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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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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.

Change history

  • 07 April 2011

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


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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



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).

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