Open access peer-reviewed chapter

Regulation of Morphological and Functional Aspects of Sexual Dimorphism in the Brain

Written By

Chitose Orikasa

Submitted: 25 November 2020 Reviewed: 29 March 2021 Published: 23 April 2021

DOI: 10.5772/intechopen.97470

From the Edited Volume

Oxytocin and Health

Edited by Wei Wu and Ifigenia Kostoglou-Athanassiou

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Abstract

Sexual dimorphism of the adult brain regulates sex-dependent functions including reproductive and neuroendocrine activities in rodents. It is determined by sex steroid hormones during a critical perinatal period in female and male rodents. Sex steroids act on each nuclear receptor in the brain and control different physiological and neuroendocrine functions and behaviors. Several regions of the brain show evident morphological sex differences that are involved in their physiological functions. This review addresses and focuses largely on the role of sex-dependent differences in the brain, and their crucial functions in animal models. Particularly, recent intriguing data concerning the diversity of neuronal functions and sexual dimorphism are discussed.

Keywords

  • Sexual dimorphism
  • Sex steroid: Estrogen
  • ERα
  • ERβ
  • Neuronal plasticity

1. Introduction

Sexual dimorphism is characterized by morphological and physiological changes driven by sex steroids. In the rodent brain, it occurs during a critical period characterized by higher plasticity of neurons allowing changes in neuronal circuits and connectivity. For instance, hormonal manipulation during this time window, such as castration in males or replacement therapy in females (injections of androgen or estrogen), resulted in the conversion of intrinsic features and alteration of structures and functions of neural circuits in the brain. In rodents, critical time span for brain sex differentiation extends from embryonic day (ED) 18 to the postnatal day 10 [1], while in human it is exclusively embryonic day (ED12–22). Post this critical period, neuronal plasticity is lost and the effects of sex steroids can be diverted to activational effects in the brain. The mechanisms involved in defining the timing and duration of the neonatal critical period for the brain sexual differentiation remains to be determined. It is proposed that epigenetic modifications such as DNA methylation and histone acetylation might control the expression of genes implicated in brain sexual dimorphism [2].

The neuroendocrine systems, which control the action of sex steroids, including that on neural circuits, are differentiated in a sex-dependent manner, resulting in the regulation of reproductive and sex-specific behaviors. The actions of sex steroids in masculinization and feminization of the brain are mediated by steroid hormone receptors. In both human and nonhuman primates, young male and females show sex differences in toy preferences [3, 4]. Girls with congenital adrenal hyperplasia (CAH) show to preference toward toys of males and to have decreased female-typical behavior [5]. These results argue that behavioral sex differences are caused by sex steroids. Estrogen is produced locally in the brain from testosterone by the aromatase cytochrome P450 enzyme [6, 7] and affects sexual differentiation by biding to estrogen receptor (ER) in rodents. Maternal and fetal estrogen can be bound by the α-fetoprotein produced by fetal liver cells and yolk-sac cells, thereby preventing their passage through the blood–brain barrier [8]. This mechanism results in female brain being free from estrogen. In contrast, in males, testosterone crosses the blood–brain barrier and is converted by aromatase to elicit sexual differentiation of the brain [6, 7, 9]. The effects of testosterone and its enzymatic derivative, estradiol, on their receptors are therefore critical for the sexual differentiation of the brain.

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2. Region-specific regulation of the ER

2.1 Sex-specific differences in the anteroventral periventricular nucleus

The crucial role of estrogens in the sexual differentiation of the brain is mediated by estrogen receptors subtypes ERα [10, 11] and ERβ [12]. The amount of steroid hormone receptors differentiated and available development differs between sexes. The anteroventral periventricular nucleus (AVPV) is greater in size and cell number in females than in males [13, 14]. In the AVPV, the distribution of ERα is similar in both sexes, but its expression levels are higher in females than in males in prepubertal and adult rats [15]. In contrast, the distribution pattern for ERβ detected by nonisotopic in situ hybridization and immunohistochemistry is different between sexes [16]. Specifically, in females, a vast majority of ERβ-positive cells is located in the most medial portion of the AVPV, whereas the ERβ-containing cells in males are dispersed more laterally in the AVPV (Figure 1). The distribution of ERβ is reversed by neonatal hormonal manipulations [16]. Therefore, sex-specific physiological functions are predictable for sexual dimorphism in the AVPV.

Figure 1.

Sexual dimorphism in the AVPV. ERβ positive cells aggregated densely in females (A-C), whereas the ERβ-containing cells in males (D-F) dispersed more laterally in the AVPV in the AVPV. Scale, 100 μm. From [16].

2.2 ERβ sexual dimorphism in the AVPV

Steroid-mediated organization of the brain might involve cell apoptosis, cell migration, neurogenesis, cell differentiation and synaptogenesis. Estrogen and androgen induce programmed cell death [17] by the sequential activation of cysteine-dependent asparate-specific proteases (caspase) during the development of the hypothalamus [18] in the dimorphism of dopaminergic neurons in the AVPV [19, 20, 21]. The total number of ERβ-positive cells within the AVPV is not different between intact females and males [15, 22]. This is assumed to be caused by mechanisms other than apoptosis namely the sexual dimorphic expression of ERβ in the AVPV. The sexual dimorphic features of the brain caused by sex steroids do not always coincide with larger nuclei exclusively in one sex. Indeed, a region-specific ERβ gene expression is observed in the AVPV [22]. Moreover, the steroids might act on specific regions in the brain [22]. In brain slices from developing mouse brain, estradiol but not dihydrotestosterone induces and modulates neuronal migration [23, 24]. These results suggest that sexual dimorphism of ERβ in the AVPV might contribute to migration rather than apoptosis or neurogenesis.

