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

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Kempermann, G., Gast, D. & Gage, F.H. Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann. Neurol. 52, 135–143 (2002).

    Article  Google Scholar 

  2. 2

    Ming, G.L. & Song, H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687–702 (2011).

    CAS  Article  Google Scholar 

  3. 3

    Cameron, H.A. & McKay, R.D. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J. Comp. Neurol. 435, 406–417 (2001).

    CAS  Article  Google Scholar 

  4. 4

    Kim, W.R., Christian, K., Ming, G.L. & Song, H. Time-dependent involvement of adult-born dentate granule cells in behavior. Behav. Brain Res. 227, 470–479 (2011).

    Article  Google Scholar 

  5. 5

    Aimone, J.B., Deng, W. & Gage, F.H. Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70, 589–596 (2011).

    CAS  Article  Google Scholar 

  6. 6

    Sahay, A. et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472, 466–470 (2011).

    CAS  Article  Google Scholar 

  7. 7

    Arruda-Carvalho, M., Sakaguchi, M., Akers, K.G., Josselyn, S.A. & Frankland, P.W. Post-training ablation of adult-generated neurons degrades previously acquired memories. J. Neurosci. 31, 15113–15127 (2011).

    CAS  Article  Google Scholar 

  8. 8

    Drew, M.R., Denny, C.A. & Hen, R. Arrest of adult hippocampal neurogenesis in mice impairs single- but not multiple-trial contextual fear conditioning. Behav. Neurosci. 124, 446–454 (2010).

    Article  Google Scholar 

  9. 9

    Snyder, J.S., Soumier, A., Brewer, M., Pickel, J. & Cameron, H.A. Adult hippocampal neurogenesis buffers stress responses and depressive behavior. Nature 476, 458–461 (2011).

    CAS  Article  Google Scholar 

  10. 10

    van Praag, H. et al. Functional neurogenesis in the adult hippocampus. Nature 415, 1030–1034 (2002).

    CAS  Article  Google Scholar 

  11. 11

    Ge, S. et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439, 589–593 (2006).

    CAS  Article  Google Scholar 

  12. 12

    Esposito, M.S. et al. Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J. Neurosci. 25, 10074–10086 (2005).

    CAS  Article  Google Scholar 

  13. 13

    Schmidt-Hieber, C., Jonas, P. & Bischofberger, J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 429, 184–187 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Overstreet Wadiche, L., Bromberg, D.A., Bensen, A.L. & Westbrook, G.L. GABAergic signaling to newborn neurons in dentate gyrus. J Neurophysiol. 94, 4528–4532 (2005).

    Article  Google Scholar 

  15. 15

    Faulkner, R.L. et al. Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain. Proc. Natl. Acad. Sci. USA 105, 14157–14162 (2008).

    CAS  Article  Google Scholar 

  16. 16

    Toni, N. et al. Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat. Neurosci. 11, 901–907 (2008).

    CAS  Article  Google Scholar 

  17. 17

    Zhao, C., Teng, E.M., Summers, R.G. Jr., Ming, G.L. & Gage, F.H. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J. Neurosci. 26, 3–11 (2006).

    CAS  Article  Google Scholar 

  18. 18

    Hastings, N.B., Seth, M.I., Tanapat, P., Rydel, T.A. & Gould, E. Granule neurons generated during development extend divergent axon collaterals to hippocampal area CA3. J. Comp. Neurol. 452, 324–333 (2002).

    Article  Google Scholar 

  19. 19

    Ge, S., Yang, C.H., Hsu, K.S., Ming, G.L. & Song, H. A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron 54, 559–566 (2007).

    CAS  Article  Google Scholar 

  20. 20

    Marín-Burgin, A., Mongiat, L.A., Pardi, M.B. & Schinder, A.F. Unique processing during a period of high excitation/inhibition balance in adult-born neurons. Science 335, 1238–1242 (2012).

    Article  Google Scholar 

  21. 21

    Kee, N., Teixeira, C.M., Wang, A.H. & Frankland, P.W. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat. Neurosci. 10, 355–362 (2007).

    CAS  Article  Google Scholar 

  22. 22

    Tashiro, A., Makino, H. & Gage, F.H. Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J. Neurosci. 27, 3252–3259 (2007).

    CAS  Article  Google Scholar 

  23. 23

    Nakashiba, T. et al. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell 149, 188–201 (2012).

    CAS  Article  Google Scholar 

  24. 24

    Zhang, F. et al. Multimodal fast optical interrogation of neural circuitry. Nature 446, 633–639 (2007).

