Dissecting the synaptic and molecular mechanisms of cell-type-specific memory computation in hippocampal CA3

About This Grant

Project Summary/Abstract The ability to flexibly learn from experience and recall past events depends on the brain’s capacity to adjust synaptic strength in response to activity. This form of synaptic plasticity is not uniformly expressed across a neuron’s dendritic arbor, but instead follows highly compartmentalized rules that enable distinct input streams to be integrated with specificity. Yet, how such compartment-specific plasticity mechanisms are coordinated within and across neurons – and how they translate into meaningful circuit-level output during learning – remains poorly understood. The hippocampal CA3 network, a central hub for memory encoding and retrieval, contains two morphologically and functionally distinct pyramidal neuron subtypes. TE⁺ cells, with their thorny excrescences (TEs), receive dense mossy fiber input from dentate gyrus (DG), whereas TE⁻ cells lack these structures and receive little or no DG drive. How such input- and subtype-specific circuitry implements memory remains unknown. This work integrates multi-scale in vivo imaging, genetic perturbations, transcriptomics, and computational modeling to link synaptic architecture and gene expression to memory computation in heterogeneous CA3 circuits. In the K99 phase, I will examine the synaptic mechanisms of input-specific plasticity using in vivo two-photon glutamate and calcium imaging to monitor compartment-specific dynamics at individual spines during learning (Aim 1.1). Direct in vivo measurement of synaptic weights will guide the development of recurrent neural network models incorporating experimentally derived integration rules (Aim 1.2). Building on these synaptic principles, I will next examine how input-specific mechanisms scale to the cellular and population levels by assessing how DG input drives subtype-specific coding in CA3 using in vivo volumetric calcium imaging (Aim 2.1) and causal genetic manipulation (Aim 2.2). In the R00 phase, I will develop a novel “morpho-tagging” approach to isolate TE⁺ and TE⁻ neurons for transcriptomic profiling (Aim 3.1), followed by in vivo gene perturbation to identify molecular mechanisms that support subtype-specific synaptic plasticity (Aim 3.2). The findings will deepen our understanding of the synaptic, cellular, and molecular mechanisms underlying learning and memory, and may inform strategies to address cognitive dysfunction. I will receive extensive training in experimental and computational methods, particularly in advanced imaging, transcriptomics, and modeling, along with structured career development in scientific writing, leadership, and project management from my mentors. I have also assembled a team of expert collaborators who will provide specialized guidance across all aims. My integrated mentorship team and rich institutional environment will ensure my successful transition to independence and the launch of a multidisciplinary neuroscience program.