2.3 Functional implications in ERα and ERβ localization in the AVPV

In the AVPV of female rats, a majority of ERβ-positive cells also express ERα [16]. It has been shown that ERα together with kisspeptin regulates ovulation, while ERβ is rather modified by these events [25]. At the molecular level, ERs bind to an estrogen responsive element (ERE) [26] after heterodimer formation [27], which allows the integration and collaboration of various signaling pathways for the completion of ovulation. The experimental infusion of antisense oligonucleotides in females results in decreased ERβ expression in the AVPV and consequently a persistent estrous [16]. Moreover, ERβ-positive cells and dopaminergic neurons have comparable distribution patterns in the AVPV [16]. Both ERα and ERβ have a role in the sexual dimorphism of dopaminergic neurons in the AVPV in both sexes [16, 28]. The secretion of luteinizing hormone (LH) is controlled by dopaminergic projections to neurons producing the gonadotropin-releasing hormone (GnRH) [29]. The cycle of female rats stalls ovulation state by small lesions of the AVPV [30]. Altogether, these data suggest that ERα and ERβ are colocalized with GnRH and are involved in LH secretion [31, 32]. In particular, ERα exerts a positive role for GnRH neurons, while ERβ exerts a negative control of those neurons [25]. Nonclassical ERE-independent ERα effects are involved in negative regulation on pulsatile GnRH secretion, while ERβ effects are involved in positive regulation on that secretion [31, 33]. It is still controversial to regulate GnRH neurons by ERs. Considering the inherent male distribution pattern of ERβ, a peculiar characteristic of the dopaminergic innervation in the AVPV [28] might be responsible for the GnRH secretion in the brain of males.

2.4 Formation of the sexually dimorphic nucleus in the preoptic area

The sexually dimorphic nucleus in the preoptic area (SDN-POA) was first characterized by Nissl staining, revealing in a larger volume in the brain of male rats than that in the brain of female rats [1, 34]. The volume of this nucleus is altered by gonadal steroids during the perinatal critical period [1]. Somatostatin might also be involved in sexual dimorphism in the SDN-POA. Indeed, during development, cells positive for somatostatin are expressed in a sex-dependent manner in the SDN-POA. Sex reversal of the dimorphism of somatostatin expression is observed in orchidectomized males and estrogen treated female pups [35]. The somatostatin mRNA-positive cells are significantly more in males than in females, but eventually the difference recedes. Somatostatin expression in females is steady during the postnatal development. The transcription of somatostatin is transient and seems to contribute to the development of the SDN-POA. Somatostatin might prompt neuronal differentiation and survival via the somatostatin receptor.

Immunostaining against calbindin D28k, a major cytoplasmic calcium-binding and buffering protein, has been successfully used to identify the rat hypothalamus [36], SDN-POA [35, 37] and provides an alternative to Nissl staining [37]. Distribution of calbindin-labeled cells in the SDN-POA is similar to somatostatin in both sexes. It has been suggested that apoptosis has a role in sexual differentiation of the SDN-POA [38]. However, no difference in the total numbers of calbindin positive cells was observed in the SDN-POA after perinatal administration of bromodeoxyuridine in both sexes [39]. On the contrary, in the postnatal SDN-POA, these neurons still show an aggregated distribution in females, while they are dispersed laterally in males [39]. Altogether, these data suggest that, besides apoptosis, cell proliferation and migration might contribute to the morphological difference in the rat SDN-POA. Moreover, ERα are reported to be expressed in the SDN-POA [40], suggesting the presence of estrogenic action in the SDN-POA sexual dimorphism.

Moreover, Nissl stained SDN-POA had not been reported in mouse until recently identified by calbindin immunohistochemistry [41] (Figure 2). The morphological sex-dependent differences of the mouse SDN-POA were first demonstrated and established in terms of morphology and linked to gonadal steroid hormones during the prenatal critical period. Male mice have a greater number of calbindin-positive cells than females [41]. Similar differences within medial POA/anterior hypothalamic area (AHA) are observed in sheep, which are smaller in females than in males [42]. The volume of this nucleus in males is smaller in male-oriented than in female-oriented individuals. In humans, interstitial nuclei of the anterior hypothalamus (INAH) are considered comparable to those of rodent and sheep. The INAH is smaller in females than in males and smaller in homosexual men than in heterosexual men [43]. These results suggested that the sexual dimorphic nucleus in the two species is involved in sexual orientation. The male mice copulatory behavior and the preference for females is attributed to this difference in the SDN-POA [44, 45, 46, 47]. Further functional analysis is required to completely understand the mechanisms involved in the sexual dimorphism of the SDN-POA.

Figure 2.

Sexual dimorphism in the SDN-POA. Calbindin (CB)-immunoreactive cells in the mouse SDN-POA in males (A-E) and in females (F-J) in the rostral-caudal direction. In males (B-D), but not females, a cell aggregate of CB-positive cells is prominent. Sale, 400 μm. From [41].

