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Genes Brain Behav. Author manuscript; available in PMC Oct 8, 2008.
Published in final edited form as:
PMCID: PMC2563427
NIHMSID: NIHMS70340

Effects of sex chromosome aneuploidy on male sexual behavior

Abstract

Incidence of sex chromosome aneuploidy in men is as high as 1:500. The predominant conditions are an additional Y chromosome (47,XYY) or an additional X chromosome (47,XXY). Behavioral studies using animal models of these conditions are rare. To assess the role of sex chromosome aneuploidy on sexual behavior, we used mice with a spontaneous mutation on the Y chromosome in which the testis-determining gene Sry is deleted (referred to as Y) and insertion of a Sry transgene on an autosome. Dams were aneuploid (XXY) and the sires had an inserted Sry transgene (XYSry). Litters contained six male genotypes, XY, XYY, XXSry, XXYSry, XYSry and XYYSry. In order to eliminate possible differences in levels of testosterone, all of the subjects were castrated and received testosterone implants prior to tests for male sex behavior. Mice with an additional copy of the Y chromosome (XYY) had shorter latencies to intromit and achieve ejaculations than XY males. In a comparison of the four genotypes bearing the Sry transgene, males with two copies of the X chromosome (XXSry and XXYSry) had longer latencies to mount and thrust than males with only one copy of the X chromosome (XYSry and XYYSry) and decreased frequencies of mounts and intromissions as compared with XYSry males. The results implicate novel roles for sex chromosome genes in sexual behaviors.

Keywords: Klinefelter syndrome, libido, male sex behavior, sex chromosome aneuploidy

Sex chromosome aneuploidy is a very common occurrence with incidence rates in men reported to be as high as 1:500, for both 47,XXY and 47,XYY (Rives et al. 2003; Simpson et al. 2003). Men with an additional Y chromosome (47,XYY) exhibit physical and behavioral features that may be a consequence of increased Y gene dosage. Longitudinal studies of XYY boys (Gotz et al. 1999; Ratcliffe et al. 1991; Walzer et al. 1991) and of XYY men (Theilgaard 1984) have shown that they are on average taller with reduced IQ; behavioral and psychological assessments suggest a tendency towards increased emotional instability and increased sexual drive. More studies of men with Klinefelter syndrome (47,XXY) have been conducted likely because they are hypogonadal and thus more often identified. These men typically report low sex drive possibly as a result of low endogenous testosterone (T) levels (Sorensen et al. 1979; Yoshida et al. 1997), although some men with Klinefelter syndrome report that low libido persists even after androgen replacement (Stewart et al. 1990; Winter 1991). This outcome may not be surprising, because circulating levels of T are not well correlated with self-reported sexual activity (Brown et al. 1978; Kraemer et al. 1976; Raboch & Starka 1973; Zverina et al. 1990). In humans, the potential direct roles of sex chromosome genes on the brain and sexual behavior, independent of differences in gonadal hormones, must be taken into account, as differences in gonadal hormone levels can affect physical and neural substrates that influence libido. Thus, all subjects in this study were gonadectomized male mice (MF1 strain) treated with identical T doses.

Even in rodents, sexual behavior is not strictly regulated by androgens. Strain differences in male mouse sexual behavior are well documented (Burns-Cusato et al. 2004; Clemens et al. 1988; Dominguez-Salazar et al. 2004; McGill & Blight 1963; McGill & Tucker 1964). These differences are often attributed to genetic differences, but the genetic bases have hardly been investigated. One study of male mouse sexual behavior investigated gonadally intact congenic mice possessing Y chromosomes from two different common mouse strains (DBA/2J and C57BL/10J). A small, but significant, difference in the percentage that displayed mounting behavior with a receptive female was reported (Shrenker & Maxson 1983). In another study using a mouse cross in which gonadal and chromosomal sex were uncoupled, XYSry males (that have a Y chromosomal with a spontaneous deletion of the Sry gene, plus an autosomal Sry transgene that induces development of testes) and XXSry males did not differ in masculine sexual behavior, but differed from normal XY males in latency to thrust (De Vries et al. 2002).

Here we use phenotypic male littermates that include six different genotypes, in which numbers and combinations of the sex chromosomes were varied. Males were castrated in adulthood and sexual behavior was assessed after T replacement. We used a series of planned comparisons to assess the contributions of an additional Y chromosome, the effect of the Sry transgene and differences in sex chromosome complement on male sexual behavior.

