Santiago Segovia

Sexual dimorphism in the vomeronasal pathway and sex differences in reproductive behaviors

Several years ago we hypothesized that the vomeronasal system (VNS), a complex neural network involved in the control of reproductive behavior, might be sexually dimorphic. This hypothesis sprung from several facts; (a) the existence of steroid receptors in the VNS; (b) sexual dimorphism was already described in some structures that receive vomeronasal input, such as the medial preoptic area, the ventromedial hypothalamic nucleus, the ventral region of the premammillary nucleus and the medial amygdaloid nucleus; and (c) the vomeronasal organ, which is the receptor organ of the VNS, was also sexually dimorphic. After that point, the accessory olfactory bulb (AOB), the bed nucleus of the accessory olfactory tract (BAOT) and the bed nucleus of the stria terminalis were found to be sexually dimorphic. The aim of the present review is to show the experimental facts that confirm our earlier hypothesis and, consequently, to present the existence of a sexually dimorphic multisynaptic pathway for the first time in mammals. Sexual dimorphism in the VNS might provide a comprehensive approach to understanding the neural bases of sexually dimorphic reproductive behavior and it is suggested here that the greater number of neurons which male rats present in relation to females in most VNS structures might contribute to the inhibition of the expression of feminine copulatory behavior (lordosis) and maternal behavior in males. In addition, the mechanisms that control the development of sexual dimorphism in the VNS are discussed. The discussion takes into account the two patterns of sexual dimorphism found in the rat brain. Estrogens seem to promote the development of sexual dimorphism in both male and female rats. However, an inhibitory role of androgens might be necessary to hypothesize when males or females present a lower number of neurons and/or volume than the opposite sex. There are experimental data supporting this hypothesis in the female, since dihydrotestosterone seems to facilitate neuronal death in VNS structures, such as the AOB and the BAOT, in which females present a lower number of neurons and volume than male rats. Finally, since the lateral division of the bed nucleus of the stria terminalis, which belongs to the main olfactory system (MOS), is sexually dimorphic and presents anatomical relationships with some VNS structures the MOS might be sexually dimorphic.

Early effects of gonadal steroids on the neuron number in the medial posterior region and the lateral division of the bed nucleus of the stria terminalis in the rat

This work investigates the possible existence of sex differences in the number of neurons in the medial posterior region (BNSTMp) and the lateral division (BNSTL) of the bed nucleus of the stria terminalis in the rat. These two zones of the bed nucleus of the stria terminalis belong, respectively, to the vomeronasal system (VNS), and to the main olfactory system (MOS). In the BNSTMp, males showed a greater number of neurons than females. Early postnatal (Day 1 after birth) orchidectomy in males, and androgenization in females, eliminated and reversed these differences. In the BNSTL, sexual dimorphism was restricted to its anterior region (BNSTLa). Females showed there a greater number of neurons than males. Male orchidectomy on Day 1 after birth increased the number of neurons, while female androgenization produced the opposite effect. The results obtained in this study support the hypothesis that the VNS is sexodimorphic, and suggest that sex differences exist in MOS, and that these differences are controlled by gonadal steroids during the perinatal period.

The bed nucleus of the stria terminalis in the rat: regional sex differences controlled by gonadal steroids early after birth☆

The effects of postnatal (on day 1 (D1) after birth) male orchidectomy and female androgenization on the bed nucleus of the stria terminalis (BNST) were studied. The volume of the medial posterior region of the BNST was greater in the control males than in the control females. Postnatal treatment reversed these differences. Sex differences were also found in the medial anterior region of the BNST where female rats always showed a greater volume than did the males. Female androgenization on D1 did not affect the volume of the BNST medial anterior region. However, D1 male orchidectomy did increase significantly the volume of this region. No sex differences were found in lateral, ventral or intermediate BNST divisions.

Sex differences in the vomeronasal system.

