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.

  • Article
  • Published:

Male pheromone–stimulated neurogenesis in the adult female brain: possible role in mating behavior.

Nature Neuroscience volume 10, pages 1003–1011 (2007)Cite this article

This article has been updated

Abstract

The regulation of female reproductive behaviors may involve memories of male pheromone signatures, formed in part by neural circuitry involving the olfactory bulb and hippocampus. These neural structures are the principal sites of adult neurogenesis; however, previous studies point to their independent regulation by sensory and physiological stimuli. Here we report that the pheromones of dominant (but not subordinate) males stimulate neuronal production in both the olfactory bulb and hippocampus of female mice, which are independently mediated by prolactin and luteinizing hormone, respectively. Neurogenesis induced by dominant-male pheromones correlates with a female preference for dominant males over subordinate males, whereas blocking neurogenesis with the mitotic inhibitor cytosine arabinoside eliminated this preference. These results suggest that male pheromones are involved in regulating neurogenesis in both the olfactory bulb and hippocampus, which may be important for female reproductive success.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Male pheromones simultaneously enhance cell proliferation in the SVZ and dentate gyrus.
Figure 2: Male pheromones simultaneously increase neurogenesis in the olfactory bulb and dentate gyrus.
Figure 3: PRLR is expressed in the SVZ and choroid plexus, whereas LHR is expressed in both the SVZ and dentate gyrus of female mice.
Figure 4: LH and PRL independently mediate male pheromone–induced cell proliferation in the DG and SVZ, respectively.
Figure 5: Neurogenesis in the adult female brain is required for female mate preference.

Similar content being viewed by others

Change history

  • 12 February 2008

    The Supplementary Methods section to this article was not posted at the time the paper was published. The error has been corrected.

References

  1. Bakker, J. Sexual differentiation of the neuroendocrine mechanisms regulating mate recognition in mammals. J. Neuroendocrinol. 15, 615–621 (2003).

    Article  CAS  Google Scholar 

  2. Brennan, P.A. The nose knows who's who: chemosensory individuality and mate recognition in mice. Horm. Behav. 46, 231–240 (2004).

    Article  CAS  Google Scholar 

  3. Brennan, P. & Keverne, E.B. Something in the air? New insights into mammalian pheromones. Curr. Biol. 14, R81–R89 (2004).

    Article  CAS  Google Scholar 

  4. Dulac, C. & Torello, A.T. Molecular detection of pheromone signals in mammals: from genes to behavior. Nat. Rev. Neurosci. 4, 551–562 (2003).

    Article  CAS  Google Scholar 

  5. Ganem, G., Ginane, C., Ostrowski, M. & Orth, A. Assessment of mate preference in the house mouse with reference to investigations on assortative mating. Biol. J. Linn. Soc. 84, 461–471 (2005).

    Article  Google Scholar 

  6. Kavaliers, M., Choleris, E. & Pfaff, D.W. Recognition and avoidance of the odors of parasitized conspecifics and predators: differential genomic correlates. Neurosci. Biobehav. Rev. 29, 1347–1359 (2005).

    Article  Google Scholar 

  7. Liberles, S.D. & Buck, L.B. A second class of chemosensory receptors in the olfactory epithelium. Nature 442, 645–650 (2006).

    Article  CAS  Google Scholar 

  8. Slotnick, B. Animal cognition and the rat olfactory system. Trends Cogn. Sci. 5, 216–222 (2001).

    Article  CAS  Google Scholar 

  9. Simerly, R.B. Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain. Annu. Rev. Neurosci. 25, 507–536 (2002).

    Article  CAS  Google Scholar 

  10. Davis, R.L. Olfactory learning. Neuron 44, 31–48 (2004).

    Article  CAS  Google Scholar 

  11. Doetsch, F. & Hen, R. Young and excitable: the function of new neurons in the adult mammalian brain. Curr. Opin. Neurobiol. 15, 121–128 (2005).

    Article  CAS  Google Scholar 

  12. Ming, G.L. & Song, H. Adult neurogenesis in the mammalian central nervous system. Annu. Rev. Neurosci. 28, 223–250 (2005).

    Article  CAS  Google Scholar 

  13. Lois, C. & Alvarez-Buylla, A. Long-distance neuronal migration in the adult mammalian brain. Science 264, 1145–1148 (1994).

    Article  CAS  Google Scholar 

  14. Enwere, E. et al. Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J. Neurosci. 24, 8354–8365 (2004).

    Article  CAS  Google Scholar 

  15. Rochefort, C., Gheusi, G., Vincent, J.D. & Lledo, P.M. Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. J. Neurosci. 22, 2679–2689 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Shors, T.J. et al. Neurogenesis in the adult is involved in the formation of trace memories. Nature 410, 372–376 (2001).

    Article  CAS  Google Scholar 

  18. Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Kempermann, G., Kuhn, H.G. & Gage, F.H. More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493–495 (1997).