Methods

Animals

Mice in this study were in the random bred MF1 background. Paul S. Burgoyne (National Institute for Medical Research, Mill Hill, UK) started this cross by breeding transgenic XYSry males, in which the Y chromosome was of C56BL/10 strain origin and the autosomally located Sry originated from the 129S8/SvEv-Gpi1c Hprt1b-m2/J strain (Jackson Laboratories, Stock #002027), with XXY females carrying the variant 129 YTdym1 (here called Y) that is deleted for Sry (Gubbay et al. 1992) (male and female are defined here by gonadal type). Mice with the XXY genotype are female (ovary bearing) and fertile, and XYSry males (testis bearing) are likewise fertile. The dams produce X or XY ova. The sires produce X or Y bearing sperm and with the Sry transgene segregating independently. The progeny of this cross includes two female genotypes (XX and XXY), which were not studied and gonadal males with six genotypes: XY, XYY, XYSry, XYYSry, XXSry and XXYSry.

Breeding pairs were shipped to the University of Virginia from the National Institute for Medical Research, at Mill Hill, London, UK. All subjects were born and raised at the University of Virginia School of Medicine animal facility. Tissue was collected at weaning to obtain DNA and RNA for genotyping. We amplified a segment of the Y-linked gene Ssty to establish presence of the Y chromosome using primers SSTY1: 5′-CTGGAGCTCTAC AGTGATGA-3′ SSTY2: 5′-CAGTTACCAATCAACACATCAC-3′. We measured Xist mRNA as in indication of the numbers of X chromosomes; Xist is expressed by the inactivated X chromosome, thus its presence indicates two or more X chromosomes. The primers used for Xist forward were 5′-TAAGGACTACTTAACGGGCT-3′ Xist reverse: 3′-TACTCAGACATTCCCTGGCA-3′. We assessed the presence of the Sry transgene (Burgoyne et al. 2001) using transgene-specific primers SRY forward: 5′-CATCACCATGTGGCAATACC-3′ and SRY reverse: 5′-CTCAGTGTGGAATTCATCTGC-3′. Semi-quantitative polymerise chain reaction (PCR) of Ssty, which was conducted under similar conditions as the PCR to detect the Y chromosome, was carried out to discriminate among males with one vs. two copies of the Y chromosome. Because the amount of product produced by PCR roughly correlates to the amount of the starting material, animals that have two copies of Y have double the amount of product and thus will show a band on the gel after 22 cycles (vs. 35 cycles for the PCR for the Y chromosome) as opposed to samples with one copy of Y (see Table 1 for a summary of the genetic differences between genotypes).

Table 1
Characteristics of the six male genotypes

At 21 days of age, subjects were weaned and housed in same sex sibling cages. Between 2 and 4 months of age the subjects were gonadectomized and implanted with Silastic capsules (Dow Corning, Midland, MI, USA) filled with crystalline T (1 cm length, 1.02 mm inner diameter, 2.16 mm outer diameter). Animals were then moved into individual home cages. All mice were housed in a 12:12 light/dark cycle (lights off at 1200 h Eastern Daylight Time) where they received food and water ad libitum in the University of Virginia Animal Care Facility. All animal procedures were conducted in accordance with our animal protocol, approved by the University of Virginia Committee on Animal Care and Use.

Sexual behavior tests

Mice were tested when they were of appropriate age after gonadectomy and T implants were given between 2 and 4 months of age. With 10 pairs of breeders, ~9 months were needed to generate all the males used for this study. A total of 21 litters were bred, consisting of an average of 3.3 ± 0.3 males per litter. Five rounds of behavioral testing with 2–4 males per genotype that were age matched were conducted over the ~9-month period.

Seven days following gonadectomy, mice were habituated to other animals (Wersinger & Rissman 2000); social exposure decreases the latencies of the display of many male-typical behaviors in sexually naïve male mice that have been raised in isolation after weaning (Sipos & Nyby 1998). After at least 1 week of recovery from surgery, each animal was given a series of social experiences with gonad-intact, C57BL/6J male and female mice. During each exposure, the stimulus animals were individually placed in the subject's home cage for 2 min. The order of presentation of the stimulus mice was alternated with each exposure. Each subject interacted with both a male and a female daily over a 5-day period.

