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Sex differences in the developing brain as a source of inherent riskDiferencias por sexo en el desarrollo cerebral como fuente de riesgo inherenteLes différences selon le sexe dans le développement cérébral comme source de risque inhérent

Margaret M. McCarthy

Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA

Margaret M. McCarthy, Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA;
This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Brain development diverges in males and females in response to androgen production by the fetal testis. This sexual differentiation of the brain occurs during a sensitive window and induces enduring neuroanatomical and physiological changes that profoundly impact behavior. What we know about the contribution of sex chromosomes is still emerging, highlighting the need to integrate multiple factors into understanding sex differences, including the importance of context. The cellular mechanisms are best modeled in rodents and have provided both unifying principles and surprising specifics. Markedly distinct signaling pathways direct differentiation in specific brain regions, resulting in mosaicism of relative maleness, femaleness, and sameness through-out the brain, while canalization both exaggerates and constrains sex differences. Non-neuronal cells and inflammatory mediators are found in greater number and at higher levels in parts of male brains. This higher baseline of inflammation is speculated to increase male vulnerability to developmental neuropsychiatric disorders that are triggered by inflammation.

Keywords: autism, androgen, early life sự kiện, estrogen, schizophrenia, sex difference

El desarrollo cerebral difiere en hombres y mujeres en respuesta a la producción de andrógenos por los testículos fetales. La diferenciación sexual del cerebro ocurre durante una ventana sensible e induce cambios neuroanatómicos y fisiológicos duraderos que influyen profundamente en la conducta. Todavía está surgiendo el conocimiento acerca de la contribución de los cromosomas sexuales, por lo que es destacable la necesidad de integrar múltiples factores en la comprensión de las diferencias por sexo, incluyendo la importancia del contexto. Los mecanismos celulares están mejor modelados en roedores y han proporcionado tanto principios unificadores como supresores específicos. De manera muy diferente las vías de señales dirigen la diferenciación en regiones cerebrales específicas, resultando en un mosaicismo de masculinidad, feminidad e igualdad relativas a través del cerebro, mientras que la canalización exagera y restringe las diferencias por sexo. Las células no neuronales y los mediadores inflamatorios se encuentran en mayor número y en niveles más altos en zonas de los cerebros de los machos. Se especula que esta mayor basal de inflamación aumenta la vulnerabilidad en los machos para desarrollar trastornos neuropsiquiátricos que son desencadenados por la inflamación.

Les testicules du foetus mâle produisent des androgènes responsables d”un développement cérébral différent chez les hommes et chez les femmes. Cette différentiation cérébrale selon le sexe survient lors d”une fenêtre (sensitive ou délicate ?) et entraîne des changements neuroanatomiques et physiologiques durables qui influent profondément sur le comportement. Notre connaissance de l”implication des chromosomes sexuels est encore nouvelle, il faut donc intégrer de nombreux facteurs, dont l”importance du contexte, pour comprendre les différences selon le sexe. Les mécanismes cellulaires, mieux modélisés chez les rongeurs, ont fourni à la fois des principes communs et des spécificités surprenantes. Des voies de signalisation très distinctes orientent la différentiation dans des régions cérébrales spécifiques : il en résulte une mosaïque de masculinité, de féminité, de similarité relatives dans le cerveau, les différences selon le sexe étant à la fois exagérées et limitées par la canalisation. Les cellules non neuronales et les médiateurs inflammatoires sont plus nombreux et à des niveaux plus élevés dans des morceaux de cerveaux masculins. Ce plus haut degré d”inflammation initiale augmenterait la vulnérabilité des hommes aux troubles neuropsychiatriques du développement déclenchés par l”inflammation.

Introduction

Effective treatments for neuropsychiatric disorders with origins in development remain as elusive today as at the beginning of the “decade of the brain” in 1990. Our understanding of brain development and how genetic and environmental factors contribute to a dysregulation of that development has certainly accelerated, but we remain relatively stymied in the avenue of new therapeutics and treatments. This is probably a combination of the complexity of developmental disorders and our still-incomplete understanding of the key sources of vulnerability to the developing brain. One essential variable that has long been ignored is sex. Being male imparts a major risk for the development of a developmental neurological or neuropsychiatric disorder, whereas being female appears to afford some protection from the same. Identifying the biological origins of male vulnerability and female protection will generate novel targets for therapeutic intervention and prevention. Animal models are essential to this effort not only because of the experimental advantages but also because we can divorce sex and gender as only humans possess a gender, a combination of self and societal perception of one”s sex. This review focuses largely on lessons learned from animal models in a historical context with the goal of informing the design and interpretation of clinical research.

