Interstrain variability in hippocampal learning and gene expression after acute adolescent alcohol exposure
Restricted (Penn State Only)
- Author:
- Seemiller, Laurel
- Graduate Program:
- Molecular, Cellular, and Integrative Biosciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- August 01, 2022
- Committee Members:
- Nikki Crowley, Outside Field Member
Janine Kwapis, Outside Unit Member
Thomas Gould, Chair & Dissertation Advisor
Helen Kamens, Major Field Member
Melissa Rolls, Program Head/Chair
David Vandenbergh, Major Field Member - Keywords:
- Genetics
Alcohol
Inbred
Mouse
Learning
Memory
Fear conditioning
RNA-seq
DBA/2J
Strain - Abstract:
- Adolescent alcohol use is prevalent and problematic. It is especially dangerous because adolescent drug use is a known risk factor for adult addiction and other behavioral disorders. Adolescents are protected from some immediate negative consequences of alcohol (e.g. hangover symptoms, motor impairments), which can support drinking larger amounts of alcohol per occasion than adults. However, adolescents are often more susceptible than adults to long-term negative consequences of alcohol (e.g. affective disorders, cognitive impairments). This creates a dangerous pattern in which adolescents may feel more inclined to drink while being more severely damaged by alcohol than adults. Alcohol use disorders (AUD) are estimated to be 50% heritable. In humans, it is known that genetic factors can influence various aspects of AUD vulnerability during adolescence, including age of initiation and frequency of alcohol use. These findings suggest that age and genetic background may interact to determine sensitivity to alcohol, which can influence vulnerability to AUD. While a growing body of research is investigating the genetics of alcohol sensitivity, little is known about the genetic factors influencing alcohol’s cognitive effects during adolescence. These can be studied in rodent models, where cognitive effects of other drugs have been shown to be determined by genetic background. Understanding the genetic factors underlying susceptibility to alcohol’s effects during adolescence is critical for understanding adolescent alcohol use vulnerability and outcomes. In this dissertation, we explored the genetic factors influencing susceptibility to alcohol-induced learning deficits in adolescence. Data from our laboratory suggested that adolescent susceptibility to contextual fear learning deficits varied between two mouse strains. To investigate the extent and mechanism of genetic background’s influences on adolescent learning after alcohol exposure, we examined how genetic differences across inbred mouse strains impacted vulnerability to alcohol in dorsal hippocampus-dependent and dorsal hippocampus-independent learning tasks. We demonstrated significant strain- and sex-dependent effects of acute alcohol exposure on adolescent and adult fear learning, with alcohol having pronounced effects on dorsal hippocampus-dependent contextual fear learning. Learning data were compared with Blood Ethanol Concentrations (BEC) to assess whether strain differences in alcohol metabolism contributed to strain differences in learning after alcohol exposure. There were no clear relationships between BEC and learning outcomes, suggesting that strains differed in learning outcomes for reasons other than strain differences in alcohol metabolism, such as alcohol effects on dorsal hippocampal gene expression. We then analyzed dorsal hippocampal gene expression after alcohol and/or learning in two strains, C57BL/6J and DBA/2J, that exhibited different learning outcomes after alcohol. We found that alcohol disrupted pathways known to be involved in learning and memory, including plasticity- and Protein Kinase A (PKA)- associated pathways, and we found that the strains differed in expression of Chrna7 and Fmr1, genes associated with sensitivity to alcohol-related learning deficits and general cognitive abilities, respectively. These results inform our understanding of the genetic vulnerability to alcohol-induced hippocampal learning effects during adolescence.