Three days after social habituation ended, sexual behavior was tested under dim red lights during the dark phase of a light/dark cycle every 3–4 days for a total of four tests (Wersinger et al. 1997). Behavior tests were conducted in an 18×30 cm clear Plexiglas testing cage, and the cage was placed on a ventral viewing stand so intromissions could be accurately quantified. Stimulus C57BL/6J females were ovariectomized and implanted s.c. with estradiol (50μg/0.025 ml sesame oil in a Silastic implant; 1.98 mm i.d., 3.17 mm o.d.). Three to 5 h prior to testing, stimulus females were injected s.c. with 500μg progesterone.

All subjects were sexually naïve at the time of the first test. Each subject was placed alone in the testing cage and allowed to acclimate for 1 h. The stimulus females were placed in the cage and the latencies to mount (time from the introduction of a receptive female to the first mount), thrust (time from the introduction of a receptive female to the first thrust), intromit (time from the introduction of a receptive female to the first intromission) and ejaculate (time from the introduction of a receptive female to the first ejaculation) and the number of mounts (the number of mounts not accompanied by thrusts or intromissions that preceded the ejaculation or the termination of the test), mounts with thrusts (the number of mounts accompanied by thrusts that preceded the ejaculation or the termination of the test), intromissions (the number of intromissions that preceded the first ejaculation or the termination of the test) and ejaculations were recorded. Tests were terminated when males ejaculated or after 1 h (whichever occurred first). If a male never exhibited a given behavior, the latency was recorded as 3600s.

The following groups were formed: XY (n = 12), XYY (n = 13), XYSry (n = 11), XYYSry (n = 13), XXSry (n = 13) and XXYSry (n = 7). The experimenter who scored the behavioral data was blind to the genotype of the subjects. Frequency data were lost for four individuals.

Testosterone assay

Samples were collected at two time points, occurring at 50–70 days of age in gonad-intact males and after the males were castrated and given a T implant at the conclusion of all behavioral tests. All blood samples were taken within 3–4 h after dark onset. In all cases blood was collected by cardiac puncture for T assay. Assays for T were conducted using radioimmunoassay performed by the University of Virginia Core Ligand and Assay Laboratory. Animals were anesthetized with halothane inhalant. A cardiac puncture was used to collect 250μl of blood. Samples were run in singlet in a single assay to eliminate inter-assay variability. The range of the assay was from 0.1 to 10 ng/ml. The mean coefficient of variation was 5.75 ± 2.1%.

Statistics

Using chi-squared tests, we determined which groups had a significantly different proportion of males that ejaculated during the testing series; significant pairwise differences between groups were based on Fisher's exact P value.

The six genotypes were separated into two categories for two separate statistical analyses: those without the Sry transgene (XY and XYY) and those with the Sry transgene (XXSry, XXYSry, XYSry and XYYSry). After calculating the averages over the four behavioral tests of each of the components of male sexual behavior, one-way analyses of variance (anovas) were used to analyze the effect of an additional Y on male sexual behavior in the two groups without an Sry transgene. In addition, averages over the four tests from the subpopulation of males that exhibited a complete copulatory sequence were used in a one-way anova to analyze differences in mating behavior. Two-way anovas with between subject factors Y (present, absent) and number of X chromosomes (1, 2) were also conducted on the averages over the four behavioral tests of the four groups with the Sry transgene; similar analyses were conducted on the males in these four groups that exhibited an ejaculation on at least one test. One-way anovas were conducted between groups when a factor was determined to be significant.

Additional analyses were conducted to determine the effect of the presence of Y (XYY and XYYSry) or the Sry transgene (XYSry and XYYSry). Two-way anovas were used to analyze the averages over the four behavioral tests for each of the components of male sexual behavior; in addition, averages over the four tests from mice that ejaculated were used in a two-way anova to analyze differences in mating behavior within the subpopulation of males that exhibited a complete copulatory sequence.

The testosterone data were analyzed across the six groups by a one-way anova with genotype as the variable for each time-point (from intact males and from males after castration with a T implant).

All significant pairwise differences between groups were tested with the post-hoc Fisher's PLSD, which corrects for multiple comparisons. The significance level was set at 0.05. All of the statistics were calculated using Statview 5 (SAS Institute, Cary, NC, USA).

Results

Proportion of males that ejaculate is not influenced by genotype

There were no differences statistically in the proportion of males that ejaculated between any of the groups (Fig. 1a; P > 0.05 for all comparisons). However, the differences between the proportion of XXYSry males that ejaculated compared to the proportion of the XYY2(1) = 5.5, P = 0.06) and XYYSry2(1) = 5.5, P = 0.06) males nearly reached significance.

