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:

Increased dopamine after mating impairs olfaction and prevents odor interference with pregnancy

Nature Neuroscience volume 11, pages 949–956 (2008)Cite this article

Abstract

In rodents, social odor sensing influences female reproductive status by affecting neuroendocrine cascades. The odor of male mouse urine can induce ovulation or block pregnancy within 3 d post coitus. Females avoid the action of such olfactory stimuli after embryonic implantation. The mechanisms underlying these changes are unknown. Here we report that shortly after mating, a surge in dopamine in the mouse main olfactory bulb impairs the perception of social odors contained in male urine. Treatment of females at 6.5 d post coitus with a dopamine D2 receptor antagonist restores social odor sensing and favors disruption of pregnancy by inhibition of prolactin release, when administered in the presence of alien male urine odors. These results show that an active sensory barrier blocks social olfactory cues detrimental to pregnancy, consistent with the main olfactory bulb being a major relay through which social odor modulates reproductive status.

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: Kinetics of tyrosine hydroxylase (TH) expression in the MOB of pseudopregnant females.
Figure 2: Tyrosine hydroxylase (TH) modulation in JGD cells of two mouse strains during pregnancy.
Figure 3: Progression of pregnancy is associated with loss of social olfactory discrimination.
Figure 4: Threshold of detection of LMW male urine fraction by C57BL/6J estrous or pregnant females.
Figure 5: c-Fos immunoreactivity (c-Fos–ir) is a marker of neuronal activation.
Figure 6: After embryonic implantation, the night surge of PRL is hampered by alien male odor in females treated with the D2R antagonist spiperone.
Figure 7: Alien male odors compromise pregnancy.

Similar content being viewed by others

References

  1. Halpern, M. & Martinez-Marcos, A. Structure and function of the vomeronasal system: an update. Prog. Neurobiol. 70, 245–318 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Freeman, M.E., Kanyicska, B., Lerant, A. & Nagy, G. Prolactin: structure, function and regulation of secretion. Physiol. Rev. 80, 1523–1631 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Galosy, S.S. & Talamantes, F. Luteotropic actions of placental lactogens at midpregnancy in the mouse. Endocrinology 136, 3993–4003 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Erskine, M.S. Prolactin release after mating and genitosensory stimulation in females. Endocr. Rev. 16, 508–528 (1995).

    CAS  PubMed  Google Scholar 

  5. Bruce, H.M. An exteroceptive block to pregnancy in the mouse. Nature 184, 105 (1959).

    Article  CAS  PubMed  Google Scholar 

  6. Rosser, A.E., Remfry, C.J. & Keverne, E.B. Restricted exposure of mice to primer pheromones coincident with prolactin surges blocks pregnancy by changing hypothalamic dopamine release. J. Reprod. Fertil. 87, 553–559 (1989).

    Article  CAS  PubMed  Google Scholar 

  7. Lloyd-Thomas, A. & Keverne, E.B. Role of the brain and accessory olfactory system in the block to pregnancy in mice. Neuroscience 7, 907–913 (1982).

    Article  CAS  PubMed  Google Scholar 

  8. Chung, H.J., Reyes, A.B., Watanabe, K., Tomogane, H. & Wakasugi, N. Embryonic abnormality caused by male pheromonal effect in pregnancy block in mice. Biol. Reprod. 57, 312–319 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Arkaravichien, W. & Kendle, K.E. Critical progesterone requirement for maintenance of pregnancy in ovariectomized rats. J. Reprod. Fertil. 90, 63–70 (1990).

    Article  CAS  PubMed  Google Scholar 

  10. Milligan, S.R. & Finn, C.A. Minimal progesterone support required for the maintenance of pregnancy in mice. Hum. Reprod. 12, 602–607 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Dulac, C. & Wagner, S. Genetic analysis of brain circuits underlying pheromone signaling. Annu. Rev. Genet. 40, 449–467 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Meisami, E. & Bhatnagar, K.P. Structure and diversity in mammalian accessory olfactory bulb. Microsc. Res. Tech. 43, 476–499 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Baker, H. Species differences in the distribution of substance P and tyrosine hydroxylase immunoreactivity in the olfactory bulb. J. Comp. Neurol. 252, 206–226 (1986).

