No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Incorporating Sex As a Biological Variable in Neuropsychiatric Research: Where Are We Now and Where Should We Be?
Abstract
Understanding the multiplicity of ways in which sex can alter the brain is essential to crafting policies and treatments that are beneficial for all human beings. This is particularly true for the field of neuropsychopharmacology, as many neuropsychiatric disorders exhibit gender bias in frequency, severity, or response to treatment. The goal of this Circumspective is to provide two views on the current state-of-the-art of the relations between sex and the brain, relations that are studied almost exclusively by comparing females and males on specific endpoints, from gene expression to behavior. We start by suggesting a framework for defining what is being measured and what it means. We suggest that 'sex differences' can be classified on four dimensions: 1) persistent versus transient across the lifespan; 2) context independent versus dependent; 3) dimorphic versus continuous; and 4) a direct versus an indirect consequence of sex. To accurately classify a sex difference along these dimensions one may need to compare females and males under varied conditions. We next discuss current data on the mechanisms of sexual differentiation of the brain and of sex differences in the brain to conclude that the brain of each male and female is a mosaic of relative masculinization, feminization and sameness, which theoretically could produce an infinite variety of individuals. We also raise the possibility that sex differences in the brain are canalized, which may act to both enhance and restrain variation between males and females. We end by discussing ways to consider sex when studying neuropsychiatric disorders.Neuropsychopharmacology accepted article preview online, 31 May 2016. doi:10.1038/npp.2016.79.
... The sexual differentiation of the nervous system has been subject to continuous research, advancing from reproductive to non-reproductive actions of gonadal hormones and involving genetics, morphology, electrophysiology, neuroendocrinology, neural networks, and behavioral display along ontogenetic stages of different species (Matsumoto, 1999;Simerly, 2002;Hansberg-Pastor et al., 2015;Nelson and Kriegsfeld, 2016;Dalpian et al., 2019;Rubinow and Schmidt, 2019;Zamora-Moratalla and Martín, 2021;and references therein). An important point is to define what are evident "sexual dimorphism" and "sex difference" or "hormonally modulated responses" when comparing variables between males and females (McCarthy and Konkle, 2005;Joel and McCarthy, 2017). In addition, differences can occur due to "gender", a social construct that varies from society to society and can change over time, or "gender identity", which "refers to a person's deeply felt, internal and individual experience of gender, which may or may not correspond to the person's physiology or designated sex at birth" (World Health Organization, 2021a). ...
... The multitude of these cellular actions of ovarian steroids in various brain areas were nicely reviewed in Srivastava et al. (2013) and Rubinow and Schmidt (2019). Sex differences have been studied on various dimensions: (1) persistent or transient across the lifespan; (2) context-independent or context-dependent; (3) dimorphic or continuous; (4) a direct or an indirect consequence of sex (Joel and McCarthy, 2017), and (5) rapid and/or long-term rewiring of neural circuits (Srivastava et al., 2013). At the same time, "It is challenging to separate sex chromosome from hormonal effects on sex differences in the brains of humans. ...
... When asking "Is there a male brain and a female brain?", McCarthy (from Joel and McCarthy, 2017) addressed this issue as follows: "My personal research goal is to discover the basic cellular and molecular mechanisms by which sex differences in the brain are established by hormones early in development. Within this framework, we have identified multiple signal transduction cascades that are induced by estradiol. ...
Abstract. Our study took place in the Southern Siberian and North Caucasus mountains: Barguzin Ridge (N 54° 20'; E 109° 30'), where 8 plots were situated at the coast, low-, middle- and high mountains; Chechen Republic (42°88'N 46°44'E) where 12 plots were situated at the plain, foothills and mountains. Beetles of three species – Carabus odoratus, Pterostichus montanus,Carabus exaratus were trapped and measured by six linear traits. The total sample size was more than 3000 individuals. Traits size monotonically decreased towards the high elevations in Carabus species, in P. montanus body size variation was saw-tooth. Direction of size changes was not similar in females and males sometimes. Sexual Size Dimorphism (SSD) was always female-biased and was expressed mostly in elytra width and head parameters. Its value was the highest in high mountains in Carabus species and in low mountains – in P. montanus and positively correlated with population density at those elevations. Towards high altitudes sex ratio (females/males) decreased, sensitivity in males (by RMAII results) increased. The steepness of body size variation in altitude gradient (by ANOVA and regression analysis results) was similar in males and females in all three species studied.
... Sex and gender are both multi-component umbrella constructs (Box 1); they are distinct but inter-correlated because of interplaying biological and sociological mechanisms 52 . Sex-related constructs are biological attributes that were initially conceptualized on the basis of the reproduction of organisms and include chromosomal, genetic, gonadal, hormonal, genital and other anatomical and physiological components 53 . ...
... Notably, gender-related attributes can influence biological outcomes that are thought to be primarily driven by sex-related attributes (for example, brain biology, hormonal status and related behaviours) 57,58 . Sex-related and gender-related attributes separately and jointly act as moderators of many human health outcomes 7,52 . ...
Health-related conditions often difer qualitatively or quantitatively
between individuals of diferent birth-assigned sexes and gender
identities, and/or with diferent gendered experiences, requiring
tailored care. Studying the moderating and mediating efects of sexrelated and gender-related factors on impairment, disability, wellbeing
and health is of paramount importance especially for neurodivergent
individuals, who are diagnosed with neurodevelopmental conditions
with uneven sex/gender distributions. Researchers have become aware
of the myriad infuences that sex-related and gender-related variables
have on the manifestations of neurodevelopmental conditions, and
contemporary work has begun to investigate the mechanisms through
which these efects are mediated. Here we describe topical concepts
of sex and gender science, summarize current knowledge, and discuss
research and clinical challenges related to autism, attention-defcit/
hyperactivity disorder and other neurodevelopmental conditions.
We consider sex and gender in the context of epidemiology, behavioural
phenotypes, neurobiology, genetics, endocrinology and neighbouring
disciplines. The available evidence supports the view that sex and
gender are important contributors to the biological and behavioural
variability in neurodevelopmental conditions. Methodological caveats
such as frequent confation of sex and gender constructs, inappropriate
measurement of these constructs and under-representation of specifc
demographic groups (for example, female and gender minority individuals
and people with intellectual disabilities) limit the translational potential
of research so far. Future research and clinical implementation should
integrate sex and gender into next-generation diagnostics, mechanistic
investigations and support practices.
... Our study extends this observation to multivariate, male-shifted characteristics in brain structure. Importantly, the findings are in line with the notion that there is no strict sexual dimorphism in human neuroanatomy (70,71), but brains exhibit a "multimorphic" mosaic of male-like and female-like features (72,73) that can reliably distinguish males from females with above-chance to high accuracy (72,74,75). This means that not all autistic individuals have an "extreme male brain," but multivariate patterns characteristic of neurotypical males are on average more common in a subset of autistic individuals who are overall shifted toward the male neurophenotype. ...
... It is likely that these age-related patterns are influenced by dynamically unfolding interactions between sex-differential and neurodevelopmental process across the lifespan. Sex differentiation emerges in utero, and many on-average sex differences persist into adulthood, while others are transient and context dependent, meaning they become apparent at specific developmental stages depending on factors such as hormonal milieu and experiences (71). For example, sex steroid hormones are thought to initially act organizationally during perinatal development, and then activationally during puberty to influence the formation and expression of sex differences at different developmental windows (106). ...
Objective:
The male preponderance in prevalence of autism is among the most pronounced sex ratios across neurodevelopmental conditions. The authors sought to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression.
Methods:
Using a novel deep learning framework trained to predict biological sex based on T1-weighted structural brain images, the authors compared sex prediction model performance across neurotypical and autistic males and females. Multiple large-scale data sets comprising T1-weighted MRI data were employed at four stages of the analysis pipeline: 1) pretraining, with the UK Biobank sample (>10,000 individuals); 2) transfer learning and validation, with the ABIDE data sets (1,412 individuals, 5-56 years of age); 3) test and discovery, with the EU-AIMS/AIMS-2-TRIALS LEAP data set (681 individuals, 6-30 years of age); and 4) specificity, with the NeuroIMAGE and ADHD200 data sets (887 individuals, 7-26 years of age).
Results:
Across both ABIDE and LEAP, features positively predictive of neurotypical males were on average significantly more predictive of autistic males (ABIDE: Cohen's d=0.48; LEAP: Cohen's d=1.34). Features positively predictive of neurotypical females were on average significantly less predictive of autistic females (ABIDE: Cohen's d=1.25; LEAP: Cohen's d=1.29). These differences in sex prediction accuracy in autism were not observed in individuals with ADHD. In autistic females, the male-shifted neurophenotype was further associated with poorer social sensitivity and emotional face processing while also associated with gene expression patterns of midgestational cell types.
