Behavioral and Genetic Architecture of Fear Conditioning and Related Phenotypes
Open Access
- Author:
- Zeid, Dana
- Graduate Program:
- Biobehavioral Health
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 22, 2021
- Committee Members:
- Thomas Gould, Chair & Dissertation Advisor
Stephen Wilson, Outside Unit & Field Member
David Vandenbergh, Major Field Member
Helen Kamens, Major Field Member
Thomas Gould, Program Head/Chair - Keywords:
- contextual fear conditioning
BxD
mouse behavior
factor analysis
Ptprd
Hacd4
Post-shock freezing
Pre-CS freezing - Abstract:
- Classical fear conditioning is a behavioral paradigm with external validity to cognitive and psychiatric variables. Contextual fear conditioning is a hippocampus-dependent form of associative learning in which an assimilated set of cues (context) come into association with an aversive stimulus. This versatile behavior is used in human and rodent research to model anxiety disorders and basic learning processes. In mouse models, conditioned fear is typically assessed through measurement of immobility behavior, which reflects a naturally-selected fear response to predators with limited visual capacity to detect motionless targets. Thus, this dependent variable is the sum of multiple processes including, but not limited to associative learning, configural learning, fear and anxiety, and general activity. These intersecting phenotypes that sum to affect freezing behavior are innate constituents of the fear learning process and should not necessarily be dismissed as potential confounds. That is, contextual fear conditioning in the functioning organism represents the ethologically relevant aggregate of all its underlying effectors. Understanding the behavioral and biological context in which contextual fear conditioning occurs promotes better modeling of parallel human conditions as well as ethologically informed interpretation of this phenotype in animal models. This dissertation aimed to characterize behavioral and genetic architecture underlying performance in contextual fear conditioning and correlated behaviors using a mouse model of genetic diversity. This research utilized a preliminary fear conditioning dataset in the BxD recombinant inbred strain panel for QTL mapping of contextual fear conditioning. This mapping was used to identify candidate genes for contextual fear learning. High and low fear conditioning strains, as well as intermediate BxD parental strains, were selected for additional testing in a behavioral battery comprising measures of configural learning, anxiety, activity, and fear conditioning. Expression of candidate genes for contextual fear conditioning was quantified in battery animals. Finally, gene expression and behavioral data were analyzed using an exploratory factor analysis in order to identify underlying phenotypic dimensions impacting fear conditioning and correlated behaviors. Exploratory factor analysis revealed five distinct phenotypic constructs representing activity/anxiety/exploration, associative fear learning, anxiety, post-shock freezing, and open field activity phenotypes. These findings contextualize fear conditioning within the broader murine behavioral architecture. Associative learning and expression of one candidate gene for contextual fear conditioning emerged as a unique construct within the factor analysis. Post-shock freezing during the fear conditioning training trial and expression of a second candidate gene for contextual fear conditioning emerged as an additional unique construct, highlighting the independence of this measure within the fear conditioning paradigm. These findings additionally support a link between adaptive prey behaviors expressed in anxiety, activity, and exploratory phenotypes. Between-strain comparisons on composite variables informed by the factor analysis further allowed for preliminary behavioral profiling of tested strains. These findings inform understanding of fear conditioning in terms of its secondary measures, underlying biological mechanisms, and interaction with other mouse behaviors.