    CAS  Article  Google Scholar 

  25. 25

    Nagel, G. et al. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc. Natl. Acad. Sci. USA 100, 13940–13945 (2003).

    CAS  Article  Google Scholar 

  26. 26

    Nicoll, R.A. & Schmitz, D. Synaptic plasticity at hippocampal mossy fibre synapses. Nat. Rev. Neurosci. 6, 863–876 (2005).

    CAS  Article  Google Scholar 

  27. 27

    Lin, J.Y., Lin, M.Z., Steinbach, P. & Tsien, R.Y. Characterization of engineered channelrhodopsin variants with improved properties and kinetics. Biophys. J. 96, 1803–1814 (2009).

    CAS  Article  Google Scholar 

  28. 28

    Gunaydin, L.A. et al. Ultrafast optogenetic control. Nat. Neurosci. 13, 387–392 (2010).

    CAS  Article  Google Scholar 

  29. 29

    Alle, H. & Geiger, J.R. Combined analog and action potential coding in hippocampal mossy fibers. Science 311, 1290–1293 (2006).

    CAS  Article  Google Scholar 

  30. 30

    Yoshimura, Y. et al. Involvement of T-type Ca2+ channels in the potentiation of synaptic and visual responses during the critical period in rat visual cortex. Eur. J. Neurosci. 28, 730–743 (2008).

    Article  Google Scholar 

  31. 31

    Randall, A.D. & Tsien, R.W. Contrasting biophysical and pharmacological properties of T-type and R-type calcium channels. Neuropharmacology 36, 879–893 (1997).

    CAS  Article  Google Scholar 

  32. 32

    Snyder, J.S., Kee, N. & Wojtowicz, J.M. Effects of adult neurogenesis on synaptic plasticity in the rat dentate gyrus. J. Neurophysiol. 85, 2423–2431 (2001).

    CAS  Article  Google Scholar 

  33. 33

    Chow, B.Y. et al. High-performance genetically targetable optical neural silencing by light-driven proton pumps. Nature 463, 98–102 (2010).

    CAS  Article  Google Scholar 

  34. 34

    Morris, R.G., Garrud, P., Rawlins, J.N. & O'Keefe, J. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982).

    CAS  Article  Google Scholar 

  35. 35

    Kim, J.J. & Fanselow, M.S. Modality-specific retrograde amnesia of fear. Science 256, 675–677 (1992).

    CAS  Article  Google Scholar 

  36. 36

    Deng, W., Aimone, J.B. & Gage, F.H. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci. 11, 339–350 (2010).

    CAS  Article  Google Scholar 

  37. 37

    Bezprozvanny, I. & Tsien, R.W. Voltage-dependent blockade of diverse types of voltage-gated Ca2+ channels expressed in Xenopus oocytes by the Ca2+ channel antagonist mibefradil (Ro 40–5967). Mol. Pharmacol. 48, 540–549 (1995).

    CAS  PubMed  Google Scholar 

  38. 38

    Bergquist, F. & Nissbrandt, H. Influence of R-type (Cav2.3) and T-type (Cav3.1–3.3) antagonists on nigral somatodendritic dopamine release measured by microdialysis. Neuroscience 120, 757–764 (2003).

    CAS  Article  Google Scholar 

  39. 39

    Kerr, A.M. & Jonas, P. The two sides of hippocampal mossy fiber plasticity. Neuron 57, 5–7 (2008).

    CAS  Article  Google Scholar 

  40. 40

    Ge, S., Sailor, K.A., Ming, G.L. & Song, H. Synaptic integration and plasticity of new neurons in the adult hippocampus. J. Physiol. (Lond.) 586, 3759–3765 (2008).

    CAS  Article  Google Scholar 

  41. 41

    Sahay, A., Wilson, D.A. & Hen, R. Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70, 582–588 (2011).

    CAS  Article  Google Scholar 

  42. 42

    Teixeira, C.M., Pomedli, S.R., Maei, H.R., Kee, N. & Frankland, P.W. Involvement of the anterior cingulate cortex in the expression of remote spatial memory. J. Neurosci. 26, 7555–7564 (2006).

    Article  Google Scholar 

Download references

Acknowledgements

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).

Author information

Affiliations

Authors

Contributions

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.

Corresponding authors

Correspondence to Paul W Frankland or Shaoyu Ge.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 and Supplementary Table 1 (PDF 3052 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading