Optical controlling reveals time-dependent roles for adult-born dentate granule cells


Accumulating evidence suggests that global depletion of adult hippocampal neurogenesis influences its function and that the timing of the depletion affects the deficits. However, the behavioral roles of adult-born neurons during their establishment of projections to CA3 pyramidal neurons remain largely unknown. We used a combination of retroviral and optogenetic approaches to birth date and reversibly control a group of adult-born neurons in adult mice. Adult-born neurons formed functional synapses on CA3 pyramidal neurons as early as 2 weeks after birth, and this projection to the CA3 area became stable by 4 weeks in age. Newborn neurons at this age were more plastic than neurons at other stages. Notably, we found that reversibly silencing this cohort of 4-week-old cells after training, but not cells of other ages, substantially disrupted retrieval of hippocampal memory. Our results identify a restricted time window for adult-born neurons essential in hippocampal memory retrieval.

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Figure 1: Adult-born neurons form functional synapses on CA3 pyramidal neurons.
Figure 2: Adult-born neurons at 4 weeks of age show enhanced plasticity at output synapses.
Figure 3: Reversibly silencing 4-week-old adult-born neurons impairs hippocampal memory retrieval.
Figure 4: Temporary silencing of 4-week-old newborn neurons impairs expression of a fear conditioning memory.
Figure 5: Behavioral roles of adult-born DGCs are sensitive to their age.
Figure 6: Task-switching experiments showing that adult-born DGCs at 4 wpi are important for memory retrieval.


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We thank J. Bischofberger, G. Matthews, L. Role and H. Song for their critical comments, and Q. Xiong and J. Tucciarone for technical support. We thank the members of F. Gage's laboratory for sharing their behavioral protocols. This work was supported by US National Institutes of Health (NS065915), American Heart Association (0930067N), Feldstein Medical Foundation and State University of New York Research Excellence in Academic Health grants to S.G. and Canadian Institutes of Health Research grants to P.W.F. (MOP86762) and S.A.J. (MOP74650).

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Y.G. conducted all of the electrophysiological, immunohistochemical and confocal imaging analyses. Y.G. and M.A.-C. performed all of the behavioral analyses. J.W. engineered retroviral constructs and Y.G. produced retrovirus. S.R.J. helped with some initial manuscript preparation. S.G. and P.W.F. supervised the project. S.G., P.W.F., S.A.J., Y.G. and M.A.-C. wrote the manuscript. All of the authors read and discussed the manuscript.

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Correspondence to Paul W Frankland or Shaoyu Ge.

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Gu, Y., Arruda-Carvalho, M., Wang, J. et al. Optical controlling reveals time-dependent roles for adult-born dentate granule cells. Nat Neurosci 15, 1700–1706 (2012). https://doi.org/10.1038/nn.3260

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