Date of Award
Open Access Dissertation
Charles F. Mactutus
The marked increase in life expectancy for individuals with human immunodeficiency virus type 1 (HIV-1), following the great success of combination antiretroviral therapy (cART), necessitates an investigation of the progression of HIV-1 associated neurocognitive disorders (HAND), and associated neural mechanisms, across the functional lifespan. Furthermore, given the persistence of HAND in the post-cART era, there remains a critical need to develop adjunctive therapeutics targeting the neural mechanisms underlying HAND. Thus, the guiding hypothesis for the present study was threefold. First, that there will be a differential progression of NCI in HIV-1 Tg and control animals. Second, that synaptodendritic dysfunction will mechanistically underlie NCI and progress throughout the early lifespan. Third, that the altered developmental trajectory of NCI, as a function of the HIV-1 transgene, will be restored with SE, targeting synaptodendritic dysfunction. Neurocognitive and neuroanatomical assessments were utilized to critically test these hypotheses.
The HIV-1 transgenic (Tg) rat, resembling HIV-1 seropositive individuals on lifelong cART, exhibits age-related progressive neurocognitive impairments in the absence of sensory or motor system deficits and comorbidities. Independent of biological sex, the HIV-1 Tg rat exhibits a differential progression of long-term episodic memory, temporal processing, stimulus-reinforcement learning, sustained attention, and flexibility and inhibition. Synaptic dysfunction in pyramidal neurons from layers II-III of the medial prefrontal cortex (mPFC) were characterized by alterations in dendritic branching complexity, synaptic connectivity and dendritic spine morphology.
Critically testing the therapeutic efficacy of SE in the HIV-1 Tg rat revealed an innovative therapeutic approach for the prevention of NCI in HAND; a therapeutic that, at least partially, restores the developmental trajectory of neurocognitive function. Mechanistically, SE remodels neuronal circuitry at the synaptic level, evidenced by profound long-term modifications in neuronal morphology and dendritic spines in pyramidal neurons from layers II-III of the mPFC.
A longitudinal experimental design was subsequently utilized to assess the progression of synaptic function from postnatal day (PD) 30 to PD 180. Prominent developmental alterations in regressive (i.e., pruning) processes, as well as synaptic function, were observed, independent of biological sex, in pyramidal neurons from layers II-III of the mPFC in the HIV-1 Tg rat, supporting a key neural mechanism underlying HAND. Taken together, the present studies have defined HAND as a neurodegenerative disease characterized by age-related, progressive neurocognitive impairments and synaptic dysfunction; a disease which can be modified by therapeutics (i.e., SE) that mechanistically target synaptic dysfunction.
McLaurin, K. A.(2020). Theraputic Strategies for Altering the Trajectory of Neurocognitive Impairments in HIV-1 Associated Neurocognitive Disorders in the Post-Cart Era. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/5808