ORCID

https://orcid.org/0000-0002-3501-7262

Date of Award

3-11-2024

Author's School

Graduate School of Arts and Sciences

Author's Department

Philosophy/Neuroscience, and Psychology

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

While inflammation is an important mechanism for the return to homeostasis post insult or injury, inflammation in the central nervous system (CNS) can lead to irreparable damage. To mitigate this process, the brain is protected from circulating neurotoxic molecules as well as peripheral immune cells through the tightly regulated blood-brain barrier (BBB). The balance between pro- and anti- inflammation in the CNS rapidly shifts towards a neurotoxic proinflammatory state during acute bacterial or viral infections or chronic neuroinflammatory diseases. Excessive inflammatory responses are also coupled with extensive BBB leakage and breakdown, allowing rampant entry of peripheral inflammatory cells and mediators into the brain. Recent evidence suggest that many aspects of immune function exhibit pronounced 24- hour rhythms which are controlled by the circadian system. Immune cell activation and trafficking, cytokine production, and pgp-transporter efflux across the BBB are all modulated by circadian rhythms. Using a mouse model of sepsis, we found that there is diurnal variation in the severity of inflammatory BBB breakdown and that this evening susceptibility is driven through the activation of glial cells – including microglia and astrocytes. Neurodegenerative diseases, such as Alzheimer’s disease (AD), are characterized by chronic rather than acute inflammation still have rhythms in immune response. We found that the pro-inflammatory chemokine CXCL5 is rhythmically expressed in astrocytes, under the control of the molecular clock, and increases in expression in mouse models of AD. Using an astrocyte-specific overexpression model, we observed that increased levels of CXCL5 induces greater amyloid-beta plaque load. This increase in disease pathology was due to an increase in plaque count and occurred independently of glial activation, suggesting astrocyte-derived CXCL5 induces loss of glial support and increased amyloid-beta deposition. Altogether, these data highlight the importance of considering all aspects of circadian biology when studying chronic and acute inflammation in both the periphery and CNS.

Language

English (en)

Chair and Committee

Erik S Musiek

Committee Members

Marco Colona, Richard Daneman, Jason Ulrich, Gregory Wu

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