Historical overview

What seems inherently obvious today—that neuroanatomical substrates contribute to, and at times direct, sex differences in brain and behavior—was not always the case. Pioneers in the burgeoning field of behavioral endocrinology in the 1950s contemplated the origins of sex differences in courtship, copulatory, and parental behaviors in animals and argued in favor of the view that it was somatic aspects of males and females that induced them to behave in particular ways. The brain was only there to execute the fixed -action pattern response that was dictated by the presence of primary and secondary sex characteristics such as genitalia and plumage coloration. This is not a particularly unreasonable view. The brain resides within a toàn thân after all, and that toàn thân is tremendously influenced by the sex of the individual. But the notion of the toàn thân directing behavior was gradually put to rest starting with an iconic publication in 1959 in which treatment of pregnant guinea pigs with testosterone resulted in daughters that showed the copulatory pattern of males as adults despite not having a penis1 (but note that this required that the females be supplied with additional testosterone in adulthood to activate the preprogramming effects of the gestational exposure). The work of Phoenix and colleagues1 set the stage for concluding that the brain was the critical organ that had been modified by prenatal hormone exposure, but it did not close the case. Reports of subtle and limited sex differences in neuronal morphology in the rodent models in the 1960s hinted at the potential for neural substrates regulating sex differences in behavior, but it was not until the 1970s that irrefutable evidence convinced the world that male and female brains differed, at least in birds. Male canaries sing a complex and beautiful tuy nhiên, whereas females only twitter. Reasoning that this must have origins in the brain, Art Arnold and his mentor Fernando Nottebohm identified a nucleus of the songbird brain that was markedly larger in males than females.2 Shortly thereafter, a much less impressive but nonetheless reliable sex difference was found in the size of a nucleus in the rodent (rat) brain and given the lofty name of the “sexually dimorphic nucleus of the preoptic area,” or SDN for short.3 A star was born.

The discovery of the SDN spawned a cottage industry of looking for and finding sex differences in the size (volume) of particular subregions of the brain, varying from small nuclei to entire hemispheres, and the size of major fiber tracks such as the corpus callosum. Early in the 1980s, the advent of the AIDS epidemic, combined with increasing interest in the potential biological origins of human homosexuality, created the opportunity to examine large numbers of postmortem brains from men, women, and homosexual men. A hypothalamic nucleus deemed analogous to the rodent SDN was found to be larger in heterosexual men than heterosexual women and homosexual men.4 Interest in how the brain could impact complex behaviors differently in men and women was both at a fever pitch in some quarters and completely ignored or denigrated in others. The suggestion that women”s brains were “different” was not a welcome message at a time when feminism was seriously taking hold.

And so a funny thing happened—two things actually. The first was that sex differences in the brain were relegated to the arena of reproduction and the discipline of neuroendocrinology, which became a poor cousin to the mothership of neuroscience. The second was a series of startling reports from the McEwen lab at Rockefeller University (the same place Arnold and Nottebohm had conducted their bird studies 20 years earlier) reporting that the dendritic synapse density of hippocampal pyramidal neurons varied by up to 30% across the female estrus cycle.5 Initially met with incredulity but ultimately accepted in the face of overwhelming data, this finding had the effect of relegating females to the scientific bench as researchers sought to avoid variability, thus sealing the fate of the overwhelming majority of future studies on hippocampal physiology, which were conducted only in males. And so it has been for the past 25 years.6

Today, a perfect storm of increased awareness, new policies, and novel findings—some discovered by accident and others on purpose—have generated renewed interest in sex differences in the brain. Equally compelling is the undeniable gender bias in most if not all neuropsychiatric and neurological disorders which demands our attention.

Sex differences in brain versus sex differences in behavior

A primary goal of neuroseience is to understand the governing principles by which the brain directs behavior. That this is a challenging goal is evident in the initial breakthroughs being those in the simplest organisms with simple behaviors, such as the gill withdrawal reflex of the marine snail Aplysia or swimming behavior of the flat worm Caenorhabditis elegans.

