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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Trivers, R. L. Parent–offspring conflict. Am. Zool. 14, 249–264 (1974)
Sommer, V. & Vasey, P. L. Homosexual Behaviour in Animals: An Evolutionary Perspective (Cambridge Univ. Press, 2006)
Price, E. O. & Wallach, S. J. Development of sexual and aggressive behaviors in Hereford bulls. J. Anim. Sci. 69, 1019–1027 (1991)
Erwin, J. & Maple, T. Ambisexual behavior with male–male anal penetration in male rhesus monkeys. Arch. Sex. Behav. 5, 9–14 (1976)
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)
Leypold, B. G. et al. Altered sexual and social behaviors in trp2 mutant mice. Proc. Natl Acad. Sci. USA 99, 6376–6381 (2002)
Hull, E. M., Muschamp, J. W. & Sato, S. Dopamine and serotonin: influences on male sexual behavior. Physiol. Behav. 83, 291–307 (2004)
Hull, E. M. & Dominguez, J. M. Sexual behavior in male rodents. Horm. Behav. 52, 45–55 (2007)
Ferguson, J. et al. “Hypersexuality” and behavioral changes in cats caused by administration of p-chlorophenylalanine. Science 168, 499–501 (1970)
Malmnäs, C. & Meyerson, B. p-Chlorophenylalanine and copulatory behaviour in the male rat. Nature 232, 398–400 (1971)
Salis, P. & Dewsbury, D. p-Chlorophenylalanine facilitates copulatory behaviour in male rats. Nature 232, 400–401 (1971)
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)
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)
Guo, Z. & Holy, T. E. Sex selectivity of mouse ultrasonic songs. Chem. Senses 32, 463–473 (2007)
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)
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)
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)
Blanchard, D. et al. Failure to produce conditioning with low-dose trimethylthiazoline or cat feces as unconditioned stimuli. Behav. Neurosci. 117, 360–368 (2003)
Nadler, J. J. et al. Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav. 3, 303–314 (2004)
Ferguson, J. N. et al. Social amnesia in mice lacking the oxytocin gene. Nature Genet. 25, 284–288 (2000)
Yan, Z. et al. Precise circuitry links bilaterally symmetric olfactory maps. Neuron 58, 613–624 (2008)
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)
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)
Alenina, N. et al. Growth retardation and altered autonomic control in mice lacking brain serotonin. Proc. Natl Acad. Sci. USA 106, 10332–10337 (2009)
Koe, B. K. & Weissman, A. p-Chlorophenylalanine: a specific depletor of brain serotonin. J. Pharmacol. Exp. Ther. 154, 499–516 (1966)
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)
Kobayakawa, K. et al. Innate versus learned odour processing in the mouse olfactory bulb. Nature 450, 503–508 (2007)
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)
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)
Mustanski, B. S. et al. A genomewide scan of male sexual orientation. Hum. Genet. 116, 272–278 (2005)
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.).
The authors declare no competing financial interests.
This file contains Supplementary Figures 1-11 with legends and Supplementary Dataset 1. (PDF 973 kb)
Mating of a wt target male by a Lmxb1-/- male. A Lmxb1-/- male mounted a wt male. (ZIP 8108 kb)
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)
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)
Mating of a wt target male by a Tph2-/- male. A Tph2-/- male mounted a wt male. (ZIP 4393 kb)
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)
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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