Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

Many neuropsychiatric disorders exhibit differences in prevalence, age of onset, symptoms or course of illness between males and females. For the most part, the origins of these differences are not well understood. In this article, we provide an overview of sex differences in psychiatric disorders including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), anxiety, depression, alcohol and substance abuse, schizophrenia, eating disorders and risk of suicide. We discuss both genetic and nongenetic mechanisms that have been hypothesized to underlie these differences, including ascertainment bias, environmental stressors, X‐ or Y‐linked risk loci, and differential liability thresholds in males and females. We then review the use of twin, family and genome‐wide association approaches to study potential genetic mechanisms of sex differences and the extent to which these designs have been employed in studies of psychiatric disorders. We describe the utility of genetic epidemiologic study designs, including classical twin and family studies, large‐scale studies of population registries, derived recurrence risks, and molecular genetic analyses of genome‐wide variation that may enhance our understanding sex differences in neuropsychiatric disorders.     

Sex differences in social interaction behavior following social defeat stress in the monogamous California mouse (Peromyscus californicus)

Stressful life experiences are known to be a precipitating factor for many mental disorders. The social defeat model induces behavioral responses in rodents (e.g. reduced social interaction) that are similar to behavioral patterns associated with mood disorders. The model has contributed to the discovery of novel mechanisms regulating behavioral responses to stress, but its utility has been largely limited to males. This is disadvantageous because most mood disorders have a higher incidence in women versus men. Male and female California mice (Peromyscus californicus) aggressively defend territories, which allowed us to observe the effects of social defeat in both sexes. In two experiments, mice were exposed to three social defeat or control episodes. Mice were then behaviorally phenotyped, and indirect markers of brain activity and corticosterone responses to a novel social stimulus were assessed. Sex differences in behavioral responses to social stress were long lasting (4 wks). Social defeat reduced social interaction responses in females but not males. In females, social defeat induced an increase in the number of phosphorylated CREB positive cells in the nucleus accumbens shell after exposure to a novel social stimulus. This effect of defeat was not observed in males. The effects of defeat in females were limited to social contexts, as there were no differences in exploratory behavior in the open field or light-dark box test. These data suggest that California mice could be a useful model for studying sex differences in behavioral responses to stress, particularly in neurobiological mechanisms that are involved with the regulation of social behavior.     

The evolutionary origins of mood and its disorders

The term 'mood' in its scientific usage refers to relatively enduring affective states that arise when negative or positive experience in one context or time period alters the individual's threshold for responding to potentially negative or positive events in subsequent contexts or time periods. The capacity for mood appears to be phylogenetically widespread and the mechanisms underlying it are highly conserved in diverse animals, suggesting it has an important adaptive function. In this review, we discuss how moods can be classified across species, and what the selective advantages of the capacity for mood are. Core moods can be localised within a two-dimensional continuous space, where one axis represents sensitivity to punishment or threat, and the other, sensitivity to reward. Depressed mood and anxious mood represent two different quadrants of this space. The adaptive function of mood is to integrate information about the recent state of the environment and current physical condition of the organism to fine-tune its decisions about the allocation of behavioural effort. Many empirical observations from both humans and non-human animals are consistent with this model. We discuss the implications of this adaptive approach to mood systems for mood disorders in humans.     

Post-translational histone modifications and their interaction with sex influence normal brain development and elaboration of neuropsychiatric disorders

Sex differences in the risk for and expression of various brain disorders have been known for some time. Yet, the molecular underpinnings of these sex differences as well as how sex modifies normal brain development are still poorly understood. It has recently become known that epigenetic mechanisms play an essential role in establishing and maintaining sex differences in neurodevelopment and disease susceptibility. Epigenetic mechanisms such as post-translational modifications of histones (histone PTMs) integrate various hormonal and external environmental influences to affect genomic output, and this appears to occur in a sex-dependent manner. The present review aims to highlight current understanding of the role of histone PTMs in the sexual differentiation of the brain under normal conditions and how sex-specific modulation of histone PTMs may be involved in psychiatric conditions including autism spectrum disorder (ASD), schizophrenia, and major depressive disorder (MDD). The role of sex chromosome genes as sex-specific histone modifiers and their importance in sexually differentiating the brain will be discussed. Further, the contribution of sex-specific histone PTM marks in the placenta in programming the sexually dimorphic developmental course of the brain and susceptibility to diseases/disorders will be reviewed. Prenatal programming may have a long-lasting effect on the adult brain and behavior but due to the interaction of histone PTMs and its modifiers with fluctuating hormone levels and external influences over the lifespan, the process remains dynamic. Although a few studies indicate an association between sex and histone PTM-related mechanisms in ASD, schizophrenia, and MDD, more research is needed to fully appreciate the interactive effects of histone PTMs and sex in the development and manifestation of these disorders. Understanding the interactions between sex and histone PTMs will advance our understanding of psychiatric disorders and potentially guide development of future treatments tailored specifically to each sex.     

