The ability of memories to last after the consolidation is known as persistence, a critical aspect of long-term memory (LTM) (Bekinschtein et al., 2010). However, not all learning experiences lead to durable LTM. Recent studies have suggested that acute physical exercise (PE) may be a potential strategy to enhance memory persistence (Bouchet et al., 2017; Fernandes et al., 2016). When applied after a learning that generates only a brief LTM, acute PE can extend memory for several days (Vargas et al., 2017). Although the underlying mechanisms of this effect are not yet fully understood, it is believed that acute PE acts on memory consolidation processes that facilitate a long-lasting LTM by supporting the growth and maintenance of synapses and enhancing neural plasticity (Fernandes et al., 2016; Soya et al., 2007; Venezia et al., 2019). However, it's uncertain whether acute PE depends on hippocampal protein synthesis, an essential mechanism for LTM formation, to improve memory.

While there are known mechanisms of acute PE that explain its modulatory effects on episodic memory, at least to the best of our knowledge, none specifically address the protein synthesis requirement. Studies have shown that acute PE increases dopamine and noradrenaline levels in the hippocampus, which act on the D1/D5 dopamine and β-adrenergic receptors in the CA1 area to achieve their effects (Vargas et al., 2017, 2020). Additionally, acute PE has been linked to the synthesis of growth factors such as brain-derived neurotrophic factor (BDNF), which plays a critical role in modulating synaptic plasticity and memory consolidation (Aguiar et al., 2011; Huang et al., 2006). The interaction between exercise-induced changes in neurotransmitter levels and growth factor synthesis may provide a mechanism by which acute PE could enhance memory persistence and suggest a possible dependence on protein synthesis in the hippocampus.

The behavioral tagging (BT) hypothesis is a potential mechanism to explain the effects of acute PE on memory persistence (Loprinzi et al., 2018). This hypothesis suggests that the plasticity-related mechanisms activated during memory formation can also be strengthened by other neural events that occur close in time (Ballarini et al., 2009; Moncada and Viola, 2007). The molecular mechanism behind this is explained by the parallel event protein-related plasticity (PRP) synthesis, which is subsequently captured by synapses tagged by memory stimuli (Straube et al., 2003). This avoids the long-term potentiation (LTP) decay, which is fundamental for forming a stable LTM (Li et al., 2003; Tomaiuolo et al., 2015). This phenomenon usually explains the effect of novelty on memory improvement. Exposure to a novel context shortly after learning in the novel object recognition (NOR) task, which typically generates only a transient LTM, can promote memory persistence for several days (Lima et al., 2021b). Interestingly, novelty and acute PE share very similar neural mechanisms, both acting on dopaminergic mechanisms in the hippocampus and requiring PKA signaling (Lima et al., 2021a, 2021b). Furthermore, both stimulate the hippocampal dopamine release (Menezes et al., 2015; Vargas et al., 2017), a neurotransmitter strictly required to synthesize PRP (Duszkiewicz et al., 2019). Thus, acute PE is a potential plasticity tool to BT, triggering physiological and biochemical changes in neurons and synapses that can modulate the plasticity induced by parallel events, such as memory stimuli.

The hypothesis that acute PE stimulates the synthesis of PRP in the hippocampus raises questions about the mechanisms by which it modulates memory (Loprinzi et al., 2018). Specifically, it is unclear whether protein de novo synthesis in the hippocampus is necessary for the effects of acute PE on memory persistence or if acute PE can enhance learning through other mechanisms. Some studies have proposed that stimulus that increases arousal can consolidate memories even in the presence of protein synthesis inhibitors (Alberini, 2008; Gold, 2008), suggesting that acute PE may enhance memory consolidation through multiple mechanisms beyond PRP synthesis. Therefore, further research is necessary to fully understand the complex processes underlying the effects of acute PE on learning and memory.

One possible approach involves using compounds such as anisomycin (ANI), which inhibits protein synthesis by preventing the translocation of ribosomes, or rapamycin (RAPA), which blocks protein synthesis through the inhibition of the mammalian target of rapamycin (mTOR) signaling (Myskiw et al., 2013). Thus, using both compounds can determine whether the protein synthesis inhibition alone is sufficient to prevent memory consolidation or if the inhibition of the mTOR pathway also plays a crucial role. By manipulating protein synthesis with these compounds, we could investigate the contribution of hippocampal protein synthesis to the modulatory effects of acute PE on NOR memory consolidation and persistence. Additionally, we explored whether the acute PE protocol we employed could enhance BDNF synthesis in the hippocampus during the initial hours following exercise.