ORCID

http://orcid.org/0000-0001-5270-8500

Date of Award

Spring 5-15-2020

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Neuroinflammation plays a pivotal role in a variety of diseases of the CNS associated with cognitive impairment, including Alzheimerճ Disease, Parkinsonճ Disease with dementia, Multiple Sclerosis, anti-NMDA receptor encephalitis, and West Nile Virus Neuroinvasive disease (WNND). Despite strong evidence that infiltration of peripheral immune cells and activation of resident microglia and astrocytes occurs in these various diseases, very little is known about how this altered immune environment may influence normal cognitive function. Given that communication between the nervous and immune system is essential for normal cognitive function, the central motivation of my thesis work is to understand the mechanisms by which immune activation, which is vital for pathogen control, may influence cognitive recovery in the setting of viral infection of the CNS. First, using a recovery model of WNND in which intracranial infection of adult mice with an attenuated strain of West Nile Virus leads to spatial learning deficits on the Barnes Maze behavioral task, we demonstrate that following viral clearance activated astrocytes express the cytokine interleukin-1 (IL-1) which decreases neurogenesis and increases the generation of astrocytes. Animals deficient in the receptor for IL-1 (IL1R1-/-) are protected from this decrease in neurogenesis and display early recovery of synaptic terminals and protection from virus-induced spatial learning deficits. In addition, treatment of mice with Anakinra, an FDA-approved IL-1R antagonist, during acute disease similarly led to protection from spatial learning deficits. Next, using the same recovery model of WNND, we demonstrate that T cells persist in the hippocampus for weeks following viral clearance and continue to express the cytokine interferon-gamma (IFNg) leading to persistent activation of microglia. Animals deficient in the receptor for IFNg (IFNgR-/-) are protected from microglial activation and spatial learning deficits, despite delayed viral clearance and increased persistence of viral RNA in the hippocampus compared to wildtype controls. Conditional deletion of IFNgR from microglia upon tamoxifen administration to Cx3CR1-CreER x IFNgR-fl/fl mice was sufficient to protect animals from spatial learning deficits. These results were confirmed in animals infected with Zika-virus (ZIKV), a related flavivirus with different neural tropism, suggesting a common mechanism by which altered immune activation in the CNS leads to long term cognitive deficits. These studies provide valuable insights into the neuroimmune processes that influence tissue repair and cognitive recovery in the hippocampus following viral encephalitis, and identify IFNg signaling in microglia as a critical signal underlying diverse recovery mechanisms.

Language

English (en)

Chair and Committee

Robyn S. Klein

Committee Members

Michael Diamond, Keiko Hirose, Jonathan Kipnis, Haina Shin,

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