In the early eighties we found sex differences in the vomeronasal organ (VNO) and hypothesized that the vomeronasal system (VNS), a complex neural network involved in the control of reproductive behavior, might be sexually dimorphic. At that time sex differences had already been described for some structures that receive VNO input, such as the medial amygdala, the medial preoptic area, the ventromedial hypothalamic nucleus, and the ventral region of the premammillary nucleus. Since then, we have shown sex differences in the accessory olfactory bulb (AOB), the bed nucleus of the accessory olfactory tract (BAOT), and the bed nucleus of the stria terminalis (BST). When new VNS connections were found, all of them ended in nuclei that present sex differences. In general, sex differences in the olfactory system show two morphological patterns: one in which males present greater morphological measures than females, and just the opposite. To explain the morphometric measures of males in the latter, it has been hypothesized that androgens serve as inhibitors. Our work on the involvement of the GABA(A) receptor in the development of AOB and maternal behavior sex differences also suggests that neonatal changes in neuronal membrane permeability to the ion Cl- differences. This might be the first animal model to help us to understand the situation in which human genetic and gonadal sex do not agree with brain and behavioral sex. Finally, we stress that sex differences in the VNS constitute a neurofunctional model for understanding sex differences in reproductive behaviors.

Effects of sex steroids on the development of the locus coeruleus in the rat

The effects of postnatal (on day 1 (D1) after birth) male orchidectomy and female androgenization on the locus coeruleus (LC) are studied. Normal adult female rats show greater LC volume and cell number than males. Testosterone treatment of females on D1 eliminates these differences. However, D1 male orchidectomy does not affect either the volume or the number of cells.

The development of sex differences in the locus coeruleus of the rat

Development of sex differences in the locus coeruleus (LC) is investigated. The LC is a sexually dimorphic structure in which the female manifests a larger volume and greater number of neurons than do males. Male and female Wistar rats were sacrificed on prenatal days (E) 16 and 20 and postnatally (P) on days 1, 3, 7, 15, 35, 45, 60, and 90. Male and female rats show a continuous increase in the number of neurons after birth that stops in the males by P45 and in females by P60. These findings point out the existence of different patterns of development in male and female rats and may suggest that sex differences could be established because of the existence of a differential period of neurogenesis in both sexes in the postpubertal period.

White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study

BACKGROUND Some gray and white matter regions of the brain are sexually dimorphic. The best MRI technique for identifying subtle differences in white matter is diffusion tensor imaging (DTI). The purpose of this paper is to investigate whether white matter patterns in female to male (FtM) transsexuals before commencing cross-sex hormone treatment are more similar to that of their biological sex or to that of their gender identity. METHOD DTI was performed in 18 FtM transsexuals and 24 male and 19 female heterosexual controls scanned with a 3 T Trio Tim Magneton. Fractional anisotropy (FA) was performed on white matter fibers of the whole brain, which was spatially analyzed using Tract-Based Spatial Statistics. RESULTS In controls, males have significantly higher FA values than females in the medial and posterior parts of the right superior longitudinal fasciculus (SLF), the forceps minor, and the corticospinal tract. Compared to control females, FtM showed higher FA values in posterior part of the right SLF, the forceps minor and corticospinal tract. Compared to control males, FtM showed only lower FA values in the corticospinal tract. CONCLUSIONS Our results show that the white matter microstructure pattern in untreated FtM transsexuals is closer to the pattern of subjects who share their gender identity (males) than those who share their biological sex (females). Our results provide evidence for an inherent difference in the brain structure of FtM transsexuals.

