Beyond the binary: Characterizing the relationships between sex and neuropeptide receptor binding density measures in the rat brain.

Sex differences exist in numerous parameters of the brain. Yet, sex-related factors are part of a large set of variables that interact to affect many aspects of brain structure and function. This raises questions regarding how to interpret findings of sex differences at the level of single brain measures and the brain as a whole. In the present study, we reanalyzed two datasets consisting of measures of oxytocin, vasopressin V1a, and mu opioid receptor binding densities in multiple brain regions in rats. At the level of single brain measures, we found that sex differences were rarely dimorphic and were largely persistent across estrous stage and parental status but not across age or context. At the level of aggregates of brain measures showing sex differences, we tested whether individual brains are 'mosaics' of female-typical and male-typical measures or are internally consistent, having either only female-typical or only male-typical measures. We found mosaicism for measures showing overlap between females and males. Mosaicism was higher a) with a larger number of measures, b) with smaller effect sizes of the sex difference in these measures, and c) in rats with more diverse life experiences. Together, these results highlight the limitations of the binary framework for interpreting sex effects on the brain and suggest two complementary pathways to studying the contribution of sex to brain function: (1) focusing on measures showing dimorphic and persistent sex differences and (2) exploring the relations between specific brain mosaics and specific endpoints.

How hype and hyperbole distort the neuroscience of sex differences.

Sex/gender differences in the human brain attract attention far beyond the neuroscience community. Given the interest of nonspecialists, it is important that researchers studying human female-male brain difference assume greater responsibility for the accurate communication of their findings.

An Exploration of the Relations Between Self-Reported Gender Identity and Sexual Orientation in an Online Sample of Cisgender Individuals.

The present study explored the relations between self-reported aspects of gender identity and sexual orientation in an online sample of 4756 cisgender English-speaking participants (1129 men) using the Multi-Gender Identity Questionnaire and a sexual orientation questionnaire. Participants also labeled their sexual orientation. We found a wide range of gender experiences in the sample, with 38% of the participants feeling also as the "other" gender, 39% wishing they were the "other" gender, and 35% wishing they had the body of the "other" sex. Variability in these measures was very weakly related to sexual orientation, and these relations were gender-specific, being mostly U shaped (or inverted-U shaped) in men and mostly linear asymptotic in women. Thus, in women, feeling-as-a-woman was highest in the exclusively heterosexual group, somewhat lower in the mostly heterosexual group, and lowest in the bisexual, mostly homosexual, and exclusively homosexual groups, which did not differ, and the reverse was true for feeling-as-a-man (i.e., lowest in the exclusively heterosexual group and highest in the bisexual, mostly homosexual, and exclusively homosexual groups). In men, feeling-as-a-man was highest at both ends of the sexual orientation continuum and lowest at its center, and the reverse was true for feeling-as-a-woman. Similar relations were evident also for the other aspects of gender identity. This study adds to a growing body of literature that questions dichotomous conventions within the science of gender and sexuality. Moreover, our results undermine the tight link assumed to exist between sexual and gender identities, and instead posit them as weakly correlated constructs.

Sex beyond the genitalia: The human brain mosaic.

Whereas a categorical difference in the genitals has always been acknowledged, the question of how far these categories extend into human biology is still not resolved. Documented sex/gender differences in the brain are often taken as support of a sexually dimorphic view of human brains ("female brain" or "male brain"). However, such a distinction would be possible only if sex/gender differences in brain features were highly dimorphic (i.e., little overlap between the forms of these features in males and females) and internally consistent (i.e., a brain has only "male" or only "female" features). Here, analysis of MRIs of more than 1,400 human brains from four datasets reveals extensive overlap between the distributions of females and males for all gray matter, white matter, and connections assessed. Moreover, analyses of internal consistency reveal that brains with features that are consistently at one end of the "maleness-femaleness" continuum are rare. Rather, most brains are comprised of unique "mosaics" of features, some more common in females compared with males, some more common in males compared with females, and some common in both females and males. Our findings are robust across sample, age, type of MRI, and method of analysis. These findings are corroborated by a similar analysis of personality traits, attitudes, interests, and behaviors of more than 5,500 individuals, which reveals that internal consistency is extremely rare. Our study demonstrates that, although there are sex/gender differences in the brain, human brains do not belong to one of two distinct categories: male brain/female brain.

Behavioral and neural effects of intra-striatal infusion of anti-streptococcal antibodies in rats.

