PROJECT SUMMARY (See instructions): Cognitive maps allow humans to mentally represent their spatial environments and are thus essential for navigation and memory in everyday life. Humans use different types of cognitive maps to guide their behavior: egocentric cognitive maps, in which spatial information such as locations and directions is encoded relative to the subject, and allocentric cognitive maps, in which spatial information is encoded relative to the external world. This project will use computational modeling and human single-neuron recordings in epilepsy patients during a virtual-reality task to demonstrate the neural circuits that underlie egocentric and allocentric cognitive maps in humans (Aim 1), guided by extensive research on spatial cells in animals. Combining predictions from our computational models of navigation and memory with our prior discovery of egocentric cells in the human medial temporal lobe, we will test for neurons that are egocentrically tuned to boundaries, objects, and reference points and thus underlie egocentric cognitive maps. Going beyond our description of human grid and place cells, we will also identify neurons that are allocentrically tuned to boundaries, objects, and locations as the neural basis of allocentric cognitive maps. In tight feedback loops, we will extend our computational models to integrate the empirical observations. Beyond navigation, we will analyze and simulate how egocentric and allocentric spatial cells reactivate when humans use cognitive maps to recall spatial memories (Aim 2). To show how cognitive maps become populated with non-spatial information to generate complex memories, we will identify how spatial cells become linked to neurons that represent non-spatial features to encode object location memories (Aim 3). We will test empirically and investigate computationally whether sharp wave ripples play a role in the encoding and retrieval of such complex memories by triggering synchronous activity in spatial and non-spatial cells. Applying confined and diffuse neuron loss to our models, we will mimic memory disorders and examine their effects on behavior. Overall, this project will lead to new insights into the cellular mechanisms of spatial navigation and memory, helping us to identify the working principles of the human brain. Our discoveries will be instrumental in understanding the cognitive effects of mental illnesses, and they will provide the ground for developing treatment options of memory disorders such as electrical brain stimulation to restore cognitive functioning.