Figure 1
Ejaculatory behavior of six male genotypes

Males with an additional Y chromosome in the absence of the Sry trangene displayed enhanced male sexual behavior

The mean latencies to intromit (F1,23 = 5.45, P < 0.03) and achieve ejaculations (F1,23 = 9.03, P < 0.006) based on the averages of the four behavioral tests were shorter in XYY than in XY males (Fig. 2a). Latencies to mount (F1,23 = 2.57, P = 0.12) and thrust (F1,23 = 0.67, P = 0.42) did not differ between the groups. The average number of ejaculations over the four tests were greater in XYY than XY males (F1,23 = 6.60, P = 0.02; Fig. 1b and Table 2).

Figure 2
Latencies of male sexual behaviors of XY and XYY males
Table 2
Measures of sexual behavior averaged over the four tests in males that achieved at least one ejaculation on any of the four behavioral tests (±SEM)

When the analysis was limited to the group of males that ejaculated, again, latencies to intromit (F1,13 = 8.42, P = 0.01) and ejaculate (F1,13 = 5.29, P = 0.04) were faster for XYY than XY mice (Fig. 2b and Table 2).

Male sexual behavior was affected by genotype in the groups with the Sry transgene

There was a main effect of the number of X chromosomes on the average over the four behavioral tests for mount latency (F1,40 = 12.10, P = 0.001), thrust latency (F1,40 = 10.15, P = 0.003), intromission latency (F1,40 = 5.17, P = 0.03), mounts (F1,39 = 6.77, P = 0.01), intromissions (F1,39 = 9.90, P = 0.003) and ejaculations (F1,39 = 5.20, P = 0.03; Figs 3 and and4).4). There was no main effect of the number of X chromosomes on the average over the four behavioral tests for ejaculation latency (F1,40 = 1.93, P = 0.17) or for thrusts (F1,39 = 3.68, P = 0.06). Because only one XXYSry male displayed the complete ejaculatory behavioral sequence, two-way anovas were not conducted on the data from the subpopulations of the males that ejaculated.

Figure 3
Latencies of male sexual behaviors of males with the Sry transgene
Figure 4
Frequencies of male sexual behaviors of males with the Sry transgene

There was no main effect of the presence or absence of Y on the average over the four behavioral tests for mount latency (F1,40 = 0.56, P = 0.11), thrust latency (F1,40 = 0.87, P = 0.14), intromission latency (F1,40 = 0.09, P = 0.06), ejaculation latency (F1,40 = 0.36, P = 0.09), mounts (F1,39 = 1.24, P = 0.18), thrusts (F1,39 = 1.37, P = 0.20), intromissions (F1,39 = 0.55, P = 0.11) and ejaculations (F1,39 = 1.10, P = 0.17). These results indicate that the additional Y chromosome had no impact on male sexual behavior between XXSry and XXYSry males and between XYSry and XYYSry males.

No significant interaction effect was found between the number of X chromosomes and the presence or absence of Y was found on the average over the four behavioral tests for mount latency (F1,40 = 0.64, P = 0.12), thrust latency (F1,40 = 0.15, P = 0.07), intromission latency (F1,40 = 0.48, P = 0.10), ejaculation latency (F1,40 = 0.27, P = 0.08), number of mounts (F1,39 = 0.58, P = 0.11), thrusts (F1,39 = 0.83, P = 0.14), intromissions (F1,39 = 0.17, P = 0.07) and ejaculations (F1,39 = 0.51, P = 0.10).

Effect of the presence of Y or the Sry transgene among XY, XYY, XYSry and XYYSry males on male sexual behavior

There were no main effects of either the presence of Y or the Sry transgene or their interaction among XY, XYY, XYSry and XYYSry males on the averages over the four behavioral tests for all behavioral components measured (P > 0.05 for all comparisons). When only the data of the males that ejaculated were analyzed, there was a significant interaction between the two factors for mounts (F1,25 = 7.11, P = 0.01) and ejaculations (F1,25 = 8.18, P = 0.01) and a main effect of Y for thrusts (F1,25 = 6.28, P = 0.02). Further analyses showed that XYSry males mounted significantly more than XY (P = 0.03) and XYYSry males (P = 0.03; Fig. 5a), and that XYSry males thrusted significantly less than XYY males (P = 0.01; Fig. 5b). XYY males displayed a greater average number of ejaculations over 4 tests than XY (P = 0.004), XYSry (P = 0.03) and XYYSry males (P = 0.003; Fig. 5d). There were no main effects found for either of the two factors or their interaction for mount, thrust, intromission, or ejaculation latencies (P > 0.05 for all comparisons).

