PROJECT SUMMARY When a new route is learned, what happens in the hippocampus? How fast do these changes occur? Are all hippocampal subfields involved in memory encoding? Decades of research have shown that the hippocampus is necessary for spatial memory. However, the neural foundation of spatial learning and memory and its link to hippocampal architecture remain major study topics. According to animal research, learning alters the functional, chemical, and structural properties of hippocampal cells. Unfortunately, we know considerably less about humans' microstructural basis of learning and memory. An accurate assessment of learning-induced hippocampal neuroplasticity —the ability of the hippocampus to modify its function and structure in response to information—would significantly enhance human memory research. For decades, we have lacked the noninvasive technology necessary to evaluate neuroplasticity with the same biological precision as animals. Diffusion Magnetic Resonance imaging (dMRI) holds the most promise among non-invasive technology to reveal the microstructural substrate of learning and memory in humans. Initial studies in healthy humans have shown that dMRI can be sensitive to changes during learning. But technological limitations in gradient technology have diminished the expectations of what the diffusion MRI signal can reveal in term of specificity to the different cellular processes that are thought to be involved in neuroplasticity. This K99/R00 proposal takes advantage of newly available ultra-high gradient strength dMRI at the MGH Martinos Center to create a noninvasive marker of learning-induced neuroplasticity in the human hippocampus subfields during human navigation with a high level of biological specificity. I will combine behavioral testing, high-resolution functional MRI, state-of-the-art multi-compartment gray matter dMRI models, and ultra-high gradient strength (500 mT/m) high-resolution dMRI data acquired with our center's BRAIN Initiative-funded Connectome 2.0 MRI scanner to achieve a unified view of the structural-functional response of the human hippocampus in spatial memory. The in vivo neuroplasticity marker developed in this proposal might be used as a diagnostic tool in Alzheimer's disease to detect early indications of pathological hippocampus remodeling or to assess the efficacy of deep brain stimulation (DBS) techniques for memory impairment repair. The project makes use of the vast expertise of my mentors and collaborators in cognitive neuroscience, high-gradient strength dMRI, hippocampal anatomy, and high-resolution functional MRI. The candidate aims to get the necessary skills to begin an independent long-term research program focused on developing the next generation of in vivo functional and diffusion MRI technologies to connect cellular-specific information with cognition and brain functioning. The training component of the K99/R00 award will enrich the candidate's prior strong expertise in mathematical modeling, diffusion image acquisition, and reconstruction, with complementary skills in behavioral testing, fMRI analysis, hippocampus anatomy, and the validation of dMRI biomarkers of brain microstructure.

PROJECT NARRATIVE Studies of brain neuroplasticity during learning and memory have been so far restricted to animal research. A significant reason has been the lack of non-invasive imaging technology to probe neuroplasticity with high biological specificity. This project aims to develop and validate a non-invasive marker of neuroplasticity during learning in the human hippocampus subfields of living humans with the latest ultra-high gradient strength diffusion Magnetic Resonance Imaging technology. The marker can be used to detect early signs of pathological remodeling of the hippocampus in Alzheimer’s disease or assess the efficacy of invasive tools for memory function repair.