Intrinsic hippocampal circuit dynamics underlying episodic memory

About This Grant

PROJECT SUMMARY The hippocampus is necessary for episodic memory. It is believed that spatial episodic memory is supported by ensembles of hippocampal place cells, with each cell responding selectively to specific spatial locations. Recently, we and others have demonstrated that the responses of hippocampal place cells are not stable but rather drift over time, raising questions about how exactly these drifting representations can support stable and specific memories and whether this drift can be targeted at the circuit level to influence memory function. I aim to address these questions by employing a novel approach that combines ultra-high-density recordings, circuit modeling, and cell-type-specific optogenetic perturbations in behaving mice. In Aim 1, I will perform ultra-high-density recordings in the dorsal hippocampal CA1 area while mice perform a spatial memory task across different mazes to test two competing hypotheses regarding hippocampal drift: whether the dynamic ensembles perform meaningful computations through temporal evolution or whether the neural instability is merely noise. This will be enabled by a novel analytical method to identify latent structures of population dynamics. In Aim 2, I will use theoretical modeling to predict potential circuit mechanisms underlying hippocampal drift, and I will further identify the circuit mechanisms by causally testing these predictions with cell- type-specific optogenetic manipulations. Next, I will evaluate the causal role of hippocampal drift in memory- guided behavior using the identified circuit-specific perturbation protocol. In Aim 3, I will explore the nature and role of dorsal-ventral hippocampal interactions during representational drift in flexible memory-guided decision- making. To achieve this, I will perform dual-site recordings in both regions with brain-region-specific optogenetic manipulation while mice learn to flexibly adjust their choice strategies. By linking circuit connectivity, neural dynamics, and behavior, this proposal will provide a new framework for understanding hippocampal computations through dynamic cell ensembles for episodic memory, reveal the circuit mechanisms underlying representational drift, and establish a causal link between this drift and memory-guided behavior. Moreover, these Aims will deepen our understanding of the neural mechanisms associated with various diseases and disorders related to episodic memory impairment, including epilepsy, Alzheimer’s, and schizophrenia. I will achieve these aims with the guidance of an exceptional mentoring team led by Antonio Fernandez- Ruiz and Alex Kwan, and in collaboration with Azahara Oliva and Christiane Linster. During my mentored phase, I will gain expertise in theoretical modeling, cell-type-specific optogenetics, and ultra-high-density recording in deep brain structures, such as the ventral hippocampus. These new technical skills I will acquire will be crucial for the proposed experiments and for laying the groundwork for my independent laboratory's research program on dorsal-ventral hippocampal interactions. Additionally, the complementary skills I will acquire through training in writing, project management, and leadership will further propel me into launching my independent career.