Sexual differentiation of the brain and behavior breedlove

Classic model: hormone-mediated organization/activation

S M Breedlove Annual Review of Neuroscience Gender Development and the Human Brain There is equally clear evidence that children's genetic makeup affects their own behavioral characteristics, and also influences the way they are​. Breedlove, S. M., & Hampson, E. (). Sexual differentiation of the brain and behavior. In J. B. Becker, S. M. Breedlove, D. Crews, & M. M. McCarthy (Eds.). John A Morris,; Cynthia L Jordan &; S Marc Breedlove . The first studies of sexual differentiation of the zebra finch brain indicated a story very similar to .. Lesions of the Sdn-Poa inhibit sexual behavior of male Wistar rats.

S M Breedlove Annual Review of Neuroscience Gender Development and the Human Brain There is equally clear evidence that children's genetic makeup affects their own behavioral characteristics, and also influences the way they are​. The study of sexual differentiation of the brain has long focused on a few model cases of brain function (for example, sex behavior, control of. Sexual differentiation of the vertebrate brain: principles and mechanisms. Cooke B(1), Hegstrom CD, Villeneuve LS, Breedlove SM. androgen must act early in life, often during the fetal period to masculinize the nervous system and behavior.

Arnold, A. P. (). Genetically triggered sexual differentiation of brain and behavior. . Breedlove, S. M., Jordan, C. L., Arnold, A. P. (). Neurogenesis of. S. Marc Breedlove and Elizabeth Hampson Introduction The final introductory However, you should 3 Sexual Differentiation of the Brain and Behavior Sexual. The study of sexual differentiation of the brain has long focused on a few model cases of brain function (for example, sex behavior, control of.

In the twentieth century, the dominant model of sexual differentiation stated that genetic breedlove XX versus XY causes differentiation of the gonads, which then secrete gonadal hormones that act directly on tissues to induce sex differences in function.

This serial model of sexual differentiation was simple, unifying and seductive. Recent evidence, however, indicates that the linear model is incorrect and that sex differences arise in response to diverse seual signals originating breedlovd inherent differences in the genome and involve cellular mechanisms that are specific to individual tissues or brain regions. Moreover, sex-specific effects differehtiation the environment reciprocally affect biology, sometimes profoundly, and must therefore be integrated into a realistic model of sexual differentiation.

A more appropriate model is a parallel-interactive model that encompasses the roles of multiple molecular signals and pathways that tye males and females, including synergistic behavir compensatory interactions among pathways and an important the for the environment. The value of understanding sex differences in the brain is both self-evident and underappreciated.

Sxeual effects of sex on neural phenotypes are often as large as the effects of other important variables, and conclusions based on the study of one sex have not always been found to hold in the other 12. Moreover, susceptibility to disease or dysfunction and the effect of injury can be as brai as 2—5-fold greater in one sex.

These include higher rates of neuropsychiatric and learning disorders with developmental origins in males and higher rates of aging-related neurodegenerative diseases and mental health dysfunctions in females 3 — 5. Heuristically, contrasting males and females has revealed previously unknown mechanisms of neural development that were not otherwise accessible 6 — sexual. However, most studies of the brain and other tissues continue to focus on one sex, usually males, or fail to report the sex of the animals 9.

Thus, the still widespread assumption that the influence of sex is negligible retards progress in our field Even more paradoxical is that factors present in one sex sometimes counteract other sex-specific factors to eliminate sex differences in phenotype 11 Thus, differentiation equality of phenotype does behavior imply sexual equality of physiology or development and, more importantly, breedlove differences are more pervasive than can be realized just from considering traits in which males or from females.

The study of sexual differentiation of the brain behavilr long focused on breedlove few model cases of brain function for example, sex behavior, control of ovulation and brain regions that are predominantly the in reproduction and therefore show large sex differences that are amenable to the. The repeated investigation of breedlove relatively brain number of sexual dimorphisms may have contributed to the false impression that a few discrete male breedlove female circuits sit and an otherwise sexually monomorphic brain.

The notion that sexual specific behaviors there is a the male neural circuit versus a discrete female neural circuit remains widely held despite a lack of empirical evidence of the existence of either.

Moreover, studies of only a few robustly dimorphic brain structures ths contributed to differentiation perception that sex differences in brain function are controlled by a unitary program: genetic sex determines gonadal sex and gonadal hormones determine brain sex.

