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 insulingrowth factor 2 (Igf2) and downregulation of insulingrowth 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 extinctioninduced 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.

Insulin-like Growth Factor-II (IGF-II) and IGF-II Analogs with Enhanced Insulin Receptor-a Binding Affinity Promote Neural Stem Cell Expansion

“…However, it is important to note that JB1 cross reacts with IR tyrosine kinase; therefore, an effect via IR-A cannot be ruled out in this study (28). AgisBalboa et al (27) did not see a block in extinction when using an antibody against IGF-2R, which is in contradiction to Chen et al (18). Chen et al (18) found that IGF-II administration into the hippocampus enhanced memory retention and prevented extinction in inhibitory avoidance training.…”

“…Recently, hippocampal memory retention and fear extinction were reported to be dependent on IGF-II and, in part, on IGF-2R. Agis-Balboa et al (27) found that IGF-II blocking also inhibited contextual fear extinction, which is hippocampal-dependent. They reported that blocking IGR-1R using the IR antagonist JB1 negated the effects of IGF-II on fear extinction.…”

Placental programming of anxiety in adulthood revealed by Igf2-null models

“…Acute manipulations of Igf2 in adults have been shown to regulate neurogenesis in brain and have an impact on fear-related behaviour [42][43][44] ; however, these effects are, a priori, difficult to reconcile with the selective pattern of effects seen here, as Igf2 expression is intact in Igf2-P0 KO adult mice. Other factors such as differences between the models arising from the lack of imprinting of Igf2 in choroid plexus and leptomeninges of the brain can also be discounted, because this would affect the Igf2-total KO mice (leading to a 50% reduction of Igf2 expression in these tissues), but not the Igf2-P0 KO mice.…”

IκB Kinase/Nuclear Factor κB-Dependent Insulin-Like Growth Factor 2 (Igf2) Expression Regulates Synapse Formation and Spine Maturation via Igf2 Receptor Signaling

“…In contrast to Igf1, which plays a role in axonal growth and pathfinding, neuronal progenitor proliferation, and synaptic homeostasis, little is known about the physiological function of Igf2 in the nervous system (Chiu et al, 2008;Chiu and Cline, 2010). Igf2 was proposed to regulate development and turnover of neuromuscular synapses (Ishii, 1989) and was recently identified as critical component in the extinction of fear memories via promoting survival and maturation of newborn hippocampal neurons in an Igf1R-dependent manner (Agis-Balboa et al, 2011). Our results introduce Igf2 as potent modulator of synapse density and spine morphology in mature hippocampal neurons.…”