Inhibition of mRNA and Protein Synthesis in the CA1 Region of the Dorsal Hippocampus Blocks Reinstallment of an Extinguished Conditioned Fear Response

Abstract

Memories are extinguished by the repeated presentation of a conditioned stimulus in the absence of an unconditioned stimulus to which it has been associated. It is believed that extinction establishes a new hierarchy of responses rather than an actual forgetting of the original response, which can usually reappear spontaneously after interruption of the extinction process. In this study, our aim was to analyze how profound extinction can be. Rats were trained in a one-trial, step-down inhibitory avoidance paradigm and then were exposed to several extinction sessions in which they were allowed to freely explore the apparatus for 30 sec after having stepped down. Extinction was complete enough so that there was no spontaneous recovery, and test session performance could not be enhanced by pharmacological agents with well known facilitative actions on retrieval. After being submitted to a new training session, control animals reacquired the avoidance response; however, animals failed to do so after receiving bilateral intra-CA1 infusions of either the protein synthesis inhibitor anisomycin or the mRNA synthesis blocker 5,6-dichloro-1-␤-d-ribofuranosyl benzimidazole 15 min before the retraining session. Our results indicate that extinction can be carried to a point at which reinstallment of the conditioned response requires, like the original learning, de novo gene expression and protein synthesis in the CA1 region of the dorsal hippocampus.

Retrieval induces reconsolidation of fear extinction memory

“…Nevertheless, as can be seen in Fig. 3C, extinction of the recovered IA response was also blocked by ANI given into dorsal CA1 immediately after nonreinforced retrieval [t (24) = 3.40, P < 0.01 for ANI/VEH vs. ANI/ANI] suggesting that, as happens for extinction of the original avoidance memory (20), the occurrence of a protein synthesis-dependent process is also required for extinction of the recovered IA trace.…”

“…If this procedure is repeated once a day for 5 consecutive days, it induces clear-cut extinction of the avoidance response that lasts for at least 14 d (Fig. 1A) and requires protein synthesis in dorsal CA1 during a short postretrieval time window to occur (20).…”

“…If this procedure is repeated once a day for 5 consecutive days, it induces clear-cut extinction of the avoidance response that lasts for at least 14 d (Fig. 1A) and requires protein synthesis in dorsal CA1 during a short postretrieval time window to occur (20).Rats trained in the IA task were submitted to the extinction procedure described above (first session, 24 h posttraining), and 24 h after the last extinction session, extinction memory was reactivated. Immediately or 6 h later, the animals received bilateral intra-CA1 infusions of the protein synthesis inhibitor anisomycin (ANI; 160 μg per side) (21-23).…”

Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories

“…65 Similarly, mice with a congenitally reduced hippocampal commissure were shown to have impaired extinction of contextual fear. 66 A series of studies by Izquierdo and co-workers [67][68][69][70][71] suggests that extinction of inhibitory avoidance learning is blocked with a variety of kinase, NMDA, mRNA and protein synthesis inhibitors into the dorsal hippocampus. However, the specific role of protein synthesis within the hippocampus for extinction of contextual fear has been questioned.…”

Profile of Ivan Izquierdo

“…Izquierdo showed that prolonged exposure to the platform without the foot shock accelerated and deepened fear extinction (7).…”