Sex Differences Shape Brain Development and Function,in Health and Disease: Policy Implications

Abstract

Sex differences profoundly impact health and disease. Despite this, the inclusion of females in clinical and fundamental research lags far behind advances in other aspects of medicine, especially in the brain sciences. Regardless of whether neuroscientists are intrinsically interested in sex differences per se, observing a sex disparity in the incidence or presentation of a given neurological disorder provides a significant clue into the neurobiology of that disorder. Autism spectrum disorder (ASD) is one of the most sex-biased disorders, with a 4:1 male-to-female ratio, an important aspect of its etiology and biology that has largely been ignored in the preclinical literature. This article briefly overviews what is known about the sexual differentiation of the developing healthy brain, with a focus on the preclinical literature. This places observed sex differences in neurological disorders such as ASD into the context of known sex differences in neurobiology—along with insight from known sex-specific mechanisms in other systems that impact the brain (e.g., immune system, microbiome). Finally, the article provides recommendations for progress forward.

Keywords

autism microglia brain development microbiome immune

Sex differences in disorders such as autism spectrum are underexplored but can provide critical insight into origins and neurobiology.

Key Points

Females are underrepresented in basic and preclinical research.

There are sex differences in the incidence or severity of many neurological disorders.

Most early-onset disorders affect males, whereas later-onset disorders affect females.

In heterogeneous disorders like autism, sex is the primary predictor of disease.

Sex differences in neuroimmune function strikingly map onto sexual differentiation of the brain by hormones, suggesting convergent mechanisms.

The study of sex differences should be an indispensable ingredient in any research program.

Introduction

Modern neuroscience is changing at a breathtaking pace, with new technologies and methods of analysis enabling scientists to peer deeper, to examine in greater detail, and to ascribe causality among related factors, more so than at any point in our discipline’s history. Intrinsic to progress in this field is also a conceptual one, namely, the recognition that brain function, and dysfunction, is critically interrelated with other body systems—for instance, the hormones of the body, the immune system, and the microbial ecosystem of the gut and other organs. Each system continually communicates with the other systems, in health and disease. Our understanding of these integrated relationships has allowed the development of truly groundbreaking therapeutic approaches within the last few years—for instance, immunotherapies directed at brain cancer, which harnesses a basic understanding of T cell biology and its specificity and uses it for targeted tissue (tumor) destruction or defense, a breakthrough that is transforming the treatment of cancer and likely has indications for brain disorders. Another example comes from the study of the microbiome, in which fecal transplants from healthy donors to recipients, which are used with astounding success in the treatment of pervasive and debilitating intestinal infections such as Clostridium difficile, are currently being considered for a myriad of neurological disorders, from depression to Parkinson’s disease to autism, based on emerging literature that the gut profoundly impacts the brain.

Despite these successes, one facet of biomedical research lags far behind—the study of sex and gender. We increasingly hear about the underrepresentation of females in clinical research (Nowogrodzki, 2017). The National Institutes of Health (NIH) instituted a new mandate in 2015 to include the consideration of sex as a biological variable in basic (also called fundamental or preclinical) research, where appropriate (https://grants.nih.gov/grants/guide/notice-files/not-od-15-102.html). This is a laudable goal but has fallen short of increasing the study of biological sex differences in health and disease and in the brain sciences in particular. The reasons are undoubtedly complicated. However, foremost among these reasons may be a failure of neurobiologists to recognize the critical role of sexual differentiation of the central nervous system (CNS) as a primary mechanism underlying both normal brain development and function, and dysfunction. And thereby, sexual differentiation is intrinsic to most (if not all) neurological disorders, in males as well as in females. To use a simplistic example, every cell in the body possesses a genetic sex. Even if this difference does not translate into a functional sex difference intrinsic to each cell, neurons growing up in a male brain encounter a distinct set of neurobiological rules and conditions compared with neurons growing up in a female brain. If scientists observe a sexual dimorphism or bias in the incidence or presentation of a given disorder, it is a large clue into the neurobiology of that disorder. A starting point of “different” can lead researchers to inquire whether the mechanisms leading to sexual differentiation of the CNS are parallel to (and thus largely distinct from) those mechanisms impacting disease or whether they are common or convergent pathways. Thus, setting aside the value of fostering an interest in sex differences per se, scientists should pay attention to the role of sex in disease because it is very likely intrinsic to the biology of the disease. Program officers should take note as well.

