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The Journal of Neuroscience, January 14, 2009, 29(2):402-413; doi:10.1523/JNEUROSCI.4639-08.2009

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Behavioral/Systems/Cognitive
Brain Region-Specific Gene Expression Activation Required for Reconsolidation and Extinction of Contextual Fear Memory

Nori Mamiya,¹ Hotaka Fukushima,¹ Akinobu Suzuki,¹ Zensai Matsuyama,¹ Seiichi Homma,¹ Paul W. Frankland,² and Satoshi Kida^1,3

¹Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo 156-8502, Japan, ²Program in Neurosciences and Mental Health, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada M5G 1X8, and ³Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan

Correspondence should be addressed to Satoshi Kida, Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan. Email: kida{at}nodai.ac.jp

During fear conditioning, animals learn an association between a previously neutral or conditioned stimulus (CS) and an aversive or unconditioned stimulus (US). Subsequent reexposure to the CS alone triggers two competing processes. Brief reexposure to the CS initiates reconsolidation processes that serve to stabilize or maintain the original CS–US memory. In contrast, more prolonged reexposure to the CS leads to the formation of an inhibitory extinction (CS–no US) memory. Previous studies have established that both reconsolidation and extinction require gene expression. Consistent with this, here we first show that genetic disruption of cAMP-responsive element-binding protein (CREB)-mediated transcription blocks both reconsolidation and long-term extinction of contextual fear memory. We next asked whether reconsolidation and extinction engage CREB-mediated transcription in distinct brain regions. Accordingly, we used immunohistochemical approaches to characterize the activation of the transcription factor CREB [as well as the expression of the CREB-dependent gene Arc (activity-regulated cytoskeleton-associated protein)] after brief versus prolonged reexposure to a previously conditioned context. After brief reexposure, we observed significant activation of CREB-mediated gene expression in the hippocampus and amygdala. In contrast, after the prolonged reexposure, we observed significant activation of CREB-mediated gene expression in the amygdala and prefrontal cortex. Finally, we showed that blocking protein synthesis in either the hippocampus or the amygdala blocked reconsolidation of contextual fear memory, whereas similar blockade in the amygdala and prefrontal cortex prevented the formation of extinction memory. These experiments establish that reactivated contextual fear memories undergo CREB-dependent reconsolidation or extinction in distinct brain regions.

Key words: reconsolidation; extinction; CREB; hippocampus; amygdala; mPFC

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Received Sept. 26, 2008; revised Nov. 10, 2008; accepted Nov. 19, 2008.

Correspondence should be addressed to Satoshi Kida, Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan. Email: kida{at}nodai.ac.jp

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