Abstract
Associative long-term memories (LTMs) support long-lasting behavioral changes resulting from sensory experiences. Retrieval of a stable LTM by means of a large number of conditioned stimulus (CS) alone presentations produces inhibition of the original memory through extinction. Currently, there are two opposing hypotheses to account for the neural mechanisms supporting extinction. The unlearning hypothesis posits that extinction affects the original memory trace by reverting the synaptic changes supporting LTM. On the contrary, the new learning hypothesis proposes that extinction is simply the formation of a new associative memory that inhibits the expression of the original one. We propose that detailed analysis of extinction-associated molecular mechanisms could help distinguish between these hypotheses. Here we will review experimental evidence regarding the role of protein kinases and phosphatases (K&P) on LTM formation and extinction. Even though K&P regulate both memory processes, their participation appears to be dissociated. LTM formation recruits kinases, but is constrained by phosphatases. Memory extinction presents a more diverse molecular landscape, requiring phosphatases and some kinases, but also being constrained by kinase activity. Based on the available evidence, we propose a new theoretical model for memory extinction: a neuronal segregation of K&P supports a combination of time-dependent reversible inhibition of the original memory [CS-unconditioned stimulus (US)], with establishment of a new associative memory trace (CS-noUS).
Highlights
Having a brain allows animals to integrate environmental and internal sensory information to generate adaptive behaviors
Later studies showed that during training β-ARs initiate two different molecular processes, AMPARs phosphorylation at Ser845, which contributes to memory acquisition, and extracellular regulated kinase (ERK) activation, which contributes to memory consolidation (Schiff et al, 2017)
Fyn-deficient mice show no increase in tyrosine phosphorylation after fear conditioning in the hippocampus, and fail to form STM and long-term memories (LTMs) (Isosaka et al, 2008) suggesting that Fyn is required for memory formation
Summary
Having a brain allows animals to integrate environmental and internal sensory information to generate adaptive behaviors. Later studies showed that during training β-ARs initiate two different molecular processes, AMPARs phosphorylation at Ser845, which contributes to memory acquisition, and extracellular regulated kinase (ERK) activation, which contributes to memory consolidation (Schiff et al, 2017). In line with the proposed role of these kinases in consolidation, ERK1/2 is transiently activated by associative learning experience in the LA and its blockade affects LTM, but not STM (Schafe et al, 2000).
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