Fear No More

Science Signaling  11 Oct 2011:
Vol. 4, Issue 194, pp. ec282
DOI: 10.1126/scisignal.4194ec282

Fear is a critical emotional response intended to prevent reexposure to danger. However, excessive fear can lead to anxiety and mood disorders. Fear extinction is the process by which fear-induced behaviors can be reduced or eliminated by repeated exposure to the fear-inducing stimulus in the absence of any negative consequences. Agis-Balboa et al. performed a genome-wide transcriptional array analysis of the hippocampi of mice exposed to fear conditioning compared with those exposed to fear conditioning followed by fear extinction treatment. They identified 137 genes, including several associated with insulin-like growth factor (IGF) signaling, that exhibited changes in expression after fear extinction. In particular, IGF2 and IGF binding protein 7 (IGFBP7), an antagonist of IGF2, exhibited inverse regulation, with IGF2 increasing in transcript and protein abundance in the dentate gyrus region of the hippocampus and IGFBP7 exhibiting reduced abundance. Intrahippocampal injection of an antibody to block IGF2 activity or recombinant IGFBP7 impaired fear extinction, but the mice did exhibit fear extinction after the injections were stopped. By quantifying the number of newly formed neurons in vivo in the mice exposed to fear conditioning or both fear conditioning and fear extinction treatment, the authors showed that fear conditioning decreased the survival of 17- to 19-day-old neurons and that fear extinction promoted the survival of neurons of this age. Apoptotic cell death was also reduced in the dentate gyrus of mice that were exposed to fear extinction training compared with those that only experienced fear conditioning. Furthermore, blocking IGF2 reduced neuronal survival, as well as blocking fear extinction, and injection of recombinant IGF2 enhanced the rate at which fear extinction was achieved and enhanced the survival of 17- to 19-day-old neurons in the hippocampus. Injection of IGFBP7 had the opposite effects, compromising fear extinction and reducing the survival of the 17- to 19-day-old neurons. Thus, IGF2 signaling appears to contribute to adult neurogenesis and survival that may contribute to the reduction of fear memories.

R. C. Agis-Balboa, D. Arcos-Diaz, J. Wittnam, N. Govindarajan, K. Blom, S. Burkhardt, U. Haladyniak, H. Y. Agbemenyah, A. Zovoilis, G. Salinas-Riester, L. Opitz, F. Sananbenesi, A. Fischer, A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories. EMBO J. 30, 4071–4083 (2011). [PubMed]