DOI
https://doi.org/10.25772/PA43-W681
Author ORCID Identifier
https://orcid.org/0000-0001-6104-0987
Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Dr. Jennifer Wolstenholme
Abstract
Ethanol is the most consumed drug among adolescents, which can cause long-term effects on memory and changes in gene and protein expression. While both adolescents and adults engage in binge drinking, the neurological and behavioral effects differ, with adolescents showing fewer adverse physiological effects but greater memory deficits than adults. Sex differences related to ethanol occur with women showing higher BEC than men and similar cognitive deficits despite fewer years of ethanol consumption. During adolescence the mPFC and dHPC undergo maturation development with both brain regions playing a role in spatial and recognition memory. Proteins critically involved in memory and transcription, CREB and CBP, are decreased following ethanol exposure with decreased protein expression resulting in memory deficits. This dissertation examines how binge ethanol may differentially impact memory performance, myelin-related gene expression, memory-related protein expression, and memory-related protein interactions due to sex and developmental age of ethanol exposure. We hypothesized that binge ethanol would result in a recognition and spatial memory impairment in adolescent exposed animals but not adult exposed, and would be associated with decreased CBP protein expression and interactions. Additionally, we hypothesized that females would be more impacted by ethanol exposure than males due to a higher BEC. To investigate age and sex differences following binge ethanol exposure, we exposed adult and adolescent DBA/2J male and female mice to the same ethanol paradigm (intermittent oral ethanol 4g/kg) from either PND 29-42 or PND 64-77. First, we behaviorally characterized the adult and adolescent exposure model finding adolescent ethanol exposure but not adult impaired recognition memory, while age-by-ethanol effects also impacted sociability and acute ethanol locomotor tolerance. Sex impacted ethanol sedation, but age and not sex impacted BEC with adolescents displaying lower BEC than adults. Additionally, adult ethanol exposure resulted in one myelin-related gene expression change. Next, adolescent ethanol impacted spatial learning and impaired spatial memory, while sex impacted spatial learning in the adult cohort and spatial memory in the adolescent cohort. At the same timepoint as the observed memory deficits, CBP protein expression was unchanged by ethanol, while CREB was altered by an ethanol by sex interaction in both brain regions. CREB protein interactions in the dHPC and CRE-mediated transcription in the mPFC, did not differ by ethanol in any age group. Lastly, we unbiasedly explored upstream targets of the adolescent ethanol gene list and found two potential upstream regulators of lasting gene expression changes in the PFC, NRG1and CD40, with roles in neurogenesis and synapse assembly. Therefore, dendritic spines and basal or activity dependent neurogenesis may be impaired following adolescent ethanol exposure and may play a role in the observed memory deficits. Together, these experiments provide evidence that binge ethanol differentially impacts myelination, recognition memory, and spatial memory depending on the age of ethanol exposure, but the underlying molecular differences between the two age-exposed groups remains to be understood.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
7-10-2024