This article briefly overviews what is known about the sexual dimorphism of the developing healthy brain—aiming to place observed sex differences in neurological disorders into the context of known sex differences in neurobiology; this includes parallels with other systems of the body (e.g., the microbiome) that most certainly impact brain function as well. The review highlights autism spectrum disorder (ASD) as one of the most sex-biased disorders, with greater incidence in males, with potential clues into its mysterious pathophysiology. The article ends with a subset of recommendations for future study and investment.

Sexual Differentiation of the Developing Brain

Sex differences exist in many neurodevelopmental processes, which are critical for establishing differences in physiology and behavior between males and females. Sexual differentiation of the brain begins in utero with the chromosomes XX versus XY which determine the gonads—ovaries in females and testes in males—which secrete hormones that are largely responsible for sexual differentiation of the brain (reviewed in detail in McCarthy, 2008, 2010; McCarthy, Nugent, & Lenz, 2017). In male rodents, testosterone production begins around embryonic day (E) 18 with a significant peak shortly thereafter and a second larger peak at birth. Testosterone circulates throughout the body, including the brain, and is converted to estradiol within brain cells via the enzyme aromatase; it is estradiol that primarily influences the developmental patterning of the male brain. Testosterone itself or its other primary conversion product, dihydrotestosterone (DHT), can also affect the development of the male brain. Sex differences in the genes expressed directly on the sex chromosomes (e.g., on the Y chromosome of the male) can additionally influence the development of the male brain. However, estradiol is the primary mechanism by which the male brain is shaped and determined for sex-specific behaviors in adulthood. In the absence of testosterone secretion, a “female” brain develops, regardless of sex chromosomes.

The mechanisms by which estradiol impacts the developing brain are diverse (described in detail elsewhere; see McCarthy, 2008, for review). Briefly, estradiol affects cell birth and cell death to impact many neural structures and functions: the number of neurons in particular brain nuclei; their extensions (dendritic growth and branching) and the number of connections (synapses) among individual neurons in many brain regions; the morphology of distinct cell types (e.g., neurons and the glial cells that support them) within different brain regions; and various cells’ extensions (e.g., axonal growth) and the density of particular fiber tracts, among other functions.

Of interest here is the recent discovery that immune cells and so-called “inflammatory” signals within the brain are also critical for the sex-specific patterning of the brain; these respond to hormonal signals (Lenz & McCarthy, 2015; Lenz, Nugent, Haliyur, & McCarthy, 2013) and potentially to infectious and other environmental signals as well (McCarthy et al., 2017). This matters because of strong evidence that immune system function is altered, or sensitized, in the brains of individuals with ASD and other neurological disorders. Maternal immune activation (MIA) by infectious or other factors has emerged as one of the strongest preclinical models for ASD (Bilbo, Block, Bolton, Hanamsagar, & Tran, 2017). Due to the striking overlap between normal sexual differentiation of the CNS via an inflammatory pathway and inflammation as a prominent risk factor for ASD the next sections focus on this emerging literature.

Sex Differences in Neurological Disorders

Most neurological disorders exhibit a sex difference in incidence, progression, or severity (Loke, Harley, & Lee, 2015; Young & Pfaff, 2014). These same disorders tend to segregate by time of onset, with early-onset disorders (e.g., ASD, learning disabilities, cerebral palsy) disproportionately affecting males and later-onset disorders (e.g., depression, anxiety, Alzheimer’s disease) disproportionately affecting females. Females are more affected by autoimmune disorders than males, though again this pattern depends on the age of onset. Sex and time dependencies in the epidemiological data provide two large (and oft ignored) clues to the underlying neurobiology, namely, that the mechanisms that create a male versus female body and brain likely converge with or share mechanisms that underlie disease.

The propensity for males to develop certain disorders, and females to develop different ones, urges attention to the conditions creating a male versus female brain to better understand why things go awry. Thus, the value of studying both sexes goes beyond “women’s health” (e.g., ensuring that therapies and pharmaceuticals are equally effective in females compared with males, though that is a laudable goal). Specifically, the value lies in “what makes female development different from male development?” as these differences are likely the most relevant for disease. We are far behind in our understanding of this question, as these differences almost certainly extend beyond those mechanisms arising directly because of chromosomal sex (e.g., X-linked genes) or due directly to sex hormone exposure.