Conclusions:
The results demonstrate an increased resemblance in both autistic male and female individuals' neuroanatomy with male-characteristic patterns associated with typically sex-differential social cognitive features and related gene expression patterns. The findings hold promise for future research aimed at refining the quest for biological mechanisms underpinning the etiology of autism.
... Some investigators suggest that although there are many differences, human brains cannot be categorized as female brains and male brains (Joel et al. 2015;Ritchie et al. 2018). Many previously-reported sex differences in brain morphology and function have low statistical power (Joel et al. 2015;Joel and McCarthy 2017;Ritchie et al. 2018). On the contrary, Ritchie and colleagues (Ritchie et al. 2018) used a large sample size, including MRI images and behavior records of 2750 females and 2466 males, to assess sex difference. ...
... However, the question of whether or not there is a "female brain" and a "male brain" still remains (Hyde et al. 2019;Joel et al. 2015;Joel and McCarthy 2017;Ritchie et al. 2018;Shansky and Woolley 2016). The introduced studies mostly used the method of compare means to detect sex differences, while the method will meet difficulties in revealing difference between individuals in high dimensional data. ...
It remains unclear whether human species exhibits sexual dimorphism in brain activities, and how the dimorphisms associated with sex-characterized behaviors. Here, in a large dataset from Human Connectome Project, we investigated sex differences of resting-state network structure by using local and global network graph similarity analysis. The “typical male” and “typical female” resting-state networks were highly similar. However, we found significant inter-sex difference in all local brain networks compared with sex-label permutations. The global and many local network topologies showed significant higher intra-female similarity, while males’ network topologies were more dissimilar to each other. Additionally, by using global graph similarity analysis, we found that female individuals whose brain network were more similar to the average pattern present lower social-related anger, lower social distress and better companionships, while similar effects were not detected for males. Our study confirms the existence of sex-related resting-state network topology. Female’s intrinsic brain is closer to a typical pattern than male’s, and they may more fulfill the “similarity breeds connection” principle in building social ties.
... ; https://doi.org/10.1101/2022.03.18.22272409 doi: medRxiv preprint neurotypical adults. We thus attribute observed age-related patterns to the fact that sex-differential and neurodevelopmental processes are dynamically unfolding across the lifespan (65). It remains to be established how experiential, environmental, genetic and organizational and activational hormonal effects interact to differentially contribute to observed patterns across different stages of sexual differentiation (e.g., fetal/neonatal development, puberty and menopause). ...
... Even though our samples span wide age-ranges and results imply the likely involvement of neurodevelopmental mechanisms, only when investigating a longitudinal cohort will we be able to make causal inferences. Further, we address neither social, cultural or experiential factors (98) which can influence sex-differential brain development (65), nor gender identity which might differ from sex assigned at birth, especially in autistic individuals (99). In addition, while utilising a highly accurate approach for sex-classification, the high level of non-linearity intrinsic to the CNN model makes straightforward interpretations more difficult compared to simpler linear models. ...
Objectives
The male preponderance in autism spectrum conditions (ASC) prevalence is among the most pronounced sex ratios across different neurodevelopmental conditions. Here, we aimed to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression.
Methods
Using a novel deep learning framework trained to predict biological sex, we compared sex prediction model performance across neurotypical and autistic males and females. Multiple large-scale datasets were employed at different stages of the analysis pipeline: a) Pre-training: the UK Biobank sample (>10.000 individuals); b) Transfer learning and validation: the ABIDE datasets (1,412 individuals, 5-56 years of age); c) Test and discovery: the EU-AIMS/AIMS-2-TRIALS LEAP dataset (681 individuals, 6-30 years of age) and d) Specificity: the Neuroimage and ADHD200 datasets (887 individuals, 7-26 years of age).
Results
Across both ABIDE and LEAP we showed that features positively predictive of neurotypical males were on average more predictive of autistic males ( P =1.1e-23). Features positively predictive of neurotypical females were on average less predictive of autistic females ( P =1.2e-22). These accuracy differences in autism were not observed in individuals with ADHD. In autistic females the male-shifted neurophenotype was further associated with poorer social sensitivity and emotional face processing while also with associated gene expression patterns of midgestational cell types.
Conclusions
Our results demonstrate a shift in both autistic male and female individuals’ neuroanatomy towards male-characteristic patterns associated with typically sex-differential, social cognitive features and related gene expression patterns. Findings hold promise for future research aimed at refining the quest for biological mechanisms underpinning the etiology of autism.
... Furthermore, while there exist two distinct classes of human genitalia, this fact does not imply that brains are also sexually dimorphic 79 . Both "male" and "female" features exist in both male and female brains, though some features are more common in one sex than the other 79,80 . As a result, there may be more meaningful variance in neurologic phenotypes within each sex than between sexes. ...
Executive function emerges late in development and displays different developmental trends in males and females. Sex differences in executive function in youth have been linked to vulnerability to psychopathology as well as to behaviors that impinge on health. Yet, the neurobiological basis of these differences is not well understood. Here we test the hypothesis that sex differences in executive function in youth stem from sex differences in the controllability of structural brain networks as they rewire over development. Combining methods from network neuroscience and network control theory, we characterize the network control properties of structural brain networks estimated from diffusion imaging data acquired in males and females in a sample of 882 youth aged 8-22 years. We summarize the control properties of these networks by estimating average and modal controllability, two statistics that probe the ease with which brain areas can drive the network towards easy- versus difficult-to-reach states. We find that females have higher modal controllability in frontal, parietal, and subcortical regions while males have higher average controllability in frontal and subcortical regions. Furthermore, average controllability values in the medial frontal cortex and subcortex, both higher in males, are negatively related to executive function. Finally, we find that average controllability predicts sex-dependent individual differences in activation during an n-back working memory task. Taken together, our findings support the notion that sex differences in the controllability of structural brain networks can partially explain sex differences in executive function. Controllability of structural brain networks also predicts features of task-relevant activation, suggesting the potential for controllability to represent context-specific constraints on network state more generally.
... Pattern (a) appears to be most prevalent in our findings, having been observed in all global brain volumes as well as various regional volumes (e.g., caudate nucleus, anterior cingulate cortex, corpus callosum, etc.). It has previously been proposed that sex differences can be categorised as either "persistent", such that they are established early in development and persist throughout the lifespan, or "transient", such that they are temporary to a specific developmental period [79]. Under this framework, the findings identified in pattern (a) can be classified as persistent sex differences, although these differences might still be dynamic over development. ...
Background
Sex differences in human brain anatomy have been well-documented, though remain significantly underexplored during early development. The neonatal period is a critical stage for brain development and can provide key insights into the role that prenatal and early postnatal factors play in shaping sex differences in the brain.
Methods
Here, we assessed on-average sex differences in global and regional brain volumes in 514 newborns aged 0–28 days (236 birth-assigned females and 278 birth-assigned males) using data from the developing Human Connectome Project. We also assessed sex-by-age interactions to investigate sex differences in early postnatal brain development.
Results
On average, males had significantly larger intracranial and total brain volumes, even after controlling for birth weight. After controlling for total brain volume, females showed significantly greater total cortical gray matter volumes, whilst males showed greater total white matter volumes. After controlling for total brain volume in regional comparisons, females had significantly increased white matter volumes in the corpus callosum and increased gray matter volumes in the bilateral parahippocampal gyri (posterior parts), left anterior cingulate gyrus, bilateral parietal lobes, and left caudate nucleus. Males had significantly increased gray matter volumes in the right medial and inferior temporal gyrus (posterior part) and right subthalamic nucleus. Effect sizes ranged from small for regional comparisons to large for global comparisons. Significant sex-by-age interactions were noted in the left anterior cingulate gyrus and left superior temporal gyrus (posterior parts).
Conclusions
Our findings demonstrate that sex differences in brain structure are already present at birth and remain comparatively stable during early postnatal development, highlighting an important role of prenatal factors in shaping sex differences in the brain.
... These unexplored facets necessitate further investigation, potentially highlighting the need for targeted prevention strategies tailored to this specific cohort of vulnerable children. Another topic in need of further investigation is the family aggregation of neuropsychiatric symptoms in relation to the sibling's sex (Bolte et al., 2023;Joel & McCarthy, 2017), since neurodevelopmental conditions have a male preponderance in childhood (Brainstorm et al., 2018;Loomes et al., 2017;Mathews & Grados, 2011;Meoni et al., 2020;Schrag et al., 2019). A recent paper from our study group reported more severe tics in boys compared to girls (Garcia-Delgar et al., 2022). ...
