Early life adversity (ELA) during critical periods of early development increases the risk of neuropsychiatric disorders. Adversity such as abuse, neglect and poverty can lead to activation of the immune system and alter the development of the brain. ELA can also impact the regulation of neuronal networks by microglia, the innate immune cells of the brain. This neuro-immune dysregulation can result in neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia (SZ) and others. We are also investigating the functions of toll-like receptor 7 (TLR7), a sensor of single-stranded viruses such as influenza and rubella that is highly conserved between humans and rodents. Immune activation induced by in utero administration of the TLR7 agonist imiquimod activates the immune system and is characterized by a phenotype of fragmented social behavior and reduced anxiety-like behavior with a sex bias for males. While it is a strong risk factor, maternal immune activation alone does not always lead to offspring developmental disorders, but it seems to increase the susceptibility to other risk factors. Previous research has shown that a mouse model of ELA resulted in sex-specific alterations in behaviors that are relevant to the clinical manifestations of neurodevelopmental disorders. In this study, we employed a two-hit model of early-life resource deprivation, stress in the form of limited bedding and nesting (LBN) in combination with maternal immune activation via in utero TLR7 stimulation. We then investigated the ability of this two-hit paradigm to induce neural and behavioral alterations and investigate offspring communicative, social, and perseverative behaviors, along with brain proteomic alterations. / 2026-03-07T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/48372 |
| Date | 08 March 2024 |
| Creators | Ruseva, Virzhiniya Mincheva |
| Contributors | Gerstenfeld, Louis C., Bordt, Evan A. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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