Route-dependent spatial engram tagging in mouse dentate gyrus

The dentate gyrus (DG), a subregion of the hippocampal formation, is hypothesized to act as a pattern separator that distinguishes between similar input patterns during memory formation and retrieval (Marr, 1971, McNaughton and Morris, 1987, O’Reilly and McClelland, 1994, Treves and Rolls, 1994, Hasselmo and Wyble, 1997, Leutgeb et al., 2007, Neunuebel and Knierim, 2014). Sparse ensembles of DG memory-associated granule cells, or engram cells, have been optogenetically targeted to successfully influence memory-associated behavior (Liu et al., 2012, Ramirez et al., 2013, Denny et al., 2014, Redondo et al., 2014) even after consolidation (Kitamura et al., 2017) and pathogenic aging leading to natural recall failure (Roy et al., 2016). These findings support the hypothesis that the DG encodes the contextual dimension of memories. Another body of literature emphasizes the spatial representations of DG granule cells, which exhibit place fields similar to those in CA1 (O’Keefe and Dostrovsky, 1971, Neunuebel and Knierim, 2012, Neunuebel and Knierim, 2014, GoodSmith et al., 2017, Hainmueller and Bartos, 2018, Cholvin et al., 2021). Lesions of the DG granule cell population impair spatial memory (McLamb et al., 1988, McNaughton et al., 1989, Nanry et al., 1989, Xavier et al., 1999; for a review, see Xavier & Costa, 2009) and reduce both spatial specificity of CA3 place cells and reward-associated sharp-wave-ripple rate (Sasaki et al., 2018). Reconciling how the DG contributes to both novel contextual learning and spatial representations would offer important insight into the contribution of this region for learning and memory.

To that end, our study investigated the role of the DG in distinguishing between multiple routes within a single T-maze context during a spatial navigation task. Male and female mice were trained on a delayed-non-match-to-position (DNMP) task with two routes. A population of active DG granule cells was visualized using an immediate-early-gene strategy of labeling cFos positive cells active during exposure on Day 1 to a novel 2-route T-maze (Guzowski et al., 1999, Reijmers et al., 2007, Liu et al., 2012, Ramirez et al., 2013). Another population of cFos positive cells activated on Day 2 by a second behavioral context was visualized with immunohistochemical staining for comparison. We hypothesized that the DG of mice exposed to a 1-route maze on Day 2 would show more overlap between the two cell populations than chance, but less overlap than mice re-exposed to the full 2-route maze from Day 1. Our findings support this hypothesis and additionally reveal the size and degree of ensemble reactivation are largely independent of behavioral performance in the arenas. Our results indicate that the DG plays a role in encoding particular sub-routes of a 2D environment during ongoing spatial navigation.

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