Understanding neural circuits for associative memory in the lateral entorhinal cortex

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Abstract The entorhinal cortex (EC) and the hippocampus are the brain areas which are critically involved in the formation and retrieval of declarative memory, and damage to this circuit results in memory impairment. In order to cure dementias, including Alzheimer’s disease, which currently affects 5 million people in the United States, it is critical to forward an understanding of the cellular and circuit mechanisms involved in the encoding and retrieval of memory in this entorhinal-hippocampal circuit. The EC is anatomically segregated into two halves, the lateral entorhinal cortex (LEC), and the medial entorhinal cortex (MEC). Although previous studies have significantly advanced our understanding of the functional role of the MEC in spatial memory and navigation, our understanding of the functions of the LEC remain largely unclear. Here we propose studies to investigate the function of the LEC in the associative memory to address this critical gap in knowledge. Our approach involves multi-faceted analytical methods including in vivo electrophysiology, associative learning tasks, optogenetic circuit analysis methods, optical imaging and transgenic mouse lines that express Cre mice under the promoter of cell-type-specific markers. There are three Specific Aims to the studies: (Aim 1) identify functional roles of LEC layer II cell types in associative learning; (Aim 2) identify the role of LEC dopamine input in associative learning; and (Aim 3) determine the causal role of LEC 20-40Hz oscillations in associative learning. If successful, our studies will identify the circuit mechanisms for associative memory formation in the LEC and will help establish new frameworks for understanding how the entorhinal-hippocampal circuit enables the formation of declarative memory via the integration of multiple dimensions of sensory information.