THE ORIGIN AND FUNCTION OF SENSORY CUE AND PLACE RESPONSES IN THE DENTATE GYRUS

Project Summary Human patients with the neurological disorders of Alzheimer’s disease and age-related dementia commonly show defects in spatial navigation, which correlates strongly with dysfunction in other aspects of cognition such as episodic 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. Accordingly, the hippocampus has also been found to exhibit pathological changes in many disorders of learning and memory. 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, and therefore may underlie the dysfunction in human cognitive disorders. 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 and self-motion, respectively. Thus it has been suggested that 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 documented strong sensory cue responses in dentate granule cells during spatial tasks in head fixed mice, but it is unknown to what degree cue representations are integrated with purely spatial information in the DG. In this proposal we will examine the microcircuitry of cue and spatial representations in the dentate gyrus using modern in vivo population imaging, circuit tracing, and optogenetic technologies combined with precise behaviors designed to isolate independent cue and spatial influences on dentate granule cell activity. We will leverage these powerful techniques along with cutting edge analytical tools to test the hypothesis that cue and spatial representations remain distinct at the level of the dentate gyrus, and thus the DG population consists of separate classes of “cue cells” driven primarily by the LEC and “place cells” driven by the MEC. Furthermore, we will utilize the new light-and-activity dependent gene expression system FLiCRE to selectively label and manipulate functionally distinct cue and place cell populations, in order to determine their inputs and role in spatial behavior. Together, these experiments will help us better understand the progressive transformation of information within the hippocampus in the formation of a cognitive map of an environment, and how these processes may be defective in human cognitive disorders of learning and memory.