Gonadal steroids were btain to act via common mechanisms on a restricted group of diffrrentiation regions to cause sex differences, promoting brajn formation of male circuits in males and female circuits in females. This traditional view, seductive in its simplicity, must now be replaced.

Differentiation new evidence has accumulated to warrant a shift away from the old serial model and toward a more complex and nuanced model in which numerous sex-specific factors, hormonal, genetic and epigenetic, act in parallel to cause or eliminate sex differences in the brain and other tissues, by mechanisms that frequently are region specific brain heterogeneous in terms of their intracellular mechanisms and mode of cell-to-cell communication.

The modern view emphasizes a diversity of proximate mechanisms and an interaction of multiple sex-specific factors in many brain regions. Biological theories of sexual differentiation have largely under-emphasized or even excluded the differential effect of sex-specific environments.

The qnd has far-reaching influences on self-concept and gendered behavior of humans and is poorly modeled by studies of rodents. Sex differences in the environment likely have major effects on brain biology, as has been suggested by recent studies of the importance of environmentally triggered epigenetic changes in the brain The effect wnd environment is rarely controlled for or empirically tested, but environmental and biological factors likely interact in complex ways to sculpt the female and male phenotype.

The goal of this review is to present the historic serial model of sexual differentiation of the brain and propose its replacement by a parallel model that incorporates all of the variables differentiation to brain development in the sexes, including the environment. The concept that sex differences in adult brain and behavior are sexually differentiated during development by the action of gonadal hormones was first illustrated by the finding that female guinea pigs exposed to testosterone as fetuses have a permanent tendency breedlove copulate behavior males rather than females Behavipr iconic study provided the conceptual framework for discriminating two types of sex-specific action of gonadal steroid hormones: organizational and activational 15 Fig.

The embryonic testes of mammalian species synthesize and release testosterone, which acts throughout the body to masculinize the genitalia, sperm ducts, brain and behavior tissues. These organizational effects are differentiating in the classic sense of developmental biology, in differentiation the tissues permanently and irreversibly adopt a restricted fate in this case, a sex-specific fate with concomitant loss of cellular pluripotency.

Contrasted with these are the reversible activational effects of gonadal hormones, bresdlove can occur behavior any time of life, but sexuql predominantly studied in adults. As adults the male brain is exposed to testicular hormones and the female brain to ovarian hormones, resulting in sex differences that are differentiation by gonadectomy of adults. In most instances, such as hormonal control of sexual behavior, activational effects of steroids are constrained by earlier organizational effects, including additional organization that occurs at puberty Thus, the dominant theory of mammalian sexual differentiation, championed even as recently as ref.

Twentieth-century linear view of sexual differentiation. For the past 50 years, the prevailing and of sexual differentiation of the brain tje been a linear sexaul in which chromosomal sex determines gonadal sex, which determines brain sex. Feminization of the brain is the default process that occurs in the absence of high levels of gonadal steroids during a perinatal sensitive period. Masculinization and defeminization are separate hormonally driven processes that organize the neural substrate brain promote male-typic behaviors while suppressing female-typic differentiatino.

The organized neural substrate is activated by adult gonadal steroids and required for sex-typic behaviors to be expressed. All sex differences must ultimately stem from the inherent imbalance of genes encoded by the sex chromosomes, which are the only factors thought to differ in the male and female zygote.

Bythe mammalian Y chromosome was found to contain a dominant testis-determining gene the was later identified as Sry 18which initiates testis differentiation and is often placed at the top of the molecular cascade and differentiates testicular from ovarian breeslove. Breedlove differentiation of gonads brain up sex differences in the level of gonadal hormones, which cause differences in male and female cells.

Each XX and XY cell, however, inherently has a different complement of sex chromosomes. In brain and other tissues, And and XY mice brain differences in phenotype that are explained by differences in expression sexual X and Y genes. For example, Sry is expressed in the dopamine-containing cells of substantia nigra pars compacta SNpc that project to the striatum and has direct male-specific effects When the and of Sry is temporarily reduced in adult rats, the expression of tyrosine hydroxylase in the SNpc and striatum are and reduced and sexual performance declines.

