A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits

Abstract

We tested the hypothesis that genes encoded on the sex chromosomes play a direct role in sexual differentiation of brain and behavior. We used mice in which the testis-determining gene (Sry) was moved from the Y chromosome to an autosome (by deletion of Sry from the Y and subsequent insertion of an Sry transgene onto an autosome), so that the determination of testis development occurred independently of the complement of X or Y chromosomes. We compared XX and XY mice with ovaries (females) and XX and XY mice with testes (males). These comparisons allowed us to assess the effect of sex chromosome complement (XX vs XY) independent of gonadal status (testes vs ovaries) on sexually dimorphic neural and behavioral phenotypes. The phenotypes included measures of male copulatory behavior, social exploration behavior, and sexually dimorphic neuroanatomical structures in the septum, hypothalamus, and lumbar spinal cord. Most of the sexually dimorphic phenotypes correlated with the presence of ovaries or testes and therefore reflect the hormonal output of the gonads. We found, however, that both male and female mice with XY sex chromosomes were more masculine than XX mice in the density of vasopressin-immunoreactive fibers in the lateral septum. Moreover, two male groups differing only in the form of their Sry gene showed differences in behavior. The results show that sex chromosome genes contribute directly to the development of a sex difference in the brain.

Fig. 1.

Latencies to mount, thrust, and ejaculate during sex behavior tests (means ± SEM). Within the four genotypes generated in the core cross, males (XY⁻Sry and XXSry) had longer latencies to mount and to thrust than did females (XY⁻ and XX) (p < 0.00005). XY males, which derived from a different cross, had longer latencies to mount than XY⁻Srymales. Group sizes left to right were as follows: 8, 15, 16, 15, and 13 for latency to mount; 7, 14, 14, 10, 7 for latency to thrust; 5, 11, and 10 for latency to ejaculate.

Fig. 2.

Total mounts (means ± SEM) during sexual behavior tests with receptive female partners. Within the core cross, males (XY⁻Sry and XXSry) mounted more than did females (XY⁻ and XX) (p < 0.001). Groups sizes for groups left toright were 8, 15, 16, 15, and 13.

Fig. 3.

Time spent sniffing an anesthetized female in a 10 min social exploration test (means ± SEM). Within the core cross, males (XY⁻Sry and XXSry) spent more time sniffing the stimulus female than did females (XY⁻ and XX) (p < 0.0005).

Fig. 4.

Numbers of visits (means ± SEM) to the chambers in the three-chambered box, regardless of whether it contained a male or female stimulus animal (top), and visits to the chamber that contained the anesthetized male in the social exploration tests. Males (XY⁻Sry and XXSry) paid more visits to the stimulus male than did females (XY⁻ and XX) (p< 0.05). XY males paid more visits to the chambers with the stimulus male or female and also visited the stimulus male more often than did XY⁻Sry males (p < 0.05).

Fig. 5.

Number of SNB motoneurons (means ± SEM). Males of the core cross (XY⁻Sry and XXSry) had more SNB neurons than females (XY⁻ and XX) did (p < 0.0001) but did not differ from XY males derived from a different cross.

Fig. 6.

Number of TH-ir neurons in the AVPV (means ± SEM). Within the core cross, males (XY⁻Sry and XXSry) had fewer neurons than females (XY⁻ and XX) did (p < 0.000003). Paradoxically, XY males had a feminine number of TH-ir neurons and therefore significantly more TH-ir neurons than did XY⁻Sry males (p = 0.08).

Fig. 7.

Density of vasopressin immunoreactive fibers in the lateral septum (means ± SEM). Black andhatched bars represent the results from the first and second experiments, respectively. Within the core cross, males (XY⁻Sry and XXSry) had a higher density than did females (p < 0.000001). XY⁻Sry males had a higher density than XXSry males (p< 0.05), showing an effect of sex chromosome complement on this trait.

Fig. 8.

Density of vasopressin immunoreactive fibers in the lateral septum in mice from all-female litters (means ± SEM). XY⁻ females had a higher density than XX females did (p < 0.02).