As an example, ASD is one of the most sex-skewed brain disorders, with at least a 4:1 male:female ratio. ASD is a complex cluster of neurodevelopmental disorders with early childhood-onset. These disorders, with presently no cure and only limited treatments, are typically associated with significant lifelong cognitive, social, communication, and behavioral impairments (Birtwell, Willoughby, & Nowinski, 2016; Magiati et al., 2016). The prevalence of ASD has been progressively increasing and is more common than previously thought (Centers for Disease Control and Prevention, 2014). Though a component is certainly genetic, hundreds of diverse genes are now linked to ASD, each of which contributes to only a very small percentage of the affected population. Due to the profound heterogeneity of ASD, the sex bias—whether one is male or female—may well be the most reliable predictor of ASD within vulnerable populations. A recent sibling study confirms this—parents with one child with ASD are more likely to have a second child with ASD, especially if that child is male (Palmer et al., 2017).

A common assumption in ASD has been that the higher prevalence in males is due to ASD-risk gene variants residing on the X chromosome, lending protection in females via the duplicate (unaffected) X allele. This is certainly the case for Fragile X and for Rett syndrome, the latter of which is present only in females because males do not survive the mutation. However, a recent report refutes this idea for most idiopathic (unknown origin) ASD, demonstrating that known ASD-risk genes are neither X-linked nor among the most sexually dimorphic in expression. Rather, genes important for the function of one cell type (glial cells called microglia and astrocytes) are the most differentially expressed between ASD and normal brain; these same genes are more highly expressed in males, absent any disease (Werling, Parikshak, & Geschwind, 2016). Microglia and astrocytes are the primary immunocompetent cells in the CNS that are critical for normal brain development and function as well (e.g., in synapse formation and refinement).

This study therefore supplies two crucial pieces of information. First, the genes important for neuroimmune function are the most sexually dimorphic within the normal brain (higher in males), and, second, the sexual dimorphism in the expression of these genes during normal development likely plays a critical role in the greater ASD prevalence in males. This information also carries profound implications for environmental signals that may impact glial cell function during development (e.g., infection, stressors, or trauma) which are increasingly linked to ASD and elicit inflammatory responses from glia, particularly microglia.

Early-life Immune Activation and ASD

The heterogeneous clinical and biological phenotypes observed in ASD’s symptoms strongly suggest that in genetically susceptible individuals, environmental risk factors combine to create a tipping or threshold point for dysfunction. Immune molecules aid normal brain development. This recent recognition has led to the working hypothesis that inflammatory events during pregnancy or early in life (e.g., in response to infection) may disrupt the normal expression of immune molecules during critical stages of neural development—and thereby contribute to the risk for neurodevelopmental disorders such as ASD (Bilbo et al., 2017; Bilbo & Schwarz, 2012). This hypothesis has in large part been shepherded by the work of the late Paul Patterson and colleagues, demonstrating that a single bacterial or viral infection (or injection of an infectious mimetic to pregnant mice) significantly and persistently impacts offspring immune and nervous system function, changes that underlie ASD-like behavioral dysfunction including social and communication deficits (Patterson, 2011). Subsequent studies by many labs—in humans and in nonhuman animal models—have supported the hypothesis that ongoing disrupted immune molecule expression and/or neuroinflammation contributes to at least a significant subset of ASD. Animal studies showing a link between these so-called “maternal immune activation (MIA)” models and ASD-like outcomes in offspring have in recent years expanded to involve different species and diverse environmental factors associated with ASD in humans, beyond infection, including toxin exposures, maternal stress, and maternal obesity, among others, all of which impact inflammatory or immune pathways (Bilbo et al., 2017).

Sex Differences in Neuroimmune Function

Though less explored, sex differences shape the impact of MIA on ASD-like outcomes, with a greater impact in males in most models that have reported the use of both sexes (Schaafsma et al., 2017; Xuan & Hampson, 2014). Indeed, males tend to be more vulnerable than females to many different insults that occur early in life (prenatally or early postnatally), including hypoxia, infection, trauma, and growth restriction; this led pediatric neurologists to coin the term “wimpy boy syndrome,” referring to the poorer outcomes many premature boys experience. What mechanisms might account for males’ greater vulnerability early in life and hence the increased incidence of autism? Here again, it is useful to think about mechanisms that lead to sex differences in normal neuroimmune function and in brain development and how these intersect in seeking clues to the sex bias in neurological outcomes following early insult.

