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The Journal of Neuroscience, November 19, 2008, 28(47):12383-12395; doi:10.1523/JNEUROSCI.1662-08.2008

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Behavioral/Systems/Cognitive
The Activity-Regulated Cytoskeletal-Associated Protein (Arc/Arg3.1) Is Required for Memory Consolidation of Pavlovian Fear Conditioning in the Lateral Amygdala

Jonathan E. Ploski,¹ Vicki J. Pierre,¹ Jason Smucny,^1,2 Kevin Park,¹ Melissa S. Monsey,¹ Kathie A. Overeem,^1,3 and Glenn E. Schafe^1,2

¹Department of Psychology and ²Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06520, and ³University of Canterbury, Christchurch 8140, New Zealand

Correspondence should be addressed to Dr. Glenn E. Schafe, Department of Psychology, Yale University, 2 Hillhouse Avenue, Box 208205, New Haven, CT 06520. Email: glenn.schafe{at}yale.edu

The activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) is an immediate early gene that has been widely implicated in hippocampal-dependent learning and memory and is believed to play an integral role in synapse-specific plasticity. Here, we examined the role of Arc/Arg3.1 in amygdala-dependent Pavlovian fear conditioning. We first examined the regulation of Arc/Arg3.1 mRNA and protein after fear conditioning and LTP-inducing stimulation of thalamic inputs to the lateral amygdala (LA). Quantitative real-time PCR, in situ hybridization, Western blotting and immunohistochemistry revealed a significant upregulation of Arc/Arg3.1 mRNA and protein in the LA relative to controls. In behavioral experiments, intra-LA infusion of an Arc/Arg3.1 antisense oligodeoxynucleotide (ODN) was observed to be anatomically restricted to the LA, taken up by LA cells, and to promote significant knockdown of Arc/Arg3.1 protein. Rats given intra-LA infusions of multiple doses of the Arc/Arg3.1 ODN showed an impairment of LTM (tested 24 later), but no deficit in STM (tested 3 h later) relative to controls infused with scrambled ODN. Finally, to determine whether upregulation of Arc/Arg3.1 occurs downstream of ERK/MAPK activation, we examined Arc/Arg3.1 expression in rats given intra-LA infusion of the MEK inhibitor U0126. Relative to vehicle controls, infusion of U0126 impaired training-induced increases in Arc/Arg3.1 expression. These findings suggest that Arc/Arg3.1 expression in the amygdala is required for fear memory consolidation, and further suggest that Arc/Arg3.1 regulation in the LA is downstream of the ERK/MAPK signaling pathway.

Key words: Arc; LTP; amygdala; fear conditioning; ERK; classical conditioning

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Received April 16, 2008; revised Sept. 12, 2008; accepted Oct. 9, 2008.

Correspondence should be addressed to Dr. Glenn E. Schafe, Department of Psychology, Yale University, 2 Hillhouse Avenue, Box 208205, New Haven, CT 06520. Email: glenn.schafe{at}yale.edu

This article has been cited by other articles:

				S. Loebrich and E. Nedivi The Function of Activity-Regulated Genes in the Nervous System Physiol Rev, October 1, 2009; 89(4): 1079 - 1103. [Abstract] [Full Text] [PDF]

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