Dissecting the neural circuit for discrete cue representation in the Dentate Gyrus

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The goal of this project is to provide the building blocks for an independent research program focused on the mechanisms by which neural networks incorporate multisensory cues into episodic memories. Discrimination of different contexts composed of distinct constellations of multisensory cues is a hallmark of both episodic memory and spatial navigation, two functions ascribed to the mammalian hippocampus. The Dentate Gyrus of the hippocampus is central to spatial and contextual discrimination; yet the neural mechanisms by which contextual representations are encoded by principal granule cells has remained a significant knowledge gap. Preliminary data based on in vivo two photon imaging indicates a novel elevation of cue-associated activity in the granule cells that correlates with spatial discrimination, both of which are reduced in mice without adult hippocampal neurogenesis. Thus, this project proposes to test the hypothesis that specialized cue cells in the dentate gyrus are critical for anchoring contextual representations and are modulated both by adult neurogenesis and by entorhinal cortical inputs. These studies represent a number of firsts in linking the physiology and behavioral function of the Dentate Gyrus during learning of spatial discrimination by investigating 1) the evolution of spatial and cue-associated activity of granule cells over time in order to support the encoding of contextual representations; 2) the activity of adult born granule cells and their distinct contributions to cue representations; and 3) the activity of the entorhinal cortex afferents to the Dentate Gyrus, and the mechanisms by which multisensory information arriving from the external world generate internal hippocampal representations. To achieve this detailed circuit dissection, I will use an integrative approach that merges in vivo imaging techniques, genetic-based circuit manipulation strategies and computational analysis of multi-neuronal activity. The technical and scientific skills that I will develop during the training period of this project will become the pillars of an independent research career investigating the function and development of the complex neural dynamics which support cognitive functions implicated in neuropsychiatric disorders. This training will be complemented by intense carrier developmental activities and mentorship that will prepare me for the practical aspects of laboratory management, teaching and fund raising. Overall, these studies will provide novel insights into how the Dentate Gyrus local and long-range circuits contribute to cue representations and facilitate contextual discrimination. Since hippocampal damage has been implicated in the cognitive discrimination impairments associated with Alzheimer’s disease and PTSD, constructing a dynamic picture of the Dentate Gyrus, an often overlooked hippocampal region, at cellular and circuit resolutions during the formation of episodic memories may have an important clinical relevance.