Congenic Mouse Strains Enable Discrimination of Genetic Determinants Contributing to Fear and Fear Memory

Abstract

The ability to learn and remember is variable within a population of a given species, including humans. This is due in part to genetic variation between individuals. However, only few genes have been identified that contribute to variation in learning and memory. Two inbred mouse strains, C57Bl/6J (B6) and DBA/2J (D2), show significant variation both in fear conditioning memory as well as primary responsiveness to fear. Several studies have identified quantitative trait loci (QTL) on chromosomes (Chr) 1 and 12 associated with performance in fear conditioning, but it is unclear if these QTL were associated with fear memory or innate fear responsiveness. To determine if these QTL are associated with fear memory or fear responsiveness, we studied congenic mouse strains harbouring D2-derived DNA from Chr1 or Chr12 on a B6 genetic background. Cohorts of D2, B6 and the congenic mice were tested throughout the process of fear conditioning by measuring a series of fear-related parameters. The Chr1 congenic mice showed clear deficits in fear memory compared to B6 mice, which established the presence of a QTL on Chr1 directly influencing fear memory. The Chr12 congenic mice also showed alterations in fear conditioning, but this was more associated with alterations in fear responsiveness. These findings thus provide evidence for the localisation of independent genetic determinants for fear memory and fear responsiveness.

Delay and trace fear conditioning in C57BL/6 and DBA/2 mice: issues of measurement and performance

“…1), D2 mice showed higher levels of freezing than B6 mice (Delay, P ¼ 0.001; Trace, P ¼ 0.014), but the same difference is not observed following the second US presentation. The basis for this early increased freezing in D2 mice is unclear, but has been observed by other groups (Gerlai 1998;Nie and Abel 2001;Fitch et al 2002;Wilson et al 2011), and is often used as evidence that reactivity to the US is not responsible for low D2 freezing during the context and CS tests. In agreement with this, we found a similar footshock threshold between these strains (B6, 0.163 + 0.008 mA; D2, 0.169 + 0.009 mA; P ¼ 0.618), which is consistent with previous reports (Lu and Wehner 1997;Liu et al 2003).…”

“…Thus, quantifying other behavioral elements could provide a better description of the overall behavioral responses to fear conditioning across differently behaving strains. A handful of alternative behaviors have been investigated, including grooming, rearing, and boli (e.g., Gerlai 1998;Fitch et al 2002;Wilson et al 2011;Choy et al 2012). We chose the two most commonly observed behaviors, grooming and rearing, and compared them across our strains in delay and trace fear conditioning.…”

“…By comparing genetically distinct lines, researchers have been able to identify chromosomal regions and individual genes that contribute to numerous behaviors, including learning and memory Wilson et al 2011;Parker et al 2012). Molecular pathways and the importance of specific brain regions for these behaviors have also been identified (Wehner et al 1990;Lu and Wehner 1997;Nguyen and Gerlai 2002).…”

Reduction of p75 neurotrophin receptor ameliorates the cognitive deficits in a model of Alzheimer's disease

“…Fear conditioning was undertaken on 4-to 7 emonth-old male mice as a modification of that previously described (Wilson et al, 2011), in a plexiglass chamber equipped with a shock grid floor made of stainless steel rods. On training day, mice were placed in the shock chamber and allowed to explore for 180 seconds before receiving a-1.0 mA shock for 3 seconds duration.…”

Comparison of the performance of DBA/2 and C57BL/6 mice in transitive inference and foreground and background contextual fear conditioning.

“…If this is the case, DBA/2 mice should perform better in foreground contextual fear conditioning compared to background contextual fear conditioning. However in different studies, DBA/2 mice perform poorly in background (Balogh, et al, 2002; Gerlai, 1998; Nguyen, et al, 2000; Nie & Abel, 2001; Owen, et al, 1997; Paylor, et al, 1994; Stiedl et al, 1999) and foreground (Paylor, et al, 1994; Wilson, Brodnicki, Lawrence, & Murphy, 2011) contextual fear conditioning. The present study examined both foreground and background contextual fear conditioning with the expectation that DBA/2 mice would show a similar magnitude of deficits for both tasks.…”