Group A ß-hemolytic streptococcal (GAS) infection is associated with a spectrum of neuropsychiatric disorders. The leading hypothesis regarding this association proposes that a GAS infection induces the production of auto-antibodies, which cross-react with neuronal determinants in the brain through the process of molecular mimicry. We have recently shown that exposure of rats to GAS antigen leads to the production of anti-neuronal antibodies concomitant with the development of behavioral alterations. The present study tested the causal role of the antibodies by assessing the behavior of naïve rats following passive transfer of purified antibodies from GAS-exposed rats. Immunoglobulin G (IgG) purified from the sera of GAS-exposed rats was infused directly into the striatum of naïve rats over a 21-day period. Their behavior in the induced-grooming, marble burying, food manipulation and beam walking assays was compared to that of naïve rats infused with IgG purified from adjuvant-exposed rats as well as of naïve rats. The pattern of in vivo antibody deposition in rat brain was evaluated using immunofluorescence and colocalization. Infusion of IgG from GAS-exposed rats to naïve rats led to behavioral and motor alterations partially mimicking those seen in GAS-exposed rats. IgG from GAS-exposed rats reacted with D1 and D2 dopamine receptors and 5HT-2A and 5HT-2C serotonin receptors in vitro. In vivo, IgG deposits in the striatum of infused rats colocalized with specific brain proteins such as dopamine receptors, the serotonin transporter and other neuronal proteins. Our results demonstrate the potential pathogenic role of autoantibodies produced following exposure to GAS in the induction of behavioral and motor alterations, and support a causal role for autoantibodies in GAS-related neuropsychiatric disorders.

Beyond the binary: Rethinking sex and the brain.

The paper reviews the relations between sex and brain in light of the binary conceptualization of these relations and the challenges posed to it by the 'mosaic' hypothesis. Recent formulations of the binary framework range from arguing that the typical male brain is different from the typical female brain to claiming that brains are typically male or female because brain structure can be used to predict the sex category (female/male) of the brain's owner. These formulations are challenged by evidence that sex effects on the brain may be opposite under different conditions, that human brains are comprised of mosaics of female-typical and male-typical features, and that sex category explains only a small part of the variability in human brain structure. These findings led to a new, non-binary, framework, according to which mosaic brains reside in a multi-dimensional space that cannot meaningfully be reduced to a male-female continuum or to a binary variable. This framework may also apply to sex-related variables and has implications for research.

The gender-binary cycle: the perpetual relations between a biological-essentialist view of gender, gender ideology, and gender-labelling and sorting.

Gender inequality is one of the most pressing issues of our time. A core factor that feeds gender inequality is people's gender ideology-a set of beliefs about the proper order of society in terms of the roles women and men should fill. We argue that gender ideology is shaped, in large parts, by the way people make sense of gender differences. Specifically, people often think of gender differences as expressions of a predetermined biology, and of men and women as different 'kinds'. We describe work suggesting that thinking of gender differences in this biological-essentialist way perpetuates a non-egalitarian gender ideology. We then review research that refutes the hypothesis that men and women are different 'kinds' in terms of brain function, hormone levels and personality characteristics. Next, we describe how the organization of the environment in a gender-binary manner, together with cognitive processes of categorization drive a biological-essentialist view of gender differences. We then describe the self-perpetuating relations, which we term the gender-binary cycle, between a biological-essentialist view of gender differences, a non-egalitarian gender ideology and a binary organization of the environment along gender lines. Finally, we consider means of intervention at different points in this cycle. This article is part of the theme issue 'The political brain: neurocognitive and computational mechanisms'.

Selective impairment of prediction error signaling in human dorsolateral but not ventral striatum in Parkinson's disease patients: evidence from a model-based fMRI study.

Animal studies have found that the phasic activity of dopamine neurons during reward-related learning resembles a "prediction error" (PE) signal derived from a class of computational models called reinforcement learning (RL). An apparently similar signal can be measured using fMRI in the human striatum, a primary dopaminergic target. However, the fMRI signal does not measure dopamine per se, and therefore further evidence is needed to determine if these signals are related to each other. Parkinson's disease (PD) involves the neurodegeneration of the dopamine system and is accompanied by deficits in reward-related decision-making tasks. In the current study we used a computational RL model to assess striatal error signals in PD patients performing an RL task during fMRI scanning. Results show that error signals were preserved in ventral striatum of PD patients, but impaired in dorsolateral striatum, relative to healthy controls, a pattern reflecting the known selective anatomical degeneration of dopamine nuclei in PD. These findings support the notion that PE signals measured in the human striatum by the BOLD signal may reflect phasic DA activity. These results also provide evidence for a deficiency in PE signaling in the dorsolateral striatum of PD patients that may offer an explanation for their deficits observed in other reward learning tasks.

Beyond sex differences and a male-female continuum: Mosaic brains in a multidimensional space.

