title: Immature doublecortin-positive hippocampal neurons are important for learning but not for remembering.
abstract: It is now widely accepted that hippocampal neurogenesis underpins critical cognitive functions, such as learning and memory. To assess the behavioral importance of adult-born neurons, we developed a novel knock-in mouse model that allowed us to specifically and reversibly ablate hippocampal neurons at an immature stage. In these mice, the diphtheria toxin receptor (DTR) is expressed under control of the doublecortin (DCX) promoter, which allows for specific ablation of immature DCX-expressing neurons after administration of diphtheria toxin while leaving the neural precursor pool intact. Using a spatially challenging behavioral test (a modified version of the active place avoidance test), we present direct evidence that immature DCX-expressing neurons are required for successful acquisition of spatial learning, as well as reversal learning, but are not necessary for the retrieval of stored long-term memories. Importantly, the observed learning deficits were rescued as newly generated immature neurons repopulated the granule cell layer upon termination of the toxin treatment. Repeat (or cyclic) depletion of immature neurons reinstated behavioral deficits if the mice were challenged with a novel task. Together, these findings highlight the potential of stimulating neurogenesis as a means to enhance learning.
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Jana
authors.initials: J
authors.lastname: Vukovic
authors.forename: Gilyana G
authors.initials: GG
authors.lastname: Borlikova
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Ruitenberg
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Robinson
authors.forename: Robert K P
authors.initials: RK
authors.lastname: Sullivan
authors.forename: Tara L
authors.initials: TL
authors.lastname: Walker
authors.forename: Perry F
authors.initials: PF
authors.lastname: Bartlett
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D055879:Gene Knock-In Techniques / Q000379:methods / Q000523:psychology*; D066257:Heparin-binding EGF-like Growth Factor; D006624:Hippocampus / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008568:Memory / Q000502:physiology*; D057567:Memory, Long-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D023421:Models, Animal; D009410:Nerve Degeneration / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D058953:Neural Stem Cells / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D012193:Reversal Learning / Q000502:physiology*; D013028:Space Perception / Q000502:physiology
chemical_list: D003598:Cytoskeletal Proteins; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C092069:activity regulated cytoskeletal-associated protein