Distinct Roles of HippocampalDe NovoProtein Synthesis and Actin Rearrangement in Extinction of Contextual Fear

Abstract

It is believed that de novo protein synthesis is fundamentally linked to synaptic changes in neuronal circuits involved in acquisition and extinction of conditioned responses. Recent studies show that neuronal plasticity may be also altered by cytoskeletal rearrangement independently of protein synthesis. We investigated the role of these processes in the hippocampus during acquisition and extinction of context-dependent conditioned fear in mice. Intrahippocampal injections of the protein synthesis inhibitors anisomycin and puromycin, or of the actin rearrangement inhibitors cytochalasin D and latrunculin A, prevented the acquisition of context-dependent fear. Unexpectedly, anisomycin and puromycin enhanced extinction without erasing the fear memory. In contrast, cytochalasin D and latrunculin A prevented extinction of context-dependent freezing. On the basis of these findings, it is suggested that certain hippocampal mechanisms mediating extinction of conditioned contextual fear are inhibited by protein synthesis and involve actin rearrangement. Such mechanisms might predominantly elicit modifications of hippocampal circuits that store the conditioning memory.

Mechanisms of fear extinction

“…Two papers, both involving context fear extinction in mice, reported either no effect 316 (see also Lattal et al 327 ) or an apparent facilitation of extinction by ANI. 315 In the latter report, ANI infused into dorsal hippocampus immediately after the first of five daily extinction exposures to context produced a loss of context fear responses that persisted for several days even though ANI was discontinued. Although this sort of deficit is characteristic of a reconsolidation impairment, Fischer et al 315 argued that it actually was due to facilitated extinction because unsignaled shock exposure restored context freezing, similar to a reinstatement effect.…”

“…315 In the latter report, ANI infused into dorsal hippocampus immediately after the first of five daily extinction exposures to context produced a loss of context fear responses that persisted for several days even though ANI was discontinued. Although this sort of deficit is characteristic of a reconsolidation impairment, Fischer et al 315 argued that it actually was due to facilitated extinction because unsignaled shock exposure restored context freezing, similar to a reinstatement effect. However, the shock was given in a novel context, which would not be expected to produce reinstatement of extinguished fear because reinstatement is context specific.…”

“…Most studies employing pre-or postextinction training administration of protein synthesis inhibitors have reported a profound impairment of extinction, despite significant differences in the organism being studied, the specifics of the training protocol, the method and timing of drug delivery, and the measure of conditioned fear 68,130,167,173,[311][312][313][314] (but see Fischer et al 315,316 and Lattal and Abel 316 ). However, as we noted in our previous review 204 and elsewhere, 317 the issue of whether extinction is dependent on protein synthesis is complicated by the procedural similarities between experiments examining extinction and those examining reconsolidation of conditioned fear.…”

Highly sensitive and quantitative FRET–FLIM imaging in single dendritic spines using improved non-radiative YFP

“…β-actin is highly enriched in filopodia and spines (Bassell et al, 1998;Eom et al, 2003), and regulates the shape of dendritic spines and filopodia during development and structural plasticity at mature synapses (Fischer et al, 2004;Honkura et al, 2008;Krucker et al, 2000;Lamprecht and LeDoux, 2004;Matus, 2000;Okamoto et al, 2004;Sekino et al, 2007). The equilibrium between the filamentous form of actin (F-actin) and globular form (G-actin) is thought to be important for the regulation of the spine structure (Okamoto et al, 2004).…”

A hippocampal Cdk5 pathway regulates extinction of contextual fear

“…A number of studies have shown that some, but not all, components of the molecular machinery that is required for the initial encoding of fear memories also regulate extinction 7-10 . Recent studies indicate that synaptic remodeling, for example, mediated by actin re-arrangement, may be important for extinction 3,6 . Actin dynamics are intimately involved in synaptic plasticity, synapse formation and neuronal morphology 6,11,12 .…”