    Article  CAS  Google Scholar 

  21. Gould, E., Beylin, A., Tanapat, P., Reeves, A. & Shors, T.J. Learning enhances adult neurogenesis in the hippocampal formation. Nat. Neurosci. 2, 260–265 (1999).

    Article  CAS  Google Scholar 

  22. Brown, J. et al. Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur. J. Neurosci. 17, 2042–2046 (2003).

    Article  Google Scholar 

  23. Shingo, T. et al. Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science 299, 117–120 (2003).

    Article  CAS  Google Scholar 

  24. Boehm, U., Zou, Z. & Buck, L.B. Feedback loops link odor and pheromone signaling with reproduction. Cell 123, 683–695 (2005).

    Article  CAS  Google Scholar 

  25. Yoon, H., Enquist, L.W. & Dulac, C. Olfactory inputs to hypothalamic neurons controlling reproduction and fertility. Cell 123, 669–682 (2005).

    Article  CAS  Google Scholar 

  26. Mucignat-Caretta, C. & Caretta, A. Chemical signals in male house mice urine: protein-bound molecules modulate interactions between sexes. Behaviour 136, 331–343 (1999).

    Article  Google Scholar 

  27. Keller, M., Douhard, Q., Baum, M.J. & Bakker, J. Destruction of the main olfactory epithelium reduces female sexual behavior and olfactory investigation in female mice. Chem. Senses 31, 315–323 (2006).

    Article  Google Scholar 

  28. Mossman, C.A. & Drickamer, L.C. Odor preferences of female house mice (Mus domesticus) in seminatural enclosures. J. Comp. Psychol. 110, 131–138 (1996).

    Article  CAS  Google Scholar 

  29. Drickamer, L.C., Gowaty, P.A. & Holmes, C.M. Free female mate choice in house mice affects reproductive success and offspring viability and performance. Anim. Behav. 59, 371–378 (2000).

    Article  CAS  Google Scholar 

  30. Lledo, P.M., Gheusi, G. & Vincent, J.D. Information processing in the mammalian olfactory system. Physiol. Rev. 85, 281–317 (2005).

    Article  Google Scholar 

  31. Rao, M.S. & Shetty, A.K. Efficacy of doublecortin as a marker to analyse the absolute number and dendritic growth of newly generated neurons in the adult dentate gyrus. Eur. J. Neurosci. 19, 234–246 (2004).

    Article  Google Scholar 

  32. Becker, J.B. et al. Strategies and methods for research on sex differences in brain and behavior. Endocrinology 146, 1650–1673 (2005).

    Article  CAS  Google Scholar 

  33. Zhang, F.P., Poutanen, M., Wilbertz, J. & Huhtaniemi, I. Normal prenatal but arrested postnatal sexual development of luteinizing hormone receptor knockout (LuRKO) mice. Mol. Endocrinol. 15, 172–183 (2001).

    Article  CAS  Google Scholar 

  34. Huhtaniemi, I., Zhang, F.P., Kero, J., Hamalainen, T. & Poutanen, M. Transgenic and knockout mouse models for the study of luteinizing hormone and luteinizing hormone receptor function. Mol. Cell. Endocrinol. 187, 49–56 (2002).

    Article  CAS  Google Scholar 

  35. Doetsch, F., Garcia-Verdugo, J.M. & Alvarez-Buylla, A. Regeneration of a germinal layer in the adult mammalian brain. Proc. Natl. Acad. Sci. USA 96, 11619–11624 (1999).

    Article  CAS  Google Scholar 

  36. Kokoeva, M.V., Yin, H. & Flier, J.S. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science 310, 679–683 (2005).

    Article  CAS  Google Scholar 

  37. Trinh, K. & Storm, D.R. Vomeronasal organ detects odorants in absence of signaling through main olfactory epithelium. Nat. Neurosci. 6, 519–525 (2003).

    Article  CAS  Google Scholar 

  38. Bole-Feysot, C., Goffin, V., Edery, M., Binart, N. & Kelly, P.A. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr. Rev. 19, 225–268 (1998).

    Article  CAS  Google Scholar 

  39. Rao, C.V. & Lei, Z.M. Consequences of targeted inactivation of LH receptors. Mol. Cell. Endocrinol. 187, 57–67 (2002).

    Article  CAS  Google Scholar 

  40. Knobil, E. & Neil, J.D. The Physiology of Reproduction (Raven Press, Ltd, New York, 1994).

  41. Dupret, D. et al. Methylazoxymethanol acetate does not fully block cell genesis in the young and aged dentate gyrus. Eur. J. Neurosci. 22, 778–783 (2005).

    Article  Google Scholar 

  42. 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  CAS  Google Scholar 

  43. Wojtowicz, J.M. Irradiation as an experimental tool in studies of adult neurogenesis. Hippocampus 16, 261–266 (2006).

