The effects of prenatal maternal immune activation on behavioral and neural outcomes in offspring across development
Date
2024
Authors
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Publisher
University of Delaware
Abstract
Exposure to maternal immune activation (MIA) during pregnancy is associated with an increased risk for offspring to be diagnosed with neurodevelopmental disorders (NDDs). The maternal and fetal immune response to infection is thought to disrupt important developmental processes in offspring that can have long-lasting effects on their neuroimmune function and behavior. NDDs – such as autism, schizophrenia, and general learning disabilities – are more common in males than females. This suggests there are sex differences in neurodevelopment that may be differently affected by MIA to contribute to the symptoms of such disorders. The goal of this dissertation is to investigate how MIA affects rat offspring by evaluating their reflex development as neonates (Aim 1), their adult anxiety, learning, and memory behaviors (Aim 2), and their neuroimmune state both at basal levels across the lifespan (Aims 1 and 3) and in response to a secondary immune challenge in adulthood (Aim 3). We hypothesized that MIA would produce a neuroinflammatory state in offspring that would negatively impact these behavioral processes, and that males would be more affected by MIA than females. ☐ The experiments of this dissertation utilized a model of MIA that exposed female Sprague-Dawley rats to lipopolysaccharide during gestation to mimic an immune response to bacterial infection. We found that MIA enhanced the development of neonatal reflexes in both male and female offspring and did not affect maternal arched-back nursing nor licking and grooming toward pups (Aim 1). In adulthood, MIA offspring displayed reduced anxiety in the elevated-plus maze and improved performance of novel object location memory (Aim 2). Additionally, MIA induced latent inhibition in female offspring that were pre-exposed to the innocuous tone during conditioned fear training and prevented latent inhibition of tone memory in male offspring (Aim 2). Finally, in the offspring medial prefrontal cortex, MIA upregulated IL-1β at P7 and downregulated IL-6 at P21 in both sexes, and decreased BDNF in the dorsal hippocampus of males at P21 (Aim 1). In adulthood (Aim 3), MIA did not affect the inflammatory immune response to adult LPS exposure but did downregulate basal gene expression in the dorsal hippocampus (IL-6, CD11b, BDNF) and amygdala (IL-1β) of male and female offspring. ☐ These findings suggest that the relationship between MIA and the etiology and manifestation of NDD-related symptoms in offspring is more complex than the literature suggests. Our data revealed that MIA elevated IL-1β expression at P7, reduced BDNF expression at P21 (in males) and in adulthood, and impacted latent inhibition learning in adult offspring, which are outcomes characteristic of human NDDs. On the other hand, MIA also downregulated neuroinflammatory gene expression in the brains of juvenile and adult offspring, reduced adult anxiety behaviors, and improved neonatal reflex development and adult novelty learning, which are phenotypes not typically associated with NDDs. Nonetheless, the results of this dissertation support that MIA can produce profound and long-lasting effects on offspring neuroimmune and behavioral processes.
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Keywords
Behavior, Development, Lipopolysaccharide, Maternal immune activation, Neurodevelopmental disorders, Neuroimmune