Critical Periods During Development: Hormonal Influences on ...

Critical Periods During Development: Hormonal Influences on Neurobehavioral Transitions Across the Life Span

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Cheryl Sisk, Joseph S. Lonstein, and Andrea C. Gore

Abbreviations

AMH AR AVPV BNSTp BPA BrdU CA1 CA3 DA DDT DNA EDC ER FSH GABA GFAP GnRH HPG IHH LH

Anti-Mullerian hormone Androgen receptor Anteroventral periventricular nucleus Posteromedial bed nucleus of the stria terminalis Bisphenol A Bromodeoxyuridine Cornu Ammonis area 1 of the hippocampus Cornu Ammonis area 3 of the hippocampus Dopamine Dichlorodiphenyltrichloroethane Deoxyribonucleic acid Endocrine disrupting chemical Estrogen receptor Follicle-stimulating hormone Gamma aminobutyric acid Glial fibrillary acidic protein Gonadotropin releasing hormone Hypothalamic-pituitary-gonadal Idiopathic hypogonadotropic hypogonadism Luteinizing hormone

C. Sisk (*) • J.S. Lonstein Department of Psychology & Neuroscience Program, Michigan State University, East Lansing, MI, USA e-mail: [email protected], [email protected] A.C. Gore Pharmacology and Toxicology, University of Texas at Austin, Austin, TX, USA e-mail: [email protected] D.W. Pfaff (ed.), Neuroscience in the 21st Century, DOI 10.1007/978-1-4614-1997-6_61, # Springer Science+Business Media, LLC 2013

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ME MeA mPOA MRI mRNA NeuN PCB PE POA PR SDN-POA SNB SON Sry SVZ

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Median eminence Medial amygdala Medial preoptic area Magnetic resonance imaging Messenger RNA Neuronal nuclear antigen Polychlorinated biphenyl Persistent estrus Preoptic area Progesterone receptor Sexually dimorphic nucleus of the preoptic area Spinal nucleus of the bulbocavernosus Supraoptic nucleus Sex-determining region of the Y chromosome Subventricular zone

Brief History Gonadal steroid hormone action in the nervous system is often dichotomized as either activational or organizational. Activational effects refer to the ability of steroids to modify the activity of target cells in ways that facilitate behavior in specific physiological or social contexts. Activational effects are transient; they come and go with the presence and absence of hormone and are most typically associated with hormone action in adulthood. In contrast, organizational effects refer to the ability of steroids to sculpt nervous system structure and connectivity during development. Structural organization is permanent and persists beyond the period of exposure to hormone. In many cases, neural networks are organized in a way that is permissive for future sex-typical behavior, but such behaviors will not be displayed until these networks are activated by hormonal triggers secreted during adulthood. In this way, organizational effects of gonadal steroid hormones program an individual’s activational responses to hormones later in life. Conceptualization of the relationship between organizational and activational effects of steroid hormones has evolved over the past 50 years. In 1959, Phoenix and colleagues first proposed that sex-typical adult behavioral (activational) responses to steroid hormones are programmed (organized) by steroid hormones acting on the nervous system during a sensitive period of early development (i.e., not in adulthood). Subsequently, scores of experiments led to the identification of a maximally sensitive period for hormone-dependent sexual differentiation of the brain during prenatal and early neonatal development in nonhuman primates and rodents. In the 1970s, Scott and colleagues laid the theoretical groundwork for the existence of multiple sensitive periods for the progressive

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organization of the nervous system across the life span, and noted that sensitive periods for behavioral development are most likely to occur during periods of rapid developmental change. It is now recognized that gonadal steroid hormones organize the mammalian nervous system not only during the prenatal and early postnatal periods of development, but also during adolescence, pregnancy and lactation, and even aging.

