A critical step during sensory processing is the extraction of relevant information about the outside world from a host of distracting sensory inputs. One mechanism for generating salience is to associate sensory information from ongoing experiences with memories derived from past sensory experiences. Where and how these functional associations occur in the brain are central questions in neuroscience. This proposal aims to fill this gap by exploring circuit interactions and single neuron computations that help assign mnemonic valence to sensory signals. In this study, we propose that the hippocampus—the center of learning and memory—plays a crucial role in gating sensory information flow through its reciprocal circuit interactions with the entorhinal cortex, a hub for processing multisensory information. To test this hypothesis, we will use anatomical and functional connectivity mapping experiments to validate how hippocampus communicates with entorhinal cortex output layers (Aim 1). We will assess how hippocampal inputs modulate the short-term plasticity dynamics of excitatory-inhibitory synaptic transmission in the entorhinal cortex (Aim 2). Finally, we will test whether the hippocampus actively modulates the synaptic strength and gain of sensory inputs to entorhinal cortex through dendritic integration and long-term plasticity mechanisms (Aim 3a) and how silencing the CA1 inputs to EC will affect contextual learning behavior (Aim 3b). Despite 60 years of research on memory processing, we know surprisingly little about the organization and function of hippocampal projection circuitry and the mechanisms by which memories modulate ongoing sensory processing in the entorhinal cortex. Our study will combine state-of-the-art in vitro and in vivo approaches, including electrophysiology, behavioral testing, and optogenetics, to provide a functional model of the unexplored hippocampal-entorhinal cortex reciprocal circuit. Exciting pilot experiments from our lab have already revealed a new pathway between the hippocampus and entorhinal cortex that implies a true reciprocal feedback circuit loop. This circuit connects the hippocampus directly to entorhinal cortex output neurons that project sensory information to the hippocampus. Our new circuit model is potentially transformative, for it describes a route by which the hippocampus directly transmits memory input to the entorhinal cortex, with minimal lag and transformation, to refine sensory output based on relevance and to quickly adapt behavior in response to changing environmental demands. Such a function could be used by the brain to facilitate reinforced learning, refine old memories, and form new memory associations. By identifying the neural circuit interactions between the hippocampus and entorhinal cortex, our study will greatly improve our understanding of the mechanisms that underlie the memory-related sensory processing deficits experienced by patients of several neurological and neuropsychia...