Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A role for adult TLX-positive neural stem cells in learning and behaviour

Abstract

Neurogenesis persists in the adult brain and can be regulated by a plethora of external stimuli, such as learning, memory, exercise, environment and stress1. Although newly generated neurons are able to migrate and preferentially incorporate into the neural network2,3,4,5, how these cells are molecularly regulated and whether they are required for any normal brain function are unresolved questions6. The adult neural stem cell pool is composed of orphan nuclear receptor TLX-positive cells7. Here, using genetic approaches in mice, we demonstrate that TLX (also called NR2E1) regulates adult neural stem cell proliferation in a cell-autonomous manner by controlling a defined genetic network implicated in cell proliferation and growth. Consequently, specific removal of TLX from the adult mouse brain through inducible recombination results in a significant reduction of stem cell proliferation and a marked decrement in spatial learning. In contrast, the resulting suppression of adult neurogenesis does not affect contextual fear conditioning, locomotion or diurnal rhythmic activities, indicating a more selective contribution of newly generated neurons to specific cognitive functions.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cell-autonomous requirement of TLX for adult NSC proliferation.
Figure 2: TLX-regulated genetic programme in adult NSCs.
Figure 3: Deficient NSC proliferation and neurogenesis in the adult hippocampus after inducible deletion of Tlx.
Figure 4: Normal contextual fear conditioning but impaired spatial learning and memory for mice with defective adult neurogenesis.

References

  1. Prickaerts, J., Koopmans, G., Blokland, A. & Scheepens, A. Learning and adult neurogenesis: survival with or without proliferation? Neurobiol. Learn. Mem. 81, 1–11 (2004)

    Article  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  3. Wang, S., Scott, B. W. & Wojtowicz, J. M. Heterogenous properties of dentate granule neurons in the adult rat. J. Neurobiol. 42, 248–257 (2000)

    Article  CAS  Google Scholar 

  4. 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. Nature Neurosci. 10, 355–362 (2007)

    Article  CAS  Google Scholar 

  5. 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)

    Article  CAS  Google Scholar 

  6. Kempermann, G., Wiskott, L. & Gage, F. H. Functional significance of adult neurogenesis. Curr. Opin. Neurobiol. 14, 186–191 (2004)

    Article  CAS  Google Scholar 

  7. Shi, Y. et al. Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature 427, 78–83 (2004)

    Article  ADS  CAS  Google Scholar 

  8. Monaghan, A. P. et al. Defective limbic system in mice lacking the tailless gene. Nature 390, 515–517 (1997)

    Article  ADS  CAS  Google Scholar 

  9. Zhang, C. L., Zou, Y., Yu, R. T., Gage, F. H. & Evans, R. M. Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1. Genes Dev. 20, 1308–1320 (2006)

    Article  CAS  Google Scholar 

  10. Hayashi, S. & McMahon, A. P. Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev. Biol. 244, 305–318 (2002)

    Article  CAS  Google Scholar 

  11. Monaghan, A. P., Grau, E., Bock, D. & Schutz, G. The mouse homolog of the orphan nuclear receptor tailless is expressed in the developing forebrain. Development 121, 839–853 (1995)

    CAS  PubMed  Google Scholar 

  12. Yu, R. T., McKeown, M., Evans, R. M. & Umesono, K. Relationship between Drosophila gap gene tailless and a vertebrate nuclear receptor Tlx. Nature 370, 375–379 (1994)

    Article  ADS  CAS  Google Scholar 

  13. Forni, P. E. et al. High levels of Cre expression in neuronal progenitors cause defects in brain development leading to microencephaly and hydrocephaly. J. Neurosci. 26, 9593–9602 (2006)

    Article  CAS  Google Scholar 

  14. van Praag, H., Kempermann, G. & Gage, F. H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neurosci. 2, 266–270 (1999)

    Article  CAS  Google Scholar 

  15. Saxe, M. D. et al. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc. Natl Acad. Sci. USA 103, 17501–17506 (2006)

    Article  ADS  CAS  Google Scholar 

  16. Winocur, G., Wojtowicz, J. M., Sekeres, M., Snyder, J. S. & Wang, S. Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus 16, 296–304 (2006)

    Article  Google Scholar 

  17. Tronche, F. et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nature Genet. 23, 99–103 (1999)

    Article  CAS  Google Scholar 

  18. Roy, K., Thiels, E. & Monaghan, A. P. Loss of the tailless gene affects forebrain development and emotional behavior. Physiol. Behav. 77, 595–600 (2002)

    Article  CAS  Google Scholar 

  19. Wiltgen, B. J., Sanders, M. J., Anagnostaras, S. G., Sage, J. R. & Fanselow, M. S. Context fear learning in the absence of the hippocampus. J. Neurosci. 26, 5484–5491 (2006)

