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C57BL6 Substrain Differences in Hippocampal-Dependent Learning and Transcriptome

ABSTRACT: Here, we evaluated B6J and B6NJ substrains in a fear conditioning paradigm with varied conditioned stimulus-unconditioned stimulus pairings to assess if the strength of learning varies between substrains. For all number of pairings, B6NJ showed enhanced contextual freezing compared to B6J. To investigate baseline and learning-induced changes in hippocampal transcriptome that may underlie the observed behavioral differences between B6J and B6NJ, dorsal and ventral hippocampi were analyzed for RNAsequencing from B6J and B6NJ male mice from three groups: direct from home cage, 30 minutes after 2-pairings of shock and cue, 30 minutes after 2 exposures to cue alone. RNASeq pathway and network analysis identified several genes related to BDNF signaling that could contribute to the differences in levels contextual fear learning observed. Together, these behavioral and transcriptomic findings confirm differences in conditioned fear between the commonly used B6 substrains B6J and B6NJ and suggest that hippocampal transcriptome differences related to BDNF may contribute to differences in learning

ORGANISM(S): Mus musculus

PROVIDER: GSE291439 | GEO | 2026/07/01

REPOSITORIES: GEO

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Project description:Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example the expression of an aversive behavior upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinctionare only beginning to emerge. Here we show that fear extinction initiates up-regulation of hippocampal insulin-growth factor 2 (Igf2) and down-regulation of insulin-growth factor binding protein 7 (Igfbp7). In line with this observation we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2-signaling during fear extinction. To this end we show that fear extinction-induced IGF2/IGFBP7-signaling promotes the survival of 17-19 day-old newborn hippocampal neurons. In conclusion, our data suggests that therapeutic strategies that enhance IGF2-signaling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory. We employed mice to investigate fear extinction in the hippocampus-dependent contextual fear conditioning paradigm. To this end, male C57BL/6J mice were exposed to the fear conditioning box (context) followed by an electric foot-shock which elicits the acquisition of conditioned contextual fear. For extinction training animals were repeatedly reexposed to the conditioned context on consecutive days (24h interval) without receiving the footshockagain (extinction trial, E). This procedure eventually results in the decline of the aversive freezing behavior. Mice that were exposed to the conditioning context without receiving fear conditioning training served as control groups. To gain a better understanding of the molecular processes underlying fear extinction we performed a genome-wide analysis of the hippocampal transcriptome during fear extinction. In the employed paradigm fear extinction is a gradual process. To capture the longitudinal course of fear extinction we decided to perform hippocampal microarray analysis at two time points: (1) After the first extinction trial (E1) when animals display high levels of aversive freezing behavior and (2) at the extinction trial on which the freezing behavior was significantly reduced when compared to E1. This extinction trial, in the case of this experiment E5, we termed “extinction trial low freezing” (ELF). Mice that were exposed to the conditioning context without receiving fear conditioning training served as control groups (3). For all three groups we hybridized 5 samples (biological replicates).

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C57BL6 Substrain Differences in Hippocampal-Dependent Learning and Transcriptome

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