Hippocampal neurons activated during encoding drive the recall of contextual fear memory. Little is known about how such ensembles emerge during acquisition and eventually form the cellular engram. Manipulating the activity of granule cells (GCs) of the dentate gyrus (DG), we reveal a mechanism of lateral inhibition that modulates the size of the cellular engram. GCs engage somatostatin-positive interneurons that inhibit the dendrites of surrounding GCs. Our findings reveal a microcircuit within the DG that controls the size of the cellular engram and the stability of contextual fear memory.

Our study identifies lateral inhibition between GCs as a mechanism that constrains the ensemble of activated neurons during SE of a new environment. In contextual fear paradigm, the lateral inhibition determines the size of the cellular engram and the stability of the memory trace. Several factors may limit the size of the active neuronal ensembles that emerge in the DG during SE. First, the number of GCs is several fold higher than the number of upstream excitatory neurons in the entorhinal cortex (Schmidt et al., 2012). Second, GCs’ dendrites strongly attenuate synaptic inputs so that the cell fires only when many inputs are concomitantly active (Krueppel et al., 2011). In addition, our results now reveal the existence of lateral inhibition among GCs. This inhibitory interaction maintains the low level of neuronal excitation in cells not immediately active during SE that is typically required for DG function (Treves and Rolls, 1994). As memory formation progresses, naturally formed neuronal ensembles acquire engram properties (i.e., they become necessary and sufficient to evoke specific memories) (Tanaka et al., 2014; Denny et al., 2014). Previous studies have manipulated the memory trace associated with naturally formed neuronal ensembles (Han et al., 2009; Ramirez et al., 2013; Cowansage et al., 2014). Here, we succeed to assign fear memory to a neuronal ensemble that was artificially generated in the hippocampus without specific context representation. Optogenetic stimulation of this subset of neurons at the time of training determines the allocation of an artificial memory trace to the active fraction of neurons. However, changes in reactivation of the ensembles due to rapid uncoupling of the context and the fear response by the non-naturalistic stimulation pattern may cause memory extinction and reduced optogenetic memory retrieval.

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Stefanelli et al., 2016, Neuron 89, 1–12 March 2, 2016