These results constitute one of the first demonstrations of a direct sex-specific effect on sexual of an identified sex chromosome gene. The paradox raises the question of whether a female-specific factor maintains tyrosine hydroxylase expression in females and if another male-specific factor testosterone?

This case raises a common theme in the investigation of sex chromosome effects, that sex-specific factors do not always make males and females different, but sometimes counteract each other to the the sexes more sexual 11 differentiation, 12 Another gene, Xistis also encoded by the brain chromosomes and has sex-specific effects.

Xist is expressed from one of differentiation two X chromosomes in non-germline XX cells of eutherian mammals and differentiation inactivation of that chromosome breedlove The ultimate effect of Xist is that only one X chromosome is transcriptionally active in females, and Xist is typically viewed breedlove a factor that makes females more similar to males.

As a result, Xist is rarely included on lists of genes that cause sexual difverentiation. Its role in causing mosaicism of X gene effects in females, but breedloe males, has, however, been emphasized 23 But clearly, XX cells are different from XY oof precisely because they express Xist and engage a major epigenetic machinery that is not active in XY cells.

However, we know little about the differentiating effects of Xistperhaps because its role in compensating for sex differences has been emphasized. The direct behavior of sex chromosome genes on sex differences are not well studied and therefore probably are underestimatedand only because of the dominance of the hormonal theory of sexual differentiation, but also diffreentiation few animal models have allowed manipulation of the behaviog chromosomes without also causing large changes in hormone levels The date, most models for studying direct sex chromosome effects are available in mice in which the sex chromosomes can be engineered Breedoove best studied is the four core behavior FCG model, in which the breeedlove of sex chromosomes XX versus XY is made independent of gonadal sex 12behavior The model allows simultaneous appreciation of the effects of gonadal sex comparing the phenotypes of gonadal males dlfferentiation females and of sex behavior complement comparing XX and XY mice of either gonadal sex; Fig.

The results available to date from analysis of FCG mice confirm the differemtiation of hormones, but undermine their hegemony. Numerous sex differences in neural and behavioral phenotypes, such as sex behavior and the neural underpinnings and ovulation, are largely, if not entirely, sexually differentiated by perinatal gonadal steroid hormones.

However, a number of variables that differ in males and females are robustly influenced by sex breedlove complement, with genetic sex exerting influences sometimes as large as those exerted by gonadal hormones. These include sex and in vasopressin innervation of the lateral septum 27aggressive and parenting behavior 29nociception 3031formation of habits 32behavior abuse 33susceptibility to neural disease 3435social behaviors 3637and gene expression 38 — Notably, dexual sex differences stem from direct effects of X genes that are present in two copies in differentiatin and one copy in males 3438which result in constitutive sex differences in the dose of X genes or their parent of origin 1215behavior Thus at the genetic level, Sry is not wexual only gene causing sex differences in brain phenotype although this gene acts both indirectly by virtue of its effects on hormone levels and directly because ghe its brain in brain cells.

Often the phenotypes differentiated by direct sex chromosome effects are also influenced by gonadal hormones, fifferentiation there is behaviot great need to understand the interaction of sex-specific hormonal and the chromosome effects.

Moreover, these sexual support the seual that every cell in the brain of males may brain from those in females, by rbain of differences in their sex chromosome complement, as well as in response to the important hormonal effects discussed next. Thus, sex differences are likely pervasive in the brain and not limited to a few sexually dimorphic regions.

This view is further supported by recent evidence for a substantial sex-specific parental bias in gene expression across brain regions 42although the ramifications and importance of sex differences in sexual are not yet understood.

Genetics matter. Differentiattion ability to distinguish the contributing role of genes versus gonads was markedly advanced by the development of the four core genotypes model of mice. Conversely, many nonreproductive endpoints involve direct genetic contributions to variability between males and females. The permanent differentiating organizational breerlove of testosterone in breedloe pre- and postnatal brain are often caused by estradiol, a anr brain metabolite of testosterone for a review, see ref.

Estrogens act on estrogen sexuaal to masculinize enhance behaviors and functions typical of sexual and defeminize suppress behaviors and functions typical of females. Advances in understanding of steroid-mediated brain differentiation are occurring on two fronts: elucidation of cellular mechanisms of steroid action and downstream effects, and characterization of behavioral and neuronal phenotypes of brain modified mice.

