Hippocampal plasticity mechanisms mediating experience-dependent learning change over time

Abstract

The requirement of NMDA receptor (NMDAR) activity for memory formation is well described. However, the plasticity mechanisms for memory can be modified by experience, such that a future similar learning becomes independent of NMDARs. This effect has often been reported in learning events conducted with a few days interval. In this work, we asked whether the NMDAR-independency is permanent or the brain regions and plasticity mechanisms of experience-dependent learning may change over time. Considering that contextual memories undergo a gradual reorganization over time, becoming progressively independent from the hippocampus and dependent upon cortical regions, we investigated the brain regions mediating a new related learning conducted at a remote time-point, when the first memory was already cortically established. First, we demonstrated that anterior cingulate cortex was not able to support a learning subsequent to a previous systems-level consolidated memory; it did require at least one functional subregion of the hippocampus (ventral or dorsal). Moreover, after replicating findings showing that a few days interval between trainings induces a NMDAR-independent learning, we managed to show that a learning following a longer interval once again becomes dependent on NMDARs in the hippocampus. These findings suggest that while the previous memory grows independent from the hippocampus over time, an experience-dependent learning following a systems-consolidated memory once again engages the hippocampus and a NMDAR-dependent plasticity mechanism.

Adolescent female rats undergo full systems consolidation of an aversive memory, while males of the same age fail to discriminate contexts

“…Detailed memories are known to depend upon the hippocampus [4[4,6] while generalized ones involve memory traces that might rely on cortical networks: at least this is what was observed in systems consolidation experiments, in which an engram became progressively independent of the hippocampus to be more permanently stored in neocortical areas [ [10,12,[30][31][32][33]. In a previous work, we showed that adult male rats exhibit both memory generalization and hippocampus-independence when tested 28 days after training, demonstrating that the loss of memory precision is a process that takes place concomitantly with the end of hippocampusdependence [4[4]is also consistent with other studies in the literature [6,13]. Here, we observed that in the adolescent male rats, memory generalization can be expressed earlier, 14 days after training, compared to male adults (Fig.…”

“…Previous studies have demonstrated that memory loses precision in a contextual discrimination task as the interval between training and test increases: as time after training passes, it becomes more generalized [4][5][6]. Modifications in brain regions that support memory retrieval also occur over time, with the memory trace retrieval becoming progressively independent from the hippocampus and reliant on cortical areas [7][8][9][10][11][12][13]. Despite not fully understood, systems consolidation appear to express itself in two dimensions, one anatomical -the gradual independence from the hippocampus -and the other, qualitative -the progressive inability to discriminate between similar contexts, i.e., memory generalization [4,6,14].…”

“…Previous studies have demonstrated that memory loses precision in a contextual discrimination task as the interval between training and test increases: as time after training passes, it becomes more generalized (de Oliveira Alvares et al, 2012; Wiltgen et al, 2010; Wiltgen and Silva, 2007). Modifications in brain regions that support memory retrieval also occur over time, with retrieval of the memory trace becoming progressively independent from the hippocampus and reliant on cortical areas (Bontempi et al, 1999; Crestani et al, 2018; Frankland et al, 2004; Martin et al, 2005; Maviel et al, 2004; Quillfeldt, 2019; Quillfeldt et al, 1996). Despite not fully understood, systems consolidation appears to express itself in two different dimensions, one neuroanatomical – the gradual independence from the hippocampus – and the other, qualitative – the progressive inability to discriminate between similar contexts, i.e., display memory generalization (Cullen et al, 2015; de Oliveira Alvares et al, 2012; Rudy, 2009; Wiltgen et al, 2010).…”

Metaplasticity contributes to memory formation in the hippocampus

“…If so, NMDAR-independent learning should disappear over time. Consistent with this idea, a recent study found that NMDARs are required for both learning (in context A) and relearning (in context B) if the fear conditioning sessions are separated by several weeks [30].…”

Temporal Flexibility of Systems Consolidation and the Synaptic Occupancy/Reset Theory (SORT): Cues About the Nature of the Engram

“…First/new learning plasticity would have to produce its engrammatic embodiment working with a fixed subset of available synapses , with plasticity directed to select and connect to specific neocortical target areas establishing a memory trace, while other, reactivation-induced plasticities would be able to somehow induce an increase in the total number of synapses in the variable subset of available synapses , at least within certain limits. The cognitive process induced by reactivation studied above was mainly reconsolidation (De Oliveira Alvares et al, 2012, 2013; Cassini et al, 2013; Sierra et al, 2013; Crestani et al, 2015; Haubrich et al, 2015), but processes mobilizing a change in the number of available synapses may also include extinction (Bouton and Moody, 2004; Sotres-Bayon et al, 2006; Myskiw and Izquierdo, 2012; Cassini et al, 2013, 2017; Sierra et al, 2017; Haubrich et al, 2017) and possibly even the intermediary category known as subsequent learnings (Tayler et al, 2011; Crestani and Quillfeldt, 2016; Crestani et al, 2018a,b). Of course non-reactivating, plain retrieval is proposed as a process as inert as the consequence of a cognitively poor, uneventful life (as criticized, e.g., by Neisser, 1967): in these cases, an automatic reset would take place at regular intervals, acting as a putative maintenance mechanism.…”