Posttraining ablation of adult-generated neurons degrades previously acquired memories.
New neurons are continuously generated in the subgranular zone of the adult hippocampus and, once sufficiently mature, are thought to integrate into hippocampal memory circuits. However, whether they play an essential role in subsequent memory expression is not known. Previous studies have shown that suppression of adult neurogenesis often (but not always) impairs subsequent hippocampus-dependent learning (i.e., produces anterograde effects). A major challenge for these studies is that these new neurons represent only a small subpopulation of all dentate granule cells, and so there is large potential for either partial or complete compensation by granule cells generated earlier on during development. A potentially more powerful approach to investigate this question would be to ablate adult-generated neurons after they have already become part of a memory trace (i.e., retrograde effects). Here we developed a diphtheria toxin-based strategy in mice that allowed us to selectively ablate a population of predominantly mature, adult-generated neurons either before or after learning, without affecting ongoing neurogenesis. Removal of these neurons before learning did not prevent the formation of new contextual fear or water maze memories. In contrast, removal of an equivalent population after learning degraded existing contextual fear and water maze memories, without affecting nonhippocampal memory. Ablation of these adult-generated neurons even 1 month after learning produced equivalent memory degradation in the water maze. These retrograde effects suggest that adult-generated neurons form a critical and enduring component of hippocampal memory traces.
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.
Maithe
M
Arruda-Carvalho
Masanori
M
Sakaguchi
Katherine G
KG
Akers
Sheena A
SA
Josselyn
Paul W
PW
Frankland
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects; D001973:Bromodeoxyuridine; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects; D018891:Dentate Gyrus / Q000166:cytology; D004167:Diphtheria Toxin / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects / Q000502:physiology; D000089622:Doublecortin Domain Proteins; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005239:Fear / Q000187:drug effects; D000882:Haplorhini; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007381:Intermediate Filament Proteins / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D026901:Membrane Transport Proteins / Q000235:genetics; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009281:Naphthalenes; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D010082:Oxepins; D013028:Space Perception / Q000187:drug effects / Q000502:physiology; D013629:Tamoxifen / Q000494:pharmacology; D013649:Taste / Q000187:drug effects / Q000235:genetics
C461941:1-phenyl-1,4-epoxy-1H,4H-naphtho(1,8-de)(1,2)dioxepin; C491049:Aif1 protein, mouse; D018931:Antineoplastic Agents, Hormonal; D002135:Calcium-Binding Proteins; D004167:Diphtheria Toxin; D000089622:Doublecortin Domain Proteins; D047628:Estrogen Receptor alpha; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007381:Intermediate Filament Proteins; D026901:Membrane Transport Proteins; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D009479:Neuropeptides; D010082:Oxepins; D013629:Tamoxifen; D001973:Bromodeoxyuridine