    Article  CAS  PubMed  Google Scholar 

  14. Ennis, M. et al. Dopamine D2 receptor–mediated presynaptic inhibition of olfactory nerve terminals. J. Neurophysiol. 86, 2986–2997 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Coopersmith, R., Weihmuller, F.B., Kirstein, C.L., Marshall, J.F. & Leon, M. Extracellular dopamine increases in the neonatal olfactory bulb during odor preference training. Brain Res. 564, 149–153 (1991).

    Article  CAS  PubMed  Google Scholar 

  16. Harley, C.W. Norepinephrine and dopamine as learning signals. Neural Plast. 11, 191–204 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yue, E.L., Cleland, T.A., Pavlis, M. & Linster, C. Opposing effects of D1 and D2 receptor activation on odor discrimination learning. Behav. Neurosci. 118, 184–190 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Halasz, N., Johansson, O., Hokfelt, T., Ljungdahl, A. & Goldstein, M. Immunohistochemical identification of two types of dopamine neuron in the rat olfactory bulb as seen by serial sectioning. J. Neurocytol. 10, 251–259 (1981).

    Article  CAS  PubMed  Google Scholar 

  19. Dluzen, D.E., Park, J.H. & Kim, K. Modulation of olfactory bulb tyrosine hydroxylase and catecholamine transporter mRNA by estrogen. Brain Res. Mol. Brain Res. 108, 121–128 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Arbogast, L.A. & Voogt, J.L. Progesterone reverses the estradiol-induced decrease in tyrosine hydroxylase mRNA levels in the arcuate nucleus. Neuroendocrinology 58, 501–510 (1993).

    Article  CAS  PubMed  Google Scholar 

  21. Tashiro, Y., Kaneko, T., Nagatsu, I., Kikuchi, H. & Mizuno, N. Increase of tyrosine hydroxylase–like immunoreactive neurons in the nucleus accumbens and the olfactory bulb in the rat with the lesion in the ventral tegmental area of the midbrain. Brain Res. 531, 159–166 (1990).

    Article  CAS  PubMed  Google Scholar 

  22. Thanky, N.R., Son, J.H. & Herbison, A.E. Sex differences in the regulation of tyrosine hydroxylase gene transcription by estrogen in the locus coeruleus of TH9-LacZ transgenic mice. Brain Res. Mol. Brain Res. 104, 220–226 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Wersinger, S.R. & Baum, M.J. Sexually dimorphic activation of midbrain tyrosine hydroxylase neurons after mating or exposure to chemosensory cues in the ferret. Biol. Reprod. 56, 1407–1414 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Wei, C.J., Linster, C. & Cleland, T.A. Dopamine D(2) receptor activation modulates perceived odor intensity. Behav. Neurosci. 120, 393–400 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Keller, M., Pierman, S., Douhard, Q., Baum, M.J. & Bakker, J. The vomeronasal organ is required for the expression of lordosis behaviour, but not sex discrimination in female mice. Eur. J. Neurosci. 23, 521–530 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Spehr, M. et al. Essential role of the main olfactory system in social recognition of major histocompatibility complex peptide ligands. J. Neurosci. 26, 1961–1970 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Meredith, M. Vomeronasal, olfactory, hormonal convergence in the brain. Cooperation or coincidence? Ann. NY Acad. Sci. 855, 349–361 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Brennan, P.A. & Zufall, F. Pheromonal communication in vertebrates. Nature 444, 308–315 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Halem, H.A., Cherry, J.A. & Baum, M.J. Central forebrain Fos responses to familiar male odors are attenuated in recently mated female mice. Eur. J. Neurosci. 13, 389–399 (2001).

    CAS  PubMed  Google Scholar 

  32. Choi, G.B. et al. Lhx6 delineates a pathway mediating innate reproductive behaviors from the amygdala to the hypothalamus. Neuron 46, 647–660 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Pierman, S., Douhard, Q. & Bakker, J. Evidence for a role of early oestrogens in the central processing of sexually relevant olfactory cues in female mice. Eur. J. Neurosci. 27, 423–431 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Marchlewska-Koj, A. Pheromones and mammalian reproduction. Oxf. Rev. Reprod. Biol. 6, 266–302 (1984).

    CAS  PubMed  Google Scholar 

  35. Robarts, D.W. & Baum, M.J. Ventromedial hypothalamic nucleus lesions disrupt olfactory mate recognition and receptivity in female ferrets. Horm. Behav. 51, 104–113 (2007).

