A central function of the brain is to create internal representations of stimuli and experiences from the outside world to guide behavior. Here, we examine the circuit mechanisms underlying the neural representation of external space, a representation essential to spatial memory and navigation, and impacted by neurodegenerative and psychiatric diseases. The neural basis for the representation of space depends, in part, on circuits in the medial entorhinal cortex, which translate the external environment into an internal map of space. The resolution of the entorhinal neural map of space is topographically organized, with the firing rate tuning curves of spatial and directional neurons progressively increasing along the dorsal to ventral entorhinal axis. This topography has been proposed to allow dorsal versus ventral entorhinal neural codes to support different behaviors, with dorsal regions playing a larger role in spatial learning. While our previous work revealed that the dorsal to ventral gradient in the spatial scale of entorhinal representations impacts spatial memory, the degree to which dorsal versus ventral neural codes for spatial position act as discrete or coordinated circuits to support spatial memory or navigation remains incompletely understood. Here, we propose to combine electrophysiology using silicon probes with spatial and memory tasks in behaving mice. Until now, electrophysiological approaches had to contend with the difficulty of accessing ventral cortical regions and limited recording channel counts, resulting in a lack of studies in which the activity of entorhinal neurons were simultaneously considered across the dorsal- ventral axis. However, new versions of silicon probes have allowed us to record hundreds (>500) of neurons simultaneously along nearly the entire length of mouse entorhinal cortex. This, combined with virtual reality tasks that can rapidly incorporate a diverse set of sensory and non-metric (positive or negative stimuli) cues, will enable us to reveal how neural activity across the dorsal-ventral entorhinal axis is restructured after learning about important environmental features and how this information is then communicated across the entorhinal structure to drive behavior. Achieving significant insight along these fonts will provide a novel understanding of how entorhinal maps of space support spatial memory and navigation.
The treatment of psychiatric diseases, including highly intractable clinical conditions such as depression, has been held back by a limited understanding of the underlying principles of healthy brain circuit function. This proposal focuses on the representation of external space, which exists in many elements of memory and cognitive processes, from recalling where you parked your car to encoding a sequence of locations that help you navigate through the world. We focus on the mechanisms and function of neural circuits in the medial entorhinal cortex, a brain region that contains neural circuits highly associated with navigation and memory that can go awry in a range of mood and neural disorders; understanding how normal medial entorhinal circuits support behavior could lead to new, more precise treatments that reduce the memory- related symptoms of brain disease.