Background
Tourette syndrome (TS) is associated with neuropsychiatric comorbidities, such as autism spectrum disorder (ASD), attention‐deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD). Even though comorbidities are the main source of impairment in individuals with TS, family aggregation between TS and other neuropsychiatric disorders has been little explored. We therefore investigated associations of tic severity in probands with symptoms of ASD, ADHD, and ODD in their siblings and the influence of tic severity, age, and sex.
Methods
The sample of the present study stems from the European Multicenter Tics in Children Study (EMTICS), a longitudinal observational study, with the present subsample of 196 probands with TS and their 220 full siblings (54.1% girls). We analyzed associations of probands’ tic severity with ASD, ADHD, and ODD symptoms in their siblings using generalized linear mixed‐effect negative binomial regression models.
Results
Higher tic severity in probands was associated with higher scores of ASD symptoms in their siblings (IRR = 1.48, 95% confidence interval [95% CI] 1.03–2.12, p = 0.034); after excluding the three items in the Autism Spectrum Screening Questionnaire linked to stereotypies (that may be misinterpreted as tic‐like behaviors; IRR = 1.44 [95% CI] 0.99–2.09, p = 0.057) the effect size remained similar, yet reaching only near‐significance. Moreover, we demonstrated a significant interaction between probands’ tic severity and sex upon siblings’ symptoms of ADHD and ODD. Female siblings of probands with higher tic severity displayed more symptoms of ADHD and ODD, whereas this effect was absent in male siblings.
Conclusions
This multicenter study demonstrated a link between probands’ current tic severity and siblings’ neuropsychiatric symptoms. Our study suggests a familial link between TS and ASD‐like symptoms, competencies as well as sex‐specific associations with ADHD and ODD symptoms in female siblings. The current study sheds light on a broader family tendency and highlights the need for targeted prevention in this vulnerable population. Our findings, however, call for further studies to better understand the genetic and environmental aggregation of influences between individuals with TS, ADHD, and ODD and their siblings.
... Intersex identities), components of sex can be multi-categorized (Joel & Mccarthy, 2017). ...
The inclusion of a chapter on intersectional autism and LGBTQ+ identities within a book focused on autism in girls and women accords with calls for greater attention to both gender and assigned sex in autism research. For example, any study of autistic “girls” or “women” or “female” autistic people must consider gender identity, assigned sex, and broader gender expression-related characteristics. The chapter provides an overview of the existing literature on intersectional autism and gender and sexuality diversity. It also provides a critique regarding notable gaps in the literature, contextualizing the particular focus researchers have placed on intersectional autism and gender diversity and the relative lack of research on autism and sexual orientation diversity. The chapter begins by presenting a conceptual framework for understanding gender and sexuality diversity in autism. A review of the literature on broad LGBTQ+ identities and autism is followed by reviews of gender diversity and autism and sexual diversity and autism. Co-created by an authorship team of autistic LGBTQ+ co-authors, the chapter concludes with a contemporary commentary on the state of the literature, as contextualized by autistic LGBTQ+ people. The autistic LGBTQ+ co-authors also reflect on the daily lives of autistic LGBTQ+ individuals across a range of contexts. Several themes emerge in the commentary including the importance of research and advocacy across nations (as much research has been conducted in more affirming countries), the need for attention to mental health and clinical needs, and the need for societal acceptance and inclusion for individuals with multiple marginalized identities.
... Notwithstanding their commonalities, males and females differ due to biology and socialization, and findings observed in single-sex samples should not be assumed to generalize to the other sex. Indeed, this attention to sex differences echoes calls to consider the variable of sex in neuroscience, psychiatry, psychology, and biomedicine [10,11]. ...
... Pattern (a) appears to be most prevalent in our findings, having been observed in all global brain volumes as well as various regional volumes (e.g., caudate nucleus, anterior cingulate cortex, corpus callosum, etc.). It has previously been proposed that sex differences can be categorised as either "persistent", such that they are established early in development and persist throughout the lifespan, or "transient", such that they are temporary to a specific developmental period (65). Under this framework, the findings identified in pattern (a) can be classified as persistent sex differences, although these differences might still be dynamic over development. ...
Sex differences in human brain anatomy have been well-documented; however, their underlying causes remain controversial. Neonatal research offers a pivotal opportunity to address this long-standing debate. Given that postnatal environmental influences (e.g., gender socialisation) are minimal at birth, any sex differences observed at this stage can be more readily attributed to prenatal influences. Here, we assessed on-average sex differences in global and regional brain volumes in 514 newborns (236 birth-assigned females and 278 birth-assigned males) using data from the developing Human Connectome Project. On average, males had significantly larger intracranial and total brain volumes, even after controlling for birth weight. After controlling for total brain volume, females showed higher total cortical gray matter volumes, whilst males showed higher total white matter volumes. After controlling for total brain volume
in regional comparisons, females had increased white matter volumes in the corpus callosum and increased gray matter volumes in the bilateral parahippocampal gyri (posterior parts), left anterior cingulate gyrus, bilateral parietal lobes, and right caudate nucleus. Males had increased gray matter volumes in the right medial and inferior temporal gyrus (posterior part) and right subthalamic nucleus. Effect sizes ranged from small for regional comparisons to large for global comparisons. While postnatal experiences likely amplify sex differences in the brain, our findings demonstrate that several global and regional on-average sex differences are already present at birth.
... This raises the issue of a wider challenge to the existing binary female/male model which, to date, has mainly informed the full gamut of autism research, including brain differences. Different ways of exploring these are emerging with the advent of, for example, the notion of brains as unique mosaics of structural characteristics [141,142]. Although incorporating previously overlooked autistic females into neuroscience research is certainly a step in the right direction, careful attention should be paid to the extent to which pre-existing assumptions about the binary nature of brains might distort research enquiries [143]. ...
Autism is a neurodevelopmental condition, behaviourally identified, which is generally characterised by social communication differences, and restrictive and repetitive patterns of behaviour and interests. It has long been claimed that it is more common in males. This observed preponderance of males in autistic populations has served as a focussing framework in all spheres of autism-related issues, from recognition and diagnosis through to theoretical models and research agendas. One related issue is the near total absence of females in key research areas. For example, this paper reports a review of over 120 brain-imaging studies of social brain processes in autism that reveals that nearly 70% only included male participants or minimal numbers (just one or two) of females. Authors of such studies very rarely report that their cohorts are virtually female-free and discuss their findings as though applicable to all autistic individuals. The absence of females can be linked to exclusionary consequences of autism diagnostic procedures, which have mainly been developed on male-only cohorts. There is clear evidence that disproportionately large numbers of females do not meet diagnostic criteria and are then excluded from ongoing autism research. Another issue is a long-standing assumption that the female autism phenotype is broadly equivalent to that of the male autism phenotype. Thus, models derived from male-based studies could be applicable to females. However, it is now emerging that certain patterns of social behaviour may be very different in females. This includes a specific type of social behaviour called camouflaging or masking, linked to attempts to disguise autistic characteristics. With respect to research in the field of sex/gender cognitive neuroscience, there is emerging evidence of female differences in patterns of connectivity and/or activation in the social brain that are at odds with those reported in previous, male-only studies. Decades of research have excluded or overlooked females on the autistic spectrum, resulting in the construction of inaccurate and misleading cognitive neuroscience models, and missed opportunities to explore the brain bases of this highly complex condition. A note of warning needs to be sounded about inferences drawn from past research, but if future research addresses this problem of male bias, then a deeper understanding of autism as a whole, as well as in previously overlooked females, will start to emerge.
... To the contrary, when effect sizes are calculated, females and males show a high degree of overlap in most traits, and individual differences within the members of each of these categories can be as large or even larger than that existing between their averages (e.g., (Hyde, 2014;Maney, 2016;Reis and Carothers, 2014;Ritchie et al., 2018;Zell et al., 2015). There have been repeated calls to cease this misleading and uniformizing use of the term "sexual dimorphism" and to classify female-male differences according to their statistical characteristics and other criteria (DeCasien et al., 2022;Eliot et al., 2023Eliot et al., , 2021Joel, 2011;Joel and McCarthy, 2017;McCarthy et al., 2012). Nevertheless, these claims have had little effect on how researchers ordinarily report their findings, and the misuse of the term "sexual dimorphism" continues feeding back the same binary framework based on averages that initially motivated its use (Fig. 4A). ...
