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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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).
Ming, G.L. & Song, H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687–702 (2011).
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).
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).
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).
Sahay, A. et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472, 466–470 (2011).
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).
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).
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).
van Praag, H. et al. Functional neurogenesis in the adult hippocampus. Nature 415, 1030–1034 (2002).
Ge, S. et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439, 589–593 (2006).
Esposito, M.S. et al. Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J. Neurosci. 25, 10074–10086 (2005).
Schmidt-Hieber, C., Jonas, P. & Bischofberger, J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 429, 184–187 (2004).
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).
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).
Toni, N. et al. Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat. Neurosci. 11, 901–907 (2008).
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).
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).
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).
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).
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).
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).
Nakashiba, T. et al. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell 149, 188–201 (2012).
Zhang, F. et al. Multimodal fast optical interrogation of neural circuitry. Nature 446, 633–639 (2007).
Nagel, G. et al. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc. Natl. Acad. Sci. USA 100, 13940–13945 (2003).
Nicoll, R.A. & Schmitz, D. Synaptic plasticity at hippocampal mossy fibre synapses. Nat. Rev. Neurosci. 6, 863–876 (2005).
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).
Gunaydin, L.A. et al. Ultrafast optogenetic control. Nat. Neurosci. 13, 387–392 (2010).
Alle, H. & Geiger, J.R. Combined analog and action potential coding in hippocampal mossy fibers. Science 311, 1290–1293 (2006).
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).
Randall, A.D. & Tsien, R.W. Contrasting biophysical and pharmacological properties of T-type and R-type calcium channels. Neuropharmacology 36, 879–893 (1997).
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).
Chow, B.Y. et al. High-performance genetically targetable optical neural silencing by light-driven proton pumps. Nature 463, 98–102 (2010).
Morris, R.G., Garrud, P., Rawlins, J.N. & O'Keefe, J. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982).
Kim, J.J. & Fanselow, M.S. Modality-specific retrograde amnesia of fear. Science 256, 675–677 (1992).
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).
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).
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).
Kerr, A.M. & Jonas, P. The two sides of hippocampal mossy fiber plasticity. Neuron 57, 5–7 (2008).
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).
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).
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).
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).
The authors declare no competing financial interests.
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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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