Project Summary: Memory enables animals to acquire, store, and recall knowledge of the world through experience and use this knowledge to maximize reward and avoid danger. Understanding the circuit mechanisms within and between brain regions that underlie the formation and recall of memories is considered one of the great scientific challenges of our time and has the potential to drastically influence the treatment of memory disorders. The hippocampus is both necessary and sufficient for the formation and recall of episodic memories—memories of experiences placed in time and space. These memories are encoded in the hippocampus by the firing activity of populations of neurons called place cells, which fire at specific locations as animals move around their environment, creating a cognitive map. Understanding how cognitive maps form, evolve with experience, and are retrieved is therefore essential for understanding the neurobiology of memory and the function of the hippocampus in this process. However, a major pathway that has been overwhelmingly neglected in the study of memory and the hippocampus is the across hemispheres projection between the CA3 and CA1 region of the hippocampus. This projection provides major excitatory drive to the CA1 region, yet the information these projections convey to CA1 is unknown, as is their impact on CA1 memory encoding. Technical limitations have prevented direct recordings and comparisons of within-hemisphere versus across- hemisphere CA3 inputs to CA1 during memory processing. To solve this problem, we will implement an innovative approach to directly measure and manipulate the spiking activity of within-hemisphere versus across-hemisphere CA3 axons in CA1. We will also simultaneously record the spiking activity of large populations of CA1 place cells during spatial learning — novel environment exposure. Functional imaging of activity plus optogenetic manipulation of CA3 axons in hippocampus will reveal the contribution of within-hemisphere versus across-hemisphere CA3 inputs on cognitive map formation, evolution and retrieval. This will provide the first insight into the information being carried by within-hemisphere versus across-hemisphere CA3 axons directly in CA1 during spatial learning and will reveal how these inputs contribute to memory representations in CA1. These insights could reveal novel targets or processes for the treatment of memory disorders.