A Role for Notch Pathway Signaling in Amygdala-Dependent Fear Learning Open Access

Goodman, Jared Vega (2013)

Permanent URL: https://etd.library.emory.edu/concern/etds/1544bp740?locale=en
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Abstract

Fear and anxiety are evolutionarily conserved mental states that are caused by cues that predict aversive stimuli. Each is mediated by the amygdala, a region in the medial temporal lobe that has been implicated in both the storage of emotional memories and the output of their stereotyped behavioral and physiological responses. Previous literature has implicated the developmentally crucial Notch pathway in hippocampal-dependent memory tasks (Conboy et al., 2007). Our work used an auditory fear conditioning paradigm to implicate Notch signaling in amygdala-dependent fear consolidation wherein an auditory cue (CS) is paired with a mild foot-shock (US). The present study shows that ligand (Jag1, Dll1), receptor (Notch1), and effector (Hes5) amygdala mRNA levels are transiently decreased 2 hours after fear conditioning in the CS/US paired group. At 6 hours, Jag1 and Notch1 mRNA levels remained reduced in the paired group. Interestingly, there also is downregulation of each of these genes at the 2-hour time point in a behavioral group that does not result in any associative learning wherein the CS and US are unpaired. The hippocampus also shows decreased Jag1 and Dll1 expression 2 hours after fear conditioning in this same unpaired group, suggestive of an already published role for Notch in contextual fear memory consolidation. Furthermore, a single intraperitoneal injection of γ-secretase inhibitor DAPT (an inhibitor of Notch signaling) after fear training enhances cued and contextual fear memory consolidation. These data suggest a role for Notch pathway signaling in the amygdala during memory consolidation. Specifically, we find that Notch signaling is transiently decreased during fear consolidation and that pharmacological inhibition of the pathway enhances fear learning. We hypothesize that Notch signaling may serve to inhibit synaptic plasticity at baseline, and that transient decreases in Notch signaling serve to permit neural plasticity required for learning. These data provide a convincing base for further study of Notch in amygdala-dependent memory formation.

Table of Contents

Introduction.............................1

Materials and Methods...............8

Results..................................11

Discussion..............................14

References.............................21

Figure 1.................................28

Figure 2.................................29

Figure 3.................................30

Figure 4.................................31

Figure 5.................................32

Figure 6.................................33

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Table 1...................................43

Table 2...................................44

Table 3...................................45

Table 4...................................46

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