2.5 Sexual dimorphic expression and function of ERs in the preoptic area

In the preoptic area (POA), ERα expression is much higher in females than in males [48]. This sex difference occurs during the perinatal period. After birth, the expression of ERs is down regulated in the POA by estrogen [49]. The decreased ERα expression occurs in both sexes but the differential expression in the POA between females and males persists throughout life. Although the ERα levels are higher in females than in males, a comparable distribution pattern of ERα is observed [16, 48]. The POA has been implicated to be involved in steroid activation of the male copulatory behavior [50]. In particular, dopamine neurons in the mPOA prompt male sexual behavior [51]. ERα and oxytocin containing neurons in the mPOA participate to control copulatory behavior in male rats [52, 53, 54]. In females, the POA and the adjacent bed nucleus of the stria terminalis (BNST) is considered essential for controlling maternal [55, 56, 57, 58] and mating behaviors [59]. ERα in the mPOA is involved in the regulation of maternal care, maternal aggression and sexual behavior [56]. ERβ is detected by in situ hybridization and immunohistochemistry in the medial preoptic nucleus (mPOA) and more caudally in the BNST [16] (Figure 3). In males, ERβ in the mPOA is involved in aggressive behavior [60]. Overall in rodents, identical brain regions control specific behaviors depending on the sex. Recently, it is shown that the male-typical mounting behavior and female-typical pup retrieval behavior are induced by ERα located in the same region of the POA [61]. These data suggest that the sex specific neural circuits are able to control opposite behaviors. Therefore, sex-typical behaviors are likely induced by the harmonic expression of sex specific receptors together with sex steroid. Besides the neural circuit with a high degree of plasticity in the sexual dimorphic nervous system assuring precise sex-specific behavior events, there may be a possible the involvement of circumstances in ensuring responsiveness of the sex steroids.

Figure 3.

Schematic representation of the distribution of ERβ mRNA-positive cells in the forebrain of rats through rostrocaudal axis. Scale, 100 μm. AC, anterior commissure; AVPV, anteroventral periventricular nucleus; BST, bed nucleus of the stria terminals; Fx, fornix; MPN, medial preoptic nucleus; OC, optic chiasm; SCN, suprachiasmatic nucleus; V3, third ventricle. From [16].

2.6 Functional diversity of the ventromedial hypothalamus

The volume of the ventromedial hypothalamus (VMH) is larger in males than in females [62, 63]. ERα and ERβ are expressed in the VMH of rodents [22, 48]. However, ERα expression is abundant in the ventrolateral portion of the VMH and is higher in female rats than in male rats [48]. The sex difference is most likely due to the conversion of testosterone into estrogen, which downregulates ERα expression. Moreover, the aromatase signal in males is more robust than in females [64]. A sex difference in ERβ expression is observed in both postnatal day 14 and in the adult rat brain, indicating that the sexual dimorphism is also maintained throughout life [22]. ERβ expression in the adult VMH is downregulated by estrogen or testosterone administration. The difference in expression is reversed by administration of estrogen in female rats or orchidectomy male rats. This sexual dimorphism is entirely attributable to the effects of sex steroids on the brain organization and plasticity during the critical neonatal period of the brain. Estrogen, converted from circulating androgen in males, downregulates ERα and ERβ expression in the VMH [22, 48] and consequently physiological functions. Estrogen together with progesterone in the VMH induces female sexual reproductive behavior such as lordosis, sexual receptivity and odor preference [65].

In adult males, the expression of ERα is lower than that in females. Cells in the male VMH are activated during fighting [66]. In these processes, ERα is involved in sexual [67] and aggressive behaviors in mice [68, 69], whereas ERβ is assume to be inhibitory to the aggressive behavior [68]. Other studies have demonstrated that male sexual behavior is not affected by ERβ in the VMH [70], but is profoundly regulated by ERα and the androgen receptor (AR), suggesting a possible distinct role for ERβ and ERα on each behavior. Opposing social behaviors, such as mounting and attack, are regulated by ERα [67] or progesterone receptor [71] cells located in discrete regions of the VMH. Sex steroid receptor expression in the VMH is induced by environmental hormonal milieu during the critical period and in turn controls the dynamic action of the sex hormones on sex-specific behavior in adults [66, 72]. These data suggest that males and females seem to exhibit identical neural circuits in the VMH, but the activated receptors might contribute to inducing the sex-typical behavior. The sex-specific neural circuit dictated by sex steroids could work in conjunction with estrogen-mediated ERs.

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3. Alternative mechanism for sexual dimorphism in the medial amygdala

The medial amygdala (MeA) is larger volume in males than in females [73] and this difference is abolished after castration in males and androgen treatment in females [74]. In adults, the size and volume of neurons is modified by circulating androgen. After castration of adult male rats, the cell soma size in the posterodorsal MeA (MePD) is similar to the one observed in females [74]. However, the number of MeA neurons in both sexes is not affected by adult androgens [75]. Steroid hormones also influence the organization of the MePD during the neonatal period [76, 77] and its metabolite, estrogen, results in masculinization of the MePD. ERα and ERβ are abundantly expressed in the MePD [22, 48, 78, 79] where the aromatase enzyme is also detected [80, 81]. ERs mediate estrogen-induced modifications in the MePD associated with masculinization and male-specific behaviors [82]. However, the masculinization in the MePD in the adult brain is mostly driven by circulating androgen [82]. Both the action of ER [82] and AR [83] in the MePD on the size of neuronal somas and in the sexual behavior mostly occurs in the adults [82]. In adults, there is no sex-dependent difference in ER subtype and expression in the MePD, but there is a sexual dimorphic expression of ERβ but not ERα in newborns [84]. Neonatal hormonal manipulations could not reverse the sex differences in ERβ in both sexes, suggesting that ERβ-mediated estrogen actions are not involved in the sexual dimorphism in the MePD. Furthermore, ERβ is highly expressed in the MePD of adult female and male rats and is not affected by gonadectomy or estrogen treatment in both sexes [22]. Therefore, the ERβ expression also acts independent of activity in this structure.