Cellular and molecular alterations in mice with deficient and reduced serotonin transporters

The function of serotonin transporters (SERTs) is related to mood regulation. Mice with deficient or reduced SERT function (SERT knockout mice) show several behavioral changes, including increased anxiety-like behavior, increased sensitivity to stress, and decreases in aggressive behavior. Some of these behavioral alterations are similar to phenotypes found in humans with short alleles of polymorphism in the 5-hydroxytryptamine (5-HT) transporter-linked promoter region (5-HTTLPR). Therefore, SERT knockout mice can be used as a tool to study 5-HTTLPR-related variations in personality and may be the etiology of affective disorders. This article focuses on the cellular and molecular alterations in SERT knockout mice, including changes in 5-HT concentrations and its metabolism, alterations in 5-HT receptors, impaired hypothalamic-pituitary-adrenal gland axis, developmental changes in the neurons and brain, and influence on other neurotransmitter transporters and receptors. It also discusses the possible relationships between these alterations and the behavioral changes in these mice. The knowledge provides the foundation for understanding the cellular and molecular mechanisms that mediate the SERT-related mood regulation, which may have significant impact on understanding the etiology of affective disorders and developing better therapeutic approaches for affective disorders.     

Immune signaling in sex-specific neural and behavioral development: Adolescent opportunity

Sex differences in neural and behavioral development are integral to understanding neurodevelopmental, mental health, and neurodegenerative disorders. Much of the literature has focused on late prenatal and early postnatal life as a critical juncture for establishing sex-specific developmental trajectories, and data are now clear that immune signaling plays a central role in establishing sex differences early in life. Adolescence is another developmental period during which sex differences arise. However, we know far less about how immune signaling plays a role in establishing sex differences during adolescence. Herein, we review well-defined examples of sex differences during adolescence and then survey the literature to speculate how immune signaling might be playing a role in defining sex-specific adolescent outcomes. We discuss open questions in the literature and propose experimental design tenets that may assist in better understanding adolescent neurodevelopment.     

Sex‐specific aging in animals: Perspective and future directions

Sex differences in aging occur in many animal species, and they include sex differences in lifespan, in the onset and progression of age‐associated decline, and in physiological and molecular markers of aging. Sex differences in aging vary greatly across the animal kingdom. For example, there are species with longer‐lived females, species where males live longer, and species lacking sex differences in lifespan. The underlying causes of sex differences in aging remain mostly unknown. Currently, we do not understand the molecular drivers of sex differences in aging, or whether they are related to the accepted hallmarks or pillars of aging or linked to other well‐characterized processes. In particular, understanding the role of sex‐determination mechanisms and sex differences in aging is relatively understudied. Here, we take a comparative, interdisciplinary approach to explore various hypotheses about how sex differences in aging arise. We discuss genomic, morphological, and environmental differences between the sexes and how these relate to sex differences in aging. Finally, we present some suggestions for future research in this area and provide recommendations for promising experimental designs.     

Mitochondria,endoplasmic reticulum and innate immune dysfunction in mood disorders: Do Mitochondria-Associated Membranes (MAMs) play a role?

