Restoring the chemical connectome: Mechanisms of peptidergic volume transmission failure in the aging brain
Dr. Sun’s lab investigates why memory declines with age even when the neurons that store memories remain alive. The team proposes that aging creates “diffusive isolation”, in which chemical messages needed for memory recall become too weak or obstructed to reach their targets. Using mature adult and aged mice, they will label neurons involved in long-term fear memories and map the neuropeptides, receptors, support cells, and extracellular barriers surrounding them. Advanced spatial transcriptomics and imaging will reveal whether dense perineuronal nets, lipid-filled microglia, and impaired glutamate clearance create local “diffusion shadows” that silence otherwise intact memory circuits. The researchers will also develop a Signaling Potential Index to quantify each memory cell’s capacity to send and receive chemical signals. By distinguishing reversible communication failure from permanent neuronal loss, Dr. Sun’s work may identify new strategies to preserve or restore memory by improving chemical signaling and the brain’s extracellular environment during aging.