The distribution of glial fibrillary acidic protein in the adult rat brain is influenced by the neonatal levels of sex steroids

Sex steroids during the perinatal period are able to modify the postnatal development of neurons within steroid-sensitive areas in the rat brain. This study was designed to test the possible influence of the early postnatal levels of sex steroids on the morphology of the astrocytes. The experimental manipulation of the neonatal levels of sex steroids was performed by the androgenization of females with a single injection of testosterone propionate and by the orchidectomy of males on the day of birth. Control females received a single injection of vehicle and control males were sham operated. All the animals were sacrificed at 3 months of age postnatally. The immunohistochemical distribution of the glial fibrillary acidic protein (GFAP), a marker of astrocytic filaments, was studied on coronal sections of the dorsal hippocampus, the globus pallidus and the hypothalamic arcuate nucleus. The number of GFAP immunoreactive cells, the number of GFAP immunoreactive primary processes per cell and the surface density of the GFAP immunoreactive material were evaluated. This morphometric evaluation revealed a decreased surface density of GFAP immunoreactive material in the hippocampus, globus pallidus and the ventral part of the arcuate nucleus of orchidectomized males when compared to control males. Sex differences in the distribution of GFAP immunoreactivity were detected in the hippocampus and globus pallidus. These differences were abolished by the androgenization of females. The number of GFAP immunoreactive cells was similar in all the experimental groups, indicating that the differences in surface density represent an effect of sex steroids on the growth of astrocytic processes rather than on the proliferation of astrocytes.

Expression of intracellular progesterone receptors in rat brain during different reproductive states, and involvement in maternal behavior

Progesterone is one of a complex of hormones which influences the occurrence of maternal behavior in rats. The present study provides information on progesterones mechanism and possible neural site(s) of action with respect to maternal responsiveness. Progesterone can exert cellular effects by acting on membrane receptors or by acting on intracellular receptors. In the first experiment we show that RU 486 can antagonize progesterones inhibitory effect on maternal behavior. Since RU 486 acts as an antagonist to progesterones action at its intracellular receptor, these results support the involvement of that receptor in maternal behavior control. The second experiment employs immunocytochemical techniques to detect the number of cells in various forebrain regions which contain intracellular progesterone receptors during different reproductive states. The number of cells which contained progesterone receptors was higher toward the end of pregnancy (progesterone is presumably exerting its effects on maternal behavior at this time) when compared to either early pregnancy or lactation in the following forebrain regions: anteroventral periventricular nucleus of the preoptic area; medial preoptic area; ventral part of the bed nucleus of stria terminalis; ventrolateral division of the ventromedial nucleus; arcuate nucleus; anterior paraventricular nucleus of the hypothalamus; and medial amygdala. The possible involvement of these regions as a site or sites where progesterone might exert its effects on maternal behavior is discussed.

Lesions in the medial posterior region of the BST impair sexual behavior in sexually experienced and inexperienced male rats

Previous studies have showed that lesions in the bed nucleus of the stria terminalis of experienced male rats impair some parameters of sexual behavior. The aim of this study was to examine the contribution of the medial posterior region of the bed nucleus of the stria terminalis (BSTMP), a sexually dimorphic region of this nucleus that pertains to the vomeronasal system, to the modulation of sexual behavior of the male rat. Small electrolytic bilateral lesions in the BSTMP were made in male heterosexual experienced and inexperienced rats. Sham lesioned animals were also tested as a control of the effects of the general surgical procedures. Behavioral tests were then performed to obtain standard measures of masculine sexual behavior. Our results indicate that the sexually experienced male rats with lesioned BSTMPs showed increases in the number of mounts and the number of intromissions and, consequently, in ejaculation latency. In contrast, the sexually naive male rats showed increases in first mount and intromission latencies and in ejaculation latency, but the latter occurred due to increases in the interintromission intervals. This group also showed low correlations between olfactory investigation of the anogenital area of the female and initiation and maintenance of copulatory behavior. The results suggest that sexual experience obtained in the very artificial conditions of laboratory tests could supply some of the cues provided by the BSTMP in the process of sensorial integration, which we hypothesize modulates the initiation and pacing of copulation. However, sexual experience does not apparently supply any other kinds of cues provided or processed in the BSTMP that are involved in modulating the elicitation of intromissions and ejaculations.