In the MePD, sexual dimorphism involves mechanisms distinct from other regions of the brain. The MePD receives inputs from the olfactory and pheromonal systems, suggesting a functional role of this structure in sex arousal and regulation of adult social behaviors, including mating, aggressive [85, 86], and territorial behavior [87]. Acquisition of mating stimuli induces Fos in the ERs in the MeA [88]. Finally, the mechanisms induced by the ERs in the MeA and those involved in sexual stimuli [89], gonadotropin secretion [90], ovulation [91] sex and courtship behaviors [87], onset of puberty [92], parenting, and reproduction [85, 89, 93] still remain to be identified.

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4. Conclusion

Sexual dimorphism is characterized by morphological differences in several regions of the brain. Morphological sex differences in the POA/AHA and the INAH were revealed in sheep and human brains, which are assumed to be important for determining sexual orientation. Expression of the phenotypes i.e., behavioral sex differences, are suggested to be derived from morphological sex differences in the brain. However, the morphological sex differences are subtly evident in other human brain regions; hence, their association with functional sex differences in the human brain remains controversial. Consequently, CAH results in masculinized female brain, thereby leading to male-typical preferences, which are the congenital characteristics inherently caused by steroid and not acquired by learning. Striking sex differences in animal models contribute in establishing the mechanisms of sexual dimorphism in the brain of all living beings.

ER expression levels contribute substantially to the physiological and behavioral differences. However, the extent to which the amounts of ER control the development of sexual dimorphism remains to be clarified. Sex-specific neural circuits activated by sex steroids might contribute to the functional role of ERs activated by estrogens. Recently it was evidenced that a high neuronal plasticity rate in neural circuits is necessary to ensure precise sex-specific responsiveness to sex steroids. The mechanism involved in the regulating the local action of sex steroids remains to be elucidated. Particularly, the expression and regulation of genes implicated in sexual dimorphism must be investigated.

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Acknowledgments

This work was supported, in part, by grants-in-aid for scientific research from the Japanese Ministry of Education, Science, Sports and Culture [19 K12738 (2019-2021)] (C.O.).

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Declarations interest

None.