In the last two decades, the 60 years old view that in utero exposure to testosterone irreversibly masculinizes the brain of males away from a default female form has been replaced by a complex scenario according to which sex affects the brains of both females and males via multiple mechanisms, which are susceptible to internal and external factors. These observations led to the "mosaic" hypothesis-the expectation that the degree of "maleness"/"femaleness" of different features within a single brain would not be internally consistent. Following a short review of the animal studies providing the basis of the mosaic hypothesis, I describe three studies conducted in humans that assessed internal consistency in regional volume, cortical thickness, and connectivity as revealed by magnetic resonance imaging (MRI); in neuronal numbers in the postmortem hypothalamus; and in changes in regional volume and cortical thickness (assessed with MRI) following exposure to extreme real-life stress. The conclusion from these studies, that human brains are largely composed of unique mosaics of female-typical and male-typical features, was supported by recent findings that the brain "types" typical of women are also typical of men, and vice versa. Lastly, I discuss criticism of the mosaic hypothesis and suggest replacing the framework of a male-female continuum with thinking about mosaic brains residing in a multidimensional space.

The Complex Relationships between Sex and the Brain.

In the past decennia, our understanding of the sexual differentiation of the mammalian brain has dramatically changed. The simple model according to which testosterone masculinizes the brain of males away from a default female form, was replaced with a complex scenario, according to which sex effects on the brain of both females and males are exerted by genetic, hormonal, and environmental factors. These factors act via multiple partly independent mechanisms that may vary according to internal and external factors. These observations led to the "mosaic" hypothesis-the expectation of high variability in the degree of "maleness"/"femaleness" of different features within a single brain. Here, we briefly review animal data that form the basis of current understanding of sexual differentiation; present, in this context, the results of co-analyses of human brain measures obtained by magnetic resonance imaging or postmortem; discuss criticisms and controversies of the mosaic hypothesis and implications for research; and conclude that co-analysis of several (preferably, many) features and going back from the group level to that of the individual would advance our understanding of the relations between sex and the brain in health and disease.

A mosaic of sex-related structural changes in the human brain following exposure to real-life stress.

Whereas sex differences in the brain's response to stress have been reported in both humans and animals, it is unknown whether they 'add up' consistently within individual brains. Here, we studied this question in a unique data set of magnetic resonance imaging (MRI) scans obtained before and after exposure to extreme real-life stress in the form of combative military service in 34 (15 women) young (18-19 years old) healthy soldiers. Across two data sets, one of regional volume and one of cortical thickness, only a few regions (seven and three, respectively) showed sex/gender-specific changes (i.e., the most common structural change in women and men was different). The number of internally consistent brains (a male-typical or a female-typical response in all regions) was not different from the number expected by chance nor from that observed in regions showing a sex-similar response, and was lower than the number of mosaic brains (at least one region with a male-typical response and one with a female-typical response). Although these findings do not reveal the source of sex/gender differences in response to stress and of within-brain variability in this response, they demonstrate that these differences do not consistently add up to create a female-typical and a male-typical neural response to stress.

Macro- and microstructural gray matter alterations in sexually assaulted women.

BACKGROUND: Studies with trauma survivors documented structural alterations in brain regions involved in posttraumatic stress disorder (PTSD) neurocircuitry. Nonetheless, whether such alterations exist in women who were sexually assaulted in adulthood is not clear. We investigated the macro- and microstructure of key regions implicated in PTSD pathophysiology, namely the amygdala, hippocampus, anterior cingulate cortex (ACC), and insula, in this population. METHODS: Thirty-eight sexually assaulted women (PTSD, n = 25; non-PTSD, n = 13) and 24 non-exposed controls (NEC) were studied with T1- and diffusion-weighted MRI. Gray matter volume, mean diffusivity (MD), and fractional anisotropy (FA) were calculated for each region. Between-group comparisons and correlations with PTSD symptom severity were performed. RESULTS: Volumetric analyses revealed lower amygdala and insula volumes in the PTSD compared with the non-PTSD group. In contrast, altered microstructure was observed in both traumatized groups compared with NEC, including higher MD and lower FA in the right amygdala, and higher FA in the ACC bilaterally. Finally, the non-PTSD group had higher FA in the right insula compared with the PTSD group. PTSD symptom severity was correlated with amygdala and insula volumes, as well as with hippocampal FA and MD. LIMITATIONS: Sample size may have led to reduced statistical power. CONCLUSIONS: Sexual assault and the development of PTSD in women are linked with structural alterations in key regions implicated in PTSD following other trauma types (e.g., combat), though hippocampal and ACC volumes were preserved. Further studies are needed to disentangle the unique contribution of trauma type and of sex/gender to these observations.

