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Distinct roles of hippocampal de novo protein synthesis and actin rearrangement in extinction of contextual fear - PubMed

  • ️Thu Jan 01 2004

Distinct roles of hippocampal de novo protein synthesis and actin rearrangement in extinction of contextual fear

André Fischer et al. J Neurosci. 2004.

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.

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Figures

Figure 1.
Figure 1.

Inhibition of de novo protein synthesis impairs conditioned freezing after extinction trials without affecting retrieval. A, Dose-dependent impairment consolidation of contextual fear by anisomycin. There were nine mice per group. B, Anisomycin (50 μg, i.h.) injected after the first nonreinforced trial (US-) also decreased context-dependent freezing without affecting tone-dependent freezing (C) when compared with the vehicle group. D, Anisomycin injected after a reinforced trial did not affect freezing. E, Anisomycin injected without memory reactivation did not affect freezing. F, Anisomycin did not affect freezing when it was injected intrahippocampally 1 hr before the first or second (G) memory test. Statistically significant differences: *p < 0.01, **p < 0.001 versus vehicle control; ap < 0.01 versus test 1. Arrow indicates the anisomycin or vehicle injection. T, Training.

Figure 2.
Figure 2.

Inhibition of de novo protein synthesis after memory reactivation does not permanently erase the fear memory. A, Fear-conditioned mice exposed to a reminder shock 24 hr after the last extinction trial reinstated freezing behavior. In contrast, nonconditioned mice did not show freezing after the reminder shock. B, Representative immunoblots demonstrating the biochemical effects of anisomycin and puromycin injected intrahippocampally immediately after training. Both inhibitors completely prevented the production of the cFos protein, as determined 1 hr after training. In addition, anisomycin increased the level of p-cJun [percentage increase (mean ± SEM) vs vehicle, 212 ± 28%) and p-ATF2 (percentage increase vs vehicle, 57 ± 11%), whereas puromycin did not exert a significant effect. The experiment was replicated twice with three mice per group. C, Injection of anisomycin (50 μg, i.h.) or puromycin (25 μg, i.h.) after training prevented the consolidation of contextual fear. A reminder shock failed to reinstate freezing behavior in this group. D, A reminder shock reinstated freezing behavior of mice injected with anisomycin or puromycin after the first nonreinforced memory test. Statistical differences: *p < 0.01 versus vehicle control; ap<0.01 versus test 1; bp < 0.01 versus conditioning context. RS, Reminder shock.

Figure 3.
Figure 3.

Acquisition and extinction of context-dependent fear involve actin rearrangement. A, Cytochalasin D and latrunculin A (125 ng each per hippocampus) injected intrahippocampally immediately after training prevented the consolidation of context-dependent fear. B, Representative immunoblots demonstrating the biochemical effects of the inhibitors injected intrahippocampally immediately after training. The inhibitors did not affect the production of the cFos protein or the phosphorylation of cJun and ATF2 in hippocampal lysates prepared 1 hr after training. The experiment was replicated twice with three mice per group. C, The same doses of cytochalasin D and latrunculin A injected intrahippocampally after each nonreinforced memory test prevented the extinction of context-dependent freezing (compared with the vehicle group). D, Cytochalasin D and latrunculin A injected intrahippocampally after extinction did not result in increased conditioned freezing. Statistical differences: *p < 0.01, **p < 0.01 versus vehicle control; ap < 0.01 versus test 1.

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