Subtype-specific rules of memory encoding and retrieval in dentate gyrus granule cells

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Memories are crucial for everyday life, determining how we view the past and shaping how we respond to the future. Stemming from this importance, one of the foundational goals of basic neuroscience lies in understanding how the brain mediates memory. Revealing the precise roles that specific cells play across the stages of memory - from the initial formation of memory to subsequent memory retrieval - is an essential component of accomplishing this goal. In this proposed research, we will study these precise cellular roles in the hippocampus, a brain region critical for learning and memory. Specifically, our research will focus on the input cells of this brain region, the so-called "granule cells" of the dentate gyrus. A rich collection of work has illustrated that granule cells can play important roles in many different types of memory; however, whether there are specific subtypes of mature granule cells that play precise roles in memory has not been investigated. We will seek to identify the subtype-specific organization of granule cells, providing critical insight into the first layer of hippocampal-dependent memory. Leveraging multidisciplinary research in both experiment and computation, my laboratory will examine the rules of granule cell participation in memory by combining cutting-edge neuroscience techniques with "Big Data" analysis. To begin, in mice that have gone through memorable experiences in a laboratory setting, we will examine the rules by which the same granule cells are used for both formation and subsequent retrieval of memories. To complement these experiments, we will measure the expression of every gene in the mouse genome for hundreds of individual granule cells, providing a Big Data framework to identify whether there are specific subtypes of granule cells that could play different roles in memory formation and retrieval. Finally, we will manipulate identified subtypes of granule cell types during memory formation, and identify whether this manipulation evokes different behaviours following memory retrieval. This work will provide essential insight into the first layer of cellular processing in hippocampal-dependent memory, and has important implications for a variety of disciplines. For the general neuroscientific community, understanding how the brain computes memory is a central goal of basic neuroscience. Moreover, clarifying the precise cell-type-specific rules of memory in the brain may be of broad interest to the fields of cognitive neuroscience, computer science, and machine learning.