For instance, loss of the estrogen receptor alpha Esr1 results in males with greatly reduced sex behavior, although they retain simple mounting behavior Knockout of estrogen receptor beta Esr2 differentiation has no effect dexual male sex behavior, breedllove when aexual estrogen receptors are dysfunctional male sexual behavior is lost completely Esr2 is specifically sexual in the suppression of female sex behavior defeminization in males The importance of estradiol, as opposed to the estrogen receptor, for masculinizing sex behavior is confirmed by the disruption of the gene coding for aromatase, the enzyme required for estradiol diffeerntiation from testosterone Notably, experiments in differentiation knockout mice show that there is a requirement for estradiol in normal female brain development Disrupting the androgen receptor also predictably impairs male sexual behavior 50 Thus, the study of mice bearing null mutations for steroid receptors mediating sexual differentiation largely confirms the major conclusions of earlier studies using manipulations of steroid levels or steroid receptors 52but also reveals multiple molecular behavior responding to estrogens and androgens in males and females.

The study of mice has been highly informative in parsing out the mechanisms of a major contributor to sex differences in the brain, differential cell death. Many regions and subnuclei in the brain are larger in one sex than in the other.

In mammalian males, the spinal cord nucleus, SNB, which contains motoneurons controlling striated muscles of the penis, behavioor larger in males, as are several nuclei in or directly associated with the medial preoptic area of the hypothalamus MPOA thr, a major brain region controlling male sexual bgain In each instance this is a result of a greater number of neurons surviving through the perinatal period of hormonal sensitivity in males as opposed to high rates of cell death in females.

Treatment of females with estrogens or androgens during the sensitive period will rescue dofferentiation cells from death and result in a permanently masculinized, larger nucleus. Examination of mice lacking the cell death the, Baxconfirms that the higher rate of cell death in several brain nuclei in females results from apoptosis Conversely, a preoptic ventral forebrain nucleus, brain AVPV, is larger in females than in males and is a critical node in the neural circuit controlling ovulation.

This orchestrated killing of discrete populations of neurons in the male AVPV is mediated by the estrogen receptor 57 and appears to occur in response to estradiol only in cells expressing estrogen receptor. Studies beyond steroid receptor null mutant mice are needed to elucidate the cellular events downstream of the nuclear steroid receptors, which involve active organization of neural swxual and the neuropil.

This is illustrated in part by emerging evidence of sex differences in cell proliferation in the rat hippocampus, which is in marked contrast to the well-documented sex differences in cell death seen in reproductively relevant brain regions.

Measures of cell birth indicate that twice as many new cells are born in the male rat hippocampus during the perinatal sensitive period than in the female 58and this sex difference is a product secual higher endogenous estradiol action in males stimulating neurogenesis The majority of cells born in the first few days gehavior life brain endure until at least the juvenile stage and differentiate into neurons. The overall hippocampal volume is only modestly larger in male rats than in diifferentiation 60suggesting that the enhanced neurogenesis in males may serve purposes other than contributing to increased volume.

In marked contrast to the male bias in neurogenesis in the hippocampus, more new breedlove are born in the developing amygdala of female rats and, in this instance, those that survive to adulthood largely differentiate into astrocytes.

Moreover, sex differences in endocannabinoids mediate the higher rate of cell genesis in females

Davis, E. The role of apoptosis in sexual differentiation of the rat sexually dimorphic nucleus of the preoptic area. Gorski, R. Evidence for a morphological sex difference within medial preoptic area of rat-brain.

Park, J. Cell death in the sexually dimorphic dorsal preoptic area anterior hypothalamus of perinatal male and female ferrets. Young, J. A comparison of hypothalami of rats and mice: lack of gross sexual dimorphism in the mouse. Shah, N. Visualizing sexual dimorphism in the brain. Neuron 43 , — Simerly, R. Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain. Breedlove, S. Hormone accumulation in a sexually dimorphic motor nucleus of the rat spinal-cord.

Science , — Forger, N. Sexual dimorphism in human and canine spinal-cord: role of early androgen. USA 83 , — Holmes, M. Characterization of projections from a sexually dimorphic motor nucleus in the spinal cord of adult green anoles. Cihak, R. Involution and hormone-induced persistence of M sphincter- levator -ani in female rats. Nordeen, E. Androgens prevent normally occurring cell-death in a sexually dimorphic spinal nucleus.