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But, ultimately, we seek to understand emotion, cognition, and motivation, which together encapsulate every essential behavior, ranging from the drive to eat to the ability to send a man to the moon. But causally connecting specific neuroanatomical or physiological traits in the brain to those behaviors remains an elusive goal. This is equally true in the arena of sex differences in brain and behavior, but is a truism often forgotten. Even the most minor findings of sex differences in the brain are often assumed to directly drive and determine sex differences in behavior. More appropriate is to assume that sex differences in the brain create predispositions or differentially weighted valences for responding to specific stimuli that can shift the probability in favor of a particular behavioral response in one sex versus the other. But all complex behaviors are influenced by current context and past experience, the influence of which can far outweigh that of an underlying neurophysiological sex difference at any given moment.

Brain sex differences in context

The more we learn, the more we don”t know when it comes to sex differences in the brain. What is clear is that the types, origins, and impact of such differences are complex, multifactorial, and vary by species. It is useful to provide boundaries and operationally defined definitions of types of sex differences. In a recent “Circumspective” piece in Neuropsychopharmacology, Joel and McCarthy proposed four not-mutually exclusive dimensions along which sex differences can be defined.7 These are: (i) persistent versus transient; (ii) context-independent versus -dependent; (iii) dimorphic versus continuous; and (iv) a direct versus indirect consequence of sex. These dimensions overlap in a classic Venn diagram fashion as they share some features but are unique in others (Figure 1 ).

Conceptualizing sex differences. (A) The effects of sex on the brain organize along overlapping domains. Some sex differences are programmed early in life and persist throughout the life span, whereas others might also be programmed early but appear or disappear as a function of context (eg, age, circumstances, etc). Other sex differences are transient, which can be due to context or the result of the adult hormonal milieu, which differs in males and females and profoundly effects brain and behavior. Many sex differences that are programmed early in life in response to hormones also require hormonal activation in adulthood in order to manifest. Many sex differences can be considered direct, ie, due to hormones or sex chromosome complement, whereas others are indirect. Indirect effects include different rearing of male versus female offspring, physical constraints due to somatic sex differentiation, and in the case of humans, the impact of sex.7 (B) Additional consideration in the study of sex is whether an end point is continuous or dimorphic. End points that are continuous can exhibit sex differences, meaning males and females vary on average along that continuum. Sometimes, both sexes are at the same point on the continuum at baseline but diverge in response to a challenge, such as stress. Other times, the two sexes converge on the same point from divergent beginnings. This can occur as a consequence of the cost of the reproductive profile of either sex, such as the lack of a natural induction of parenting behavior in males, which do not experience the hormonal profile of pregnancy, parturition, and lactation. Lastly, there are some end points that take on two forms, one in males and one in females, and these are considered sexually dimorphic.

Sex-determined and sexually dimorphic differences

Sex-determined differences between males and females would be an example of a persistent difference that is established early in development by the programming effects of gonadal steroids and/or chromosome complement. Such end points are often sexually dimorphic, meaning there are two forms, one in males and one in females, and they may undergird behaviors that are highly sex-typic. For example, the neural circuitry controlling singing in songbirds is highly dimorphic in that some nuclei are only present in male brains, and only males of those species exhibit the complex songs of courtship. The tuy nhiên nuclei are differentiated early in development; however, they also show seasonal plasticity. So the sex difference is permanent, but there is a transience in the magnitude of that sex difference. As another example, most animals exhibit sex-typic forms of copulatory behavior that are determined by sexual differentiation of neural circuits. The circuit controlling mating differs between males and females in numbers of neurons, connectivity, neurochemistry, and synaptic profile. However, in mammals, there is no evidence that separate neural circuits regulate male mounting behavior versus female receptivity. Instead, there is a single circuit for sexual behavior, but it is differentially weighted in its response to olfactory, auditory, and somatosensory cues in males versus females (see ref 8 for review). Sex-determined neuroanatomical or neurophysiological end points such as this are not expected to change significantly across the life span or to shift dramatically in response to context or experience, although the behaviors they are associated with might. Sexual behavior is only engaged in when the moment is right, meaning the right season, the right phase of the female reproductive cycle, and the right age, but the underlying neural circuits for both sexual motivation and engagement are always at the ready.