Figure 5
Frequencies of male sexual behaviors of XY, XYSry, XYY, XYYSry males

Testosterone concentrations are unaffected by genotype

Males in all six genotypes had equivalent concentrations of T in plasma at both time points (F5,55 = 0.41, P = 0.84 for intact males and F5,46 = 0.44, P = 0.82 for castrated males; Table 3). Testosterone concentrations in the gonad-intact males tended to be higher than the levels achieved (about 1–2 ng/ml) in males with the implants. This is in agreement with past studies using this T-implant dose (Scordalakes & Rissman 2003).

Table 3
Testosterone concentrations (±SEM) in plasma of adult males prior to castration and after gonadectomy and T replacement. No genotype effects are present in the samples taken from intact males. In addition, the hormone implants after castration ...

Discussion

In the present study, we probed the effects of the presence of the Y chromosome, the presence of two X chromosomes, or the Sry transgene on male copulatory behavior. Addition of the Y chromosome enhanced male sexual behavior as evidenced by shorter latencies to intromit or ejaculate and higher frequency of ejaculations, of XYY males compared to XY males. In the subset of males that mated to ejaculation, mean latencies to intromit or ejaculate were shorter in XYY than XY males, but mean frequencies of behaviors within mating bouts did not differ. The major source of genetic variation between XY and XYY males is the presumed overexpression of Y chromosome genes in the XYY, with the exception of the Sry gene, which was deleted from the Y chromosome and therefore present as a single endogenous copy on the Y chromosome in both genotypes. Differences between these groups are also potentially attributable to allelic differences in Y genes, because the Y chromosome derives from strain 129 YTdym1, and the Y chromosome derives from the MF1 strain. Our results suggest that the Y chromosome genes likely have effects on male reproduction, not only because of the testis-determining role of Sry in gonadal differentiation and the role of the Y genes in spermatogenesis, but also because of the action of non-Sry Y gene(s) that facilitate(s) male sexual behavior, such as gene(s) located within the pseudoautosomal (PAR) region of the Y chromosome (possibly steroid sulfatase, Sts). Increased Sts dosage is potentially responsible for the effect of an additional Y chromosome reported here. Differences in sexual behavior between different strains of mice have been documented, but a contribution of Y chromosome genes to masculine sexual behavior has only been reported once before (Shrenker & Maxson 1984). In that study, DBA/2 males were significantly more likely to mount receptive females, than were congenic males with a Y from the DBA/1 strain, thus implicating a non-PAR Y chromosome gene(s). It will be interesting in future studies to determine which Y gene(s) are responsible for these behavioral effects. Although the present results offer support for the role of Y genes, other than Sry, in male sexual behavior, it is important to realize that the expression of Y gene protein products may be higher than levels found in normal males if the presence of a second Y chromosome increases expression of those genes.

The addition of a Y chromosome did not, however, lead to increases in copulatory behavior under all circumstances. Very few differences were found in male sex behavior of XYSry vs. XYYSry males or XXSry vs. XXYSry males. In the case of XYSry and XYYSry males, all males have two copies of Sry, one endogenous and one from the transgene, which may have masked or in some way interfered with the effects of the addition of Y genes. In the comparison of XXYSry vs. XXSry, we did not detect a phenotypic effect of an additional dose of Y genes when two X chromosomes were present. Thus, the effects of presumed overexpression of Y genes (other than Sry) appear to be mitigated if the Sry transgene is present or if two X chromosomes are present.

