Spaced Training Enhances Contextual Fear Memory via Activating Hippocampal 5-HT2A Receptors.

Lizhu Jiang,Liping Wang,Chao Liu,Dafu Yu,Yan Yin,Qixin Zhou,Rongrong Mao,Lin Xu,Mengke Huo

doi:10.3389/fnmol.2019.00317

Abstract

Spaced training is robustly superior to massed training, which is a well-documented phenomenon in humans and animals. However, the mechanisms underlying the spacing effect still remain unclear. We have reported previously that spacing training exerts memory-enhancing effects by inhibiting forgetting via decreasing hippocampal Rac1 activity. Here, using contextual fear conditioning in rat, we found that spaced but not massed training increased hippocampal 5-HT2A receptors’ expression. Furthermore, hippocampal administration of 5-HT2A receptor antagonist MDL11939 before spaced training blocked the enhanced memory, while hippocampal administration of 5-HT2A receptor agonist TCB-2 before massed training promoted the memory. Moreover, MDL11939 activated hippocampal Rac1, while TCB-2 decreased hippocampal Rac1 activity in naïve rats. These results indicated the possibility of interaction between 5-HT2A receptors and Rac1, which was demonstrated by co-immunoprecipitation experiments. Our study first demonstrates that activation of hippocampal 5-HT2A is a mechanism underlying the spacing effect, and forgetting related molecular Rac1 is engaged in this process through interacting with 5-HT2A receptors, which suggest a promising strategy to modulate abnormal learning in cognitive disorders.

Highlights

Spaced training is more effective than massed training in producing long-term memory, which was first discovered by Ebbinghaus (1885) and called it the spacing effect
We found that the levels of 5-HT2A receptors in the hippocampus were significantly different among the groups (one-way ANOVA, F(6,21) = 4.844, p < 0.05, n = 4)
Thirty minutes after fear conditioning, the pixel density of 5-HT2A receptors’ positive staining in the CA1 area was significantly enhanced in the spaced group (p < 0.01, Figure 1D) but not in the massed group (Figure 1E) compared with naive group. These results demonstrated that the spacing but not massed training increased the expression of hippocampal 5-HT2A receptors in contextual fear conditioning, which indicated that the activation of hippocampal 5-HT2A receptors may be involved in the spacing effect

Summary

Introduction

Spaced training is more effective than massed training in producing long-term memory, which was first discovered by Ebbinghaus (1885) and called it the spacing effect. Spaced Training Activates Hippocampal 5-HT2A Receptors have been reported to modulate the spacing effect (Genoux et al, 2002; Pagani et al, 2009; Naqib et al, 2012; Smolen et al, 2016). Our previous study shows that spacing training improves contextual fear memory by inhibiting hippocampal Rac activity in rats (Jiang et al, 2016b). Administration of 5-HT2A receptor agonist TCB-2 is found to facilitate consolidation and extinction of fear memory (Zhang et al, 2013). These results support the view that activation of 5-HT2A receptor may enhance memory, whether 5-HT2A receptors improve memory by regulating the spacing effect is still unknown

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