Mood disorders like major depression and bipolar disorder (BD) are among the most prevalent forms of mental illness. Current knowledge of the neurobiology and pathophysiology of these disorders is still modest and clear biological markers are still missing. Thus, a better understanding of the underlying pathophysiological mechanisms to identify potential therapeutic targets is a prerequisite for the design of new drugs as well as to develop biomarkers that help in a more accurate and earlier diagnosis.Multiple pieces of evidence including genetic and neuro-imaging studies suggest that mood disorders are associated with abnormalities in endoplasmic-reticulum (ER)-related stress responses, mitochondrial function and calcium signalling. Furthermore, deregulation of the innate immune response has been described in patients diagnosed with mood disorders, including depression and BD. These disease-related events are associated with functions localized to a subdomain of the ER, known as Mitochondria-Associated Membranes (MAMs), which are lipid rafts-like domains that connect mitochondria and ER, both physically and biochemically.This review will outline the current understanding of the role of mitochondria and ER dysfunction under pathological brain conditions, particularly in major depressive disorder (MDD) and BD, that support the hypothesis that MAMs can act in these mood disorders as the link connecting ER-related stress response and mitochondrial impairment, as well as a mechanisms behind sterile inflammation arising from deregulation of innate immune responses. The role of MAMs in the pathophysiology of these pathologies and its potential relevance as a potential therapeutic target will be discussed.     

Cellular and molecular alterations in mice with deficient and reduced serotonin transporters.

The function of serotonin transporters (SERTs) is related to mood regulation. Mice with defi- cient or reduced SERT function (SERT knockout mice) show several behavioral changes, including increased anxiety-like behavior, increased sensitivity to stress, and decreases in aggressive behavior. Some of these behavioral alterations are similar to phenotypes found in humans with short alleles of polymorphism in the 5-hydroxytryptamine (5-HT) transporter-linked promoter region (5-HTTLPR). Therefore, SERT knockout mice can be used as a tool to study 5-HTTLPRrelated variations in personality and may be the etiology of affective disorders. This article focuses on the cellular and molecular alterations in SERT knockout mice, including changes in 5-HT concentrations and its metabolism, alterations in 5-HT receptors, impaired hypothalamic- pituitary-adrenal gland axis, developmental changes in the neurons and brain, and influence on other neurotransmitter transporters and receptors. It also discusses the possible relationships between these alterations and the behavioral changes in these mice. The knowledge provides the foundation for understanding the cellular and molecular mechanisms that mediate the SERTrelated mood regulation, which may have significant impact on understanding the etiology of affective disorders and developing better therapeutic approaches for affective disorders.     

Sex, stress, and mood disorders: at the intersection of adrenal and gonadal hormones

The risk for neuropsychiatric illnesses has a strong sex bias, and for major depressive disorder (MDD), females show a more than 2-fold greater risk compared to males. Such mood disorders are commonly associated with a dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis. Thus, sex differences in the incidence of MDD may be related with the levels of gonadal steroid hormone in adulthood or during early development as well as with the sex differences in HPA axis function. In rodents, organizational and activational effects of gonadal steroid hormones have been described for the regulation of HPA axis function and, if consistent with humans, this may underlie the increased risk of mood disorders in women. Other developmental factors, such as prenatal stress and prenatal overexposure to glucocorticoids can also impact behaviors and neuroendocrine responses to stress in adulthood and these effects are also reported to occur with sex differences. Similarly, in humans, the clinical benefits of antidepressants are associated with the normalization of the dysregulated HPA axis, and genetic polymorphisms have been found in some genes involved in controlling the stress response. This review examines some potential factors contributing to the sex difference in the risk of affective disorders with a focus on adrenal and gonadal hormones as potential modulators. Genetic and environmental factors that contribute to individual risk for affective disorders are also described. Ultimately, future treatment strategies for depression should consider all of these biological elements in their design.     

Selective disruption of dopamine D2-receptors/beta-arrestin2 signaling by mood stabilizers

Abstract

Mood stabilizers are a heterogeneous class of drugs having antidepressant and anti-manic effects in bipolar disorders, depression and schizophrenia. Despite wide clinical applications, the mechanisms underlying their shared actions and therapeutic specificity are unknown. Here, we examine the effects of the structurally unrelated mood stabilizers lamotrigine, lithium and valproate on G protein and beta-arrestin-dependent components of dopamine D2 receptor signaling and assess their contribution to the behavioral effects of these drugs. When administered chronically to mice lacking either D2 receptors or beta-arrestin 2, lamotrigine, lithium and valproate failed to affect Akt/GSK3 signaling as they do in normal littermates. This lack of effect on signaling resulted in a loss of responsiveness to mood stabilizers in tests assessing “antimanic” or “antidepressant”-like behavioral drug effects. This shows that mood stabilizers lamotrigine, lithium and valproate can exert behavioral effects in mice by disrupting the beta-arrestin 2-mediated regulation of Akt/GSK3 signaling by D2 dopamine receptors, thereby suggesting a shared mechanism for mood stabilizer selectivity.     