To determine the effects of sex chromosome complement in males with a Sry trangene, male sexual behaviors were analyzed in XXSry, XXYSry, XYSry and XYYSry males. A decrease in male sexual behavior was evidenced by longer latencies to mount, thrust and intromit in males bearing two X chromosomes. The deficits observed in the XXYSry males are interesting as these mice have a similar chromosomal makeup to men with Klinefelter's syndrome (XXY). None of the dyadic comparisons of the present study is equivalent to the comparison of XXY Klinefelter vs. normal XY human males, because some of the comparisons (XXYSry vs. XYYSry and XYSry vs. XXSry males) involve more than just the addition of the second X as in Klinefelter's, and other comparisons (XY vs. XXYSry) involve changes in the number of X chromosomes confounded with the type of Y chromosome (MF1 in XY vs. 129 YTdym1 in XXYSry). Nevertheless, the trends that we have observed in comparison of the mice with the Sry transgene suggest that the behavioral differences may be the result of increased expression of X genes that may have escaped inactivation in XX vs. single-X mice. Alternatively, the presence of a paternal X imprint in mice with two X chromosomes, but not in mice with a single X, could also have contributed to the differences. Further tests are needed to confirm the potential effects of increased X chromosome dosage.

In slight contrast to our results, differences in male sexual behavior were not observed between XYSry and XXSry males (De Vries et al. 2002), although there are several variables that may account for this discrepancy. XYSry males in this study possessed both the endogenous Sry gene and the Sry transgene which may have affected male sexual behavior. In addition, the parents that produced the litters evaluated here versus those used to produce the four core genotypes (XX, XY, XXSry and XYSry) are not the same genotypes and parental/pup interactions might affect adult sexual behavior (reviewed in Moore 1992). Finally, as the genotypes of the offspring are different, as is the sex ratio of the offspring, the intra-uterine environments are not equivalent (Meisel & Ward 1981; vom Saal & Bronson 1978; vom Saal et al. 1983).

Interestingly the mice did not differ significantly in the level of plasma T in adulthood at the time of castration or after they received the T implants. Thus, the addition of an extra Y chromosome, an autosomal copy of Sry, or differences in sex chromosome complement did not increase or decrease plasma T in adulthood. Lue et al. (2005), using a different model for sex chromosome aneuploidy in mice, reported that XXY males had 50% less plasma T than XY males. Background strain differences (C57 vs. MF1) and differential genetic effects of the transgene vs. the wild-type gene may account for this discrepancy between the two studies. Although the group differences in behavioral phenotype reported here are not attributable to group differences in the level of T at the time of testing, they could have resulted from group differences in the levels of T at other times of life, for example pre-or postnatally, which have long lasting effects (Corbier et al. 1983; Roffi et al. 1987; Thomas & Gerall 1969). These other time points have not been assessed in either mouse model, or in humans with sex chromosome aneuploidy.

The results suggest that the behavioral abnormalities found in human aneuploids may be modeled by our studies of aneuploid mice. Two of the most common human sex chromosomal aneuploidy diseases are 47,XYY and Klinefelter syndrome (47,XXY; reviewed in Boone et al. 2001; Lanfranco et al. 2004; Smyth & Bremner 1998). A recent paper using a mouse model for XXY reported a small cognitive deficit in XXY mice in a Pavlovian conditioning task (Lue et al. 2005). Because the mice were tested with intact gonads and the XXY males had 50% less T than XY mice, it is not clear if this behavioral effect is caused by hormones or more direct effects of sex chromosome genes on hormone levels or on the brain. Human XXY aneuploids are abnormal both in the genetic constitution of their brain cells and in the secretion of gonadal steriods, so it is difficult to tease apart the hormonal and direct genetic effects on the brain. In addition, the comparison of mouse and humans is complicated, in part because the human Y has genes not encoded on the mouse Y. Teasing apart direct genetic and endocrine-mediated effects of the Y chromosome is difficult in humans, but will be easier in studies of mice.

Importantly, these studies provide us with several experimental paradigms in which two groups of mice differ in behavior because of the action of Y chromosome genes. These same group comparisons can therefore be exploited to determine which Y genes are responsible, whether Y genes are expressed in brain regions controlling sexual behavior, whether expression of Y genes is tightly correlated with the expression of the behavior and how the Y genes interact with androgens to influence social behaviors.

Acknowledgments

We thank Aileen Wills for technical assistance. We are indebted to Dr. Paul Burgoyne for providing advice, guidance and the breeder pairs we used to generate subjects for this work. This work was supported by NIH grants R01 NS043196 (A.P.A.) and R01 NS055218 (E.F.R.). M.B.-C. was supported by F32 HD049214. J.H.P. was supported by the Center for Cellular and Molecular Studies in Research Training grant (T32 HD07382). The Virginia Core Ligand and Assay Laboratory is supported by NICHD/NIH through co-operative agreement (U54 HD28934) and is part of the Center for Cellular and Molecular Studies in Reproduction.

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