Brain region-specific expression of genes mapped within quantitative trait loci for behavioral responsiveness to acute stress in Fisher 344 and Wistar Kyoto male rats

Abstract

Acute stress responsiveness is a quantitative trait that varies in severity from one individual to another; however, the genetic component underlying the individual variation is largely unknown. Fischer 344 (F344) and Wistar Kyoto (WKY) rat strains show large differences in behavioral responsiveness to acute stress, such as freezing behavior in response to footshock during the conditioning phase of contextual fear conditioning (CFC). Quantitative trait loci (QTL) have been identified for behavioral responsiveness to acute stress in the defensive burying (DB) and open field test (OFT) from a reciprocal F2 cross of F344 and WKY rat strains. These included a significant QTL on chromosome 6 (Stresp10). Here, we hypothesized that the Stresp10 region harbors genes with sequence variation(s) that contribute to differences in multiple behavioral response phenotypes between the F344 and WKY rat strains. To test this hypothesis, first we identified differentially expressed genes within the Stresp10 QTL in the hippocampus, amygdala, and frontal cortex of F344 and WKY male rats using genome-wide microarray analyses. Genes with both expression differences and non-synonymous sequence variations in their coding regions were considered candidate quantitative trait genes (QTGs). As a proof-of-concept, the F344.WKY-Stresp10 congenic strain was generated with the Stresp10 WKY donor region into the F344 recipient strain. This congenic strain showed behavioral phenotypes similar to those of WKYs. Expression patterns of Gpatch11 (G-patch domain containing 11), Cdkl4 (Cyclin dependent kinase like 4), and Drc1 (Dynein regulatory complex subunit 1) paralleled that of WKY in the F344.WKY-Stresp10 strain matching the behavioral profiles of WKY as opposed to F344 parental strains. We propose that these genes are candidate QTGs for behavioral responsiveness to acute stress.

Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F2Cross of Selectively-Bred Rats

“…red=increased expression in the rat model of internalizing behavior, green=increased expression in the reference group): ([1]: (Meckes et al, 2018)) Wistar Kyoto vs. Fischer 344; ([2]: (Wilhelm et al, 2013)) Flinders sensitive vs. Sprague-Dawley; ([3]: (Blaveri et al, 2010) Flinders sensitive vs.…”

“…red=increased expression in the rat model of internalizing behavior, green=increased expression in the reference group): ([1]: (Meckes et al, 2018)) Wistar Kyoto vs. Fischer 344; ([2]: (Wilhelm et al, 2013)) Flinders sensitive vs. Sprague-Dawley; ([3]: (Blaveri et al, 2010) Zhou et al, 2019). Green dots reflect genes identified by a convergence of evidence supporting their association with bHR/bLR-related behavior (FDR<0.10 in either the F0 or late-generation meta-analysis or p<0.05 and consistent direction of effect in both) and bHR/bLR phenotypical behavior in the F2s (listed in panel A).…”

“…The table is formatted similarly to Fig 8A . The final column provides the references for the publications that found similar hippocampal differential expression in association with a genetic rat model targeting internalizing behavior: ([1]: (Meckes et al, 2018)) Wistar Kyoto vs. Fischer 344; ([2]: (Wilhelm et al, 2013)) Flinders sensitive vs. Sprague-Dawley; ([3]: (Blaveri et al, 2010))…”

“…rat model targeting internalizing behavior:([1]:(Meckes et al, 2018)) Wistar Kyoto vs. Fischer 344;([2]:(Wilhelm et al, 2013)) Flinders sensitive vs. Sprague-Dawley;([3]:(Blaveri et al, 2010)) Flinders sensitive vs. Flinders resistant;([4]:(Díaz-Morán et al, 2013)) NIH-HS high anxiety vs. NIH-HS low anxiety;(([5]:(Raghavan et al, 2017) & [6]:(Andrus et al, 2012))) Wistar more immobile vs. Wistar less immobile. B.…”

Hypothalamic Gene Expression and Postpartum Behavior in a Genetic Rat Model of Depression

“…Once isolated, 1 µg of the total RNA was reverse transcribed using the SuperScript VILO cDNA Synthesis Kit (Thermo Fisher Scientific, Waltham, MA, USA). All of these methods have been described previously (Raghavan et al, 2017;Lim et al, 2018a,b;Meckes et al, 2018).…”