This is an application for an Administrative Supplement for an existing R01, NINDS R01NS109362 entitled “Synaptic and Circuit Interactions to Shape Multisensory Processing”. Reciprocal interactions between entorhinal cortex and hippocampus could mediate the interplay between sensory processing and memory recall. The canonical cortico-hippocampal circuit model posits that entorhinal cortex layer II/III sends multimodal information to hippocampus but only receives hippocampal memory feedback indirectly via layer V. The ongoing work through the parent R01 revealed a previously unidentified direct connection from hippocampus to entorhinal cortex LII/III, the very layers that provide it with sensory input. This administrative supplement proposal will enable the PI to add more animal subjects and support new freely moving experiments necessary for examining the in vivo function of the reciprocal projection circuitry between hippocampus and entorhinal cortex. Experiments for the R01 in the first four years, determined that several more animals than originally budgeted are required to complete each experiment, due to off-target viral infections and fiber optic cannula targeting resulting in a higher than expected failure rate. Further, there is a change in the direction of the in vivo behavioral experimental plan – where freely moving behavior experiments combined with optogenetics need to be added to the head -fixed two photon optogenetics and behavior experiments. Based on preliminary data, freely moving tasks including novel object-location and spatial maze tasks allows for more naturalistic activity in medial entorhinal cortex, the primary target region of the hippocampal projections. Further one-photon dual fiber-optic coupled optogenetic photostimulation provides optimal targeting ability and silencing efficacy to parse out the effects of silencing the projection axons to LII/III vs LV. The new freely moving experiments proposed here alongside piezo driven volumetric two photon silencing of axonal fibers are critical for a comprehensive understanding of the reciprocal circuit function and successful completion of the study. The findings of this study are transformative as a sensory- memory feedback loop may impart the salient context to update online cortical sensory processing iteratively to generate adaptive learned behaviors with environmental changes and novel experiences. Inappropriate integration of memory and sensory inputs stemming from abnormalities in this circuit may underlie the memory-related sensory processing deficits observed in autism, schizophrenia, post-traumatic stress disorder, and Alzheimer’s disease.

Our study will examine the circuit interactions between the hippocampus and entorhinal cortex, two brain areas necessary for multisensory memory processing, implicated in the pathophysiologies of Alzheimer’s disease, autism, schizophrenia and post-traumatic stress disorder. Deficits in the processing and gating of multisensory information, and in the formation of contextual memories, are hallmark symptoms widely experienced by patients of these neurological and neuropsychiatric disorders. By identifying the neural mechanisms by which memories of past experiences shape ongoing sensory processing in the healthy brain, our study will provide insight on abnormalities in the brain’s cellular communication and wiring that may underlie these deficits.