Dynamic Hemispheric Asymmetry in the Hippocampus Throughout Memory Formation and Retrieval

Abstract

The hippocampus is critical for forming and stabilizing spatial memories. Within the classic trisynaptic circuit inside the hippocampus, CA1 is the output region of the hippocampus and place cells in CA1 are considered to collectively support spatial representations. While the contribution of unilateral or bilateral CA3 inputs to CA1 (Schaffer collateral pathway) have been well characterized, less is known about how inputs from the left and right CA3 differentially shape spatial representation in CA1. Most models of hippocampal function treat CA3 as a unified region and overlook the possibility of hemispheric specialization within its projections. Recent work has pointed to lateralized features of hippocampal circuitry primarily at the molecular and behavioral levels, yet the functional relevance of this hemispheric asymmetry among place cells in vivo remains poorly understood. In this dissertation, I examine how left and right CA3 projections differentially contribute to the development and stabilization of spatial representations in right CA1 (CA1R) during learning. Using two-photon calcium imaging and optogenetic inhibition in head-fixed mice navigating a virtual environment, I characterize how CA1R spatial maps evolve over experience and how CA3 inputs support this process across distinct phases of learning. I find that CA1R maps emerge upon immediate novel exposure but are initially inaccurate. Over repeated laps, spatial maps gradually improve and stabilize after ~10 laps (early-phase), with later laps marking stability (late-phase). In the early phase, both CA3 inputs contribute to place field formation, but right CA3 inputs predominantly drive high-amplitude, reliable fields that support the development of accurate spatial representations. In the late phase, left CA3 inputs become more prominent, supporting the maintenance of stable and reliable fields. Complementary recordings of CA3 axonal activity within CA1R further reveal this dynamic hemispheric shift. Right CA3 axons exhibit elevated activity during the early phase, consistent with a role in supporting novel experience encoding. As learning continues and the environment becomes familiar, left CA3 axons show increased activity, aligning with their involvement in maintaining stable representations. These findings reveal a dynamic, experience-dependent shift in hemispheric contributions to spatial coding in CA1, moving from right-dominant during early learning to left-dominant during later stabilization. Taken together, these results suggest that CA3 inputs are functionally lateralized and that their roles in spatial representation evolve across phases of learning. In Chapter 1, I introduce the motivation for this work and review prior literature on hippocampal lateralization and familiarization in novel environments. In Chapter 2, I describe the computational methods I developed to detect and functionally analyze the activity of CA3 inputs with axonal resolution. In Chapter 3, I present evidence for hemispheric differences in the dynamics and influence of CA3 projections on CA1 spatial representations and how these differences switch between learning and post-learning phases of experiences. This work provides new insight into how dynamic lateralized hippocampal inputs support the evolution of spatial representations and lays the foundation for future work on experience-dependent memory processing.