Sex Differences in Microglial Development

The immunocompetent microglial cells show some striking sex differences during development. In neonatal rats, males have more microglia than do females, in several brain regions, including the cortex, hippocampus, and hypothalamus (Schwarz, Sholar, & Bilbo, 2012). Females eventually catch up to males in cell number, around puberty. When looking at gene transcription/expression in the developing mouse hippocampus, male and female microglia again follow distinct developmental trajectories (assessed by analyzing whole transcriptome profiling of purified microglia genes over development, alongside morphological changes; Hanamsagar et al., 2017). Specifically, the percentage of genes that increase over normal development (a proxy for maturation) is delayed in males relative to females, and an acute immune activation is sufficient to accelerate the developmental maturity of male microglia, while the female microglia remain unchanged by immune stimulation (Hanamsagar et al., 2017). These data suggest that sex-specific developmental trajectories in cell number and gene expression in normal brain development may serve to make male and female microglia differentially responsive to immune challenge, which in turn alters their developmental path.

Microglial Prostaglandin E2 (PGE2) and Sexual Differentiation

An elegant mechanism may explain how microglia not only exhibit sex differences in their development and activity (reviewed in Lenz & McCarthy, 2015) but also are critical for the masculinization of the brain. As described previously, testosterone surges around the time of birth in males, which masculinizes the developing brain following its conversion to estradiol (McCarthy, 2010). This is not accomplished directly (through estrogenic receptor signaling) but rather indirectly (through a neuroimmune pathway in which estradiol stimulates the production of cyclooxygenase 1/2 and subsequently PGE2 [COX1/2 → PGE2; Amateau & McCarthy, 2004]). What is so surprising is that these enzymes are classically known for their functions in inflammation, for example, in response to infection or injury. Male microglia respond to this PGE2 signal by amplifying PGE2 activity, in a feedforward loop, ultimately resulting in sex-specific neural architecture and behavior (Lenz et al., 2013). A transient inactivation or depletion of microglia during this critical perinatal window thus has profound, permanent effects on male sex-specific brain and behavior.

Combined, the previous examples—that (a) male but not female microglial development is accelerated by immune challenge, and (b) sex steroid hormones work to masculinize the male brain early in life by acting on a classically “inflammatory” pathway in microglia—carry implications for the impact that immune activation could have for brain development, and thus the risk of disorders such as ASD, with greater effects in males than in females. That is, because neuroimmune mechanisms are themselves sexually dimorphic, and because these mechanisms work to create sexual dimorphisms in brain structure and function, they are implicated in disorders that present with a large sex bias. In the sections that follow, we briefly extend the discussion of sex differences to known mechanisms of sex-biased biology outside the nervous system, which nonetheless profoundly impact brain function, and the lessons to be learned therein.

Beyond the Brain—Sex Differences in Interacting Systems

Pain

Chronic pain—both prevalence and severity—is more common in females: specifically, maladaptive inflammatory or neuropathic pain, which are increasingly described as neuroimmune disorders. Indeed, research in mice demonstrates that microglia in the spinal cord are required for pain hypersensitivity to develop following a nerve injury or inflammatory challenge, but strikingly only in males. Moreover, this role for microglia in males is dependent on testosterone (Sorge et al., 2015). In females, an entirely different mechanism is at work. T cells that infiltrate from outside the CNS perform the same neuroimmune signaling functions as do microglia in males; specifically, the release of proinflammatory cytokines and other mediators acts on nociceptive neurons to induce pain. If true in humans as well as mice (research that is currently underway), these data indicate that the treatment of pain will require fundamentally different therapeutic approaches in males and females, a realization that has come to light in only the past 5 years, despite decades of work on this debilitating condition.

