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Title:Early-life viral infection impacts brain development in the piglet
Author(s):Conrad, Matthew
Director of Research:Johnson, Rodney W.
Doctoral Committee Chair(s):Johnson, Rodney W.
Doctoral Committee Member(s):Juraska, Janice M.; Rhodes, Justin S.; Sutton, Bradley P.
Department / Program:School of Molecular & Cell Bio
Discipline:Neuroscience
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Infection
Brain Development
Magnetic resonance imaging (MRI)
Piglet
Microglia
Inflammation
Abstract:During infancy and childhood, almost every person will impacted by infection. Neonates, due to their immature immune system, are especially vulnerable to respiratory infection and are more prone to hospitalization. Peripheral immune activation in adulthood has been shown to have neurobehavioral effects, but little is known about how it can impact brain development. Gliogenesis, synaptogenesis, and myelination peak during the neonatal period and are all prone to environmental insults, including infection. Therefore, the broad aim of this research was to characterize the impact of early-life respiratory viral infection on brain growth and development. Previous work in our lab has shown that porcine reproductive and respiratory syndrome virus (PRRSV) causes microglia activation, neuroinflammation, and cognitive deficits in piglets. This work further expands on these findings to look at changes to brain development from a macro and microscopic perspective. In order to non-invasively track macro changes to brain development, magnetic resonance imaging (MRI) procedures were developed to measure brain region volumes in the piglet. Using these methods, the normal brain development of the domestic pig was characterized in order to compare brain growth trajectories to what is known for humans. Additionally, advanced analysis methods for determining gray and white matter changes using voxel based morphometry is now possible due to creation of an averaged piglet brain and MRI-based atlas. This method, along with diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MR-Spec), allow for in vivo quantification of brain growth and development. Using these imaging methods, the impact of neonatal PRRSV infection was characterized. Reductions in gray and white matter in the primary visual cortex were found in the PRRSV piglets. Additionally, there was a trend for a decrease in fractional anisotropy in the corpus callosum suggesting either delayed or disrupted myelination in the PRRSV piglets. MR-Spec analysis revealed a significant change in three metabolites in the hippocampus. N-acetylaspartate, creatine, and myo-inositol were all decreased in PRRSV piglets showing that infection caused an energy imbalance and may have impacted neuron and astrocyte health. Collectively, these data show that early-life infection can affect grey and white matter development and cause metabolite disturbances. In addition to the regional changes to brain development above, changes at the cellular level were explored. Since PRRSV causes deficits in hippocampal-dependent learning and memory, changes to neurogenesis and neuron morphology were assessed as they have been shown to contribute to hippocampal learning. A sexual dimorphism was found in the number of surviving newly divided cells (BrdU+) where males had increased levels compared to females. PRRSV infection caused a significant reduction in males only. Cell fate analysis showed that 80% of the newly divided cells form neurons in controls and this is reduced to 57% in PRRSV piglets. Fifteen percent of the newly formed cells become microglia and this is stable across sex and PRRSV infection. A sexual dimorphism was also found in dentate granule neuron morphology where males had more complex dendritic trees than females in the outer cell layer. PRRSV infection caused a change in the dendritic tree shape where the initial branch point was further away from the cell soma in the inner granule cell layer. No differences were found in dendritic spine density. Taken together, PRRSV causes changes to neurogenesis and neuron morphology, which may contribute to the deficits in learning and memory. In order to mitigate the changes to brain development caused by PRRSV, minocycline was used to prevent microglia activation. Minocycline is a second generation tetracycline antibiotic which has been shown to reduce microglia activation and provide protection in rodent models of neuroinflammation. Three weeks of high dose minocycline administration failed to provide neuroprotection in the PRRSV model. Minocycline treatment caused increased microglia activation and pro-inflammatory cytokine production. The high dose of minocycline may have led to increased intracranial pressure or bilirubin-induced neuroinflammation causing the neuroinflammation. These findings suggest that high dose chronic minocycline treatment is not appropriate attenuating microglia activation in neonates. Together, these novel data show that early-life respiratory viral infection can impact brain development. Inflammation can disrupt sensitive developmental processes, some in a sexually dimorphic manner. Long-term studies are needed to see if these changes are permanent or if the brain is able to recover.
Issue Date:2014-05-30
URI:http://hdl.handle.net/2142/49835
Rights Information:Copyright 2014 Matthew Conrad
Date Available in IDEALS:2014-05-30
2016-09-22
Date Deposited:2014-05


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