References

  1. 1. Gorski, R.A., 1968. Influence of age on the response to paranatal administration of a low dose of androgen. Endocrinology. 82, 1001-1004
  2. 2. Forger, Philos Trans RSoc Lond B Biol Sci. 2016;371(1688):20150114
  3. 3. Berenbaum, S.A., 1999. Effects of early androgens on sex-typed activities and interests in adolescents with congenital adrenal hyperplasia. Horm. Behav. 35, 102-110
  4. 4. Grabowska, A., 2017. Sex on the brain: Are gender-dependent structural and functional differences associated with behavior? J Neurosci Res. 95, 200-212
  5. 5. Spencer, D., Pasterski, V., A S Neufeld, S.A.N., Glover, V., Thomas G O'Connor, T.G., Hindmarsh, P.C., Ieuan A Hughes, I.A., Acerini,C.L., Melissa Hines, M., 2021. Prenatal androgen exposure and children's gender-typed behavior and toy and playmate preferences Horm Behav. 127, 104889
  6. 6. MacLusky, N.J., Philip, A., Hurlburt C, Naftolin F. Estrogen formation in the developing rat brain: sex differences in aromatase activity during early post-natal life. Psychoneuroendocrinology. 1985, 10, 355-361
  7. 7. McEwen, B.S., Lieberburg, I., Chapta,l C., Krey, L., 1977. Aromatization: important for sexual differentiation of the neonatal rat brain. Horrn. Behav. 9, 249-263
  8. 8. MacLusky, N.J., Lieberburg, I., McEwen, B.S., 1979. The development of estrogen receptor systems in the rat brain: perinatal development. Brain Res. 178, 129-142
  9. 9. MacLusky, N.J., Naftolin, F., 1981. Sexual differentiation of the central nervous system. Science. 211, 1294-1303
  10. 10. Green, S., Walter, P., Kumar, V., Krust, A., Bornert, J.M., Argos, P., Chambon, P., 1986. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature. 320, 134-139
  11. 11. Koike, S., Sakai, M., Muramatsu, M., 1987. Molecular cloning and characterization of rat estrogen receptor cDNA. Nucleic Acids Res. 15, 2499-2513
  12. 12. Kuiper, G.G.J.M., Enmark, E. Pelto-Huikko, M. Nilsson, S., Gustaffsson J.-A. 1996. Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc. Natl. Acad. Sci. USA. 93, 5925-5930
  13. 13. Davis, E.C., Shryne, J.E., Gorski, R.A., 1996. Structural sexual dimorphisms in the anteroventral periventricular nucleus of the rat hypothalamus are sensitive to gonadal steroids perinatally, but develop peripubertally. Neuroendocrinology. 63, 142-148
  14. 14. Simerly, R.B., 1998. Organization and regulation of sexually dimorphic neuroendocrine pathways. Behav. Brain Res. 92, 195-203
  15. 15. Kanaya, M., Morishita, M., Tsukahara S., 2018. Temporal Expression Patterns of Genes Related to Sex Steroid Action in Sexually Dimorphic Nuclei During Puberty. Front Endocrinol (Lausanne). 9, 213
  16. 16. Orikasa, C., Kondo, Y., Hayash,i S., McEwen, B.S., Sakuma, Y., 2002. Sexually dimorphic expression of estrogen receptor beta in the anteroventral periventricular nucleus of the rat preoptic area: implication in luteinizing hormone surge. Proc Natl Acad. Sci. U.S.A. 99, 3306-3311
  17. 17. Arai, Y., Murakami, S., Nishizuka, M., 1994. Androgen enhances neuronal degeneration in the developing preoptic area: apoptosis in the anteroventral periventricular nucleus (AVPvN-POA). Horm. Behav. 28, 313-319
  18. 18. Thompson, C.K., Brenowitz, E.A., 2008. Caspase inhibitor infusion protects an avian song control circuit from seasonal-like neurodegeneration. J. Neurosci. 28,7130-7136
  19. 19. Forger, N.G., 2006. Cell death and sexual differentiation of the nervous system. Neuroscience. 138, 929-938
  20. 20. Tsukahara, S., 2009. Sex differences and the roles of sex steroids in apoptosis of sexually dimorphic nuclei of the preoptic area in postnatal rats. J. Neuroendocrinol. 21, 370-376
  21. 21. Waters, E.M., Richard B Simerly, R.B., 2009. Estrogen induces caspase-dependent cell death during hypothalamic development. J. Neurosci. 29, 9714-9718
  22. 22. Orikasa, C., Sakuma, Y., 2004. Sex and region-specific regulation of oestrogen receptor beta in the rat hypothalamus. J. Neuroendocrinol. 16, 964-969
  23. 23. Henderson, R.G., Brown, A.E., Tobet, S.A., 1999. Sex differences in cell migration in the preoptic area / anterior hypothalamus of mice. J. Neurobiol. 41, 252-266
  24. 24. Knoll, J.G., Wolfe, C.A., Tobet, S.A., 2007. Estrogen modulates neuronal movements within the developing preoptic area-anterior hypothalamus. Eur. J. Neurosci. 26, 1091-1099
  25. 25. Roa, J., Vigo, E., Castellano, J.M., Gaytan, F., Navarro, V.M., Aguilar, E., Dijcks, F.A. Ederveen, A.G.H., Pinilla, L., van Noort, P.I., Tena-Semper, M., 2008. Opposite roles of estrogen receptor (ER)-alpha and ERbeta in the modulation of luteinizing hormone responses to kisspeptin in the female rat: implications for the generation of the preovulatory surge. Endocrinology 149, 1627-1637
  26. 26. Li, X., Huang, J., Yi, P., Bambara, R.A., Hilf, R., Muyan, M., 2004. Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways. Mol. Cell. Biol. 24, 7681-7694
