William D. Marks, Ph.D - US grants

Project Summary Episodic memory is the unique recollection of a specific event in time, requiring the processing and integration of multiple information types, including spatial context and temporal information. While numerous studies on the processing of space and time as separate events have been undertaken, the understanding of the mechanisms underlying temporal processing are limited. Additionally, the means by which these information streams are integrated to form a singular memory are poorly understood. Previous research demonstrates that the hippocampus has the capability to integrate multiple spatially bound inputs with relevant contextual and nonspatial information into a singular representation. The mechanism for this integrative event as it relates to space and time is likely found more specifically within the CA1 subfield, as a discrete input carrying temporal information from entorhinal cortex layer III synapses onto the distal segments of the apical dendrites of CA1 pyramidal cells, while contextual information from EC layer II is routed through the Dentate Gyrus and CA3 before synapsing onto the proximal segments of the CA1 pyramidal cell apical dendrites. To better understand the processes underlying temporal processing, and to test whether this circuit has integrative function in episodic memory, we propose first to develop nose-poke based timing tasks for use with in-vivo calcium imaging in freely moving mice. These tasks will allow for a more refined time cell metric, give insight into the temporal encoding process, and provide a means for optogenetic investigation of circuit components with concurrent imaging of time cells. Utilizing this capability, we will optogenetically investigate the role of MECIII inputs to CA1 on time cell function and maintenance. The role of context in time cell functionality will be examined with a held nose-poke test, in which mice are trained to maintain a nose poke for a set period across multiple contexts while passive recordings of CA1 calcium activity are taken across multiple context presentations. In the final phase of this project, we will utilize cell-type specific optogenetic manipulation to inhibit terminals projecting to CA1 from ECIII or CA3 to gain a more mechanistic understanding of the integration mechanism and context dependency in time cell activity. This project will give novel insight into the mechanisms underlying episodic memory formation, temporal encoding, and how time is integrated with other data in the brain. This project will be performed at UT Southwestern Medical Center, a top tier research institution with a large variety of institutional support available. The training plan is designed to increase the applicant?s skills in in-vitro techniques, optogenetics, and behavior while also developing the applicant?s skills in presentation, grantsmanship, and laboratory management.