Spatial-Memory Formation After Spaced Learning Involves ERKs1/2 Activation Through a Behavioral-Tagging Process

Ramiro Tintorelli,Pamela Lopes da Cunha,Maria Eugenia Villar,Pablo Budriesi,Haydée Viola,Martin Giurfa,Paul Marchal,Julieta Correa

doi:10.1038/s41598-019-57007-4

Abstract

The superiority of spaced over massed learning is an established fact in the formation of long-term memories (LTM). Here we addressed the cellular processes and the temporal demands of this phenomenon using a weak spatial object recognition (wSOR) training, which induces short-term memories (STM) but not LTM. We observed SOR-LTM promotion when two identical wSOR training sessions were spaced by an inter-trial interval (ITI) ranging from 15 min to 7 h, consistently with spaced training. The promoting effect was dependent on neural activity, protein synthesis and ERKs1/2 activity in the hippocampus. Based on the “behavioral tagging” hypothesis, which postulates that learning induces a neural tag that requires proteins to induce LTM formation, we propose that retraining will mainly retag the sites initially labeled by the prior training. Thus, when weak, consecutive training sessions are experienced within an appropriate spacing, the intracellular mechanisms triggered by each session would add, thereby reaching the threshold for protein synthesis required for memory consolidation. Our results suggest in addition that ERKs1/2 kinases play a dual role in SOR-LTM formation after spaced learning, both inducing protein synthesis and setting the SOR learning-tag. Overall, our findings bring new light to the mechanisms underlying the promoting effect of spaced trials on LTM formation.

Highlights

There are three well-known cognitive theories proposed to explain the superiority of spaced over massed training
Our results suggest that extracellular regulated kinases 1/2 (ERKs1/2) activity is probably needed to induce the protein synthesis necessary to consolidate spatial object recognition (SOR)-long-term memory (LTM)
Our results show that rats trained with a single weak SOR training sessions (wSOR) session do not form SOR-LTM; when they were exposed to two identical wSOR sessions separated by an inter-trial interval (ITI) ranging between 15 min to 7 h, they exhibited SOR-LTM

Summary

Introduction

There are three well-known cognitive theories proposed to explain the superiority of spaced over massed training. The third considers that deficient processing of the information learned in massed learning would result in information loss[9] Concerning this last theory, emerging data from behavioral and neuroscience studies point to memory consolidation as a potential process contributing to the advantages of spaced training. A necessary condition for LTM formation is the induction of the synthesis of plasticity-related proteins (PRPs)[10,11,12,13] This synthesis occurs when the acquired information contains a degree of novelty or stress, which activates attention systems[10,14]. The processes involved in the formation or improvement of LTM by retraining are frequently studied using training protocols with multiple trials and/or sessions. Our results suggest that ERKs1/2 activation in the dorsal hippocampus has a dual role, being a critical step for PRP synthesis and for the setting of the SOR learning-tag

Methods

Results

Conclusion