The hippocampal-entorhinal circuit is critical for the formation of new episodic memories, or memories of events that happen in a specific place and time. The discovery of cells in this circuit that respond to the animal's location in the environment suggests that these cells create a spatial context for such memories. Within this broad neural circuit, five key cell types have been described: place cells, grid cells, head direction cells, border cells, and cells that respond to a conjunction of these features. However, the mechanisms behind the generation of each firing pattern, and the function of each cell type, remain to be determined. Models have hypothesized that multi-peaked 'grid' responses are generated in layer II of the medial entorhinal cortex and converted into single-peaked 'place' responses in the hippocampus. Testing these models requires the capability to selectively manipulate individual elements of the circuit. The following experiments combine the cellular specificity of transgenic mice with novel optogenetic and pharmocogenetic tools to inactivate layer II of the medial entorhinal cortex while simultaneously recording ensembles of neurons in the entorhinal cortex or hippocampus. This genetic dissection will shed light on the basic operational principles of the circuit, and help distinguish between models of hippocampal-entorhinal interactions. Understanding the basic performance of the circuit will provide clues into how the circuit might malfunction in patients afflicted with Alzheimer's disease or epilepsy.
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