Sex and the Developing Brain

CHAPTER 10 Sex and the Developing Brain Jaclyn M. Schwarz University of Delaware, Department of Psychological and Brain Sciences, Newark, DE, USA 1 INTRODUCTION Our sex, whether male or female, is one of the most important defining factors of our- selves because it influences our lives in so many different ways. Our sex is determined at the earliest moment of conception via a process of random chance that almost belies the importance it has on our physiology and behavior. From the moment a mother finds out that she is expecting a new baby, the first question every family member and friend asks is, “Is it a boy or a girl?” The answer to that simple question dictates the name of the baby, the clothes he/she wears, the toys he/she receives, and the expectations that family and friends have for many aspects of the baby’s future personality from child- hood into adolescence. And yet early in development, it is just a fetus, and its sex is not defined by the external social factors that many of us associate with being either a “boy” or a “girl.” Instead, the sex of the developing fetus is determined by the individual sex chromosomes found in each and every one of its cells, and the hormones that the developing gonads produce. From the moment of conception, those sex chromosomes and hormones differentiate the developing body, brain, and future behavior of the developing baby. The sex of an individual also influences many aspects of our health and disease from the earliest moments of fetal development, and many of these “programming” effects on health and disease are maintained throughout life. Thus, it is critical that we explore the underlying processes of fetal sex determination and sexual differentiation of the developing brain with the goal of understanding how these processes influence our health and impact our risk of disease. 2 SEX DETERMINATION AND SEXUAL DIFFERENTIATION OF THE BRAIN Sex determination is the process at fertilization when the sex chromosomes of an individual are determined. We all have 23 pairs of chromosomes in our DNA. Twenty-two of these chromosome pairs are called autosomes and one of these pairs is the sex chromosomes – only the sex chromosomes are distinct between males and females. In humans, males have one X and one Y chromosome, while females have two X chromosomes. The process of sex determination occurs immediately at fertilization, when the mother’s ovum (or egg) contributes one X chromosome and the father’s sperm contributes either Sex Differences in the Central Nervous System. http://dx.doi.org/10.1016/B978-0-12-802114-9.00007-X Copyright © 2016 Elsevier Inc. All rights reserved. 221 222 Sex Differences in the Central Nervous System. Figure 10.1 The process of sex determination. At the time of fertilization, the ovum (egg) contributes one X chromosome to the developing fetus. The sperm that fertilizes the egg provides either an X or a Y chromosome. This process results in a male zygote that contains an X and a Y chromosome or a female zygote that contains two X chromosomes. Each cell in the developing embryo and brain maintains this chromosomal sex. an X or a Y chromosome, thereby establishing the chromosomal sex of the embryo as either male (XY) or female (XX) (Figure 10.1). As that single fertilized egg divides into a growing embryo, each of these cells maintains that chromosomal sex determination, meaning that each cell of the developing embryo has a chromosomal sex, either two X chromosomes (female cells) or an X and a Y chromosome (male cells) in addition to the 22 autosomes of the DNA. After sex determination, sexual differentiation is the process by which the developing fetus becomes either male or female. This process is dependent upon the expression of sex-specific genes produced by the sex chromosomes and then the hormones produced by the developing gonads. The gonads begin as bipotential organs, meaning they can be differentiated as either male or female based on cues from the developing fetus during the process of sexual differentiation. The gonads are differentiated first by the presence or absence of the SRY (sex determining region of the Y chromosome) gene found on the Y chromosome of males. The SRY gene encodes for a protein called the testes determining factor, which differentiates the bipotential gonads into the testes (Figure 10.2). In the absence of an SRY gene, in females, the bipotential gonads are formed into ovaries (Koopman et al., 1990; Sinclair et al., 1990). This process constitutes the sexual differentiation of the gonads. After the sexual differentiation of the gonads, the developing testes of the male begin to produce testosterone embryonically (Jost, 1947; Rhoda et al., 1984; Weisz and Ward, 1980). In humans, this occurs early in embryonic development around the Sex and the Developing Brain 223 Figure 10.2 Sexual differentiation of the gonads. In the developing male fetus, the Y chromosome contains the sex-determining region of the Y chromosome (SRY gene), which transcribes the testes determining factor. The testes determining factor protein differentiates a primordial gonad into the testes. In the absence of the Y chromosome, the primordial gonad differentiates into an ovary. beginning of the second trimester (13 weeks’ gestation; Hollier et al., 2014), in rodents this occurs at embryonic day 18 ( Jost, 1947; Rhoda et al., 1984; Weisz and Ward, 1980). Testosterone produced in the male fetus further differentiates the bipotential sex organs into the sex organs, including the penis, prostate, seminal vesicles, and vas deferens. In contrast to the male testes, the female ovaries produce no hormones during development, and thus in the absence of testosterone production, the bipotential sex organs differentiate into the sex organs of the female, including the fallopian tubes, uterus, cervix, and vagina. As a result, during a mother’s first ultrasound, at around 18 weeks, she can already find out whether her growing baby will be a boy or a girl because this process of gonadal differentiation has already occurred. 3 THE ORGANIZATION AND ACTIVATIONAL HYPOTHESIS OF SEX DIFFERENCES IN THE BRAIN AND BEHAVIOR Importantly, this differential exposure to testosterone that occurs between the sexes during early fetal development occurs at a time when the brain is also particularly sensitive to hormone exposure, and this period of time is defined as the critical period for sexual differentiation of the brain. A critical period is defined as a window wherein a system maintains a heightened sensitivity to particular stimuli in order to develop in a functional manner. The concept of a critical developmental period applies to multiple neuro- logical endpoints, including the visual system (Desai et al., 2002; Wong, 1999; Zhang and Poo, 2001), development of motor neurons (Hanson and Landmesser, 2004; Haverkamp 224 Sex Differences in the Central Nervous System. and Oppenheim, 1986), the control of whisker movement in the rat (Schlaggar and O’Leary, 1991, 1993), and even some aspects of language development in humans (Ruben, 1997). Sexual differentiation of the bipotential brain, just as the gonads, occurs during a critical period in all species examined to date, including primates, although the timing of various aspects can vary substantially within and between species (Arnold and Gorski, 1984; MacLusky and Naftolin, 1981; Nevison et al., 1997; Swaab, 2004). The laboratory rat is arguably one of the best characterized species for studying the sexual differentiation of the developing brain that occurs during the critical period for two primary reasons. First, the critical period of brain sexual differentiation is very well defined in the rat. Secondly, the behavioral endpoints associated with sexual differentiation of the rat brain are very well characterized. The male rat testes produce testosterone as early as embryonic day 18, and this exposure begins the process of sexual differentiation of the male brain (Figure 10.3). In the absence of hormone exposure in the female, the bipotential brain differentiates into a female brain. The organization of the brain that occurs during the critical period, followed by the activational effects of hormones on sex-specific sexual behaviors in adulthood, constitute what has been named the organizational/activational hypothesis of the brain and behavior (Arnold and Breed- love, 1985) (Figure 10.4). The rat is an exceptional model to study sexual differentiation of the brain because hormonal treatment during the organizational critical period can induce robust and reliable sex differences in the brain and the functional output can be tested by the administration of hormones in adulthood and the examination of sexual behaviors in adulthood. For example, from embryonic day 18 until around postnatal Figure 10.3 Sexual differentiation of the brain. Following the differentiation of the gonads, the developing testes begin to produce testosterone, which is necessary for masculinizing the developing brain. In contrast, the developing ovaries produce no significant levels of hormones and in the absence of any hormone exposure, the developing brain is feminized. Sex and the Developing Brain 225 Figure 10.4 The organizational and activational hypothesis of brain sexual differentiation. In males, testosterone synthesis peaks around the day of birth in rodents. This testosterone exposure organizes sex differences in the developing brain and permanently masculinizes the brain. After puberty, the testes produce continuous levels of testosterone, which activate the male brain to induce sex-specific behaviors, such as male sex behavior. In the absence of any testosterone exposure during early brain development, the female brain is permanently feminized. After puberty, the ovaries produce estro- gens and progestins necessary to activate the feminized brain and induce sex-specific behaviors, spe- cifically female sex behavior.

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