... These models acknowledge that despite there being multiple structural disparities in the brain between sexes, such as different raw volumes, surface areas, cortical thickness, or white matter tract complexity [13], these differences can be better understood as expressions of inherent heterogeneity in biology and human experience, rather than being exclusively attributable to sex. For example, ref. [14] proposes that sex differences can be classified in four dimensions: persis-Societies 2024, 14, 48 3 of 13 tent vs. transient across the lifespan, context independent vs. dependent, dimorphic vs. continuous, and direct vs. indirect consequences of sex. In essence, differences in brain structure may arise from a nuanced interplay of biological and social factors. ...
This study examines gender differences in levels of sexism among university students and evaluates variations in assessing sexist attitudes toward professors. The aim is to analyze potential disparities between men and women regarding ambivalent sexism (both hostile and benevolent) and to determine if these differences influence the evaluation of specific behaviors by teaching faculty. Additionally, the present study seeks to validate the variability hypothesis, asserting that men are over-represented in the extremes of distributions compared to women concerning analyzed sexist attitudes. Eighty university students participated voluntarily and anonymously, completing three questionnaires on ambivalent sexism, neosexism, and the assessment of sexist behaviors by their instructors. Consistent with prior research, the results reveal higher levels of sexism among men in this context. Despite these differences, both men and women align in evaluating specific behaviors in teaching faculty, irrespective of their individual levels of sexism. Finally, the data presented support the variability hypothesis, indicating greater variability in sexist attitudes among men than women. These findings suggest that general attitudes assessed in most questionnaires might not be representative of the behaviors and attitudes that people display in real specific situations. This could change how future research and interventions approach these issues.
... Thus, while we assume that the results would be similar if the full-contact social interaction had been conducted in the operant context, whether this would be the case is a subject of future research. Aside from the overall importance of conducting preclinical biomedical research in animals of both sexes (Beery and Zucker 2011;Joel and McCarthy 2017), a more practical consideration is the financial advantage of using all available mice for experimental purposes rather than limiting usage to just female mice. This becomes even more important for mouse studies using valuable transgenic mice, when it is necessary to use only a subset of mice that contain the transgene necessary to conduct a study. ...
Rationale and Objective
We recently introduced a model of operant social reward in which female CD1 mice lever press for access to affiliative social interaction with a cagemate peer mouse of the same sex and strain. Here we determined the generality of the operant social self-administration model to male CD1 mice who, under certain conditions, will lever press to attack a subordinate male mouse.
Methods
We trained male CD1 mice to lever press for food and social interaction with a same sex and strain cagemate peer under different fixed-ratio (FR) schedule response requirements (FR1 to FR6). We then tested their motivation to seek social interaction after 15 days of isolation in the presence of cues previously paired with social self-administration. We also determined the effect of housing conditions on operant social self-administration and seeking. Finally, we determined sex differences in operant social self-administration and seeking, and the effect of housing conditions on unconditioned affiliative and antagonistic (aggressive) social interactions in both sexes.
Results
Male CD1 mice lever pressed for access to a cagemate peer under different FR response requirements and seek social interaction after 15 isolation days; these effects were independent of housing conditions. There were no sex differences in operant social self-administration and seeking. Finally, group-housed CD1 male mice did not display unconditioned aggressive behavior toward a peer male CD1 mouse.
Conclusions
Adult socially housed male CD1 mice can be used in studies on operant social reward without the potential confound of operant responding to engage in aggressive interactions.
... However, a recent study reported adverse cognitive development in females whose mothers were exposed to optimally fluoridated water in pregnancy (Dewey et al., 2023). Sex specific effects are complex and depend on multiple factors including the functional outcome assessed and developmental stage that offspring are assessed (Joel & McCarthy, 2017). Indeed, male and female fetuses use different strategies to respond to placental perturbations, with the male placenta investing more resources in growth relative to females (Sandman et al., 2013). ...
Background
Prenatal fluoride exposure can have adverse effects on children’s development; however, associations with visual and cardiac autonomic nervous system functioning are unknown. We examined associations between prenatal fluoride exposure and visual acuity and heart rate variability (HRV) in 6-month-old infants.
Methods
We used data from Canadian mother-infant pairs participating in the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort. We estimated prenatal fluoride exposure using: i) fluoride concentration in drinking water (mg/L), ii) maternal urinary fluoride adjusted for specific gravity (MUFSG; mg/L) and averaged across pregnancy, and iii) maternal fluoride intake (μg/kg/day) from consumption of water, tea, and coffee, adjusted for maternal body weight (kg). We used multivariable linear regression to examine associations between each measure of fluoride exposure and Teller Acuity Card visual acuity scores (n = 435) and assessed HRV (n = 400) using two measures: root mean square of successive differences (RMSSD) and the standard deviation of N-N intervals (SDNN) measured at 6-months of age.
Results
Median (IQR) values for water fluoride, MUFSG, and daily fluoride intake were 0.20 (IQR: 0.13–0.56) mg/L; 0.44 (0.28–0.70) mg/L and 4.82 (2.58–10.83) μg/kg/day, respectively. After adjustment for confounding variables, water fluoride concentration was associated with poorer infant visual acuity (B = −1.51; 95 % CI: −2.14,-0.88) and HRV as indicated by lower RMSSD (B = −1.60; 95 % CI: −2.74,-0.46) but not SDNN. Maternal fluoride intake was also associated with poorer visual acuity (B = −0.82; 95 % CI: −1.35,-0.29) and lower RMSSD (B = −1.22; 95 % CI: −2.15,-0.30). No significant associations were observed between MUFSG and visual acuity or HRV.
Conclusion
Fluoride in drinking water was associated with reduced visual acuity and alterations in cardiac autonomic function in infancy, adding to the growing body of evidence suggesting fluoride’s developmental neurotoxicity.
... Although numerous studies highlight the importance of sex differences in gene expression and the epigenome in brain development (reviewed in (Gegenhuber and Tollkuhn, 2022) and Tollkuhn, 2019, 2020), the incorporation of sex as a variable is still inadequate in the "neuro-omics" field (Joel and McCarthy, 2017). However, several studies have investigated molecular mechanisms using high-throughput approaches and included SABV in their design. ...
... Our protocol was developed exclusively in female mice, in part to narrow the gap in biomedical and neuroscience research, in which the vast majority of studies have focused on male animals 34,35 . ...
Little is known about how social factors contribute to neurobiology or neuropsychiatric disorders. The use of mice allows one to probe the neurobiological bases of social interaction, offering the genetic diversity and versatility to identify cell types and neural circuits of social behavior. However, mice typically show lower social motivation compared with rats, leading to the question of whether mice should be used to model complex social behaviors displayed by humans. Studies on mouse social behavior often rely on measures such as time spent in contact with a social partner or preference for a social-paired context, but fail to assess volitional (subject-controlled) rewarding social interaction. Here, we describe a volitional social self-administration and choice model that is an extension of our previous work on rats. Using mice, we systematically compared female adolescent and adult C57BL/6 mice and outbred CD1 mice, showing that operant social self-administration, social seeking during periods of isolation and choice of social interaction over palatable food is significantly stronger in female CD1 mice than in female C57BL/6J mice, independently of age. We describe the requirements for building the social self-administration and choice apparatus and we provide guidance for studying the role of operant social reward in mice. We also discuss its use to study brain mechanisms of operant social reward, potentially extending its application to mouse models of neuropsychiatric disorders. The training commonly requires ~4 weeks for stable social self-administration and 3-4 additional weeks for tests, including social seeking and choice.
... Although gender differences have been a focus in ASC research, the studies mainly focused on biological sex. However, "gender" is multidimensional, not only made up by a biological component, but also involving interactions with other environmental and developmental factors, such as social gender and internal gender experience (Joel & McCarthy, 2016). Cooper et al. (2018) also suggested that gender is viewed as a spectrum more frequently by autistic people than non-autistic people. ...