High-frequency stimulation of the nucleus accumbens core and shell reduces quinpirole-induced compulsive checking in rats.

Electrical deep brain stimulation (DBS) is currently studied in the treatment of therapy-refractory obsessive compulsive disorders (OCDs). The variety of targeted brain areas and the inconsistency in demonstrating anti-compulsive effects, however, highlight the need for better mapping of brain regions in which stimulation may produce beneficial effects in OCD. Such a goal may be advanced by the assessment of DBS in appropriate animal models of OCD. Currently available data on DBS of the nucleus accumbens (NAc) on OCD-like behavior in rat models of OCD are contradictory and partly in contrast to clinical data and theoretical hypotheses about how the NAc might be pathophysiologically involved in the manifestation of OCD. Consequently, the present study investigates the effects of DBS of the NAc core and shell in a quinpirole rat model of OCD. The study demonstrates that electrical modulation of NAc core and shell activity via DBS reduces quinpirole-induced compulsive checking behavior in rats. We therefore conclude that both, the NAc core and shell constitute potential target structures in the treatment of OCD.

Ovarian hormones modulate 'compulsive' lever-pressing in female rats.

Life events related to the female hormonal cycle may trigger the onset of obsessive-compulsive disorder (OCD) or exacerbate symptoms in women already suffering from it. These observations suggest a possible role for ovarian hormones in the course of this disorder. Yet, the mechanisms that may subserve the modulatory effect of ovarian hormones are currently unknown. The aim of the present study was therefore to test the role of ovarian hormones in the signal attenuation rat model of OCD. Experiment 1 compared the behavior of pre-pubertal and adult male and female rats in the model, and found no age and sex differences in compulsive responding. Experiment 2 found that compulsive responding fluctuates along the estrous cycle, being highest during late diestrous and lowest during estrous. Acute administration of estradiol to pre-pubertal female rats was found to attenuate compulsive behavior (Experiment 3), and withdrawal from chronic administration of estradiol was shown to increase this behavior (Experiment 4). These findings extend the use of the signal attenuation model of OCD to female rats, and by demonstrating that the model is sensitive to the levels of ovarian hormones, provide the basis for using the model to study the role of ovarian hormones in OCD. In addition, the present findings support the hypothesis that the increased risk of onset and exacerbation of OCD in women post-partum may be a result of the decrease in the level of estradiol, which was elevated during pregnancy.

Self-Reported Gender Identity and Sexuality in an Online Sample of Cisgender, Transgender, and Gender-Diverse Individuals: An Exploratory Study.

The relations between self-reported aspects of gender identity and sexuality were studied in an online sample of cisgender (n = 4,954), transgender (n = 406), and gender-diverse (n = 744) groups. Aspects of gender identity and sexual fantasies, attraction, behavior, and romantic relations were assessed using the Multi-gender Identity Questionnaire (Multi-GIQ) and a sexuality questionnaire. Results show a wide spectrum of gender experiences and sexual attractions within each group, an overlap among the groups, and very weak relations between atypical gender identity and atypical sexuality. At the group level, aspects of gender identity and sexuality were mainly predicted by gender and sex-gender configuration, with little contribution of sex assigned at birth. A principal component analysis (PCA) revealed that measures of gender identity and of sexuality were independent, the structure of sexuality was mostly related to gender, whereas the structure of gender identity was mostly related to sex-gender configuration. The results of both approaches suggest that measures of gender identity could roughly be divided into three classes: one including feeling as a man and feeling as a woman; a second including measures of nonbinary and "trans" feelings; and a third including feeling as a "real" woman and feeling as a "real" man. Our study adds to current scientific data that challenge dichotomous conventions within gender identity and sexuality research. Possible social and clinical implications are discussed.

The future of sex and gender in psychology: Five challenges to the gender binary.

The view that humans comprise only two types of beings, women and men, a framework that is sometimes referred to as the "gender binary," played a profound role in shaping the history of psychological science. In recent years, serious challenges to the gender binary have arisen from both academic research and social activism. This review describes 5 sets of empirical findings, spanning multiple disciplines, that fundamentally undermine the gender binary. These sources of evidence include neuroscience findings that refute sexual dimorphism of the human brain; behavioral neuroendocrinology findings that challenge the notion of genetically fixed, nonoverlapping, sexually dimorphic hormonal systems; psychological findings that highlight the similarities between men and women; psychological research on transgender and nonbinary individuals' identities and experiences; and developmental research suggesting that the tendency to view gender/sex as a meaningful, binary category is culturally determined and malleable. Costs associated with reliance on the gender binary and recommendations for future research, as well as clinical practice, are outlined. (PsycINFO Database Record (c) 2019 APA, all rights reserved).