  27. 27. Powell, E., Shanle, E., Brinkman, A., Li, J., Keles, S., Wisinski, K.B., Wei Huang, W., Xu W., 2012. Identification of estrogen receptor dimer selective ligands reveals growth-inhibitory effects on cells that co-express ERα and ERβ. PLoS One 7, e30993
  28. 28. Simerly, R.B., Zee, M.C., Pendleton, J.W., Lubahn, D.B., Korach, K.S., 1997. Estrogen receptor-dependent sexual differentiation of dopaminergic neurons in the preoptic region of the mouse. Proc. Natl. Acad. Sci. U.S.A. 94, 14077-14082
  29. 29. Cruz, M. E., Villegas, G., Dominguez-Gonzalez, A., Chavira, R. & Dominguez,R. (2001) Brain Res. Bull.54, 339-344
  30. 30. Wiegand, S. J., Terasawa, E. & Bridson, W. E. (1978) Endocrinology 102, 1645-1648
  31. 31. Hu, L., Gustofson, R.L., Feng, H., Leung, P.K., Mores, N., Krsmanovic, L.Z., Catt, K.J., 2008. Converse regulatory functions of estrogen receptor-alpha and -beta subtypes expressed in hypothalamic gonadotropin-releasing hormone neurons. Mol. Endocrinol. 22, 2250-2259
  32. 32. Skynner, M.J., Sim, J.A., Herbison, A.E., 1999. Detection of estrogen receptor a and b messenger ribonucleic acids in adult gonadotropin-releasing hormone neurons. Endocrinology. 140, 5195-5201
  33. 33. Glidewell-Kenney, C., Hurley, L.A., Pfaff, L, Weiss, J., Levine, J.E., Jameson, J.L., 2007. Nonclassical estrogen receptor alpha signaling mediates negative feedback in the female mouse reproductive axis. Proc. Natl. Acad. Sci. U.S.A. 104, 198173-198177
  34. 34. Gorski, R.A., Harlan, R.E., Jacobson, C.D., Shryne, J.E. and Southam, A.M., 1980. Evidence for the existence of a sexually dimorphic nucleus in the preoptic area of the rat. J. Comp. Neurol. 193, 529-539
  35. 35. Orikasa, C., Kondo, Y., Sakuma, Y., 2007. Transient transcription of the somatostatin gene at the time of estrogen-dependent organization of the sexually dimorphic nucleus of the rat preoptic area. Endocrinology 148,1144-1149
  36. 36. Brager, D.H., Sickel, M.J., McCarthy, M.M., 2000. Developmental sex differences in calbindin-D(28K) and calretinin immunoreactivity in the neonatal rat hypothalamus. J. Neurobiol. 42, 315-322
  37. 37. Sickel, M.J., McCarthy, M.M., 2000. Calbindin-D28k immunoreactivity is a marker for a subdivision of the sexually dimorphic nucleus of the preoptic area of the rat: developmental profile and gonadal steroid modulation. J. Neuroendocrinol. 12, 397-402
  38. 38. Yang, S.L., Chen, Y.Y., Hsieh, Y.L., Jin, S.H., Hsu, H.K., Hsu, C. 2004. Perinatal androgenization prevents age-related neuron loss in the sexually dimorphic nucleus of the preoptic area in female rats. Dev. Neurosci. 26, 54-60
  39. 39. Orikasa, C., Kondo, Y., Usui, S., Sakuma, Y., 2010. Similar numbers of neurons are generated in the male and female rat preoptic area in utero. Neurosci. Res. 68, 9-14
  40. 40. Jeong, J.K., Ryu, B.J., Choi, J., Kim,D.H., Choi, E.J., Park, J.W., Park, J.J., Lee, B.J., 2008. NELL2 participates in formation of the sexually dimorphic nucleus of the pre-optic area in rats. J. Neurochem. 106, 1604-1613
  41. 41. Orikasa, C., Sakuma, Y., 2010. Estrogen configures sexual dimorphism in the preoptic area of C57BL/6J and ddN strains of mice. J. Comp. Neurol. 2010. 518, 3618-3629
  42. 42. Roselli, C.E., Larkin, K., Resko, J.A., Stellflug, J.N., Stormshak, F., 2004. The volume of a sexually dimorphic nucleus in the ovine medial preoptic area/anterior hypothalamus varies with sexual partner preference. Endocrinology. 145, 478-483
  43. 43. LeVay, S. 1991. A difference in hypothalamic structure between heterosexual and homosexual men. Science. 253, 1034-1037
  44. 44. Anderson, R.H., Fleming, D.E., Rhees, R.W., Kinghorn, E., 1986. Relationships between sexual activity, plasma testosterone, and the volume of the sexually dimorphic nucleus of the preoptic area in prenatally stressed and non-stressed rats. Brain Res. 370, 1-10
  45. 45. Hay-Schmidt, A., Finkielman, O.T.E., Jensen, B.A.H., Høgsbro , C.F., Holm, J.B., Johansen, K.H., Jense, T.K., 2017. Prenatal exposure to paracetamol/acetaminophen and precursor aniline impairs masculinisation of male brain and behaviour. Reproduction. 154, 145-152
  46. 46. Houtsmuller, E.J., Brand, T., de Jonge, F.H., Joosten, R.N., van de Poll, N.E., Slob, A.K., 1994. SDN-POA volume, sexual behavior, and partner preference of male rats affected by perinatal treatment with ATD. Physiol. Behav. 56, 535-541
  47. 47. Rhees, R.W., Al-Saleh, H.N., Kinghorn, E.W., Fleming, D.E., Lephart, E.D., 1999. Relationship between sexual behavior and sexually dimorphic structures in the anterior hypothalamus in control and prenatally stressed male rats. Brain Res. Bull. 50, 193-199
  48. 48. Yokosuka, M., Okamura, H., Hayash,i S. 1997. Postnatal development and sex difference in neurons containing estrogen receptor-alpha immunoreactivity in the preoptic brain, the diencephalon, and the amygdala in the rat. J. Comp. Neurol. 389, 81-93
