Characterization of NMDAR-Independent Learning in the Hippocampus

Abstract

It is currently thought that memory formation requires the activation of NMDA receptors (NMDARs) in the hippocampus. However, recent studies indicate that these receptors are not necessary for all forms of learning. The current experiments examine this issue using context fear conditioning in mice. First, we show that context fear can be acquired without NMDAR activation in previously trained animals. Mice trained in one environment (context A) are subsequently able to learn about a second environment (context B) in the presence of NMDAR antagonists. Second, we demonstrate that NMDAR-independent learning requires the hippocampus and is dependent on protein synthesis. However, unlike NMDAR-dependent learning, it is not contingent on the expression of activity-regulated cytoskeleton-associated protein (Arc). Lastly, we present data that suggests NMDAR-independent learning is only observed when recently stimulated neurons are reactivated during conditioning. These data suggest that context fear conditioning modifies synaptic plasticity mechanisms in the hippocampus and allows subsequent learning to occur in the absence of NMDAR activation.

The cellular mechanisms of memory are modified by experience

“…Our previous results indicate that context fear can be acquired in the absence of NMDAR activation in previously trained mice (Wiltgen et al 2010;Tayler et al 2011). In these experiments, animals were fear-conditioned in context B followed 5 d later by training in context A.…”

“…Despite these data, several studies indicate that prior behavioral experience can reduce or eliminate the need for NMDARs during learning. For example, animals trained on a hippocampusdependent learning task are subsequently able to acquire new information in the presence of NMDAR antagonists (Bannerman et al 1995;Saucier and Cain 1995;Sanders and Fanselow 2003;Hardt et al 2009;Wiltgen et al 2010;Tayler et al 2011). These results suggest that prior behavioral training modifies cellular plasticity mechanisms such that NMDARs are no longer required for learning.…”

“…It is possible that this novel type of learning only occurs when animals are repeatedly trained on the same behavioral task. In our previous experiments, for example, mice underwent fear conditioning in two different contexts (Wiltgen et al 2010;Tayler et al 2011). In the Morris water maze, NMDAR-independent learning was observed when rats were trained on the same version of the task in two different spatial environments (Bannerman et al 1995).…”

Epigenetic regulation of memory formation and maintenance

“…A higher degree of cellular resolution will allow researchers to restrict their analysis to specific cell populations, ideally focusing on cells that make up the memory trace for a particular behavioral paradigm. To fulfill this need, techniques that allocate memories to specific cell populations within a neural circuit (Han et al 2009;Zhou et al 2009) or that tag cells activated during memory acquisition (Reijmers et al 2007;Tayler et al 2011) could be combined with techniques such as laser capture microscopy and fluorescence-associated cell sorting. Additionally, these techniques in combination with reporter rodent models could also be used to address how epigenetic mechanisms may be differentially regulated in distinct cell populations (excitatory neurons vs. inhibitory neurons vs. glia) and how these mechanisms may integrate to regulate the function of an entire memory circuit.…”

New methods for understanding systems consolidation

“…To examine reactivation of hippocampal and neocortical neurons during context fear conditioning, our laboratory used a transgenic mouse that expresses a long-lasting, activity-dependent form of GFP (Tayler et al 2011(Tayler et al , 2013. In these mice, GFP was fused with the human histone protein HIST1H2BJ (Kanda et al 1998).…”