Estrogen receptor-dependent sexual differentiation of dopaminergic neurons in the preoptic region of the mouse

Abstract

Although it has been known for some time that estrogen exerts a profound inf luence on brain development a definitive demonstration of the role of the classical estrogen receptor (ER␣) in sexual differentiation has remained elusive. In the present study we used a sexually dimorphic population of dopaminergic neurons in the anteroventral periventricular nucleus of the hypothalamus (AVPV) to test the dependence of sexual differentiation on a functional ER␣ by comparing the number of tyrosine hydroxylase (TH)-immunoreactive neurons in the AVPV of wild-type (WT) mice with that of mice in which the ER␣ had been disrupted by homologous recombination (ERKO␣). Only a few ER␣-immunoreactive neurons were detected in the AVPV of ERKO␣ mice, and the number of TH-immunoreactive neurons was three times that of WT mice, suggesting that disruption of the ER␣ gene feminized the number of THimmunoreactive neurons. In contrast, the AVPV contains the same number of TH-immunoreactive neurons in testicular feminized male mice as in WT males, indicating that sexual differentiation of this population of neurons is not dependent on an intact androgen receptor. The number of THimmunoreactive neurons in the AVPV of female ERKO␣ mice remained higher than that of WT males, but TH staining appeared to be lower than that of WT females. Thus, the sexual differentiation of dopamine neurons in the AVPV appears to be receptor specific and dependent on the perinatal steroid environment.From an evolutionary perspective, the most adaptive physiological responses are those that ensure successful reproduction. Coordinated sex-specific behaviors and physiological mechanisms have evolved to facilitate reproduction and it is now clear that most are determined by the central action of steroid hormones during brain development. For example, only female rats display a massive surge in gonadotropin secretion in response to treatment of gonadectomized animals with estrogen and progesterone, and exposure of genetic females to high levels of gonadal hormones such as testosterone near the time of birth results in defeminization of the sexually dimorphic pattern of luteinizing hormone (LH) secretion that triggers ovulation (1-4). Abundant evidence from a variety of animal models indicates that steroid hormones secreted by the gonads during development cause profound sex-specific changes in the structure and neurochemistry of certain forebrain regions, including sexually dimorphic regions in the hypothalamus thought to play key roles in mediating the preovulatory secretion of LH (4-7). A particularly important and sexually dimorphic part of neural circuits that regulate the secretion of LH is the anteroventral periventricular nucleus of the preoptic region (AVPV). The AVPV has been shown to play a critical role in transducing hormonal feedback on LH secretion and is required for spontaneous ovulation (8, 9). Consistent with this functional role, the AVPV contains high densities of neurons that express receptors for estrogen and progesterone (10) and implan...

Sex differences and effects of neonatal aromatase inhibition on masculine and feminine copulatory potentials in prairie voles

“…ATD increased the number of TH-immunoreactive neurons in males such that a sex difference no longer existed. These data are similar to those from other rodents, which suggest that neonatal ER activation is necessary for sex differences in periventricular TH expression (Bodo et al, 2006;Simerly et al, 1997). Furthermore, they complement previous data from our lab showing that neonatal estradiol masculinizes TH expression in female prairie voles (Lansing and Lonstein, 2006).…”

Deletion of Bax eliminates sex differences in the mouse forebrain

“…Although sex differences in overall neuron number in the BNSTp have not yet been reported for mice, the cluster of androgen receptor-expressing neurons is larger in male mice than in females (27). In AVPV, overall cell density is greater in female mice than in males (5,25) and, as in rats, female mice possess about three times as many dopaminergic neurons in AVPV as do males (28). We reasoned that if Bax is essential for cell death in the BNSTp and AVPV, then sex differences in neuron number might be reduced or eliminated in Bax knockout mice.…”

New insights into the classical and non-classical actions of estrogen: Evidence from estrogen receptor knock-out and knock-in mice

“…Previous studies have clearly shown that estrogen signaling through ERα (and ERβ) in the perinatal period mediates the sexual differentiation of the AVPV, a region critical for estrogen positive feedback (Bodo et al, 2006;Simerly et al, 1997). In the AVPV, female mice have more tyrosine hydroxylase immunoreactive (TH-ir) neurons than males and ERαKO males display a feminized AVPV.…”