Immature doublecortin-positive hippocampal neurons are important for learning but not for remembering

• Published in: The Journal of neuroscience Vol. 33; no. 15; pp. 6603 - 6613
• Main Authors: Vukovic, Jana, Borlikova, Gilyana G, Ruitenberg, Marc J, Robinson, Gregory J, Sullivan, Robert K P, Walker, Tara L, Bartlett, Perry F
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 10-04-2013
• Subjects: Animals; Avoidance Learning - physiology; Cells, Cultured; Cerebral Cortex; Cytoskeletal Proteins - biosynthesis; Gene Knock-In Techniques - methods; Gene Knock-In Techniques - psychology; Heparin-binding EGF-like Growth Factor; Hippocampus - physiology; Intercellular Signaling Peptides and Proteins - genetics; Male; Memory - physiology; Memory, Long-Term - physiology; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - physiology; Models, Animal; Nerve Degeneration - genetics; Nerve Tissue Proteins - biosynthesis; Neural Stem Cells - physiology; Neurogenesis - physiology; Neuropeptides - genetics; Neuropeptides - physiology; Reversal Learning - physiology; Space Perception - physiology
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.3064-12.2013

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.