Sex differences and effects of sex

The term “sex difference” is most appropriately used when an end point varies along a continuum, and the mean is significantly different for males versus females. Important points for consideration are the magnitude of the difference in the means and the variance associated with each mean. For some end points, there can be a great khuyến mãi of overlap in the response or measurement in males and females. In this scenario, there might be a statistically significant difference between a group of males and a group of females, but the measure is not necessarily predictive of sex. There can also be a circumstance where a percentage of the population of males is closer to one end of a continuous spectrum, whereas a much smaller percentage of females is, resulting in an overall population mean that is different, but the end point would be identical in large numbers of males and females and therefore not a very accurate predictor of sex. Some would argue that in cases such as this there is an effect of sex, not a sex difference per se.9,10 The important distinction being that sex is just one of many variables that has an impact on a response, and that others such as age, disease state, genetics, etc, may be equally or more important than sex. Conversely, there are other end points that can have markedly different means in males and females with relatively little overlap, due to low variance around the mean for each sex. In this instance, there would be a sex difference, and the end point may be a relatively reliable predictor of sex.

Transience and context dependence, convergence, and divergence

Sometimes, sex differences emerge only under certain circumstances, or they may disappear under others. For instance, there is a robust and trans-species sex difference in the frequency and intensity of play behavior by juveniles.11,12 In what is referred to as rough-and-tumble play, young males will consistently engage more frequently and more intensely than females. But this sex difference is both transient and context-dependent in that once the Rubicon of puberty has been crossed, both males and females stop playing as new behavioral repertoires involving male-male competition, sexual solicitation, mate guarding, and territorial aggression emerge. Thus, the sex difference only exists during a brief period of life. The neural substrate of play remains poorly defined, and whether it changes postpuberty is not known, but it is clear that hormonal influences early in development are essential to the sex difference.13 Nonetheless, the magnitude, and even the direction, of the sex difference in play is strongly influenced by context, ie, by prior social isolation, group size and composition, familiar partner versus stranger, and age.14

Stress is one of the best examples of a contextual source for sex differences. There are hundreds of studies reporting sex differences in stress responses as evidenced by activation of the hypothalamic-pituitary-adrenal (HPA) axis, and an equal or greater number on anxious behavior as demonstrated by activity in an open field or elevated plus maze. But whether it”s the males or the females that show a greater stress response or higher anxiety varies widely and appears to be strongly influenced by the age at which the stressor occurs, the nature of the stressor, and past experience.15 Even the signal transduction pathways by which stress exerts its effects can differ in males and females.16 Thus, it can never be assumed that males and females will respond to a stressful situation in the same way, but generalities about sex differences in the stress axis and anxious behavior also cannot be made.

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Stress also provides us with one of the best examples of a divergence in responding between males and females during a particular context on a particular end point. In a series of elegant studies, Tracey Shors and colleagues have demonstrated that eye-blink conditioning, a learning and memory task, is strongly influenced by stress such that males improve at the task if stressed beforehand, whereas female performance deteriorates. Under nonstressful conditions, the two sexes perform at par. Shors further showed that a directional change in the density of dendritic spines on hippocampal neurons paralleled the change in performance, meaning males developed more dendritic spine synapses and learned better, whereas females did the opposite. But there is a caveat. The negative impact of stress on performance in females occurs only if they are under a particular hormonal state associated with the estrus cycle. If they are at another phase in the cycle or the ovaries are removed all together, the effect of stress, and therefore the sex difference, goes away.17

The above is an example of divergence, meaning males and females start at the same baseline but fly apart in the face of a challenge, and thus an example of a contextual sex difference. Conversely, sometimes the two sexes converge on the same end point starting from different origins. This was most classically illustrated in the work of Geert de Vries in which he coined the term “compensation” to describe the phenomenon whereby males of a particular species of voles have a separate neural circuit from females that drives them to show parenting behavior toward their offspring.18 The reasoning is that males do not experience pregnancy, parturition, or lactation and therefore lack the associated neural circuits that normally mediate maternal behavior. Biparental care must provide a fitness advantage in this species as males have evolved a distinct vasopressinergic neural network that drives them to behave just lượt thích newly parturient females when their young are born.19

More recently, it has become evident that convergence is also found at the cellular level and control of synaptic function. For reasons that remain mysterious, the control of both synaptic inhibition and potentiation, via γ-aminobutyric acid (GABA) and glutamate respectively, is achieved via distinct cellular signaling pathways in the hippocampus of male and female rodents. Referred to as a “latent” sex difference, the end result on synaptic efficacy is the same, but the transduction pathway is different.20,21 Given that the physiological outcome is the same, one might say what does it matter? But as Woolley and colleagues point out, the significance is in the potential for markedly different effects of drugs, toxins, or nutrients that mod ulate specific components of signal transduction pathways in males versus females. The potential for sex differences in response is essentially hidden (ie, latent), as when unperturbed the end point is the same, and highlights the fact that we can never assume there is no difference in males versus females.

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