Sex difference, i.e. biological sex has been studied quite extensively in Autism Spectrum Conditions (ASC). However, “gender” is multidimensional and not limited to the biological component of sex (Joel & McCarthy, 2016). Since gender tends to be viewed as non-binary more often by autistic than non-autistic people (Cooper et al., 2018), it is important to study other features of “gender” too. The current thesis focused on “gender role”, how much people align themselves with traditional masculinity and femininity traits. Categorized by stereotypes about gender, gender role is heavily influenced by the traditional social norms, which is in turn influenced by cultural values. This thesis aimed to discover the relationship between gender role and autistic traits, in addition to biological sex in neurotypical Malaysians. Chapter 2 (Study 1) evaluated Baron-Cohen’s extreme male brain theory of autism. This theory is based on the finding that neurotypical Western males tend to be more systemizing and less empathizing than females, and that autistic people show the same profile, or even show an extreme form of this typical male profile (e.g. Baron-Cohen, 2009; Greenberg et al., 2018). However, culture might influence the relationship between systemizing-empathizing abilities and biological sex. In Asians, males appeared more systemizing than females, but empathy seemed equally presented by males and females (e.g. Zheng & Zheng, 2015). Moreover, the extreme male brain profile in systemizing-empathizing might not extend to gender role. There are indications that gender defiance (e.g. Cooper et al., 2018) or an androgynous gender role (e.g. Kallitsounaki & Williams, 2020) is more common in ASC. Study 1 found that neurotypical Malaysian females demonstrated better empathizing than males, and empathizing correlated negatively with autistic traits. Demasculinization was observed in both sexes. Femininity was found to positively predict autistic traits in males but was independent of autistic traits in females. Moreover, the predicting relationship of masculinity and femininity on autistic traits was observed in self-reported masculinity and femininity traits , but not in self-rated masculinity and femininity . Hence, the extreme male brain theory was only partially supported, and not generalizable to gender role in Malaysia. Chapter 3 (Study 2) focused on the possible influence of gender role, personality traits, and culture on camouflaging and autistic traits. Previous studies showed that autistic females camouflaged autistic traits more than males (e.g. Schuck et al., 2019). Moreover, autistic people camouflaged more when experiencing societal pressure and expectations to “pretend to be normal” (e.g. Hull et al., 2017). This indicates that apart from biological sex, certain personality traits or stronger attachment to a culture’s value might influence camouflaging. Possible factors influencing camouflaging in both males and females could be gender role (femininity in particular) (e.g. Bargiela et al., 2016), personality traits (Big 5 personality) (e.g. Robinson et al., 2020), and culture (specifically, collectivism) (e.g. Schuck et al., 2019), as these factors might influence the desire to “fit in”. These factors might influence autistic traits as well (e.g. Cooper et al., 2018; Robinson et al., 2020). In Study 2, high self-reported masculinity , femininity traits and autistic traits, and low conscientiousness predicted more camouflaging in neurotypical Malaysians. Low extraversion indicated autistic traits in both sexes. Neuroticism and individualism positively predicted autistic traits in males only. In females, no significant effects other than extraversion were observed. In short, camouflaging and autistic traits were associated with certain personality or cultural traits. Moreover, the extreme male brain theory again did not generalize to gender role in neurotypical Malaysians. The current thesis showed that masculinized brain activities might be observed for systemizing and empathizing among neurotypical individuals with relatively high autistic traits. However, this “male brain” condition is not extendable to gender role. Masculinity and femininity are likely to be independent of autistic traits in Malaysia. Additionally, the findings provide some support that masculinity and femininity are related to camouflaging in non-autistic individuals with relatively high autistic traits. Nevertheless, the current thesis suggested a possible influence of culture in the relationship between gender role, autistic traits, and camouflaging, suggesting a possible future direction in researching the moderation and mediation effects of culture on the relationship between gender role, autistic traits, and camouflaging. It was also implied that biological sex and gender role should be considered in developing ASC assessments because gender might influence the expression of autistic traits. Certain personality traits and culture (e.g. conscientiousness, individualism) were found to be associated with autistic traits and camouflaging among neurotypical Malaysians. This might be relevant to take into account in the diagnostic process. Some recommendations, e.g. validation of measures in different cultures are suggested for future studies.
... 32 Furthermore, this non-linear development in neurophysiological network organization in females also corresponds with the known non-linear developmental trajectories in cerebral blood flow in females, from childhood to early adulthood, which also shows remarkable sex-differences from mid-adolescence. 33 iScience Article Our current work significantly extends the increasing evidence of normative brain developmental differences by sex and sex-related biological factors, 19,34 and the critical importance of accounting for such sex-differential distributions and trajectories to understand the basis of neurocognitive differences associated with sex and mechanisms of neuropsychiatric disorders with unbalanced male-female ratios 35,36 (for reviews, see [37][38][39] ). Enhanced rich-club network, as seen in our male cohort, may have both advantages and disadvantages developmentally. ...
A set of highly connected brain regions called the “rich-club” are vital in integrating information across the functional connectome. Although the literature has identified some changes in rich-club organization with age, little is known about potential sex-specific developmental trajectories, and neurophysiologically relevant frequency-dependent changes have not been established. Here we examine the frequency- and sex-dependent development of rich-club organization using magnetoencephalography in a large normative sample (N = 383) over a wide age span (4–39 years). We report strong divergence between males and females across alpha, beta, and gamma frequencies. While males show increased or no change in rich-club organization with age, females show a consistent, non-linear trajectory that increases through childhood, shifting direction in early adolescence. Using neurophysiological modalities for capturing complex inter-relations between oscillatory dynamics, age, and sex, we establish diverging, sex-specific developmental trajectories of the brain’s core functional organization, critically important to our understanding of brain health and disease.
... Since Lakoff (1975) claiming women's language are more hesitant, indirect, emotional than men's, a plethora of studies attempt to explore the relationship between sex and social factors. From this prospective, sex differences are affected by biological factors and social factors simultaneously, and are context-dependent [20]. However, social factors alone cannot explain all sex differences, due to some differences are present very early before socialization and experience. ...
... LPS injection was shown to increase the levels of IL-1β, IL-6, and TNFα in the placenta and amniotic fluid and was also demonstrated to increase TNF-α levels in the fetal brain (Calderoni, 2022). The activation of maternal immunity was shown to induce several histopathological changes in the hippocampus and negatively affect learning and memory (Joel & McCarthy, 2017). IL-17 was reported to have a special role in the maternal immune activation hypothesis (Pagnozzi et al., 2018). ...
Objective:
The medical intervention for autism spectrum disorder (ASD) is restricted to ameliorating comorbid situations. Granulocyte colony-stimulating factor (G-CSF) is a growth factor that enhances the proliferation, differentiation and survival of hematopoietic progenitor cells. In the present study, we aimed to investigate the effects of G-CSF in a maternal immune activation-induced autism model.
Methods:
Sixteen female and 6 male Wistar adult rats were included in the study. After 21 days, forty-eight littermates (8 male controls, 8 female controls, 16 male lipopolysaccharide (LPS)-exposed rats and 16 female LPS-exposed rats) were divided into groups. Sixteen male LPS-exposed and 16 female LPS-exposed rats were divided into saline and G-CSF treatment groups.
Results:
In male rats, the LPS-exposed group was found to have significantly higher levels of TNF-α, IL-2, and IL-17 than the LPS-exposed G-CSF group. Levels of nerve growth factor, brain PSD-95 and brain GAD67 were higher in the LPS-exposed G-CSF group than in the LPS-exposed group in male rats. In female rats, brain NGF levels were similar between groups. There was no difference between groups in terms of brain GAD 67 levels. Brain PSD-95 levels were higher in the control group than in both the LPS-exposed and LPS-exposed G-CSF groups in female rats. Both neuronal CA1 and neuronal CA2 levels were lower, and the GFAP immunostaining index (CA1) and GFAP immunostaining index (CA3) were higher in the LPS-exposed group than in the LPS-exposed G-CSF group in male rats. However, neuronal count CA1 and Neuronal count CA3 values were found to be similar between groups in female rats.
Conclusions:
The present research is the first to demonstrate the beneficial effects of G-CSF on core symptoms of ASD experimentally depending on male sex. G-CSF can be a good candidate for ameliorating the core symptoms of ASD without serious side effects in males.
... El mandato del "sexo como variable biológica" legitima el enfoque dicotómico en el que se enmarca la investigación en neurociencia cognitiva, y que también es cuestionado por las críticas. Pese a que la comunidad en su conjunto admita que existe un gran solapamiento en la distribución de hombres y mujeres en todas las medidas cerebrales realizadas y pese a que las propias diferencias están en discusión , la idea de dos tipos de cerebros diferenciados según el sexo pervive y se reproduce en la literatura, habitualmente sin tener en cuenta que las diferencias relacionadas con el sexo que pueden identificarse en los cerebros son de tipos y orígenes muy diversos (Joel y McCarthy, 2017). De acuerdo con esta complejidad y multidimensionalidad, Joel et al. (2015) argumentan, por ejemplo, que las diferencias entre hombres y mujeres encontradas en las estructuras cerebrales no son sexualmente dimórficas ni internamente consistentes, por lo que defienden un modelo de "mosaico cerebral" según el cual el cerebro de cada individuo es un mosaico de características, algunas de ellas más comunes en las mujeres o en los hombres, y otras neutras. ...