Actions of Gonadal Steroid Hormones Hormones exert powerful influences on mammalian nervous system development, particularly during developmental transitions associated with a change in reproductive state. These transitions include: (1) late prenatal/early postnatal life, when sexual differentiation of the nervous system is initiated, (2) puberty, when reproductive maturity is attained, (3) pregnancy and lactation, when unique demands are placed on females to nourish and protect offspring, and (4) aging, when a decline in reproductive function occurs as a natural consequence of older age. This chapter discusses these four developmental transitions, focusing on the influences of gonadal steroid hormones, their sites and mechanisms of action, and behavioral outcomes across life span development. The major emphasis of this chapter is on organizational influences of gonadal steroid hormones – that is, how early life exposures to hormones “program” cells in the nervous system to have a particular phenotype later in life. Organizational hormones, either endogenous or exogenous, alter developmental trajectory, often irreversibly, and they program sensitivity and responsiveness of the nervous system to hormones during subsequent developmental transitions. Because hormonal influences during later periods of development depend to a large extent on hormonal events that occurred during earlier periods of development, the organizational effects of gonadal steroid hormones on the nervous system are compounded over the entire life span. Thus, the overarching premise of this chapter is that hormonal life history underlies much of the complexity that characterizes individual differences in neural, behavioral, and other physiological responses to not only endogenous hormones, but also to exogenous substances that may disrupt hormonal systems and to hormonal therapies. Steroid hormones exert their influences by binding to specific hormone receptors present within target cells, including neurons. Intracellular mechanisms of hormone action are described in detail elsewhere in this volume. Briefly, activation of a steroid receptor results in a conformational change of the receptor protein, which enhances the ability of the hormone–receptor complex to bind to a hormone response element on DNA. Once bound to DNA, the receptor complex interacts with various combinations of co-regulatory proteins to influence genomic transcription. Changes in gene expression in turn can lead to changes in second-messenger systems, inducible transcription factors, peptide receptors, factors involved in growth and synaptogenesis, and neurotransmitter synthesis and release. Furthermore, activation of membrane-bound receptors for steroid hormones contributes to some much

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more rapid hormonal influences on intracellular signaling pathways and metabolism. However, the role of membrane steroid receptors in development is not currently understood, and this chapter is concerned primarily with their genomic effects mediated by receptors that function as transcription factors within the nucleus.

Influences of Endogenous Gonadal Hormones During Perinatal Life As early as embryonic life, animals are susceptible to influences of hormones on our developing brain and behavior. . .in fact, one of the most defining series of events for development is sexual differentiation, the point of physical and neurobehavioral divergence between males and females. Genotypic sex in mammals is determined by the complement of sex chromosomes contained in our genome, with males possessing an X and a Y chromosome and females possessing two X chromosomes. Peripheral and central nervous system tissues do not differ between the sexes during early embryonic development, though, and differentiation is initially carried out by genes on the Y chromosome that spontaneously trigger the events that forever diverge the sexes. The best studied of these genes, the sex-determining region of the Y chromosome (Sry), causes the bipotential gonadal anlagen to differentiate into testes. These newly formed testes release surges of testosterone and other hormones during early development that bind to their specific neural and peripheral hormone receptors to permanently organize these structures in a male-typical manner, a process termed masculinization. These hormones simultaneously affect these tissues to suppress the future expression of female-typical traits, a process termed defeminization. In primates, high levels of testosterone binding to neural androgen receptors are necessary for neurobehavioral masculinization and defeminization. However, in non-primates this process relies more on estrogen (derived from intraneuronal aromatization of testicular testosterone) binding to brain estrogen receptors, with androgen receptor activity having an impact that is apparently less crucial than that in primates. The absence of a Y chromosome and the Sry gene in females results in the bipotential gonadal tissue developing into ovaries. The perinatal ovary is not very steroidogenically active during early life. Although the traditional view of sexual differentiation posits that female development occurs in the complete absence of gonadal hormone exposure, exposure to very low levels of estradiol during development may actually be necessary to organize the female brain. Sources of low levels of steroid hormones in females may include their own gonads and adrenal glands, steroids that diffuse across amniotic membranes from male siblings, and even maternal steroids that cross the placenta but escape inactivation by plasma-binding proteins. Steroid receptors are widespread in the fetal and neonatal mammalian brain and are the target of estrogens and androgens that differentiate the nervous system. There are two isoforms for estrogen receptors (ERs), alpha and beta, and both are necessary for normal sexual differentiation. Studies using ER knock-out mice and developmental exposure to selective ER antagonists suggest that ERa is necessary for behavioral

