Post-retrieval late process contributes to persistence of reactivated fear memory

Abstract

Several studies have demonstrated the mechanisms involved in memory persistence after learning. However, little is known about memory persistence after retrieval. In this study, a protein synthesis inhibitor, anisomycin, was infused into the basolateral amygdala of mice 9.5 h after retrieval of contextual conditioned fear. Anisomycin attenuated fear memory after 7 d, but not after 2 d. In contrast, infusion of anisomycin 5-or 24-h post-retrieval was ineffective. These findings indicate that anisomycin attenuates the persistence of reactivated fear memory in a time-dependent manner. We propose that late protein synthesis is required for memory persistence after retrieval.The process of memory formation is accompanied by protein synthesis, and various studies have demonstrated that the formation of long-term fear memory is disrupted by inhibiting protein synthesis around the time of learning or shortly afterward (Rosenblum et al. 1993;Bourtchouladze et al. 1998;McGaugh 2000;Johansen et al. 2011). During memory consolidation, protein synthesis is required to transform newly learned information, acquired during the acquisition phase, into stable modifications.While the molecular mechanisms involved in the acquisition and consolidation phases have been extensively studied, little is known about memory persistence. Recent studies have shown that late protein synthesis after learning is required for memory persistence (Bekinschtein et al. 2007;Rossato et al. 2009), suggesting that consolidation-like events take place again. This was highlighted in one study by Bekinschtein et al. (2007), whereby infusion of the protein synthesis inhibitor anisomycin into the dorsal hippocampus 12 h after learning disrupted memory persistence, but not memory formation.Several studies have shown that when a stabilized memory is retrieved, it can become labile again, and its maintenance requires additional protein synthesis (Nader et al. 2000;Debiec et al. 2002;Parsons et al. 2006a;Cai et al. 2012). Thus, this process is referred to as reconsolidation. Previous findings suggest that the reconsolidation phase involves many of the same core molecular features as the consolidation phase, including transcription factors (Kida et al. 2002), and de novo mRNA and protein synthesis (Nader et al. 2000;Debiec et al. 2002;Da Silva et al. 2008;Duvarci et al. 2008). However, no studies have explicated how memory persists after retrieval. It remains unclear whether persistence of retrieved memory requires a late protein synthesis-dependent phase as the persistence of original memory does. We aimed to clarify this in the present study.To this end, we used contextual fear conditioning, employing footshock as our aversive stimulus. Our study focused on the basolateral amygdala (BLA), an area of the brain critical for the formation and maintenance of memory associated with fear (Phillips and LeDoux 1992; LeDoux 2000; Gale et al. 2004;Rudy et al. 2004;Poulos et al. 2009;Nomura et al. 2012). It has been shown that protein synthesis in the amygdala is necessa...

Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

“…The late reconsolidation process after retrieval in contextual fear memory has been demonstrated in at least two papers. The late reconsolidation of contextual fear memory requires protein synthesis in the BLA in mice (Nakayama et al, 2013). In our previous study, we demonstrated that cold water stress disrupted the late reconsolidation of contextual fear memory in rats (Yang et al, 2013).…”

Participação do sistema histaminérgico em estruturas límbicas sobre a memória de esquiva inibitória em camundongos

“…Pesquisas anteriores mostraram que a AMD é uma importante estrutura encefálica envolvida na aprendizagem de memórias aversivas, e na formação e expressão de memórias emocionais através das muitas projeções para outras regiões do encéfalo que também estão envolvidas no armazenamento da informação recém-adquirida (Jerusalinsky et al, 1992;Cahill e Mcgaugh, 1998;Izquierdo et al, 1998;Ambrogi Lorenzini et al, 1999;Fanselow e Ledoux, 1999;Mcgaugh, 2004;Wilensky et al, 2006;Moscarello e Ledoux, 2014). Além disso, já foi demonstrado que a infusão de ANI na AMD de roedores prejudica tanto a consolidação quanto a reconsolidação de memórias de medo contextual (Nader;Schafe e Le Doux, 2000; Schafe e Parsons et al, 2006;Wilensky et al, 2006;Nakayama et al, 2013). Nesse sentido, nosso presente estudo corrobora com os achados anteriores que mostram que esta estrutura límbica é importante para a consolidação de memórias de esquiva inibitória .…”

“…Esta pode durar minutos a dias, e sofre uma transição de um estado lábil para um fixo. Durante o período de consolidação, para que a informação recém-aprendida durante a fase de aquisição seja transformada em modificações estáveis, é necessário que ocorra síntese proteica (Nakayama et al, 2013). A evocação ocorre quando o animal retorna ao mesmo contexto onde houve o pareamento com o estímulo aversivo (Abel e Lattal, 2001).…”

“…Uma das estratégias utilizadas para investigação de processos mnemônicos envolve o uso de diferentes ferramentas farmacológicas como bloqueadores de canais de sódio dependentes de voltagem (lidocaína e tetrodotoxina) (Tehovnik e Sommer, 1997;Choudhary et al, 2003;Quiroz et al, 2003;Noack;Murau e Engelmann, 2015) e inibidores de síntese proteica como a cicloheximida (Diaz-Trujillo et al, 2009) e anisomicina (ANI) (Rosenblum;Meiri e Dudai, 1993;Bourtchouladze et al, 1998;Nader;Schafe e Le Doux, 2000;Naghdi;Majlessi e Bozorgmehr, 2003;Lattal e Abel, 2004;Bekinschtein et al, 2007;Chang e Gold, 2007;Cai et al, 2012;Nakayama et al, 2013).…”

“…It has already been demonstrated in various different studies that the formation of long-term memories involving fear can be impaired by inhibiting protein synthesis around the time of learning or shortly afterwards (Bourtchouladze et al, 1998;Johansen et al, 2011;Rosenblum et al, 1993). Thus, during memory consolidation protein synthesis is required to transform newly learned information, acquired during the acquisition phase, into stable behavioral modifications (Nakayama et al, 2013).…”