    Article  PubMed  Google Scholar 

  36. Lehmann, M.L. & Erskine, M.S. Glutamatergic stimulation of the medial amygdala induces steroid-dependent c-fos expression within forebrain nuclei responsive to mating stimulation. Neuroscience 136, 55–64 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. 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  PubMed  PubMed Central  Google Scholar 

  38. Mandiyan, V.S., Coats, J.K. & Shah, N.M. Deficits in sexual and aggressive behaviors in Cnga2 mutant mice. Nat. Neurosci. 8, 1660–1662 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Pro-Sistiaga, P. et al. Convergence of olfactory and vomeronasal projections in the rat basal telencephalon. J. Comp. Neurol. 504, 346–362 (2007).

    Article  PubMed  Google Scholar 

  40. La Vaque, T.J. & Rodgers, C.H. Recovery of mating behavior in the female rat following VMH lesions. Physiol. Behav. 14, 59–63 (1975).

    Article  CAS  PubMed  Google Scholar 

  41. Arey, B.J., Averill, R.L. & Freeman, M.E. A sex-specific endogenous stimulatory rhythm regulating prolactin secretion. Endocrinology 124, 119–123 (1989).

    Article  CAS  PubMed  Google Scholar 

  42. Mathiasen, J.R. & Voogt, J.L. Differential regulation of the nocturnal and diurnal prolactin surges in pregnant rats revealed by dopamine receptor antagonism. Neuroendocrinology 56, 704–711 (1992).

    Article  CAS  PubMed  Google Scholar 

  43. Keverne, E.B. & de la Riva, C. Pheromones in mice: reciprocal interaction between the nose and brain. Nature 296, 148–150 (1982).

    Article  CAS  PubMed  Google Scholar 

  44. Ma, D. et al. Selective ablation of olfactory receptor neurons without functional impairment of vomeronasal receptor neurons in OMP-ntr transgenic mice. Eur. J. Neurosci. 16, 2317–2323 (2002).

    Article  PubMed  Google Scholar 

  45. Martel, K.L. & Baum, M.J. Sexually dimorphic activation of the accessory, but not the main, olfactory bulb in mice by urinary volatiles. Eur. J. Neurosci. 26, 463–475 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Rajendren, G. & Dominic, C.J. Evaluation of involvement of accessory olfactory (vomeronasal) system in estrous cyclicity and mating in female mice. Indian J. Exp. Biol. 24, 573–577 (1986).

    CAS  PubMed  Google Scholar 

  47. Whitten, W.K. The effect of removal of the olfactory bulbs on the gonads of mice. J. Endocrinol. 14, 160–163 (1956).

    Article  CAS  PubMed  Google Scholar 

  48. Lamond, D.R. Infertility associated with extirpation of the olfactory bulbs in female albino mice. Aust. J. Exp. Biol. Med. Sci. 36, 103–108 (1958).

    Article  CAS  PubMed  Google Scholar 

  49. Lin, D.Y., Zhang, S.Z., Block, E. & Katz, L.C. Encoding social signals in the mouse main olfactory bulb. Nature 434, 470–477 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Xu, F. et al. Simultaneous activation of mouse main and accessory olfactory bulbs by odors or pheromones. J. Comp. Neurol. 489, 491–500 (2005).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to M. Hamon and F. Saurini (INSERM U288) for the tissue dopamine dosage and C. Sciarretta for comments. C.S. was supported by an EMBO fellowship.

Author information

Authors and Affiliations

  1. European Molecular Biology Laboratory, Mouse Biology Unit, Via Ramarini 32, Monterotondo, 00015, Italy

    Che Serguera, Viviana Triaca, Jakki Kelly-Barrett, Mumna Al Banchaabouchi & Liliana Minichiello

Authors
  1. Che Serguera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Viviana Triaca
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jakki Kelly-Barrett
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mumna Al Banchaabouchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Liliana Minichiello
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.S. planned and performed most of the experiments and, together with L.M., drafted the manuscript. V.T. conducted the c-Fos experiment with the help of J.K.-B. and provided conceptual input. J.K.-B. also contributed to the PRL dosage experiments. M.A.B. provided the expertise for and helped conduct the behavioral experiments. L.M. is the PI; she contributed to the experimental plans, supervised the project, provided theoretical input and wrote the manuscript.

Corresponding author

Correspondence to Liliana Minichiello.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Methods (PDF 196 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Serguera, C., Triaca, V., Kelly-Barrett, J. et al. Increased dopamine after mating impairs olfaction and prevents odor interference with pregnancy. Nat Neurosci 11, 949–956 (2008). https://doi.org/10.1038/nn.2154

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2154

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