Limited WKY chromosomal regions confer increases in anxiety and fear memory in a F344 congenic rat strain

Abstract

This study investigated the interaction between genetic differences in stress reactivity/coping and environmental challenge, such as acute stress during adolescence on adult contextual fear memory and anxiety-like behaviors. Fischer 344 (F344) and the inbred F344;WKY-Stresp3/Eer congenic strain (congenic), in which chromosomal regions from the Wistar Kyoto (WKY) strain were introgressed into the F344 background, were exposed to a modified Forced Swim Test (FST) during adolescence while controls were undisturbed. In adulthood, fear learning and memory, assessed by Contextual Fear Conditioning (CFC), were significantly greater in congenic animals compared to F344s, and stress during adolescence increased them even further in males of both strains. Anxiety-like behavior, measured by the Open Field Test (OFT), were also greater in congenics than F344s, and stress during adolescence increased it further in both strains of adult males. Whole genome sequencing of the F344;WKY-Stresp3/Eer strain revealed an enrichment of WKY genotypes in Chromosomes 9,14 and 15. An example of functional WKY sequence variations in the congenic strain, Cannabinoid Receptor Interacting Protein 1 (Cnrip1) had a Cnrip1 transcript isoform that lacked two exons. Although the original hypothesis that the genetic predisposition to increased anxiety of the WKY donor strain would exaggerate fear memory relative to the background strain was confirmed, the consequences of adolescent stress were strain independent but sex dependent in adulthood. Molecular genomic approaches combined with genetic mapping of WKY sequence variations in Chrs 9,14, and 15 could aid in finding quantitative trait genes contributing to the variation in fear memory.