title: A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories.
abstract: Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example, the expression of an aversive behaviour upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinction are only beginning to emerge. Here, we show that fear extinction initiates upregulation of hippocampal insulin-growth factor 2 (Igf2) and downregulation of insulin-growth factor binding protein 7 (Igfbp7). In line with this observation, we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2 signalling during fear extinction. To this end, we show that fear extinction-induced IGF2/IGFBP7 signalling promotes the survival of 17-19-day-old newborn hippocampal neurons. In conclusion, our data suggest that therapeutic strategies that enhance IGF2 signalling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory.
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University, Göttingen, Germany.
authors.forename: Roberto Carlos
authors.initials: RC
authors.lastname: Agis-Balboa
authors.forename: Dario
authors.initials: D
authors.lastname: Arcos-Diaz
authors.forename: Jessica
authors.initials: J
authors.lastname: Wittnam
authors.forename: Nambirajan
authors.initials: N
authors.lastname: Govindarajan
authors.forename: Kim
authors.initials: K
authors.lastname: Blom
authors.forename: Susanne
authors.initials: S
authors.lastname: Burkhardt
authors.forename: Ulla
authors.initials: U
authors.lastname: Haladyniak
authors.forename: Hope Yao
authors.initials: HY
authors.lastname: Agbemenyah
authors.forename: Athanasios
authors.initials: A
authors.lastname: Zovoilis
authors.forename: Gabriella
authors.initials: G
authors.lastname: Salinas-Riester
authors.forename: Lennart
authors.initials: L
authors.lastname: Opitz
authors.forename: Farahnaz
authors.initials: F
authors.lastname: Sananbenesi
authors.forename: Andre
authors.initials: A
authors.lastname: Fischer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear / Q000502:physiology*; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism*; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; C102529:insulin-like growth factor binding protein-related protein 1; D007335:Insulin-Like Growth Factor II