Discovering the immediate and lasting benefits of an aerobic intervention in adolescence on corpus callosum development in a rat model of fetal alcohol spectrum disorders
Date
2023
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Publisher
University of Delaware
Abstract
An estimated 1in 20 infants born annually has been exposed to alcohol prenatally, creating the largest preventable public health crisis in the U.S. (Hoyme et al., 2016). Prenatal alcohol exposure has severe consequences for neurodevelopment and the resulting diagnosable disorders are categorized as Fetal Alcohol Spectrum Disorders (FASD). FASD-related impairments to executive function are the most prevalent among affected youth and contribute to increased risk for substance abuse and employment/legal issues. Importantly, diminished visuospatial processing is linked to disruptions to corpus callosum growth and myelination in affected adolescents. Targeted interventions that support neurodevelopment in FASD-affected youth are nonexistent. To address this issue, this dissertation evaluated the capacity for an adolescent exercise intervention, a known stimulator of myelinogenesis, to upregulate corpus callosum myelination and mitigate lasting deficits to corpus callosum function in a rodent model of FASD. ☐ The studies comprising this dissertation employ an established rodent model of FASD to examine the potential therapeutic effect of adolescent exercise intervention on corpus callosum development in both sexes. In Aim 1 Experiment 1, longitudinal analysis of neuroimaging data collected pre- and post-intervention illustrated that corpus callosum myelination is delayed in alcohol-exposed rats of both sexes, concordant with the clinical literature (Treit et al., 2013). These results were validated using immunocytochemical labelling of brain tissue from rats pre- and post-intervention in Aim 2, Experiments 1 and 2. Quantification of oligoglia and myelin basic protein density showed that alcohol exposure led to a transient restriction of oligoglia proliferation and differentiation in early adolescence (pre-intervention). Conversely, the number of precursor and mature oligodendrocytes did not differ between alcohol-exposed and control groups in late adolescence. However, the myelinogenic effects of adolescent exercise intervention had a greater effect on myelin plasticity in female rats without previous alcohol exposure. ☐ Several clinical studies have correlated impairments to corpus callosum development and function with deficits in visuospatial processing in youth affected by FASD (Ware et al., 2021; Sowell et al., 2008; Inkelis et al., 2020). Findings from Experiment 2 of Aim 1, illustrate that the functional connectivity between cortical sub-regions comprising the executive control network required for fixating on a particular visual stimulus was impaired in adult female FASD rats. Moreover, electron microscopic analysis of splenium axons revealed that the diameter of axons and thickness of the myelin sheath are reduced these rats. The observed impairments to functional connectivity and ultrastructure were improved by intervention exposure in adolescence. ☐ These results provide clear evidence that increasing aerobic activity in adolescence supports white matter maturation in the FASD brain. This innovative preclinical study was uniquely suited to answer targeted questions concerning sexual dimorphisms in FASD etiology and to aid in the development of a targeted intervention for FASD-affected youth.
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Keywords
Exercise, Fetal Alcohol Spectrum Disorders, Myelination, Corpus callosum function, Prenatal alcohol exposure