Study of the entorhinal-hippocampal circuitry supporting spatial pattern separation in behaving animals

• Applicant: Dr. Marie Oulé
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Human Cognitive and Systems Neuroscience
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 428950153

Although decades of investigations have pinpointed the function of the dentate gyrus (DG) of the hippocampus in supporting memory, the neurobiological mechanisms underlying specific cognitive functions, such as pattern separation, remain elusive. Pattern separation refers to the ability to dissociate very similar memories (i.e. “where did I park my car yesterday” versus “where did I park my car today”)? Although these two events share many similarities (same car, same parking lot), their non-overlapping encoding and storage is necessary for accurate retrieval of the associated memories. At the neuronal network level, pattern separation consists of the ability to generate dissimilar outputs after integration of similar inputs. Here, I propose a set of experiments to develop a deeper understanding of the neurobiological processes involved in pattern separation. This is especially important as this cognitive function has been shown to be altered in several pathophysiological conditions including Alzheimer’s disease and schizophrenia. Specifically, the DG is known to support spatial pattern separation (i.e. the ability to discriminate similar spatial information), where spatial information reaching the granule cells (GCs) of the DG are carried by the medial entorhinal cortex (MEC), a cortical area known to sense spatial cues of the explored environment. However, the underlying mechanisms by which DG’s network activity supports spatial pattern separation remain elusive. Indeed, while DG’s neuronal activity has been shown to change across exposure to different environments sharing a certain degree a similarity, how the GCs adapt their network firing to solve learning tasks relying on spatial pattern separation is unknown. Using a combination of cutting-edge tools such as in vivo electrophysiology and in vivo calcium imaging coupled with optogenetics in freely behaving animals, this project aims to unravel the circuit operations performed by the MEC-DG network that underlie spatial pattern separation. To address this question, I will first investigate the changes in DG’s activity during a spatial discrimination task in gradual conditions of spatial pattern separation demand. This initial experiment will allow to determine which type of network activity changes in DG is associated with spatial pattern separation. A second set of experiments will take advantage of transgenic mice in which the activity of DG-projecting MEC stellate cells, known to convey spatial information to the DG, will be optogenetically controlled to determine the function of this neuronal pathway in spatial pattern separation. Thus, this project is designed to bring an important contribution to the fundamental understanding of the function of the MEC-DG circuitry in supporting spatial pattern separation.

• DFG Programme: Research Fellowships
• International Connection: Canada
• Host: Professor Mark P. Brandon, Ph.D.