Understanding output circuits of the lateral entorhinal cortex

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 6 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 remains largely unclear. Here we propose studies to investigate the function of the output layers of LEC in 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 and transgenic mouse lines that express Cre under the promoter of cell-type-specific markers. There are three Specific Aims to the studies: (Aim 1) identify the roles of serotonin inputs to LEC layer 5/6 neurons in associative learning; (Aim 2) identify the role of superficial and deep layers of target regions of LEC layer 5/6, and (Aim 3) determine oscillation mechanisms for interactions between LEC layer 5/6 neurons and neurons in target regions. 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-cortical circuit enables the formation of declarative memory via the integration of multiple dimensions of sensory information.