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masculinization while ERb activity is more important for behavioral defeminization. Both isoforms exist in many regions of the perinatal rodent brain between mid- to late gestation and birth, including the medial preoptic area (mPOA), hypothalamus, and amygdala. Androgen receptors (ARs) are also widely expressed in the late-fetal rodent and primate brain in both neurons and glia. Sites with high AR mRNA or protein density during development include the olfactory bulb, preoptic area, ventromedial and paraventricular hypothalamus, bed nucleus of the stria terminalis, amygdala, cortex, and even in more caudal structures such as the substantia nigra. Progesterone is an interesting hormone contributing to neurobehavioral development because, in contrast to testosterone from fetal origin (and its aromatized product, estradiol), the source of progesterone during prenatal life is of maternal or placental origin, and during neonatal life it is obtained through mother’s milk. Because the sources are exogenous, the sexes are exposed to similar levels of hormone. Progesterone’s role in sexual differentiation is, therefore, thought to be accomplished by sex differences in progesterone receptor (PR). Indeed, PR is first observed in the rat preoptic area and other hypothalamic sites at the very end of gestation only in males. The relevance of this differential expression is suggested by the demasculinization of copulatory behavior in male rats treated with a progestin receptor antagonist during development. A sex difference in the other direction is also found in the developing ventromedial hypothalamus, with females having more PR than males. PRs are also present in the cerebral cortex and elsewhere in the brain during perinatal development but not in a sexually dimorphic manner.

Cellular Mechanisms of Perinatal Sexual Differentiation The developing brain sexually differentiates in response to gonadal hormones via some well-studied cellular mechanisms that are also impacted by hormones during later periods of neurobehavioral development. Neurogenesis and cell death: Numerous structures in the sexually differentiated brain are larger in one sex compared to the other, which is often a consequence of steroid hormones affecting birth of new cells (including neurogenesis) and cell death (including programmed cell death, or apoptosis) during development. One of the best-studied sex differences in the brain is the sexually dimorphic nucleus of the preoptic area (SDN-POA), which is manyfold larger and contains more neurons in male rats when compared to females. In this species, the sex difference in SDN-POA volume appears within the first week of life, but the critical period for hormone influences on its development actually begins a few days before birth. This sex difference in SDN-POA volume can be completely reversed if female rats are treated with testosterone or estradiol starting in late gestation through the first few days after birth (Fig. 55.1). Conversely, the anteroventral preoptic area (AVPV) is sexually dimorphic in the opposite direction – the female AVPV is larger and has more cells than the AVPV of males, the result of greater apoptosis in developing males. This is

1720 Fig. 55.1 Perinatal hormonal influences on sexual differentiation of the rodent SDN. A naturally occurring elevation in testosterone around the time of birth masculinizes and defeminizes the SDN. The absence of the perinatal increase in testosterone in females results in a feminine SDN in adulthood. Perinatal treatment of females with testosterone masculinizes and defeminizes the SDN; similar treatment in adulthood fails to alter the organizational phenotype of the SDN (From Breedlove et al. (2010))

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Rat brain

a Male Testosterone

b Female

c Female Testosterone

d Female

Conception

Birth

Adult

Sensitive period

thought to be consistent with the role of the AVPV in generating the cyclical pattern of gonadotropin release in female mammals as compared to the tonic release in males. Differential birth of cells in males and females during development is only a minor contributor to the creation of sex differences in SDN-POA and AVPV volumes, because the number and timing of cells born are only occasionally found to differ between gestating male and female rats. More important to the development of the SDN-POA is a sex difference in apoptotic cell death. In the absence of endogenous gonadal hormones, female rats have more than twice as many apoptotic cells in the SDN-POA between approximately days 7–10 after birth than do male rats, but this can be prevented by treating developing females with either testosterone or estradiol. Furthermore, apoptosis increases in the developing SDN-POA of male rats that are castrated at birth, but this effect can be prevented by injection of exogenous gonadal hormones. Apoptosis has a very similar role in other developing sex differences in the brain and spinal cord. For example, in the nearby posteromedial bed nucleus of the stria terminalis (BNSTp), males have more cells than females due to a greater number of dying cells in the latter. Similar to the SDN-POA, this sex difference in the BNSTp can be prevented by treating females with exogenous testosterone or estradiol, or by preventing apoptosis by selectively deleting the pro-apoptosis gene, Bax, in laboratory mice (Fig. 55.2a). Conversely, treating neonatal females with exogenous testosterone or estradiol increases apoptosis in the female-biased AVPV, and the sex difference in the AVPV can be eliminated by preventing apoptosis in male mice by either knocking out the death-inducing Bax gene (Fig. 55.2b), or by overexpressing


Fig. 55.2 Bax-mediated apoptosis underlies sex differences in cell numbers in BNSTp and AVPV. (a) Wildtype (Bax þ/þ) male mice have more neurons than do females in the BNSTp and this sex difference is eliminated in knockout (Bax /) mice lacking the Bax gene. (b) Wild-type females have more cells in AVPV than do males, and this sex difference is also eliminated by Bax gene deletion (From Forger (2006))

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