Neural circuits of cue and spatial representation in the dentate gyrus

Project Summary Human patients with neurological disorders such as Alzheimer’s disease and age-related dementia commonly show defects in spatial navigation which correlate strongly with memory dysfunction. Both of these functions are thought to involve processing by the hippocampus and associated temporal lobe regions, which have been found to exhibit pathological changes in these and other disorders of learning and memory. During spatial exploration animals form an internal cognitive map of an environment by integrating online sensory input with information about the animal’s movement through space, a process which involves the hippocampus. Yet it is still unclear how different subregions of the hippocampus contribute to the integration of sensory cue and self-motion information in the formation of a spatial map for navigation. The dentate gyrus (DG) is the initial stage of the classical ‘trisynaptic circuit’ of the hippocampus, and receives its principal inputs from the lateral and medial entorhinal cortex (LEC and MEC), which are proposed to carry information about sensory cues (objects) and self-motion (space), respectively. Thus it has been suggested that as the first stage of hippocampal processing, the DG integrates cue (“what”) and spatial (“where”) information to form discrete spatial representations such as those found in place cells elsewhere in the hippocampus and which are proposed to underlie an animal’s overall map of an environment. We have however recently documented strong sensory cue responses in a subpopulation of dentate granule cells largely independent of spatial context (“cue cells”), in addition to spatially integrating “place cells” independent of local cues. This suggests that cue and spatial information are kept separate at the level of the DG. In this proposal we will examine the microcircuitry of cue and spatial representations in the dentate gyrus using modern in vivo calcium imaging, population decoding, and optogenetic circuit analysis combined with precise behaviors designed to isolate independent cue and spatial influences on the dentate circuit. We will leverage these powerful techniques along with cutting edge analytical tools to test the hypothesis that in the DG population, “cue cells” are driven primarily by the LEC and “place cells” driven by the MEC. Furthermore, we will analyze the effect of local circuit mossy cells on cue representations and utilize a new virtual-reality contextual fear conditioning task in order to determine the role of DG cue representations on contextual memory discrimination behavior. Together, these experiments will help us better understand the progressive transformation of information within the hippocampus during spatial navigation and episodic memory, and how these processes may be defective in human cognitive disorders of learning and memory.