    Article  CAS  Google Scholar 

  20. Cho, Y. H., Friedman, E. & Silva, A. J. Ibotenate lesions of the hippocampus impair spatial learning but not contextual fear conditioning in mice. Behav. Brain Res. 98, 77–87 (1999)

    Article  CAS  Google Scholar 

  21. Frankland, P. W., Cestari, V., Filipkowski, R. K., McDonald, R. J. & Silva, A. J. The dorsal hippocampus is essential for context discrimination but not for contextual conditioning. Behav. Neurosci. 112, 863–874 (1998)

    Article  CAS  Google Scholar 

  22. Monje, M. L., Toda, H. & Palmer, T. D. Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760–1765 (2003)

    Article  ADS  CAS  Google Scholar 

  23. Bush, T. G. et al. Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell 93, 189–201 (1998)

    Article  CAS  Google Scholar 

  24. Minichiello, L. et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24, 401–414 (1999)

    Article  CAS  Google Scholar 

  25. Shors, T. J., Townsend, D. A., Zhao, M., Kozorovitskiy, Y. & Gould, E. Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus 12, 578–584 (2002)

    Article  Google Scholar 

  26. Snyder, J. S., Hong, N. S., McDonald, R. J. & Wojtowicz, J. M. A role for adult neurogenesis in spatial long-term memory. Neuroscience 130, 843–852 (2005)

    Article  CAS  Google Scholar 

  27. Whishaw, I. Q. & Tomie, J. A. Of mice and mazes: similarities between mice and rats on dry land but not water mazes. Physiol. Behav. 60, 1191–1197 (1996)

    Article  CAS  Google Scholar 

  28. Raber, J. et al. Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat. Res. 162, 39–47 (2004)

    Article  ADS  CAS  Google Scholar 

  29. Meshi, D. et al. Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nature Neurosci. 9, 729–731 (2006)

    Article  CAS  Google Scholar 

  30. van Praag, H., Kempermann, G. & Gage, F. H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neurosci. 2, 266–270 (1999)

    Article  CAS  Google Scholar 

  31. Shi, Y. et al. Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature 427, 78–83 (2004)

    Article  ADS  CAS  Google Scholar 

  32. Zhang, C. L., Zou, Y., Yu, R. T., Gage, F. H. & Evans, R. M. Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1. Genes Dev. 20, 1308–1320 (2006)

    Article  CAS  Google Scholar 

  33. van Praag, H., Shubert, T., Zhao, C. & Gage, F. H. Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. 25, 8680–8685 (2005)

    Article  CAS  Google Scholar 

  34. Saxe, M. D. et al. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc. Natl Acad. Sci. USA 103, 17501–17506 (2006)

    Article  ADS  CAS  Google Scholar 

  35. Meshi, D. et al. Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nature Neurosci. 9, 729–731 (2006)

    Article  CAS  Google Scholar 

  36. Crawley, J. N. What’s Wrong with My Mouse?: Behavioral Phenotyping of Transgenic and Knockout Mice (Wiley-Liss, New York, 2000)

    Google Scholar 

Download references

Acknowledgements

We thank Y. Shi, H. Suh, M. Downes, M. Nelson, H. Juguilon, J. Havstad, B. Miller, R. Summers and M. Lucero for technical help; M. Tallquist and K. Lee for providing materials; R. Yu and M. Gage for editing; and S. Ganley and E. Ong for administrative assistance. C-.L.Z. is a Howard Hughes Medical Institute (HHMI) Fellow of the Life Sciences Research Foundation. R.M.E. is an Investigator of the HHMI and March of Dimes Chair in Molecular and Developmental Biology. F.H.G. is the Adler Professor of Age-Related Neurodegenerative Diseases. This work was funded through the support of the HHMI, Nuclear Receptor Signalling Atlas (NURSA), NICHD, NIGMS, the Lookout Fund, the McDonnell Foundation, the Picower Foundation and the NIH. R.M.E. acknowledges a grant from Merck.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Fred H. Gage or Ronald M. Evans.

Supplementary information

Supplementary Information 1

The file contains Supplementary Figures S1-S16 with Legends. (PDF 5017 kb)

Supplementary Information 2

The file contains Supplementary Data 1 analysing globally regulated genes 36 h after inducible deletion of TLX (NR2E1) in cultured adult neural stem cells. (XLS 136 kb)

Supplementary Information 3

The file contains Supplementary Data 2 analysing globally regulated genes 60 h after inducible deletion of TLX (NR2E1) in cultured adult neural stem cells. (XLS 190 kb)

Supplementary Information 4

The file contains Supplementary Data 3 analysing. genes showing changes both at 36 h and 60 h after inducible deletion of TLX (NR2E1) in cultured adult neural stem cells. (XLS 78 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, CL., Zou, Y., He, W. et al. A role for adult TLX-positive neural stem cells in learning and behaviour. Nature 451, 1004–1007 (2008). https://doi.org/10.1038/nature06562

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06562

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing