IGF-1 facilitates extinction of conditioned fear.

Laura E Maglio,Jesús Martin-Cortecero,José A Noriega-Prieto,Marta Callejo-Móstoles,David Fernández De Sevilla,Irene B Maroto,Antonio Muñoz-Callejas

doi:10.7554/elife.67267

Abstract

Insulin-like growth factor-1 (IGF-1) plays a key role in synaptic plasticity, spatial learning, and anxiety-like behavioral processes. While IGF-1 regulates neuronal firing and synaptic transmission in many areas of the central nervous system, its signaling and consequences on excitability, synaptic plasticity, and animal behavior dependent on the prefrontal cortex remain unexplored. Here, we show that IGF-1 induces a long-lasting depression of the medium and slow post-spike afterhyperpolarization (mAHP and sAHP), increasing the excitability of layer 5 pyramidal neurons of the rat infralimbic cortex. Besides, IGF-1 mediates a presynaptic long-term depression of both inhibitory and excitatory synaptic transmission in these neurons. The net effect of this IGF-1-mediated synaptic plasticity is a long-term potentiation of the postsynaptic potentials. Moreover, we demonstrate that IGF-1 favors the fear extinction memory. These results show novel functional consequences of IGF-1 signaling, revealing IGF-1 as a key element in the control of the fear extinction memory.

Highlights

Conditioned fear is an associative form of learning and memory in which a previous neutral stimulus comes to elicit a fear response when is associated with an aversive stimulus
Interactions among the amygdala, the hippocampus, and the infralimbic cortex (IL) prefrontal cortex (PFC) are important for the extinction of conditioned fear memory (Milad and Quirk, 2012; Orsini and Maren, 2012; Pape and Pare, 2010; Quirk and Mueller, 2008)
Our results demonstrate for the first time that Insulin-like growth factor-1 (IGF-1) applied to IL favors the extinction of conditioned fear memory causing an increase in layer 5 PNs (L5PNs) excitability and synaptic plasticity through the activation of the IGF-1R

Summary

Introduction

Conditioned fear is an associative form of learning and memory in which a previous neutral stimulus (called ‘conditioned stimulus’ [CS]; e.g., a tone) comes to elicit a fear response when is associated with an aversive stimulus (called ‘unconditioned stimulus’ [US]; e.g., an electric shock LeDoux, 2000; Maren, 2001; Pape and Pare, 2010). Extinction of conditioned fear is an active learning process involving inhibition of fear expression. It is a decline in conditioned fear responses (CRs) following non-reinforced exposure to the CS. Fear extinction memory does not erase the initial association between the CS and US but forms a new association (CS–No US) that inhibits expression of the previous conditioned memory (Quirk and Mueller, 2008). Dysfunctions in the neuronal circuits responsible for fear cause the development of anxiety disorders, including specific phobias and post-traumatic stress (Pavlov, 1927; Quirk and Mueller, 2008)

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Conclusion