Distinct engrams control fear and extinction memory.

Memories are stored in engram cells, which are necessary and sufficient for memory recall. Recalling a memory might undergo reconsolidation or extinction. It has been suggested that the original memory engram is reactivated during reconsolidation so that memory can be updated. Conversely, during extinction training, a new memory is formed that suppresses the original engram. Nonetheless, it is unknown whether extinction creates a new engram or modifies the original fear engram. In this study, we utilized the Daun02 procedure, which uses c-Fos-lacZ rats to induce apoptosis of strongly activated neurons and examine whether a new memory trace emerges as a result of a short or long reactivation, or if these processes rely on modifications within the original engram located in the basolateral amygdala (BLA) and infralimbic (IL) cortex. By eliminating neurons activated during consolidation and reactivation, we observed significant impacts on fear memory, highlighting the importance of the BLA engram in these processes. Although we were unable to show any impact when removing the neurons activated after the test of a previously extinguished memory in the BLA, disrupting the IL extinction engram reactivated the aversive memory that was suppressed by the extinction memory. Thus, we demonstrated that the IL cortex plays a crucial role in the network involved in extinction, and disrupting this specific node alone is sufficient to impair extinction behavior. Additionally, our findings indicate that extinction memories rely on the formation of a new memory, supporting the theory that extinction memories rely on the formation of a new memory, whereas the reconsolidation process reactivates the same original memory trace.

Calpain modulates fear memory consolidation, retrieval and reconsolidation in the hippocampus.

It has been proposed that long-lasting changes in dendritic spines provide a physical correlate for memory formation and maintenance. Spine size and shape are highly plastic, controlled by actin polymerization/depolymerization cycles. This actin dynamics are regulated by proteins such as calpain, a calcium-dependent cysteine protease that cleaves the structural cytoskeleton proteins and other targets involved in synaptic plasticity. Here, we tested whether the pharmacological inhibition of calpain in the dorsal hippocampus affects memory consolidation, retrieval and reconsolidation in rats trained in contextual fear conditioning. We first found that post-training infusion of the calpain inhibitor PD150606 impaired long-term memory consolidation, but not short-term memory. Next, we showed that pre-test infusion of the calpain inhibitor hindered memory retrieval. Finally, blocking calpain activity after memory reactivation disrupted reconsolidation. Taken together, our results show that calpain play an essential role in the hippocampus by enabling memory formation, expression and reconsolidation.

Facilitatory effect of the intra-hippocampal pre-test administration of MT3 in the inhibitory avoidance task.

The cholinergic system plays a crucial role in learning and memory. Modulatory mechanisms of this system in the acquisition and consolidation processes have been extensively studied, but their participation in the memory retrieval process is still poorly understood. Conventional pharmacological agents are not highly selective for particular muscarinic acetylcholine receptor subtypes. Muscarinic toxins (MTs) that are highly selective for muscarinic receptors were extracted from the venom of the mamba snake, like the toxin MT3, selective for the M4 receptor subtype. These toxins are useful tools in studies of the specific functions of the M4 mediated transmission. The M4 receptor selective antagonist MT3, given into the dorsal hippocampus before the test, have enhanced the memory retrieval of an inhibitory avoidance task in rats. MT3 had no effect in the habituation to a new environment, including basic motor parameters, meaning that the effect in he inhibitory avoidance is purely cognitive. Our results suggest an endogenous negative modulation of the cholinergic muscarinic system upon the retrieval of previously consolidated aversive memories, hereby shown by the facilitatory effect of MT3.