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

Journal name:
Nature
Volume:
472,
Pages:
95–99
Date published:
DOI:
doi:10.1038/nature09822
Received
Accepted
Published online
Corrected online

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.

At a glance

Figures

  1. Male-male mounting and USV by mice lacking central serotonergic neurons.
    Figure 1: Male–male mounting and USV by mice lacking central serotonergic neurons.

    ag, Numbers of mice used and statistical analysis are all included in Supplementary Data 1. ad, A test male was presented in its home cage with an adult wild-type male and its behaviour was recorded for 30min (all data shown as mean± s.e.m.). Compared with Lmx1b+/+, Lmx1b+/− or ePet1-Cre, Lmx1b−/− males mounted males at a higher percentage (a), lower latency (b), higher frequency (c) and for a longer duration (d). e, Typical USV patterns emitted by males when presented with female or male intruders. The two left panels show USVs in 2min, whereas the two right panels show parts of USV graphs at higher magnifications. f, Female intruders elicited USV from almost all ePet1-Cre, Lmx1b−/−, Lmx1b+/+, or Lmx1b+/− males . Male intruders elicited USVs more from Lmx1b/ males than from ePet1-Cre, Lmx1b+/+ or Lmx1b+/ males. g, The number of USVs emitted by Lmx1b/ males towards males is higher than those by ePet1-Cre, Lmx1b+/+ or Lmx1b+/ males, whereas ePet1-Cre, Lmx1b+/+, Lmx1b+/ and Lmx1b/ males were similar in USVs towards females. *P<0.05, **P<0.01, ***P<0.001.

  2. Lack of sexual preference by mice without central serotonergic neurons.
    Figure 2: Lack of sexual preference by mice without central serotonergic neurons.

    af, Each test male was presented with a male and an oestrous female, and its mating choice was analysed for 15min. a, More ePet1-Cre, Lmx1b+/+ and Lmx1b+/ males mounted female than male targets. A similar percentage of Lmx1b/ males mounted females and males. b, ePet1-Cre, Lmx1b+/+ and Lmx1b+/ males mounted female targets faster than male targets. Mounting latencies of Lmx1b/ males for females and males were similar. c, More than 40% of Lmx1b/ males but none of the ePet1-Cre, Lmx1b+/+ or Lmx1b+/ males chose a male as their first mounting target. d, ePet1-Cre males mounted females significantly more often than males, as did Lmx1b+/+ and Lmx1b+/ males. Lmx1b/ males mounted females as often as males (P>0.05, t-test). e, ePet1-Cre males spent more time mounting females than males, as did Lmx1b+/+ and Lmx1b+/ males. Lmx1b/ males did not show differences in mounting males or females. f, The mounting frequency ratio of Lmx1b/ was different from that of ePet1-Cre, Lmx1b+/+ and Lmx1b+/. *P<0.05, **P<0.01, ***P<0.001.

  3. Loss of sexual preference for genital odour and bedding by males without central serotonergic neurons.
    Figure 3: Loss of sexual preference for genital odour and bedding by males without central serotonergic neurons.

    a, Lmx1b+/+ males spent more time sniffing female than male genital odour, as did Lmx1b+/ males. Lmx1b/ males spent a similar amount of time on female and male genital odour. Three groups were not significantly different in male genital odour sniffing time but Lmx1b/ males spent less time sniffing female genital odour than the other two groups. b, Sniffing ratio of Lmx1b/ males was significantly different from Lmx1b+/+ and Lmx1b+/ males (P<0.05 for Lmx1b+/+ versus Lmx1b/, P<0.05 for Lmx1b+/ versus Lmx1b/, P>0.05 for Lmx1b+/+ versus Lmx1b+/; one-way ANOVA). c, Compared with Lmx1b+/+ and Lmx1b+/, a higher percentage of Lmx1b/ males spent more time sniffing male than female genital odour. d, ePet1-Cre males spent more time above female bedding than male bedding, as did Lmx1b+/+ and Lmx1b+/ males. Lmx1b/ males spent a similar amount of time above female and male bedding. Compared with ePet1-Cre, Lmx1b+/ and Lmx1b+/+, Lmx1b/ males spent less time above female bedding but more time above male bedding. e, The bedding time ratio of Lmx1b/ was different from ePet1-Cre and Lmx1b+/+. f, Compared with ePet1-Cre, Lmx1b+/+ and Lmx1b+/, a significantly higher percentage of Lmx1b−/− males spent more time above male bedding. *P<0.05, **P<0.01, ***P<0.001.

  4. Odour discrimination.
    Figure 4: Odour discrimination.

    a, Both Lmx1b+/+ and Lmx1b−/− males showed habituation and dishabituation in sniffing time. No statistical difference was found between Lmx1b+/+ and Lmx1b/ males at any point. b, After seven training sessions with male and female urine, no significant difference was detected between Lmx1b+/+ and Lmx1b/ males at any point.

