Abstract
Pavlovian fear conditioning is an associative learning paradigm in which mice learn to associate a neutral conditioned stimulus with an aversive unconditioned stimulus. In this study, we demonstrate a novel role for the transcriptional regulator Lmo4 in fear learning. LMO4 is predominantly expressed in pyramidal projection neurons of the basolateral complex of the amygdala (BLC). Mice heterozygous for a genetrap insertion in the Lmo4 locus (Lmo4gt/+), which express 50% less Lmo4 than their wild type (WT) counterparts display enhanced freezing to both the context and the cue in which they received the aversive stimulus. Small-hairpin RNA-mediated knockdown of Lmo4 in the BLC, but not the dentate gyrus region of the hippocampus recapitulated this enhanced conditioning phenotype, suggesting an adult- and brain region-specific role for Lmo4 in fear learning. Immunohistochemical analyses revealed an increase in the number of c-Fos positive puncta in the BLC of Lmo4gt/+ mice in comparison to their WT counterparts after fear conditioning. Lastly, we measured anxiety-like behavior in Lmo4gt/+ mice and in mice with BLC-specific downregulation of Lmo4 using the elevated plus maze, open field, and light/dark box tests. Global or BLC-specific knockdown of Lmo4 did not significantly affect anxiety-like behavior. These results suggest a selective role for LMO4 in the BLC in modulating learned but not unlearned fear.
Highlights
Pavlovian fear conditioning (FC) is a well characterized behavioral paradigm extensively used to study learning and memory in rodents [1,2]
Our results indicate that LMO4 expression in the basolateral complex of the amygdala (BLC) overlaps extensively with that of CaMKII-a, with LMO4 expression localized to the nucleus and CamKII-a expression in the perikarya (Figure 1)
LMO4 expression did not co-localize with any of these interneuron markers (Supplementary Figure S1). These results suggest that LMO4 is predominantly expressed in pyramidal projection neurons of the BLC
Summary
Pavlovian fear conditioning (FC) is a well characterized behavioral paradigm extensively used to study learning and memory in rodents [1,2]. In this paradigm, mice learn to associate a neutral conditioned stimulus (CS) with an aversive unconditioned stimulus (US), such that exposure to the CS by itself elicits a species-specific defensive response. Integration of the CS and US [3] in the BLC triggers long term potentiation and activity dependent changes in gene expression which in turn result in changes in synaptic structure and function that underlie the formation of long term memories [4,5,6]. Transcriptional regulators including cAMP response element binding protein (CREB) and methyl CPG binding protein 2 (MeCP2) have been shown to function in the BLC to regulate fear learning, suggesting that transcriptional regulation within the BLC may underlie aspects of aversive conditioning [9,10]
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