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Molecular regulation of sexual preference revealed by genetic studies of 5-HT in the brains of male mice

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Abstract

Although the question of to whom a male directs his mating attempts1,2 is a critical one in social interactions, little is known about the molecular and cellular mechanisms controlling mammalian sexual preference. Here we report that the neurotransmitter 5-hydroxytryptamine (5-HT) is required for male sexual preference. Wild-type male mice preferred females over males, but males lacking central serotonergic neurons lost sexual preference although they were not generally defective in olfaction or in pheromone sensing. A role for 5-HT was demonstrated by the phenotype of mice lacking tryptophan hydroxylase 2 (Tph2), which is required for the first step of 5-HT synthesis in the brain. Thirty-five minutes after the injection of the intermediate 5-hydroxytryptophan (5-HTP), which circumvented Tph2 to restore 5-HT to the wild-type level, adult Tph2 knockout mice also preferred females over males. These results indicate that 5-HT and serotonergic neurons in the adult brain regulate mammalian sexual preference.

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Figure 1: Male–male mounting and USV by mice lacking central serotonergic neurons.
Figure 2: Lack of sexual preference by mice without central serotonergic neurons.
Figure 3: Loss of sexual preference for genital odour and bedding by males without central serotonergic neurons.
Figure 4: Odour discrimination.
Figure 5: Brain chemistry and behaviours of Tph2 knockout males.
Figure 6: 5-HTP rescue of chemical and behavioural deficits in Tph2 knockout mice.

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Change history

  • 07 April 2011

    The labelling of Fig. 3 and associated legend was corrected.

References

  1. Trivers, R. L. Parent–offspring conflict. Am. Zool. 14, 249–264 (1974)

    Article  Google Scholar 

  2. Sommer, V. & Vasey, P. L. Homosexual Behaviour in Animals: An Evolutionary Perspective (Cambridge Univ. Press, 2006)

    Google Scholar 

  3. Price, E. O. & Wallach, S. J. Development of sexual and aggressive behaviors in Hereford bulls. J. Anim. Sci. 69, 1019–1027 (1991)

    Article  CAS  Google Scholar 

  4. Erwin, J. & Maple, T. Ambisexual behavior with male–male anal penetration in male rhesus monkeys. Arch. Sex. Behav. 5, 9–14 (1976)

    Article  CAS  Google Scholar 

  5. Stowers, L., Holy, T. E., Meister, M., Dulac, C. & Koentges, G. Loss of sex discrimination and male–male aggression in mice deficient for TRP2. Science 295, 1493–1500 (2002)

    Article  ADS  CAS  Google Scholar 

  6. Leypold, B. G. et al. Altered sexual and social behaviors in trp2 mutant mice. Proc. Natl Acad. Sci. USA 99, 6376–6381 (2002)

    Article  ADS  CAS  Google Scholar 

  7. Hull, E. M., Muschamp, J. W. & Sato, S. Dopamine and serotonin: influences on male sexual behavior. Physiol. Behav. 83, 291–307 (2004)

    Article  CAS  Google Scholar 

  8. Hull, E. M. & Dominguez, J. M. Sexual behavior in male rodents. Horm. Behav. 52, 45–55 (2007)

    Article  CAS  Google Scholar 

  9. Ferguson, J. et al. “Hypersexuality” and behavioral changes in cats caused by administration of p-chlorophenylalanine. Science 168, 499–501 (1970)

    Article  ADS  CAS  Google Scholar 

  10. Malmnäs, C. & Meyerson, B. p-Chlorophenylalanine and copulatory behaviour in the male rat. Nature 232, 398–400 (1971)

    Article  ADS  Google Scholar 

  11. Salis, P. & Dewsbury, D. p-Chlorophenylalanine facilitates copulatory behaviour in male rats. Nature 232, 400–401 (1971)

    Article  ADS  CAS  Google Scholar 

  12. Dailly, E., Chenu, F., Petit-Demouliere, B. & Bourin, M. Specificity and efficacy of noradrenaline, serotonin depletion in discrete brain areas of Swiss mice by neurotoxins. J. Neurosci. Methods 150, 111–115 (2006)

    Article  CAS  Google Scholar 

  13. Zhao, Z.-Q. et al. Lmx1b is required for maintenance of central serotonergic neurons and mice lacking central serotonergic system exhibit normal locomotor activity. J. Neurosci. 26, 12781–12788 (2006)

    Article  CAS  Google Scholar 

  14. Guo, Z. & Holy, T. E. Sex selectivity of mouse ultrasonic songs. Chem. Senses 32, 463–473 (2007)

    Article  Google Scholar 

  15. Ferkin, M. H. & Li, H. Z. A battery of olfactory-based screens for phenotyping the social and sexual behaviors of mice. Physiol. Behav. 85, 489–499 (2005)

    Article  CAS  Google Scholar 

  16. Moncho-Bogani, J., Lanuza, E., Herndez, A., Novejarque, A. & Martez-Garc, F. Attractive properties of sexual pheromones in mice: innate or learned? Physiol. Behav. 77, 167–176 (2002)

    Article  CAS  Google Scholar 

  17. Burwash, M. D., Tobin, M. E., Woolhouse, A. D. & Sullivan, T. P. Laboratory evaluation of predator odors for eliciting an avoidance response in roof rats (Rattus rattus). J. Chem. Ecol. 24, 49–66 (1998)