Sex differences in kappa opioid pharmacology

In recent years it has become apparent that sex is a major factor involved in modulating the pharmacological effects of exogenous opioids. The kappa opioid receptor (KOPR) system is a potential therapeutic target for pain, mood disorders and addiction. In humans mixed KOPR/MOPR ligands have been found to produce greater analgesia in women than men. In contrast, in animals, selective KOPR agonists have been found to produce greater antinociceptive effects in males than females. Collectively, the studies indicate that the direction and magnitude of sex differences of KOPR-mediated antinociception/analgesia are dependent on species, strain, ligand and pain model examined. Of interest, and less studied, is whether sex differences in other KOPR-mediated effects exist. In the studies conducted thus far, greater effects of KOPR agonists in males have been found in neuroprotection against stroke and suppression of food intake behavior. On the other hand, greater effects of KOPR agonists were found in females in mediation of prolactin release. In modulation of drugs of abuse, sex differences in KOPR effects were observed but appear to be dependent on the drug examined. The mechanism(s) underlying sex differences in KOPR-mediated effects may be mediated by sex chromosomes, gonadal hormonal influence on organization (circuitry) and/or acute hormonal influence on KOPR expression, distribution and localization. In light of the diverse pharmacology of KOPR we discuss the need for future studies characterizing the sexual dimorphism of KOPR neural circuitry and in examining other behaviors and processes that are modulated by the KOPR.     

Sex differences in molecular and cellular substrates of stress

Women are twice as likely as men to suffer from stress-related psychiatric disorders, like unipolar depression and post-traumatic stress disorder. Although the underlying neural mechanisms are not well characterized, the pivotal role of stress in the onset and severity of these diseases has led to the idea that sex differences in stress responses account for this sex bias. Corticotropin-releasing factor (CRF) orchestrates stress responses by acting both as a neurohormone to initiate the hypothalamic-pituitary-adrenal (HPA) axis and as a neuromodulator in the brain. One target of CRF modulation is the locus coeruleus (LC)-norepinephrine system, which coordinates arousal components of the stress response. Hypersecretion of CRF and dysregulation of targets downstream from CRF, such as the HPA axis and LC-norepinephrine system, are characteristic features of many stress-related psychiatric diseases, suggesting a causal role for CRF and its targets in the development of these disorders. This review will describe sex differences in CRF and the LC-norepinephrine system that can increase stress sensitivity in females, making them vulnerable to stress-related disorders. Evidence for gonadal hormone regulation of hypothalamic CRF is discussed as an effect that can lead to increased HPA axis activity in females. Sex differences in the structure of LC neurons that create the potential for hyperarousal in response to emotional stimuli are described. Finally, sex differences at the molecular level of the CRF(1) receptor that make the LC-norepinephrine system more reactive in females are reviewed. The implications of these sex differences for the treatment of stress-related psychiatric disorders also will be discussed.     

Absence of Complementary Sex Determination in the Parasitoid Wasp Genus Asobara (Hymenoptera: Braconidae)

An attractive way to improve our understanding of sex determination evolution is to study the underlying mechanisms in closely related species and in a phylogenetic perspective. Hymenopterans are well suited owing to the diverse sex determination mechanisms, including different types of Complementary Sex Determination (CSD) and maternal control sex determination. We investigated different types of CSD in four species within the braconid wasp genus Asobara that exhibit diverse life-history traits. Nine to thirteen generations of inbreeding were monitored for diploid male production, brood size, offspring sex ratio, and pupal mortality as indicators for CSD. In addition, simulation models were developed to compare these observations to predicted patterns for multilocus CSD with up to ten loci. The inbreeding regime did not result in diploid male production, decreased brood sizes, substantially increased offspring sex ratios nor in increased pupal mortality. The simulations further allowed us to reject CSD with up to ten loci, which is a strong refutation of the multilocus CSD model. We discuss how the absence of CSD can be reconciled with the variation in life-history traits among Asobara species, and the ramifications for the phylogenetic distribution of sex determination mechanisms in the Hymenoptera.     