En este trabajo se analizan las aportaciones de las críticas feministas para el debate actual sobre el papel de los valores no epistémicos en la ciencia. La revitalización de la discusión sobre los valores y la responsabilidad social de la ciencia en las últimas décadas responde a preocupaciones como la crisis de la replicabilidad, la creciente comercialización o el papel de la ciencia para la política. En todas ellas la influencia de valores de carácter no epistémico aparece como problemática. La crítica feminista, no obstante, proporciona ejemplos del funcionamiento de los valores políticos como recursos para una crítica constructiva que, acompañada de reflexividad y capacidad de autocorrección por parte de las comunidades implicadas, puede promover los propios objetivos epistémicos de la ciencia. Utilizaré dos ejemplos bien conocidos, la primatología y la neurociencia cognitiva, para discutir la interacción de lo epistémico y lo no epistémico en las críticas feministas. Los casos analizados servirán también para explorar la propia interacción de valores en la recepción de las críticas y para introducir la discusión sobre el denominado “nuevo problema de la demarcación”.
... El objetivo principal de esta Tesis fue profundizar en el conocimiento de la base genética de la IG (ICD-11) (World Health Organization, 2018) dado que es un proceso de etiología compleja en donde intervienen la acción conjunta de diferentes hormonas, receptores hormonales, genes, interacciones gen-gen y gen-ambiente, durante las etapas pre y perinatales (Joel, 2021;Joel & McCarthy, 2017;McCarthy, Herold & Stockman, 2018). ...
... While due consideration of key biological variables is not without its methodological challenges, there exists numerous aging or sex-based research centers of excellence around the United States (e.g., Nathan Shock Centers of Excellence in the Basic Biology of Aging, Tulane Center for Excellence In Sex-Based Biology and Medicine, and several workshops (e.g., International Symposium on the Neurobiology and Neuroendocrinology of Aging) providing training in the conduct of aging and/or sex-based research have been developed in recent years. In addition to informal laboratory based training, several publications laying out strategies are readily available (Bale and Epperson, 2017;Joel and McCarthy, 2017;Clayton, 2018). Especially given the profound age-related shifts in immune function, there exist numerous opportunities for productive research collaborations between immunologists, neuroendocrinologists, and biostatisticians to thoroughly address the convergence of sex, sex hormones, age, immune function, and stress responses. ...
Major depression is a significant medical issue impacting millions of individuals worldwide. Identifying factors contributing to its manifestation has been a subject of intense investigation for decades and several targets have emerged including sex hormones and the immune system. Indeed, an extensive body of literature has demonstrated that sex hormones play a critical role in modulating brain function and impacting mental health, especially among female organisms. Emerging findings also indicate an inflammatory etiology of major depression, revealing new opportunities to supplement, or even supersede, currently available pharmacological interventions in some patient populations. Given the established sex differences in immunity and the profound impact of fluctuations of sex hormone levels on the immune system within the female, interrogating how the endocrine, nervous, and immune systems converge to impact women’s mental health is warranted. Here, we review the impacts of endogenous estrogens as well as exogenously administered estrogen-containing therapies on affect and immunity and discuss these observations in the context of distinct reproductive milestones across the female lifespan. A theoretical framework and important considerations for additional study in regards to mental health and major depression are provided.
... From this perspective, dendritic spines are sexually dimorphic and/or affected by gonadal steroids (Woolley and McEwen, 1993;Rasia-Filho et al., 2012;Luine and Frankfurt, 2020), sexual experience and motherhood (Rasia-Filho et al., 2004;Zancan et al., 2018). These phenomena are relevant to sexual differentiation in healthy brain connectivity and as a biological variable in neuropsychiatric research (Joel and McCarthy, 2017;Rubinow and Schmidt, 2019;Arnold, 2020;Hidalgo-Lopez et al., 2021). ...
... However, these hypotheses remain controversial, and more research is needed to characterize environmental processes that may result in "sex-atypical" brain and behavioral features in ASD. Furthermore, the growing literature on sex differences in the brain suggests that both "masculine" and "feminine" processes interact with individual genetics and environment across development in a time-sensitive manner to produce an individual's brain "mosaic" (Joel et al. 2015;Joel and McCarthy 2017;Eliot et al. 2021). In keeping, the "female-typical" FC patterns linked to camouflaging suggest that female sex chromosomes or reproductive biology (e.g. ...
The male preponderance in autism spectrum disorder (ASD) led to the hypothesis that aspects of female biology are protective against ASD. Females with ASD (ASD-F) report more compensatory behaviors (i.e. “camouflaging”) to overcome ASD-related social differences, which may be a mechanism of protection. No studies have examined sex-related brain pathways supporting camouflaging in ASD-F, despite its potential to inform mechanisms underlying the ASD sex bias. We used functional connectivity (FC) to investigate “sex-atypical” and “sex-typical” FC patterns linked to camouflaging in adults with ASD and examined multimodal coherence of findings via structural connectometry. Exploratory associations with cognitive/emotional functioning examined the adaptive nature of FC patterns. We found (i) “sex-atypical” FC patterns linked to camouflaging in the hypothalamus and precuneus and (ii) “sex-typical” patterns in the right anterior cingulate and anterior parahippocampus. Higher hypothalamic FC with a limbic reward cluster also correlated with better cognitive control/emotion recognition. Structural connectometry validated FC results with consistent brain pathways/effect patterns implicated in ASD-F. In summary, “male-typical” and “female-typical” brain connectivity patterns support camouflaging in ASD-F in circuits implicated in reward, emotion, and memory retrieval. “Sex-atypical” results are consistent with fetal steroidogenic/neuroinflammatory hypotheses. However, female genetics/biology may contribute to “female-typical” patterns implicated in camouflaging.
... The process of transitioning is complex and can be heavily individualized, which partially explains some of the difficulties in developing a lab-based model. Despite the limited information regarding the development of human gender identity, there has been significant progress in using animal models to demonstrate the neurodevelopment pathways leading to sex differences in brain and behavior (Joel and McCarthy, 2017;Choleris et al., 2018;Theisen et al., 2019). From these studies, three main factors: environment, genes, and hormones, have all been identified as mechanisms key to understanding human gender identity. ...
... In addition, studies on the efficacy and the effectiveness of treatments could also benefit from separate analyses by sex (Joel & McCarthy, 2017). Indeed, s/g is an important variable that should be considered when designing and analyzing pharmacological randomized controlled trials (RCTs), since it influence pharmacokinetics (Anderson, 2005) as well as the rate and severity of adverse drug reactions (Tharpe, 2011). ...
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions whose shared core features are impairments in social interaction and communication as well as restricted patterns of behavior, interests, and activities. The significant and consistent male preponderance in ASD prevalence has historically affected the scientific knowledge of autism in females as regards, inter alia, the clinical presentation, the genetic architecture, and the structural brain underpinnings. Indeed, females with ASD are under-investigated as samples recruited for clinical research typically reflect the strong male bias of the disorder. In the last years, the study of the various aspects of sex/gender (s/g) differences in ASD is gaining increased clinical and research interest resulting in a growing number of investigations on this topic. Here, I review and discuss evidence emerged from epidemiological, clinical, and neuroimaging studies in the last decade focusing on s/g differences in children with ASD. These studies are the prerequisites for the development of assessment and treatment practices which take into consideration s/g differences in ASD. Ultimately, a better understanding of s/g differences aims at improving healthcare for both ASD males and females.
... Therefore, we tentatively suggest that in studies explicitly addressing the neurobiological determinant of heroin self-administration, it may not be necessary to use sex as an independent variable and double the n per experimental condition . Instead, we suggest including both males and females (preferably equal number) in each experimental condition, as advocated by Joel and McCarthy (Joel & McCarthy, 2017) for behavioural models in which sex differences are not observed. However, our data are at odds, with an earlier study reporting higher heroin intake in female compared to the male rats (Lynch & Carroll, 1999). ...
Background and purpose:
Studies using intermittent access drug self-administration show increased motivation to take and seek cocaine and fentanyl, relative to continuous access. In this study, we examined the effects of intermittent- and continuous access self-administration on heroin intake, patterns of self-administration, and cue-induced heroin seeking, after forced or voluntary abstinence, in male and female rats. We also modeled brain levels of heroin and its active metabolites.
Experimental approach:
Rats were trained to self-administer a palatable solution and then heroin (0.075 mg/kg/inf) either continuously (6-h/d; 10 d) or intermittently (6-h/d; 5-min access/30-min; 10 d). Brain levels of heroin and its metabolites were modeled using a pharmacokinetic software. Next, heroin-seeking was assessed after 1 or 21 abstinence days. Between tests, rats underwent either forced or voluntary abstinence. The estrous cycle was measured using a vaginal smear test.
