Inhibition of hippocampal protein synthesis following recall disrupts expression of episodic-like memory in trace conditioning

Abstract

Transition of short-term to long-term memory is referred to as consolidation and the process is dependent on protein synthesis. Recently, several studies have shown that expression of consolidated memory for simple forms of learning tasks (e.g., delay conditioning, contextual fear, inhibitory avoidance) becomes vulnerable to disruption by inhibition of protein synthesis when administered shortly after recall. In the present study, we address whether recall-induced dependence on protein synthesis is a fundamental property that can be applied to a form of memory requiring attentional awareness or is specific to memories for simple forms of conditioning. Trace fear conditioning is a form of learning that requires an active memory trace to associate a conditioned stimulus (CS) with an unconditioned stimulus (US) separated by time. Our data demonstrate that whether a CS-alone recall trial in a novel context acts as an extinction or reactivation trial depends on the strength of the original memory. Inhibition of protein synthesis following the recall trial in animals receiving one trace conditioning training session (that gives rise to weak memory) resulted in enhanced CS-elicited freezing compared with vehicle control, as a result of impaired extinction memory, but had no effect on contextual memory. However, inhibition of hippocampal protein synthesis following the recall trial in animals receiving two trace conditioning training sessions (that gives rise to stronger memory) resulted in impaired retention of both trace CS-US associative and contextual memory despite that the context-US association was not directly reactivated. This provides evidence that, for a robust memory, the CS-alone recall trial results in the reactivation of an episodic-like memory, including trace CS- and contextual-memory, and that hippocampal information storage for the memory as a whole is returned to a labile state requiring de novo protein synthesis. This and other studies are consistent with the role of the hippocampus in coordinating episodic memory retrieval.

Inhibition of mRNA synthesis in the hippocampus impairs consolidation and reconsolidation of spatial memory

“…As reconsolidation, extinction is also initiated by nonreinforced retrieval, and it is expressed as a reduction in the probability of emission of a previously learned response. However, extinction is currently understood as an active learning process (Quirk, 2002;Susuki et al, 2004;Bouton et al, 2006;Myers and Davis, 2007), an hypothesis supported by several reports indicating the dependence of extinction on NMDA and AMPA receptors (Falls et al, 1992;Baker and Azorlosa, 1996;Mead et al, 1999;Walker and Davis, 2002;Mao et al, 2006;Burgos-Robles et al, 2007;Zushida et al, 2007), protein synthesis (Santini et al, 2004;Cammarota et al, 2005b;Runyan and Dash, 2005;Akirav et al, 2006;Berger-Sweeney et al, 2006;Bevilaqua et al, 2006), and gene expression (Cammarota et al, 2003;Herry and Mons, 2004;Lattal et al, 2006;Bredy et al, 2007) in different areas of the brain. Taking this into account, it is hard to envisage how mRNA synthesis inhibitors could possibly enhance a process that, if something, they should be expected to block.…”

Acute cognitive impairment after lateral fluid percussion brain injury recovers by 1 month: Evaluation by conditioned fear response

“…In a retrograde amnesia paradigm after concussion brain injury, specific cognitive deficits in retrieval, rather than memory consolidation or storage, have been demonstrated [89], which may or may not resemble anterograde cognitive dysfunction. The inclusion of protein synthesis inhibitors before, during and after training could further elucidate the nature of the hippocampaldependent consolidation deficit [49,50,74]. In the amygdala, the absence of neuronal loss substantiates the absence of an amygdala-dependent cognitive deficit, leaving the conditioned context deficit likely to result from functional alterations in remaining injured hippocampal neurons [88].…”

Mechanisms of fear extinction

“…It has been reported that when re-exposure duration is held constant, weaker memories (i.e., those trained with relatively few trials) tend to be enhanced with postreactivation ANI, suggesting an extinction disruption; whereas stronger memories tend to be impaired with postreactivation ANI, suggesting a reconsolidation disruption (but see Suzuki et al, 168 Eisenberg et al 322 and Runyan and Dash 325 ).…”