Transferring knowledge towards understanding the pore stabilizing variations in K+ channels

Recent advances in structural biology underlying mechanisms of channel gating have strengthened our knowledge about how K⁺ channels can be inter-convertible between conductive and non-conductive states. We have reviewed and combined mutagenesis with biochemical, biophysical and structural information in order to understand the critical roles of the pore residues in stabilizing the pore structure and channel open state. We also discuss how the latest knowledge on the K⁺ channel KcsA may provide a step towards better understanding of distinct pore stabilizing differences among diversified K⁺ channels.     

Depletion of FKBP51 in Female Mice Shapes HPA Axis Activity

Psychiatric disorders such as depressive disorders and posttraumatic stress disorder are a major disease burden worldwide and have a higher incidence in women than in men. However, the underlying mechanism responsible for the sex-dependent differences is not fully understood. Besides environmental factors such as traumatic life events or chronic stress, genetic variants contribute to the development of such diseases. For instance, variations in the gene encoding the FK506 binding protein 51 (FKBP51) have been repeatedly associated with mood and anxiety. FKBP51 is a negative regulator of the glucocorticoid receptor and thereby of the hypothalamic–pituitary–adrenal axis that also interacts with other steroid hormone receptors such as the progesterone and androgen receptors. Thus, the predisposition of women to psychiatric disorders and the interaction of female hormones with FKBP51 and the glucocorticoid receptor implicate a possible difference in the regulation of the hypothalamic–pituitary–adrenal axis in female FKBP51 knockout (51KO) mice. Therefore, we investigated neuroendocrine, behavioural and physiological alterations relevant to mood disorders in female 51KO mice. Female 51KOs and wild type littermates were subjected to various behavioural tests, including the open field, elevated plus maze and forced swim test. The neuroendocrine profile was investigated under basal conditions and in response to an acute stressor. Furthermore, we analysed the mRNA expression levels of the glucocorticoid receptor and corticotrophin release hormone in different brain regions. Overall, female 51KO mice did not display any overt behavioural phenotype under basal conditions, but showed a reduced basal hypothalamic–pituitary–adrenal axis activity, a blunted response to, and an enhanced recovery from, acute stress. These characteristics strongly overlap with previous studies in male 51KO mice indicating that FKBP51 shapes the behavioural and neuroendocrine phenotype independent of the sex of the individual.     

Independent influences of sex steroids of systemic and central origin in a rat model of Parkinson's disease: A contribution to sex-specific neuroprotection by estrogens

This review considers evidence which reveals considerable complexity and sex differences in the response of the nigrostriatal dopaminergic (NSDA) system to hormonal influences. This pathway degenerates in Parkinson's disease (PD) and sex hormones contribute to sex differences in PD, where men fare worse than women. Here we discuss evidence from animal studies which allows us to hypothesize that, contrary to expectations, the acclaimed neuroprotective property of physiological concentrations of estradiol arises not by promoting NSDA neuron survival, but by targeting powerful adaptive responses in the surviving neurons, which restore striatal DA functionality until over 60% of neurons are lost. Estrogen generated locally in the NSDA region appears to promote these adaptive mechanisms in females and males to preserve striatal DA levels in the partially injured NSDA pathway. However, responses to systemic steroids differ between the sexes. In females there is general agreement that gonadal steroids and exogenous estradiol promote striatal adaptation in the partially injured NSDA pathway to protect against striatal DA loss. In contrast, the balance of evidence suggests that in males gonadal factors and exogenous estradiol have negligible or even harmful effects. Sex differences in the organization of NSDA-related circuitry may well account for these differences. Compensatory mechanisms and sexually dimorphic hard-wiring are therefore likely to represent important biological substrates for sex dimorphisms. As these processes may be targeted differentially by systemic steroids in males and females, further understanding of the underlying processes would provide valuable insights into the potential for hormone-based therapies in PD, which would need to be sex-specific. Alternatively, evidence that estrogen generated locally is protective in the injured male NSDA pathway indicates the great therapeutic potential of harnessing central steroid synthesis to ameliorate neurodegenerative disorders. A clearer understanding of the relative contributions and inter-relationships of central and systemic steroids within the NSDA system is an important goal for future studies.