Microbiome

The health and development of the neuroimmune system is tightly coupled with that of the gut and its commensal (indwelling) bacteria, the microbiome. Immune cells have receptors that respond to “danger” signals, such as bacterial cell wall motifs. For the immune system and natural gut bacterial ecosystem to coexist without extraneous inflammatory processes, they must form a homeostatic relationship. Dysregulation of the immune response can cause many problems, including autoimmune disorders, which present with a strong female bias after puberty (Jacobson, Gange, Rose, & Graham, 1997). The autoimmune disorder, type 1 diabetes (T1D), occurs when pancreatic β cells that secrete insulin are destroyed by autoantibody-mediated immune attack. The microbiome regulates testosterone production and thus confers male protection to T1D (at least in the nonobese diabetes [NOD] mouse model; Markle et al., 2013). NOD mice that grow up in sterile conditions without bacteria do not have a sex bias in T1D incidence. And colonization of young female NOD mice with adult male NOD fecal (stool) contents increased testosterone levels, decreased autoantibody levels, and protected from T1D (Markle et al., 2013). Moreover, sex hormone manipulation (neonatal masculinization or ovariectomy later in life) in female rats altered the gut microbiome even more than nutritional interventions, resulting in overall lower bacterial diversity (Moreno-Indias et al., 2016).

Microglial maturity and development of their immune response is regulated by the microbiome. Adult (mixed-sex) groups of germ-free mice have perpetually “immature” microglia characterized by increased proliferation and decreased immune reactivity (Erny et al., 2015). Antibiotic depletion of the microbiome in normally raised mice results in the same immature profile and can be reversed by recolonization with new commensal bacteria from a healthy mouse (Erny et al., 2015). These data have relevance to the impact of MIA on ASD-like outcomes in rodent models described previously, as recent reports suggest that in addition to social behavior deficits, prenatal infection causes dysfunction within the gut (e.g., “leaky gut,” constipation, etc.) which likely contributes to the behavioral problems, for instance by causing pain (Hsiao et al., 2013). Notably, the gut and immune symptom abnormalities in this rodent model could be corrected by treatment with the human gut bacteria Bacteroides fragilis, although the social behavior deficits remained unchanged. One caveat to these studies is that endpoints were only explored in males, which is reasonable given that ASD is male biased. However, given the previous discussion, the outcomes would likely differ in females, and the insight from mechanisms explored in females could well provide critical for effective therapeutics in males.

Conclusions and Recommendations

Females are chronically underrepresented in every stage of neuroscience research, from basic through translation to clinical. The central thesis of this article is that the study of sex differences in health and disease processes goes beyond relevance to “women’s health” but indeed is critical for the understanding of virtually every disorder at a fundamental level. This assertion rests on the evidence that sex differences in neural development and function are often the mechanisms that become dysregulated in disease. Moreover, many interacting systems, outside the nervous system, exhibit striking sex differences. Some of these mechanisms are present in both sexes but differ in their critical timing or magnitude between males and females (e.g., the sex difference in microglial maturation), whereas other mechanisms are starkly dimorphic (i.e., only present in one sex, such as the role of T cells in pain in females, vs. microglia in males). The binary sex difference in the mechanisms underlying pain, one of the most debilitating neurological disorders in our society today, is sobering given that many publications on chronic pain in mice fail to even report the sex of their experimental subjects.

On a more optimistic note, the study of such nascent fields as neuroimmune interactions in brain development and of the microbiome, among others, has the potential to make an enormous impact on our understanding and treatment of disease. At once humbling in its complexity and exciting in its potential, we have the opportunity to include males and females in all these studies going forward, an effort that should pay dividends. As with any agenda, resources and public will need to support research on both sexes. That said, the most important item on scientists’ “to-do list” may be a reframing of the discussion, to cast the study of sex differences as an indispensable ingredient in any research program, rather than a requirement or burden (Miller et al., 2017). To this end, at its broadest level, this reframing requires a bit of seeing the forest for the trees—to return to the starting point of “different” (male or female), and if present, placing the details of a given mechanism into the known cellular or molecular landscape of this sex difference. Finally, some biological and disease mechanisms will obviously not differ by sex; again, starting from a basic intent to compare presentation in males and females will help to frame the landscape of the problem to be solved early on—male/female, yes or no—and lend critical insight into its biology from the very start.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Sex Differences Shape Brain Development and Function,in Health and Disease: Policy Implications

Abstract

Keywords

Tweet

Key Points

Introduction

Sexual Differentiation of the Developing Brain

Sex Differences in Neurological Disorders

Early-life Immune Activation and ASD

Sex Differences in Neuroimmune Function

Sex Differences in Microglial Development

Microglial Prostaglandin E2 (PGE2) and Sexual Differentiation

Beyond the Brain—Sex Differences in Interacting Systems

Pain

Microbiome

Conclusions and Recommendations

Footnotes

Declaration of Conflicting Interests

Funding

References