  49. 49. DonCarlos, L.L., McAbee, M., Ramer-Quinn, D.S., Stancik, D.M., 1995. Estrogen receptor mRNA levels in the preoptic area of neonatal rats are responsive to hormone manipulation. Developmental Bram Research. 84, 253-260
  50. 50. Kondo, Y., Arai, Y., 1995. Functional association between the medial amygdala and the medial preoptic area in regulation of mating behavior in the male rat. Physiol. Behav.57, 69-73
  51. 51. Dominguez, J.M., Gil, M., Hull, E.M., 2006. Preoptic glutamate facilitates male sexual behavior. J. Neurosci. 26, 1699-1703
  52. 52. Clancy, N., D Zumpe, D., Michael, R.P., 2000. Estrogen in the medial preoptic area of male rats facilitates copulatory behavior. Horm. Behav. 38, 86-93
  53. 53. Gil, M., Renu Bhatt, R., Picotte, K.B., Hull, E.M., 2013. Sexual experience increases oxytocin receptor gene expression and protein in the medial preoptic area of the male rat. Psychoneuroendocrinology. 38, 1688-1697
  54. 54. Panzica, G.C., Viglietti-Panzica, C., Balthazart, J., 1996 The sexually dimorphic medial preoptic nucleus of quail: a key brain area mediating steroid action on male sexual behavior. Front Neuroendocrinol. 17, 51-125
  55. 55. Numan, M., Stolzenberg, D.S., 2009. Medial preoptic area interactions with dopamine neural systems in the control of the onset and maintenance of maternal behavior in rats. Front. Neuroendocrin. 30, 46-64
  56. 56. Ribeiro, A.C., Musatov, S., Shteyler, A., Simanduyev, S., Arrieta-Cruz, I., Ogawa, S., Pfaff, D.W., 2012. siRNA silencing of estrogen receptor-α expression specifically in medial preoptic area neurons abolishes maternal care in female mice. Proc. Natl. Acad. Sci. U.S.A. 109, 16324-16329
  57. 57. Tsuneoka, Y, Maruyama T, Yoshida S, Nishimori K, Kato T, Numan M, Kuroda KO. Functional, anatomical, and neurochemical differentiation of medial preoptic area subregions in relation to maternal behavior in the mouse. J Comp Neurol. 2013 May 1;521(7):1633-1663
  58. 58. Wu, Z., Autry, A.E., Bergan, J.F., Watabe-Uchida, M., Dulac, C.G., 2014. Galanin neurons in the medial preoptic area govern parental behaviour. Nature. 509, 325-330
  59. 59. McHenry, J.A, Otis, J.M., Rossi, M.A., Robinson, J.E., Kosyk, O., Miller, N.W., McElligott, Z.A., Budygin, E.A., Rubinow, D.R., Stuber, G.D., 2017. Hormonal gain control of a medial preoptic area social reward circuit. Nat. Neurosci. 20, 449-458
  60. 60. Nakata, M., Sano, K., Musatov, S., Yamaguchi, N., Sakamoto, T., Ogawa, S., 2016. .Effects of Prepubertal or Adult Site-Specific Knockdown of Estrogen Receptor beta in the Medial Preoptic Area and Medial Amygdala on Social Behaviors in Male Mice. eNeuro. 3, ENEURO.0155-15.2016
  61. 61. Wei, Y.-C., Wang, S.-R., Jiao, Z.-L., Zhang, W., Lin, J.-K., Li, X.-Y., Li, S.-S., Xin Zhang, Xu, X.-H., 2018. Medial preoptic area in mice is capable of mediating sexually dimorphic behaviors regardless of gender. Nat. Commun. 9, 279
  62. 62. Madeira, M.D., Ferreira-Silva, L., Paula-Barbosa, M.M., 2001. Influence of sex and estrus cycle on the sexual dimorphisms of the hypothalamic ventromedial nucleus: stereological evaluation and Golgi study. J. Comp. Neurol. 432, 329-345
  63. 63. Matsumoto, A., Arai, Y., 1983. Sex difference in volume of the ventromedial nucleus of the hypothalamus in the rat. Endocrinol. Jpn. 30, 277-280
  64. 64. Dugger, B.N., Morris, J. A., Cynthia L Jordan, C.L., Breedlove, S.M., 2007. Androgen receptors are required for full masculinization of the ventromedial hypothalamus (VMH) in rats. Horm. Behav. 51, 195-201
  65. 65. Robarts, D.W., Baum, M.J., 2006. Ventromedial hypothalamic nucleus lesions disrupt olfactory mate recognition and receptivity in female ferrets. Horm. Behav. 51, 104-113
  66. 66. Lin, D., 1, Maureen P Boyle, M.P., Dollar, P., Lee, H., E S Lein, E.S., 2011. Pietro Perona, David J Anderson Functional identification of an aggression locus in the mouse hypothalamus Nature. 470, 221-226
  67. 67. Lee, H., Kim, D.W., Remedios, R., Anthony, T.E., Chang, A., Madisen, L., Zeng, H., Anderson, D.J., 2014a. Scalable control of mounting and attack by Esr1+ neurons in the ventromedial hypothalamus. Nature. 509, 627-632. doi: 10.1038/nature13169.54 Hyosang Lee, 2014
  68. 68. Ogawa, S., Chester, A.E., Hewitt, S.C., Walker, V.R., Gustafsson, J.A., Smithies, O., Korach, K.S., Pfaff, D.W., 2000. Abolition of male sexual behaviors in mice lacking estrogen receptors alpha and beta (alpha beta ERKO). Proc Natl Acad Sci U S A. 97, 14737-14741
  69. 69. Wersinger, S.R., Sannen, K., Villalba, C., Lubahn, D.B., Rissman, E.F., De Vries, G.J., 1997. Masculine sexual behavior is disrupted in male and female mice lacking a functional estrogen receptor alpha gene. Horm. Behav. 32, 176-183
  70. 70. Naulé, L., Marie-Luce, C., Parmentier, C., Martini, M., Albac, C., Trouillet, A.C., Keller, M., Hardin-Pouzet, H., Mhaouty-Kodja, S., 2016. Revisiting the neural role of estrogen receptor beta in male sexual behavior by conditional mutagenesis. Horm. Behav. 80, 1-9