Key results:
Intermittent access exacerbated heroin self-administration and was characterized by a burst-like intake, yielding higher brain peaks of heroin and 6-monoacetylmorphine concentrations. Moreover, intermittent access increased cue-induced heroin-seeking during early, but not late abstinence. Heroin-seeking was higher in females after intermittent, but not continuous access and this effect was independent of the estrous cycle.
Conclusions and implications:
Intermittent heroin access in rats resembles critical features of heroin use disorder: a self-administration pattern characterized by repeated large doses of heroin and higher relapse vulnerability during early abstinence. This has significant implications for refining animal models of substance use disorder and for better understanding of the neuroadaptations responsible for this disorder.
While the brain continues to develop during adolescence, such development may depend on sex-at-birth. However, the elucidation of such differences may be hindered by analytical decisions (e.g., covariate selection to address brain-size differences) and the typical reporting of cross-sectional data. To further evaluate adolescent cortical development, we analyzed data from the Adolescent Brain Cognitive Development Study, whose cohort of 11,000+ youth participants with biannual neuroimaging data collection can facilitate understanding neuroanatomical change during a critical developmental window. Doubly considering individual differences within the context of group-level effects, we analyzed regional changes in cortical thickness, sulcal depth, surface area, and volume between two timepoints (∼2 years apart) in 9- to 12-year-olds assigned male or female sex-at-birth. First, we conducted linear mixed-effect models to gauge how controlling for intracranial volume, whole-brain volume (WBV), or a summary metric (e.g., mean cortical thickness) influenced interpretations of age-dependent cortical change. Next, we evaluated the relative changes in thickness and surface area as a function of sex-at-birth and age. Here, we showed that WBV (thickness, sulcal depth, volume) and total cortical surface area were more optimal covariates; controlling for different covariates would have substantially altered our interpretations of overall and sex-at-birth-specific neuroanatomical development. Furthermore, we provided evidence to suggest that aggregate change in how cortical thickness is changing relative to surface area is generally comparable across those assigned male or female sex-at-birth, with corresponding change happening at slightly older ages in those assigned male sex-at-birth. Overall, these results help elucidate neuroanatomical developmental trajectories in early adolescence.
Chronic exposure to drugs of abuse can cause profound and persistent alterations in the brain, particularly in the nucleus accumbens, which is a key brain reward region. These changes include variations in gene expression, neuronal morphology, and synaptic function that play critical roles in the development and maintenance of addiction. This chapter delves into the emerging field of epigenetic priming in drug addiction, focusing on chromatin-based mechanisms—so-called “chromatin scars”—that underlie the transition from recreational drug use to compulsive drug-seeking behavior, and how activity-dependent transcription contributes to the development of substance use disorders (SUDs). We then review the role of epigenetic regulation, such as DNA methylation and histone modifications, in mediating transcriptional changes and the consequent neural plasticity associated with addiction. Furthermore, we discuss the implications of these insights for understanding addiction as a complex and multifaceted disorder, and the potential of targeted epigenetic therapies for SUDs.
Alzheimer's disease (AD) has many etiologies and the impact of gender on AD changes throughout time. As a consequence of advancements in precision medical procedures and methodology, Alzheimer's disease is now better understood and treated. Several risk factors may be addressed to lower one's chances of developing Alzheimer's disease or associated dementia (ADRD).
The presence of amyloid-α protein senile plaques, intracellular tau protein neurofibrillary tangles (NfTs), neurodegeneration, and neuropsychiatric symptoms (NPS) characterizes Alzheimer's disease. NPS is common in persons with Alzheimer's disease dementia, although its presentation varies widely. Gender differences might explain this clinical variability.
The fundamental goal of this review is to 1) emphasize the function of old age, sex, and gender in the development of Alzheimer's disease, dementia, and ADRD, and 2) explain the importance of sexual hormones, education, and APOE (Apolipoprotein E) status. This is a narrative summary of new ideas and concepts on the differences in the chance of developing dementia or Alzheimer's disease between men and women.
A more thorough examination of risk and protective variables in both men and women might hasten research into the epidemiology of neurological illnesses such as dementia and Alzheimer's disease. Similarly, future preventive efforts should target men and women separately.
• This study presents what and where a biological gender resides in the human phenotype, giving further provenance to identity development and diversity separate from body sex. • Evolutionary principles, including natural and sexual selection, drive the evolution of traits that enhance survival and reproduction, leading to the prevalence of certain behaviors and psychological dispositions in males and females. These differences are adaptive for the human species as a whole and are regulated and maintained by evolutionary pressures. • Several stable and dimorphic cognitive behaviors influenced by innate sex hormones and regulated by reproductive drives play a role in the development of gender identity. • These gender differences in cognitive behavior are not solely a result of socialization. • Given the biological component of gender, what are the potential implications of studying cis- and non-cisgender communities? What are the current limitations and challenges to understanding the genetic basis of transgenderism?
Dendritic spine features in human neurons follow the up-to-date knowledge presented in the previous chapters of this book. Human dendrites are notable for their heterogeneity in branching patterns and spatial distribution. These data relate to circuits and specialized functions. Spines enhance neuronal connectivity, modulate and integrate synaptic inputs, and provide additional plastic functions to microcircuits and large-scale networks. Spines present a continuum of shapes and sizes, whose number and distribution along the dendritic length are diverse in neurons and different areas. Indeed, human neurons vary from aspiny or “relatively aspiny” cells to neurons covered with a high density of intermingled pleomorphic spines on very long dendrites. In this chapter, we discuss the phylogenetic and ontogenetic development of human spines and describe the heterogeneous features of human spiny neurons along the spinal cord, brainstem, cerebellum, thalamus, basal ganglia, amygdala, hippocampal regions, and neocortical areas. Three-dimensional reconstructions of Golgi-impregnated dendritic spines and data from fluorescence microscopy are reviewed with ultrastructural findings to address the complex possibilities for synaptic processing and integration in humans. Pathological changes are also presented, for example, in Alzheimer’s disease and schizophrenia. Basic morphological data can be linked to current techniques, and perspectives in this research field include the characterization of spines in human neurons with specific transcriptome features, molecular classification of cellular diversity, and electrophysiological identification of coexisting subpopulations of cells. These data would enlighten how cellular attributes determine neuron type-specific connectivity and brain wiring for our diverse aptitudes and behavior.
Locus coeruleus (LC) is a small nucleus located deep in the brainstem that contains the majority of central noradrenergic neurons, which provide the primary source of noradrenaline (NA) throughout the entire central nervous system (CNS).The release of neurotransmitter NA is considered to modulate arousal, sensory processing, attention, aversive and adaptive stress responses as well as high-order cognitive function and memory, with the highly ramified axonal arborizations of LC-NA neurons sending wide projections to the targeted brain areas. For over 30 years, LC was thought to be a homogeneous nucleus in structure and function due to the widespread uniform release of NA by LC-NA neurons and simultaneous action in several CNS regions, such as the prefrontal cortex, hippocampus, cerebellum, and spinal cord. However, recent advances in neuroscience tools have revealed that LC is probably not so homogeneous as we previous thought and exhibits heterogeneity in various aspects. Accumulating studies have shown that the functional complexity of LC may be attributed to its heterogeneity in developmental origin, projection patterns, topography distribution, morphology and molecular organization, electrophysiological properties and sex differences. This review will highlight the heterogeneity of LC and its critical role in modulating diverse behavioral outcomes.
Rapid advances in the neural control of social behavior highlight the role of interconnected nodes engaged in differential information processing to generate behavior. Many innate social behaviors are essential to reproductive fitness and therefore fundamentally different in males and females. Programming these differences occurs early in development in mammals, following gonadal differentiation and copious androgen production by the fetal testis during a critical period. Early-life programming of social behavior and its adult manifestation are separate but yoked processes, yet how they are linked is unknown. This review seeks to highlight that gap by identifying four core mechanisms (epigenetics, cell death, circuit formation, and adult hormonal modulation) that could connect developmental changes to the adult behaviors of mating and aggression. We further propose that a unique social behavior, adolescent play, bridges the preweaning to the post-pubertal brain by engaging the same neural networks underpinning adult reproductive and aggressive behaviors.
