Author ORCID Identifier

https://orcid.org/0009-0008-6800-516

Date Available

9-4-2024

Year of Publication

2024

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Pharmacy

Department/School/Program

Pharmaceutical Sciences

Advisor

Dr. James Pauly

Co-Director of Graduate Studies

Dr. Kimberly Nixon

Abstract

Studies of adolescent drinking show a distinct prevalence of binge drinking, including at extreme levels, and this type of drinking has been identified as increasing risk of developing an Alcohol Use Disorder (AUD). Additionally, females suffer greater levels of harm from binge drinking and AUD and in an abbreviated timeline compared to males. Neuroimmune reactivity, specifically with microglial reactivity following binge drinking, may influence the sex differences seen in negative alcohol-related health disparities.

The first set of experiments sought to examine a marker of microglial reactivity, TSPO, in adolescent females and males and found the sexes displayed different temporal and spatial patterns of expression. Adolescent females showed a brief and immediate response in the thalamus while males showed a delayed and sustained increase in TSPO in the thalamus and hippocampus. In this same model, neurodegeneration was assessed using FJB and while cell death was modest, sex differences emerged as males showed more cell death in the entorhinal cortex and females showed greater cell death in the perirhinal cortex.

The second set of experiments aimed to explore potential drivers of the sex differences identified in the first experiments and thus sought to assess the effects of ovarian hormone removal on neuroimmune activation in adolescent females. TSPO expression differed between ovariectomized (OVX) and sham-operated females, with OVX females showing a unique, hybrid expression pattern and sham females showing no significant changes in expression. Microglial morphology was also assessed in order to contextualize the microglial response. OVX females showed more robust changes in microglial number and reactivity in more regions including the thalamus and rhinal cortices while both showed changes in the hippocampus. Neurodegeneration in this model was minimal and was no different between surgery groups.

Overall, these experiments show adolescent females have a unique neuroimmune response compared to that of adolescent males and that ovarian hormones play a role. The first experiments showed different patterns of microglial reactivity and sex differences in neurodegeneration and the second experiment showed OVX animals displayed a hybrid response while the sham females showed a notable lack of changes. This implies that females during this pubertal time may have a blunted or below baseline response that could contribute to the disparities in damage and deficits from alcohol, even the progression to AUD.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2024.381

Funding Information

This study was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism RO1 grant (No. AA025591) in 2018.

This study was supported by University of Kentucky College of Pharmacy Graduate Program -Teaching Assistant Position- in the years 2020-2024.

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