  5. Brain chemistry and behaviours of Tph2 knockout males.
    Figure 5: Brain chemistry and behaviours of Tph2 knockout males.

    a, b, Compared with Tph2+/+ and Tph2+/, Tph2/ males showed a shorter latency (a) and higher frequency in mounting males (b). c, Both Tph2+/+ and Tph2+/ males significantly preferred female over male bedding, whereas Tph2/ males did not show a preference between male and female bedding. d, Both Tph2+/+ and Tph2+/ males significantly preferred female over male genital odour, whereas Tph2/ males did not show a preference between male and female genital odour. *P<0.05, **P<0.01, ***P<0.001.

  6. 5-HTP rescue of chemical and behavioural deficits in Tph2 knockout mice.
    Figure 6: 5-HTP rescue of chemical and behavioural deficits in Tph2 knockout mice.

    a, Levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were analysed in Tph2+/+ and Tph2/ males 35min after injection of either 5-HTP (40mgkg−1 body weight) or control saline. b, c, Male–male mounting in Tph2/ mice was significantly rescued by 5-HTP: the latency was lengthened and frequency reduced. d, Bedding preference was monitored between 35 and 40min after injection. 5-HTP could significantly restore the preference of female over male bedding by Tph2/ males.

Change history

Corrected online 07 April 2011
The labelling of Fig. 3 and associated legend was corrected.

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Author information

  1. These authors contributed equally to this work.

    • Yan Liu &
    • Yun’ai Jiang

Affiliations

  1. National Institute of Biological Sciences, Beijing 102206, China

    • Yan Liu,
    • Yun’ai Jiang,
    • Yunxia Si &
    • Yi Rao
  2. Graduate School of the Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China

    • Yan Liu
  3. Institute of Neuroscience, Shanghai Institute of Biological Sciences, and Graduate School of the China Academy of Science, China

    • Yun’ai Jiang
  4. Departments of Anesthesiology, Psychiatry and Developmental Biology, and the Pain Center, Washington University, School of Medicine, St Louis, Missouri 63110, USA

    • Ji-Young Kim &
    • Zhou-Feng Chen
  5. Peking University School of Life Sciences, State Key Laboratory of Membrane Biology, Beijing 100871, China.

    • Yi Rao

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.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

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Supplementary information

PDF files

  1. Supplementary Information (973K)

    This file contains Supplementary Figures 1-11 with legends and Supplementary Dataset 1.

Zip files

  1. Supplementary Movie 1 (7.9M)

    Mating of a wt target male by a Lmxb1-/- male. A Lmxb1-/- male mounted a wt male.

  2. Supplementary Movie 2 (4.4M)

    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.

  3. Supplementary Movie 3 (10.2M)

    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.

  4. Supplementary Movie 4 (4.2M)

    Mating of a wt target male by a Tph2-/- male. A Tph2-/- male mounted a wt male.

  5. Supplementary Movie 5 (7.4M)

    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.

  6. Supplementary Movie 6 (11.6M)

    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.

Comments

  1. Report this comment #19691

    Eric Snyder said:

    Fascinating work! The next step would be to show that 5HTR antagonists have a similar effect on sexual preference/behavior. If so, receptor-subtype-specific ligands might be used to determine what neurons in which pathways might be involved. Still, I wonder a) if this can be extrapolated to humans, and b) whether it can be addressed pharmacologically. People have been taking 5HT antagonists in the form of LSD, migraine medications and other drugs for many years. I have never heard of these compounds causing even an acute change in sexual preference. Of course, I haven't heard everything!

  2. Report this comment #19700

    Riccardo Gottardi said:

    I wonder if the statement in the abstract "These results indicate that 5-HT and serotonergic neurons in the adult brain regulate mammalian sexual preference." which extends the findings of this research to all mammalians, is not too extensive. The authors themselves conclude the article stating: "An unavoidable question raised by our findings is whether 5-HT has a role in sexual preference in other animals. [...] Our discovery of a role for serotonergic signalling in mouse sexual preference should stimulate further studies into the role of 5-HT in sexual interactions in particular and roles of neurotransmitters in mammalian social relationships in general." Which suggests quite a different conclusion than that stated in the abstract, that is, as the authors themselves state elsewhere in the text:"We conclude that central serotonergic signalling is crucial for male sexual preference in mice. This is the first time, to our knowledge, that a neurotransmitter in the brain has been demonstrated to be important in mammalian sexual preference. Previous studies in mammals have implicated 5-HT and dopamine in male sexual behaviours, but neither has been demonstrated to have any role in sexual preference".

    Beside the need to "completely rule out the possibility that 5-HT regulates a specific innate olfactory pathway processing sexual information", as the authors state, it would be interesting to address two further questions.
    1) does 5-HT influence also female sexual preference? if not, what influences female sexual preference?
    2) what si the role of 5-HT in human sexual preference? and, specifically, how does it affects males and females?
    Too often research on the subject of human sexuality is actually focussed on male sexuality, which limits considerably many research efforts themselves.

  3. Report this comment #19701

    Qazi Rahman said:

    Great work. I like the use of several behavioural outcomes in the study. Not so sure about the extrapolation to humans ? work on SSRIs and the like suggest impairments in sexual motivation/desire mainly. There has never been a documented case of changes in the direction of human sexual preferences (i.e., in the ?targeting? mechanism that psychologists think is central to how the brain orients attention to sexual stimuli) induced by 5HT antagonists.

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