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      Cell type-specific genetic and optogenetic tools reveal novel hippocampal CA2 circuits

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          Abstract

          The formation and recall of episodic memory requires precise information processing by the entorhinal-hippocampal network. For several decades, the trisynaptic circuit, entorhinal cortex layer II (ECII)→dentate gyrus (DG)→CA3→CA1 and the monosynaptic circuit ECIII→CA1 have been considered the main substrates of the network responsible for learning and memory. Circuits linked to another hippocampal region, CA2, have only recently come to light. Here, by using highly cell type-specific transgenic mouse lines, optogenetics, and patch-clamp recordings, we show that DG cells, long believed not to project to CA2, send functional monosynaptic inputs to CA2 pyramidal cells, through abundant longitudinal projections. CA2 innervates CA1 to complete an alternate trisynaptic circuit but, unlike CA3, projects preferentially to the deep rather than superficial sublayer of CA1. Furthermore, contrary to the current knowledge, ECIII does not project to CA2. These new anatomical results will allow for a deeper understanding of the biology of learning and memory.

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          Most cited references44

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          The hippocampus and memory: insights from spatial processing.

          The hippocampus appears to be crucial for long-term episodic memory, yet its precise role remains elusive. Electrophysiological studies in rodents offer a useful starting point for developing models of hippocampal processing in the spatial domain. Here we review one such model that points to an essential role for the hippocampus in the construction of mental images. We explain how this neural-level mechanistic account addresses some of the current controversies in the field, such as the role of the hippocampus in imagery and short-term memory, and discuss its broader implications for the neural bases of episodic memory.
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            Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion.

            Adult-born granule cells (GCs), a minor population of cells in the hippocampal dentate gyrus, are highly active during the first few weeks after functional integration into the neuronal network, distinguishing them from less active, older adult-born GCs and the major population of dentate GCs generated developmentally. To ascertain whether young and old GCs perform distinct memory functions, we created a transgenic mouse in which output of old GCs was specifically inhibited while leaving a substantial portion of young GCs intact. These mice exhibited enhanced or normal pattern separation between similar contexts, which was reduced following ablation of young GCs. Furthermore, these mutant mice exhibited deficits in rapid pattern completion. Therefore, pattern separation requires adult-born young GCs but not old GCs, and older GCs contribute to the rapid recall by pattern completion. Our data suggest that as adult-born GCs age, their function switches from pattern separation to rapid pattern completion. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network.

              Forming distinct representations of multiple contexts, places, and episodes is a crucial function of the hippocampus. The dentate gyrus subregion has been suggested to fulfill this role. We have tested this hypothesis by generating and analyzing a mouse strain that lacks the gene encoding the essential subunit of the N-methyl-d-aspartate (NMDA) receptor NR1, specifically in dentate gyrus granule cells. The mutant mice performed normally in contextual fear conditioning, but were impaired in the ability to distinguish two similar contexts. A significant reduction in the context-specific modulation of firing rate was observed in the CA3 pyramidal cells when the mutant mice were transferred from one context to another. These results provide evidence that NMDA receptors in the granule cells of the dentate gyrus play a crucial role in the process of pattern separation.
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                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nat. Neurosci.
                Nature neuroscience
                1097-6256
                1546-1726
                26 March 2014
                15 December 2013
                February 2014
                01 August 2014
                : 17
                : 2
                : 269-279
                Affiliations
                [1 ]RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
                [2 ]RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan
                [3 ]Media Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
                [4 ]Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
                Author notes
                Correspondence should be addressed to: S.T. ( tonegawa@ 123456mit.edu )
                [*]

                These authors contributed equally to this work

                [†]

                present address: Department of Environmental Preventive Medicine, Jichi Medical University, Tochigi 329-0498, Japan

                Article
                NIHMS560018
                10.1038/nn.3614
                4004172
                24336151
                55ece7e6-4a5f-4fb5-9c79-0dfa6194196a
                History
                Categories
                Article

                Neurosciences
                hippocampus,trisynaptic circuit,ca2,dentate gyrus (dg),mossy fibers (mfs),granule cells (gc),entorhinal cortex (ec),ca1 sublayers,optogenetics,cre transgenic mice,neural circuit genetics,rabies virus

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