Aging-dependent changes in the distribution, stability, and transcriptional signature of engram cells

• Autores: Miguel Fuentes Ramos
• Directores de la Tesis: Ángel Barco Guerrero (dir. tes.)
• Lectura: En la Universidad Miguel Hernández de Elche ( España ) en 2025
• Idioma: español
• Tribunal Calificador de la Tesis: Rafael Fernández Chacón (presid.), Felix Leroy (secret.), Mara Dierssen Sotos (voc.)
• Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad Miguel Hernández de Elche
• Materias:
  • Ciencias de la vida
    • Biología celular
    • Biología molecular
  • Psicología
    • Psicología experimental
      • Procesos de la memoria
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• Resumen

  • Both classical activity mapping based on the induction of activity-regulated genes and novel genetic methods to label and control the activity of neurons indicate that memories are deposited in discrete neuronal ensembles, or engrams, within the hippocampus and other brain regions involved in memory formation. However, the creation of a brain-wide map for engram formation and stability has proven to be a challenging endeavor that has been only partially tackled. Furthermore, we know that aging reduces the ability to maintain or retrieve such memories, but it remains unclear how aging affects engram formation, stability, and the molecular changes that enable their retrieval. In this study, we used the Targeted Recombination in Active Populations v2 (TRAP2) mouse strain to permanently label neurons activated within specific temporal windows. By combining this with a nuclear envelope labeling reporter, we were able to use iDISCO to automatically quantify cells involved in a contextual fear memory with unprecedented precision. At the same time, this system allowed us to isolate cells activated during different memory phases using fluorescence-activated nuclear sorting (FANS). Using advanced analytical methods, we studied the size, distribution, and stability of engrams in 378 brain regions. In addition, using various sequencing techniques to analyze transcriptomic changes, we were able to identify transcriptional signatures associated with memory encoding and retrieval. By conducting these experiments in both young and aged mice, we uncovered key age-dependent differences in engrams biology. Our findings reveal new dynamics in engram activity, highlight previously unrecognized brain regions involved in fear memory, and expose important age-related changes in engram activation that may underlie cognitive decline.