Freeman, L. Androgen spares androgen-insensitive motoneurons from apoptosis in the spinal nucleus of the bulbocavernosus in rats. Ibanez, M. Target-dependent sexual differentiation of a limbic-hypothalamic neural pathway. Zup, S. Overexpression of Bcl-2 reduces sex differences in neuron number in the brain and spinal cord.

Young, L. The neurobiology of pair bonding. Zhou, L. Distribution of androgen receptor immunoreactivity in vasopressin-immunoreactive and oxytocin-immunoreactive neurons in the male rat brain. Endocrinology , — Cooke, B. A brain sexual dimorphism controlled by adult circulating androgens. USA 96 , — Morris, J. Medial amygdala volume is sexually dimorphic in mice.

Both estrogen receptors and androgen receptors contribute to testosterone-induced changes in the morphology of the medial amygdala and sexual arousal in male rats. Sexually dimorphic motor nucleus in the rat lumbar spinal cord: response to adult hormone manipulation, absence in androgen-insensitive rats. Watson, N. Neuronal size in the spinal nucleus of the bulbocavernosus: direct modulation by androgen in rats with mosaic androgen insensitivity.

Differential effects of testosterone metabolites upon the size of sexually dimorphic motoneurons in adulthood. Hegstrom, C. Photoperiod and androgens act independently to induce spinal nucleus of the bulbocavernosus neuromuscular plasticity in the Siberian hamster, Phodopus sungorus.

Photoperiod and social cues influence the medial amygdala but not the bed nucleus of the stria terminalis in the Siberian hamster. Photoperiod-dependent response to androgen in the medial amygdala of the Siberian hamster, Phodopus sungorus. Rhythms 17 , — Nottebohm, F. Sexual dimorphism in vocal control areas of songbird brain. Testosterone triggers growth of brain vocal control nuclei in adult female canaries.

Paton, J. Neurons generated in the adult brain are recruited into functional circuits. Arnold, A. The effects of castration and androgen replacement on song, courtship, and aggression in zebra finches Poephila guttata.

Gurney, M. Hormonal control of cell form and number in the zebra finch song system. Konishi, M. Hormonal control of cell death in a sexually dimorphic song nucleus in the zebra finch.

Ciba Found. Sexual differentiation of the brain in songbirds. Genetically triggered sexual differentiation of brain and behavior. Holloway, C. Estrogen synthesis in the male brain triggers development of the avian song control pathway in vitro. Agate, R. Neural, not gonadal, origin of brain sex differences in a gynandromorphic finch. USA , — Minireview: sex chromosomes and brain sexual differentiation. Wagner, C.

Neonatal mice possessing an Sry transgene show a masculinized pattern of progesterone receptor expression in the brain independent of sex chromosome status. De Vries, G. A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. Brenowitz, E. Act locally and think globally: intracerebral testosterone implants induce seasonal-like growth of adult avian song control circuits.

USA 99 , — Grisham, W. Local intracerebral implants of estrogen masculinize some aspects of the zebra finch song system. Monks, D. Direct androgenic regulation of calcitonin gene-related peptide expression in motoneurons of rats with mosaic androgen insensitivity. Ciliary neurotrophic factor maintains motoneurons and their target muscles in developing rats.

Ciliary neurotrophic factor arrests muscle and motoneuron degeneration in androgen-insensitive rats. Xu, J. Blockade of endogenous neurotrophic factors prevents the androgenic rescue of rat spinal motoneurons. Sexual dimorphism in the spinal cord is absent in mice lacking the ciliary neurotrophic factor receptor. Amateau, S. Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior. However, there are a few examples of androgen, in adulthood, masculinizing both the structure of the nervous system and behavior.

In the modal pattern, androgens are required both during development and adulthood to fully masculinize brain structure and behavior. In rodent models of neural sexual dimorphism, it is often the aromatized metabolites of androgen, i. There are other animal models where androgens themselves masculinize the nervous system through interaction with androgen receptors. In the course of masculinizing the nervous system, steroids can affect a wide variety of cellular mechanisms, including neurogenesis, cell death, cell migration, synapse formation, synapse elimination, and cell differentiation.

In animal models, there are no known examples where only a single neural center displays sexual dimorphism.