The Role of Sensory Inputs and Cholinergic Modulation for the Coding of Location and Movement Speed in the Entorhinal Cortex

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PROJECT SUMMARY/ABSTRACT The goal of this project is to investigate potential mechanistic roles of sensory inputs and cholinergic modulation for generating neural coding of location and movement speed. The results are expected to support development of models of network mechanisms underlying psychiatric disorders. Representations for spatial location and movement speed are important for path integration and memory-guided navigation. Recordings of grid cells and theta oscillations in the medial entorhinal cortex in freely exploring mice under conditions of light and complete darkness will first address the question how long the neuronal code for location by grid cell firing and the code for movement speed by theta frequency are preserved in working memory in the absence of visual inputs. Analysis of the acquired data will test the hypothesis that changes in spatial periodic grid cell firing correlate in time with changes in the theta frequency vs. running speed relationship. The expected outcomes of these analyses will be used to inform computational models of path integration, including models of grid cell firing. Experiments under Specific Aim #2 will use fiber photometry for monitoring cholinergic activity in the medial entorhinal cortex to address the role of cholinergic modulation in forming and preserving codes for location and movement speed in the presence and absence of visual cues. Analyses will test if changes in sensory inputs, neuronal activity, and cholinergic modulation correlate at different time scales. These analyses will further our mechanistic understanding of coding principles underlying a broad range of cognitive processes associated with spatial memory. Both grid cells and cholinergic modulation are essential in current models of spatial memory and memory-guided navigation. Experiments under Specific Aim #3 will use optogenetic inhibition of cholinergic projection neurons in the medial septum in combination with grid cell recordings in the medial entorhinal cortex to test the hypothesis that cholinergic signaling is necessary for spatial periodic firing of grid cells. Finally, experiments under Specific Aim #4 will investigate if auditory and olfactory cues are sufficient to support the formation of a cognitive spatial map by grid cell firing in the medial entorhinal cortex. Simultaneous recording of grid cells in the medial entorhinal cortex and monitoring of cholinergic activity by fiber photometry in complete darkness during the presence or absence of auditory or olfactory cues will test the hypotheses that auditory and olfactory inputs in isolation can be used to form a cognitive map that supports path integration and that cholinergic modulation supports memory-guided navigation based on these maps. The experimental and computational skills developed during the training period of this project and the additional theoretical training in neural data science and computational modeling will be crucial for the accomplishment of the proposed short- and long-term scientific goals and will become the foundation for the future work as an independent researcher.