentially serve these behavioral aberrations. One theorized contributor to neurocognitive variability is a mitochondrial-induced redox imbalance of the system, although their direct impact on human neurophysiological function is unknown. Herein, we used state-of-the-art systems biology and neuroscience approaches including peripheral measures of mitochondrial respiration and superoxide concentration using Seahorse Analyzer and Electron Paramagnetic Resonance Spectroscopy, respectively, as well as antioxidant activity assays and magnetoencephalography to directly quantify spatially- and spectrally-distinct neural oscillatory dynamics serving motor function in a large sample of virally-suppressed PLWH and demographically-matched controls. First, we characterize aberrations in mitochondrial function and the redox environment in PLWH compared to their seronegative counterparts (Chapter 1) and determine their role in modulating movement-related beta oscillations and behavioral performance, sequentially, in the healthy system (Chapter 2). Next, we examine the divergent predictive capacities of the mitochondrial redox environment on sensorimotor brain-behavior dynamics in PLWH (Chapter 3). Finally, we interrogate the contribution of important HIV clinical risk factors and demographics for modulating bioenergetic-neural-behavioral pathways in the sensorimotor system of PLWH (Chapter 4). These findings provide novel mechanistic insight regarding redox-regulated neuronal dynamics in health and disease and importantly, highlight the precursors that may serve as effective targets to ameliorate age- and disease-related declines in cognitive-motor function in the future.

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