Global remapping in granule cells and mossy cells of the mouse dentate gyrus.

Hippocampal place cells exhibit spatially modulated firing, or place fields, which can remap to encode changes in the environment or other variables. Unique among hippocampal subregions, the dentate gyrus (DG) has two excitatory populations of place cells, granule cells and mossy cells, which are among the least and most active spatially modulated cells in the hippocampus, respectively. Previous studies of remapping in the DG have drawn different conclusions about whether granule cells exhibit global remapping and contribute to the encoding of context specificity. By recording granule cells and mossy cells as mice foraged in different environments, we found that by most measures, both granule cells and mossy cells remapped robustly but through different mechanisms that are consistent with firing properties of each cell type. Our results resolve the ambiguity surrounding remapping in the DG and suggest that most spatially modulated granule cells contribute to orthogonal representations of distinct spatial contexts.

Flexible encoding of objects and space in single cells of the dentate gyrus.

The hippocampus is involved in the formation of memories that require associations among stimuli to construct representations of space and the items and events within that space. Neurons in the dentate gyrus (DG), an initial input region of the hippocampus, have robust spatial tuning, but it is unclear how nonspatial information may be integrated with spatial activity in this region. We recorded from the DG of 21 adult mice as they foraged for food in an environment that contained discrete objects. We found DG cells with multiple firing fields at a fixed distance and direction from objects (landmark vector cells) and cells that exhibited localized changes in spatial firing when objects in the environment were manipulated. By classifying recorded DG cells into putative dentate granule cells and mossy cells, we examined how the addition or displacement of objects affected the spatial firing of these DG cell types. Object-related activity was detected in a significant proportion of mossy cells. Although few granule cells with responses to object manipulations were recorded, likely because of the sparse nature of granule cell firing, there was generally no significant difference in the proportion of granule cells and mossy cells with object responses. When mice explored a second environment with the same objects, DG spatial maps completely reorganized, and a different subset of cells responded to object manipulations. Together, these data reveal the capacity of DG cells to detect small changes in the environment while preserving a stable spatial representation of the overall context.

Parallel processing streams in the hippocampus.

The hippocampus performs two complementary processes, pattern separation and pattern completion, to minimize interference and maximize the storage capacity of memories. Classic computational models have suggested that the dentate gyrus (DG) supports pattern separation and the putative attractor circuitry in CA3 supports pattern completion. However, recent evidence of functional heterogeneity along the CA3 transverse axis of the hippocampus suggests that the DG and proximal CA3 work as a functional unit for pattern separation, while distal CA3 forms an autoassociative network for pattern completion. We propose that the outputs of these functional circuits, combined with direct projections from entorhinal cortex to CA1, form interconnected, parallel processing circuits to support accurate memory storage and retrieval.

Dentate Gyrus Mossy Cells Share a Role in Pattern Separation with Dentate Granule Cells and Proximal CA3 Pyramidal Cells.

The complementary processes of pattern completion and pattern separation are thought to be essential for successful memory storage and recall. The dentate gyrus (DG) and proximal CA3 (pCA3) regions have been implicated in pattern separation, in part through extracellular recording studies of these areas. However, the DG contains two types of excitatory cells: granule cells of the granule layer and mossy cells of the hilus. Little is known about the firing properties of mossy cells in freely moving animals, and it is unclear how their activity may contribute to the mnemonic functions of the hippocampus. Furthermore, tetrodes in the dentate granule layer and pCA3 pyramidal layer can also record mossy cells, thus introducing ambiguity into the identification of cell types recorded. Using a random forests classifier, we classified cells recorded in DG (Neunuebel and Knierim, 2014) and pCA3 (Lee et al., 2015) of 16 male rats and separately examined the responses of granule cells, mossy cells, and pCA3 pyramidal cells in a local/global cue mismatch task. All three cell types displayed low correlations between the population representations of the rat's position in the standard and cue-mismatch sessions. These results suggest that all three excitatory cell types within the DG/pCA3 circuit may act as a single functional unit to support pattern separation.SIGNIFICANCE STATEMENT Mossy cells in the dentate gyrus (DG) are an integral component of the DG/pCA3 circuit. While the role of granule cells in the circuitry and computations of the hippocampus has been a focus of study for decades, the contributions of mossy cells have been largely overlooked. Recent studies have revealed the spatial firing properties of mossy cells in awake behaving animals, but how the activity of these highly active cells contributes to the mnemonic functions of the DG is uncertain. We separately analyzed mossy cells, granule cells, and pCA3 cells and found that all three cell types respond similarly to a local/global cue mismatch, suggesting that they form a single functional unit supporting pattern separation.

Spatial Representations of Granule Cells and Mossy Cells of the Dentate Gyrus.

Granule cells in the dentate gyrus of the hippocampus are thought to be essential to memory function by decorrelating overlapping input patterns (pattern separation). A second excitatory cell type in the dentate gyrus, the mossy cell, forms an intricate circuit with granule cells, CA3c pyramidal cells, and local interneurons, but the influence of mossy cells on dentate function is often overlooked. Multiple tetrode recordings, supported by juxtacellular recording techniques, showed that granule cells fired very sparsely, whereas mossy cells in the hilus fired promiscuously in multiple locations and in multiple environments. The activity patterns of these cell types thus represent different environments through distinct computational mechanisms: sparse coding in granule cells and changes in firing field locations in mossy cells.

DISC1-mediated dysregulation of adult hippocampal neurogenesis in rats.

Adult hippocampal neurogenesis, the constitutive generation of new granule cells in the dentate gyrus of the mature brain, is a robust model of neural development and its dysregulation has been implicated in the pathogenesis of psychiatric and neurological disorders. Previous studies in mice have shown that altered expression of Disrupted-In-Schizophrenia 1 (Disc1), the mouse homolog of a risk gene for major psychiatric disorders, results in several distinct morphological phenotypes during neuronal development. Although there are advantages to using rats over mice for neurophysiological studies, genetic manipulations have not been widely utilized in rat models. Here, we used a retroviral-mediated approach to knockdown DISC1 expression in dividing cells in the rat dentate gyrus and characterized the morphological development of adult-born granule neurons. Consistent with earlier findings in mice, we show that DISC1 knockdown in adult-born dentate granule cells in rats resulted in accelerated dendritic growth, soma hypertrophy, ectopic dendrites, and mispositioning of new granule cells due to overextended migration. Our study thus demonstrates that the Disc1 genetic manipulation approach used in prior mouse studies is feasible in rats and that there is a conserved biological function of this gene across species. Extending gene-based studies of adult hippocampal neurogenesis from mice to rats will allow for the development of additional models that may be more amenable to behavioral and in vivo electrophysiological investigations. These models, in turn, can generate additional insight into the systems-level mechanisms of how risk genes for complex psychiatric disorders may impact adult neurogenesis and hippocampal function.