  71. 71. Yang, C.F., Chiang, M.C., Gray, D.C., Prabhakaran, M., Alvarado, M., Juntti, S.A., Unger, E.K., James A Wells, J.A., Shah, N.M., 2013. Sexually dimorphic neurons in the ventromedial hypothalamus govern mating in both sexes and aggression in males. Cell. 153, 896-909
  72. 72. Kudwa, A.E., Harada, N., Honda, S.-I. Rissman, E. F., 2007. Effects of organisational oestradiol on adult immunoreactive oestrogen receptors (alpha and beta) in the male mouse brain. J. Neuroendocrinol. 19, 767-772
  73. 73. Hines M, Allen LS, Gorski RA (1992) Sex differences in subregions of the medial nucleus of the amygdala and the bed nucleus of the stria terminalis in the rat. Brain Res 579:321-326
  74. 74. Cooke, B.M., Tabibnia, G., Breedlove, S.M., 1999. A brain sexual dimorphism controlled by adult circulating androgens. Proc. Natl. Acad. Sci. U.S.A. 96, 7538-7540
  75. 75. Morris, J.A., Jordan, C.L., Breedlove, S.M., 2008 Sexual dimorphism in neuronal number of the posterodorsal medial amygdala is independent of circulating androgens and regional volume in adult rats. J. Comp. Neurol. 506, 851-85.9
  76. 76. Meaney, M.J., McEwen, B.S., 1986. Testosterone implants into the amygdala during the neonatal period masculinize the social play of juvenile female rats. Brain Res. 398, 324-328
  77. 77. Mizukami, S., Nishizuka, M., Arai, Y., 1983. Sexual difference in nuclear volume and its ontogeny in the rat amygdala. Exp. Neurol. 79, 569-575
  78. 78. Simerly, R.B., Chang, C., Muramatsu, M., Swanson, L.W., 1990. Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study. J. Comp. Neurol. 294, 76-95
  79. 79. Shughrue, P.J., Bushnell, C.D., Dorsa, D.M., 1992. Estrogen receptor messenger ribonucleic acid in female rat brain during the estrous cycle: a comparison with ovariectomized female and intact males. Endocrinology. 131, 381-388
  80. 80. Jakab, R.L., Horvath, T.L., Leranth, C., Harada, N., Naftolin, F., 1993. Aromatase immunoreactivity in the rat brain: gonadectomy-sensitive hypothalamic neurons and an unresponsive "limbic ring" of the lateral septum-bed nucleus-amygdala complex J. Steroid. Biochem. Mol. Biol. 44, 481-498
  81. 81. Roselli, C.E., Resko, J.A., 1997. Sex differences in androgen-regulated expression of cytochrome P450 aromatase in the rat brain. J. Steroid Biochem. Mol. Biol. 61, 7365-7466
  82. 82. Cooke, B.M., Breedlove, S.M., 2003. Cynthia L Jordan Both estrogen receptors and androgen receptors contribute to testosterone-induced changes in the morphology of the medial amygdala and sexual arousal in male rats. Horm. Behav. 43, 336-346
  83. 83. Morris, J.A., Jordan, C.L., Dugger, B.N., Breedlove, S.M., 2005. Partial demasculinization of several brain regions in adult male (XY) rats with a dysfunctional androgen receptor gene. J. Comp. Neurol. 487, 217-226
  84. 84. Cao, J., Heather B Patisaul, H.B., 2013. Sex-specific expression of estrogen receptors α and β and Kiss1 in the postnatal rat amygdala. J. Comp. Neurol. 521, 465-478
  85. 85. Chen, P.B., Hu, R.K., Wu, Y.E., Pan, L., Huang, S., Micevych, P.E., Hong, W., 2019.Sexually Dimorphic Control of Parenting Behavior by the Medial Amygdala. Cell. 176, 1206-1221
  86. 86. Hong, W., Dong-Wook Kim, D.W., David J Anderson, D.J., 2014. Antagonistic control of social versus repetitive self-grooming behaviors by separable amygdala neuronal subsets. Cell. 158, 1348-1361
  87. 87. Newman, S.W., 1999. The medial extended amygdala in male reproductive behavior. A node in the mammalian social behavior network. Ann. NY Acad. Sci. 877, 242-257
  88. 88. Gréco, B., Blasberg, M.E., Kosinski, E.C., Blaustein, J.D., 2003. Response of ERalpha-IR and ERbeta-IR cells in the forebrain of female rats to mating stimuli Horm. Behav. 43, 444-453
  89. 89. Kang, N., Baum, M.J., James A Cherry, J.A., 2009. A direct main olfactory bulb projection to the 'vomeronasal' amygdala in female mice selectively responds to volatile pheromones from males. Eur. J. Neurosci. 29, 624-634
  90. 90. Parvizi, N., Ellendorff, F., 1980. beta-Endorphin alters luteinizing hormone secretion via the amygdala but not the hypothalamus. Nature. 286, 812-813
  91. 91. Sanchez, M.A., Dominguez, R., 1995. Differential effects of unilateral lesions in the medial amygdala on spontaneous and induced ovulation. Brain Res. Bull. 38, 313-317
  92. 92. Li, X.F., Hu, M.H., Hanley, B.P., Lin, Y.S., Poston, L., Lightman, S.L., O'Byrne K.T., 2015. The Posterodorsal Medial Amygdala Regulates the Timing of Puberty Onset in Female Rats. Endocrinology. 156, 3725-3736
  93. 93. Martel, K.L., Baum, M.J., 2009. A centrifugal pathway to the mouse accessory olfactory bulb from the medial amygdala conveys gender-specific volatile pheromonal signals. Eur. J. Neurosci. 29, 368-376

Written By

Chitose Orikasa

Submitted: 25 November 2020 Reviewed: 29 March 2021 Published: 23 April 2021