Project Summary Spatial navigation and memory are critical aspects of life for animals and humans. To identify how the brain supports these processes, our experiments examine how specific types of spatial and non-spatial knowledge are represented by the activity of single neurons and neuronal populations in the human medial temporal lobe. Previously, we and others showed that spatial knowledge is supported by networks of “place” and “grid cells,” each of which represent a person’s location in an environment by activating at individual locations and groups of locations, respectively. Though the human medial temporal lobe is also believed to be critical for memory, imagination, prediction, and planning, whether and how spatial cell types also support these complex forms of cognition is unknown. Here we will test the hypothesis that place- and grid-like firing patterns, as well as other cell types in the hippocampal system, support the neuronal representation of more complex spatial and non-spatial information beyond the neural coding of location for these diverse, inter-related aspects of human cognition. We examine this issue by conducting direct recordings of the human hippocampal and entorhinal network from neurosurgical epilepsy patients performing computerized virtual-reality tasks. In Aim 1 of our project we will examine whether medial temporal lobe neuronal firing patterns, including place- and grid-like firing, go beyond encoding spatial information to represent a “cognitive map” of each environment that represents which sets of locations and paths are connected and how they are rewarded. In Aim 2, we examine the role of place and grid cells in representing multiscale information, including large-scale geography. In Aim 3, we probe whether the activity of human place cells represent imagined and viewed locations in a manner similar to the activity present during active navigation. Finally, in Aim 4 we measure human “time cells” and test whether the activity of time cells in episodic memory are similar to the properties of place and grid cells during navigation. Our proposed studies are likely to create fundamental insights into the core neuronal responses and computational mechanisms that underlie both spatial and non-spatial memory and cognition.