    Article  CAS  Google Scholar 

  44. Grammer, K., Fink, B. & Neave, N. Human pheromones and sexual attraction. Eur. J. Obstet. Gynecol. Reprod. Biol. 118, 135–142 (2005).

    Article  CAS  Google Scholar 

  45. Savic, I., Berglund, H., Gulyas, B. & Roland, P. Smelling of odorous sex hormone–like compounds causes sex-differentiated hypothalamic activations in humans. Neuron 31, 661–668 (2001).

    Article  CAS  Google Scholar 

  46. Bigiani, A., Mucignat-Caretta, C., Montani, G. & Tirindelli, R. Pheromone reception in mammals. Rev. Physiol. Biochem. Pharmacol. 154, 1–35 (2005).

    CAS  PubMed  Google Scholar 

  47. Bedard, A. & Parent, A. Evidence of newly generated neurons in the human olfactory bulb. Brain Res. Dev. Brain Res. 151, 159–168 (2004).

    Article  CAS  Google Scholar 

  48. Grant, E.C. & Mackintosh, J.H. A comparison of the social postures of some laboratory rodents. Behaviour 21, 246–259 (1963).

    Article  Google Scholar 

  49. Kero, J. et al. Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex. J. Clin. Invest. 105, 633–641 (2000).

    Article  CAS  Google Scholar 

  50. Ling, C. et al. Prolactin (PRL) receptor gene expression in mouse adipose tissue: increases during lactation and in PRL-transgenic mice. Endocrinology 141, 3564–3572 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to K. Markham for providing helpful instruction on the molecular techniques used in this study. We thank A. Chojnacki, B. Kolb, K. Lukowiak, C. Morshead and Q. Pittman for comments on earlier versions of this manuscript. This work was supported by the Canadian Institutes for Health Research and the Academy of Finland. G.K.M. and C.G. were recipients of studentships from the Stem Cell Network of the Canadian Network of Centres of Excellence and the Alberta Heritage Foundation for Medical Research (AHFMR), respectively. S.W. is an AHFMR Scientist.

Author information

Author notes

  1. Emeka K Enwere & Christopher Gregg

    Present address: Current address: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute II, Ottawa, Ontario K1H 8L1, Canada; Howard Hughes Medical Institute, Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA (C.G.).,

Authors and Affiliations

  1. Department of Cell Biology & Anatomy, Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, T2N 4N1, Alberta, Canada

    Gloria K Mak, Emeka K Enwere, Christopher Gregg & Samuel Weiss

  2. Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, Turku, FIN-20520, Finland

    Tomi Pakarainen & Matti Poutanen

  3. Institute of Reproductive and Developmental Biology, Imperial College London, London, W12 ONN, UK

    Ilpo Huhtaniemi

Authors
  1. Gloria K Mak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emeka K Enwere
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher Gregg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomi Pakarainen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matti Poutanen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ilpo Huhtaniemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Samuel Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.K.M. conducted all of the experiments and co-authored the manuscript. E.E.K. and C.G. contributed to the planning and interpretation of the pheromone- and hormone-stimulated neurogenesis studies, T.P, M.P. and I.H. collaborated on studies of LH actions on neurogenesis, LHR immunochemistry and pheromone-stimulated neurogenesis in Lhcgr mice, and S.W. supervised the project and co-authored the manuscript.

Corresponding author

Correspondence to Samuel Weiss.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Paradigm for male pheromone exposure. (PDF 116 kb)

Supplementary Fig. 2

Male pheromones simultaneously increase cell proliferation in the SVZ and DG. (PDF 1984 kb)

Supplementary Fig. 3

Females exposed to novel odors do not have increased proliferation in the SVZ. or DG compared with females exposed to male pheromones. (PDF 267 kb)

Supplementary Fig. 4

Male pheromones simultaneously increase neurogenesis in the dorsolateral corner (DLC) of the SVZ and DG. (PDF 2466 kb)

Supplementary Fig. 5

Short exposure to dominant male pheromones, which result in a lack of increased adult female neurogenesis, also result in a lack of preference for dominant males. (PDF 234 kb)

Supplementary Fig. 6

Plrl?/? females exposed to dominant male pheromones for 7 d do not show a subsequent preference for dominant males. AraC infusions attenuate OB and DG neurogenesis. (PDF 173 kb)

Supplementary Fig. 7

AraC infusions attenuate OB and DG neurogenesis. (PDF 4534 kb)

Supplementary Fig. 8

Females with attenuated dominant male pheromone?induced neurogenesis in the OB and DG do not show a preference for a subordinate or dominant male. (PDF 279 kb)

Supplementary Fig. 9

Assay to determine novel odor detection and habituation. (PDF 314 kb)

Supplementary Methods (PDF 177 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mak, G., Enwere, E., Gregg, C. et al. Male pheromone–stimulated neurogenesis in the adult female brain: possible role in mating behavior.. Nat Neurosci 10, 1003–1011 (2007). https://doi.org/10.1038/nn1928

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1928

This article is cited by

Search

Advanced 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