Neuroimmune origins of behavioral disorders

Antonson, Adrienne M.

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https://hdl.handle.net/2142/101150 Copy

Description

Title

Neuroimmune origins of behavioral disorders

Author(s)

Antonson, Adrienne M.

Issue Date

2018-04-11

Director of Research (if dissertation) or Advisor (if thesis)

Johnson, Rodney W.

Doctoral Committee Chair(s)

Johnson, Rodney W.

Committee Member(s)

• Steelman, Andrew J.
• Nowak, Romana A.
• Schantz, Susan L.

Department of Study

Animal Sciences

Discipline

Animal Sciences

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Maternal immune activation
• prenatal inflammation
• neurodevelopment
• microglia
• social behavior
• PRRSV
• maternal viral infection
• prenatal insult
• neuropsychiatric disorders
• amygdala
• hippocampus

Abstract

Neuropsychiatric illnesses pose a large burden on society, including health care costs, the need for special education and counseling, and emotional hardship for both sufferers and care givers. For many, these burdens are lifelong. The etiopathologies of some psychiatric illnesses, such as Autism Spectrum Disorder (ASD) and schizophrenia, appear to originate during key stages of prenatal or early postnatal neurodevelopment, offering a time window for therapeutic intervention. Epidemiological data has revealed that infections during pregnancy increase the risk of psychiatric illnesses, such as ASD and schizophrenia, in children. Indeed, similarities in psycho- and neuropathologies between the two disorders suggest that there may be a common etiology. Animal models of maternal immune activation (MIA), developed to investigate this link, suggest that maternally derived cytokines mediate fetal neurodevelopment by signaling across the placenta and upregulating inflammatory pathways within the fetal compartment. Microglia, the resident immune cells of the brain and robust responders to cytokine signaling, have been implicated in the neuroimmune pathogenesis of psychiatric disorders, but their role in fetal neurodevelopment during maternal infection has yet to be elucidated. Thus, the primary goal of the work presented in this dissertation is to delineate the activity of prenatal and neonatal microglial cells during and immediately following maternal infection, using a highly-translatable swine model. The investigations undertaken to obtain this goal are divided into three major sections within this dissertation. First, we established a prenatal MIA paradigm in swine by inoculating pregnant gilts with a live virus, porcine reproductive and respiratory syndrome virus (PRRSV), during late gestation to induce circulating pro-inflammatory cytokines and initiate classical sickness behaviors. Using this animal model, we demonstrated that maternal viral infection altered social behaviors, but not learning and memory, in neonatal piglet offspring. Postnatal microglia isolated from these animals did not differ from controls, indicating that aberrant sociability cannot be attributed to over-activation of these cells. Thus, we hypothesized that changes in neurodevelopment, regulated by microglial cells, may be occurring during the prenatal period, manifesting as altered behaviors later in life. The second and third sections of this dissertation were designed to test this hypothesis, and focused exclusively on neurodevelopment during the fetal time point. First, we analyzed gene expression and morphology of the developing porcine hippocampus, a brain region that displays ongoing concentrated neurogenesis, making it exceptionally vulnerable to maternal insults. We found that maternal infection reduced neuron number and caused astrocyte-specific gliosis in conjunction with increased expression of select inflammatory genes, three days before anticipated parturition (five weeks-post-inoculation). Additionally, MIA resulted in a reduction in overall fetal brain weight, but not body weight, emphasizing the targeted impact of maternal viral infection on the central nervous system. Notably, there was an absence of pronounced neuroinflammation at this time, including an apparent reduction in microglial cell activation, which indicated that classical neuroinflammatory pathways, if activated by MIA, are mostly resolved by parturition. The third section of this dissertation, therefore, focused on investigating neuroinflammation, and specifically microglia activation, at earlier time points: peak maternal viral infection (7 days-post-inoculation [dpi]) and immediately following the resolution of maternal symptoms (21 dpi). At 21 dpi, we observed a reduction in fetal brain weights, but not body weights, due to maternal viral infection, replicating our previous findings. Assessment of gene expression revealed increased inflammation at the maternal-fetal interface (endometrium and placenta) at both 7 and 21 dpi. Evaluation of fetal microglia revealed an increase in the classical activation marker MHCII and altered levels of phagocytic and chemotactic activity at both time points. Using high throughput quantitative real time-PCR, we observed that genes involved in neurodevelopment, the microglia sensome, and inflammation (enriched in microglia) were differentially regulated in fetal microglia. Given that reduced sociability was evident in neonatal piglets, we also examined gene expression patterns in the fetal amygdala, a brain region integral to the regulation of social behavior, and found that a similar subset of genes was altered by MIA. We also observed that the effects of MIA on inflammatory and neurodevelopmental processes appears to be temporally regulated, evidenced by diverging patterns of microglial and amygdala gene expression from 7 to 21 dpi. Interestingly, sexual dimorphisms were evident in gene expression patterns across both tissues and time points, mimicking similar patterns observed in human neuropsychiatric disorders. Finally, we assessed microglia number and morphology in the fetal hippocampus and amygdala. While both number and morphology were relatively unchanged in the hippocampus at 7 and 21 dpi, an increase in microglia number was evident in the amygdala at 7 dpi, though this did not continue to 21 dpi. Contrary to our hypothesis, maternal viral infection did not alter microglia morphology. In conclusion, this dissertation provides evidence that maternal viral infection in swine results in altered social behaviors postnatally, and that changes in postnatal behaviors could be contributed to aberrant neurodevelopmental processes during acute maternal immune activation. Specifically, we show that fetal microglial cells are transiently sensitized during peak maternal viral infection and that insults incurred during peak infection persist after inflammation has resolved. Overall, these data emphasize the importance of prenatal interventions and provide a foundation for fetal microglial cells as potential therapeutic targets in neurodevelopmental disorders.

Graduation Semester

2018-05

Type of Resource

text

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http://hdl.handle.net/2142/101150

Copyright and License Information

Copyright 2018 Adrienne Antonson

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