    Article  CAS  Google Scholar 

  18. Blanchard, D. et al. Failure to produce conditioning with low-dose trimethylthiazoline or cat feces as unconditioned stimuli. Behav. Neurosci. 117, 360–368 (2003)

    Article  CAS  Google Scholar 

  19. Nadler, J. J. et al. Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav. 3, 303–314 (2004)

    Article  CAS  Google Scholar 

  20. Ferguson, J. N. et al. Social amnesia in mice lacking the oxytocin gene. Nature Genet. 25, 284–288 (2000)

    Article  CAS  Google Scholar 

  21. Yan, Z. et al. Precise circuitry links bilaterally symmetric olfactory maps. Neuron 58, 613–624 (2008)

    Article  CAS  Google Scholar 

  22. Gutknecht, L. et al. Deficiency of brain 5-HT synthesis but serotonergic neuron formation in Tph2 knockout mice. J. Neural Transm. 115, 1127–1132 (2008)

    Article  CAS  Google Scholar 

  23. Savelieva, K. V. et al. Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. PLoS ONE 3, e3301 (2008)

    Article  ADS  Google Scholar 

  24. Alenina, N. et al. Growth retardation and altered autonomic control in mice lacking brain serotonin. Proc. Natl Acad. Sci. USA 106, 10332–10337 (2009)

    Article  ADS  CAS  Google Scholar 

  25. Koe, B. K. & Weissman, A. p-Chlorophenylalanine: a specific depletor of brain serotonin. J. Pharmacol. Exp. Ther. 154, 499–516 (1966)

    CAS  PubMed  Google Scholar 

  26. Gawienowski, A. M. & Hodgen, G. D. Homosexual activity in male rats after p-chlorophenylalanine: effects of hypophysectomy and testosterone. Physiol. Behav. 7, 551–555 (1971)

    Article  CAS  Google Scholar 

  27. Kobayakawa, K. et al. Innate versus learned odour processing in the mouse olfactory bulb. Nature 450, 503–508 (2007)

    Article  ADS  CAS  Google Scholar 

  28. Kinnunen, L., Moltz, H., Metz, J. & Cooper, M. Differential brain activation in exclusively homosexual and heterosexual men produced by the selective serotonin reuptake inhibitor, fluoxetine. Brain Res. 1024, 251–254 (2004)

    Article  CAS  Google Scholar 

  29. Wainberg, M. et al. A double-blind study of citalopram versus placebo in the treatment of compulsive sexual behaviors in gay and bisexual men. J. Clin. Psychiatry 67, 1968–1973 (2006)

    Article  CAS  Google Scholar 

  30. Mustanski, B. S. et al. A genomewide scan of male sexual orientation. Hum. Genet. 116, 272–278 (2005)

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to E. S. Deneris for ePet1-Cre mice; to R. Johnson for Lmx1bfl mice; to M. Luo for discussions; to Z. Yan and Y. Lu for the operant conditioning apparatus; to X. Wang and Y. Wan for help with HPLC; to J. Lang and J. Yin for mouse breeding and genotyping; to P. Ding, P. Wang, H. Lu and X. Wang for technical assistance; to L. Zhao, Z. Qiu and H. Jing for animal caring; and to the Ministry of Science and Technology (973 program 2010CB833901) and Beijing Municipal Commission on Science and Technology for grant support (to Y.R.), and the NIH for grant support (to Z.-F.C.).

Author information

Authors and Affiliations

Authors

Contributions

Y.R. conceived the project, Y.R., Y.L. and Y.J. designed the experiments, Y.L., Y.J. and Y.S. performed the experiments, J.-Y.K. and Z.-F.C. contributed the Tph2 knockout mutants, Y.R., Y.L. and Y.J. wrote the paper.

Corresponding author

Correspondence to Yi Rao.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-11 with legends and Supplementary Dataset 1. (PDF 973 kb)

Supplementary Movie 1

Mating of a wt target male by a Lmxb1-/- male. A Lmxb1-/- male mounted a wt male. (ZIP 8108 kb)

Supplementary Movie 2

Mating choice of a Lmxb1+/+ littermate. A Lmxb1+/+ male was presented with two targets, one male and one estrous female. The Lmxb1+/+ male mounted the female target. (ZIP 4524 kb)

Supplementary Movie 3

Mating choice of a Lmxb1-/- male. A Lmxb1-/- male was presented with two wt targets, one male and one estrous female. The Lmxb1-/- male mounted both the male and the female targets. (ZIP 10476 kb)

Supplementary Movie 4

Mating of a wt target male by a Tph2-/- male. A Tph2-/- male mounted a wt male. (ZIP 4393 kb)

Supplementary Movie 5

Mating choice of a Tph2 +/+ littermate. A Tph2 +/+ male was presented with two targets, one male and one estrous female. The Tph2 +/+ male mounted the female target. (ZIP 7652 kb)

Supplementary Movie 6

Mating choice of a Tph2-/- male. A Tph2-/- male was presented with two wt targets, one male and one estrous female. The Tph2-/- male mounted both the male and the female targets. (ZIP 11930 kb)

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Liu, Y., Jiang, Y., Si, Y. et al. Molecular regulation of sexual preference revealed by genetic studies of 5-HT in the brains of male mice. Nature 472, 95–99 (2011). https://doi.org/10.1038/nature09822

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