Expected final online publication date for the Annual Review of Neuroscience, Volume 46 is July 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
While there is emerging evidence of sex differences in decision-making behavior, the neural substrates that underlie such differences remain largely unknown. Here we demonstrate that in mice performing a value-based decision-making task, while choices are similar between the sexes, motivation to engage in the task is modulated by action value more strongly in females than in males. Inhibition of activity in anterior cingulate cortex (ACC) neurons that project to the dorsomedial striatum (DMS) preferentially disrupts this relationship between value and motivation in females, without affecting choice in either sex. In line with these effects, in females compared to males, ACC–DMS neurons have stronger representations of negative outcomes and more neurons are active when the value of the chosen option is low. By contrast, the representation of each choice is similar between the sexes. Thus, we identify a neural substrate that contributes to sex-specific modulation of motivation by value. The authors show that action value modulates motivation to perform a decision-making task more strongly in females than in males. Anterior cingulate cortex neurons that project to the striatum contribute to this sex difference.
Gender differences have been observed in the vulnerability to drug abuse and in the different stages of the addictive process. In opiate dependence, differences between sexes have been shown in humans and laboratory animals in various phases of opiate addiction, especially in withdrawal-associated negative affective states. Using a Y-maze conditioned place aversion paradigm, we investigated potential sex differences in the expression and extinction of the aversive memory of precipitated opiate withdrawal state in morphine-dependent rats. No significant difference between sexes was observed in the occurrence of withdrawal signs following naloxone injection during conditioning. Moreover, opiate withdrawal memory expression and extinction following repeated testing was demonstrated in both male and female rats, with no significant differences between sexes. Finally, we report spontaneous recovery following extinction of opiate withdrawal memory. Altogether these data provide further evidence that persistent withdrawal-related memories may be strong drivers of opiate dependence, and demonstrate that both males and females can be used in experimental rodent cohorts to better understand opiate-related effects, reward, aversive state of withdrawal, abstinence and relapse.
The notion of psychological androgyny as a research tool loiters on in an incapacitated state. The lack of a general theory and the belief that the biological gender differences are insignificant to non-existent has been the seeds for its de-construction. Over the decades, the testing of ideas associated with androgyny has declined. Indeed, the debates over its usefulness as a construct ended long ago. The judgment nowadays is that debating the constructs of masculinity, femininity, and androgyny as behavioral traits has been long settled, and a contemporary revisiting of androgyny is not warranted. However, from another contemporary viewpoint, if androgyny is to have any future, it needs a new theory devoid of masculinity and femininity. We present a novel theory with the potential to do just that. This article details a new de-gendered theory of psychological androgyny, neo-androgyny, as a candidate to replace traditional models that are now considered outdated and irrelevant. We present five potential factors for inclusion in a de-gendered model: social efficacy, creativity, capability, eminence, and determination. We review these factors concerning the future of androgyny theory.
Most psychiatric illnesses, such as schizophrenia, show profound sex differences in incidence, clinical presentation, course, and outcome. Fortunately, more recently the literature on sex differences and (to a lesser extent) effects of sex steroid hormones is expanding, and in this review we have focused on such studies in psychosis, both from a clinical/epidemiological and preclinical/animal model perspective. We begin by briefly describing the clinical evidence for sex differences in schizophrenia epidemiology, symptomatology, and pathophysiology. We then detail sex differences and sex hormone effects in behavioral animal models of psychosis, specifically psychotropic drug-induced locomotor hyperactivity and disruption of prepulse inhibition. We expand on the preclinical data to include developmental and genetic models of psychosis, such as the maternal immune activation model and neuregulin transgenic animals, respectively. Finally, we suggest several recommendations for future studies, in order to facilitate a better understanding of sex differences in the development of psychosis.
We have used Golgi-impregnated tissue to demonstrate that apical dendritic spine density in CA1 hippocampal pyramidal cells undergoes a cyclic fluctuation as estradiol and progesterone levels vary across the estrous cycle in the adult female rat. We observed a 30% decrease in apical dendritic spine density over the 24-hr period between the late proestrus and the late estrus phases of the cycle. Spine density then appears to cycle back to proestrus values over a period of several days. In contrast, no significant changes in dendritic spine density across the estrous cycle occur in CA3 pyramidal cells or dentate gyrus granule cells. These results demonstrate rapid and ongoing dendritic plasticity in a specific population of hippocampal neurons in experimentally unmanipulated animals.
The idea of sex differences in the brain both fascinates and inflames the public. As a result, the communication and public discussion of new findings is particularly vulnerable to logical leaps and pseudoscience. A new US National Institutes of Health policy to consider both sexes in almost all preclinical research will increase the number of reported sex differences and thus the risk that research in this important area will be misinterpreted and misrepresented. In this article, I consider ways in which we might reduce that risk, for example, by (i) employing statistical tests that reveal the extent to which sex explains variation, rather than whether or not the sexes 'differ', (ii) properly characterizing the frequency distributions of scores or dependent measures, which nearly always overlap, and (iii) avoiding speculative functional or evolutionary explanations for sex-based variation, which usually invoke logical fallacies and perpetuate sex stereotypes. Ultimately, the factor of sex should be viewed as an imperfect, temporary proxy for yet-unknown factors, such as hormones or sex-linked genes, that explain variation better than sex. As scientists, we should be interested in discovering and understanding the true sources of variation, which will be more informative in the development of clinical treatments.
Studies of sex differences in the brain range from reductionistic cell and molecular analyses in animal models to functional imaging in awake human subjects, with many other levels in between. Interpretations and conclusions about the importance of particular differences often vary with differing levels of analyses and can lead to discord and dissent. In the past two decades, the range of neurobiological, psychological and psychiatric endpoints found to differ between males and females has expanded beyond reproduction into every aspect of the healthy and diseased brain, and thereby demands our attention. A greater understanding of all aspects of neural functioning will only be achieved by incorporating sex as a biological variable. The goal of this review is to highlight the current state of the art of the discipline of sex differences research with an emphasis on the brain and to contextualize the articles appearing in the accompanying special issue.
In the study of variation in brain structure and function that might relate to sex and gender, language matters because it frames our research questions and methods. In this article, we offer an approach to thinking about variation in brain structure and function that pulls us outside the sex differences formulation. We argue that the existence of differences between the brains of males and females does not unravel the relations between sex and the brain nor is it sufficient to characterize a population of brains. Such characterization is necessary for studying sex effects on the brain as well as for studying brain structure and function in general. Animal studies show that sex interacts with environmental, developmental and genetic factors to affect the brain. Studies of humans further suggest that human brains are better described as belonging to a single heterogeneous population rather than two distinct populations. We discuss the implications of these observations for studies of brain and behaviour in humans and in laboratory animals. We believe that studying sex effects in context and developing or adopting analytical methods that take into account the heterogeneity of the brain are crucial for the advancement of human health and well-being.
We have found that the density of synapses in the stratum radiatum of the hippocampal CA1 region in the adult female rat is sensitive to estradiol manipulation and fluctuates naturally as the levels of ovarian steroids vary during the 5 d estrous cycle. In both cases, low levels of estradiol are correlated with lower synapse density, while high estradiol levels are correlated with a higher density of synapses. These synaptic changes occur very rapidly in that within approximately 24 hr between the proestrus and estrus stages of the estrous cycle, we observe a 32% decrease in the density of hippocampal synapses. Synapse density then appears to cycle back to proestrus values over a period of several days. To our knowledge, this is the first demonstration of such short-term steroid-mediated synaptic plasticity occurring naturally in the adult mammalian brain.
It is commonly assumed, but has rarely been demonstrated, that sex differences in behaviour arise from sexual dimorphism in the underlying neural circuits. Parental care is a complex stereotypic behaviour towards offspring that is shared by numerous species. Mice display profound sex differences in offspring-directed behaviours. At their first encounter, virgin females behave maternally towards alien pups while males will usually ignore the pups or attack them. Here we show that tyrosine hydroxylase (TH)-expressing neurons in the anteroventral periventricular nucleus (AVPV) of the mouse hypothalamus are more numerous in mothers than in virgin females and males, and govern parental behaviours in a sex-specific manner. In females, ablating the AVPV TH(+) neurons impairs maternal behaviour whereas optogenetic stimulation or increased TH expression in these cells enhance maternal care. In males, however, this same neuronal cluster has no effect on parental care but rather suppresses inter-male aggression. Furthermore, optogenetic activation or increased TH expression in the AVPV TH(+) neurons of female mice increases circulating oxytocin, whereas their ablation reduces oxytocin levels. Finally, we show that AVPV TH(+) neurons relay a monosynaptic input to oxytocin-expressing neurons in the paraventricular nucleus. Our findings uncover a previously unknown role for this neuronal population in the control of maternal care and oxytocin secretion, and provide evidence for a causal relationship between sexual dimorphism in the adult brain and sex differences in parental behaviour.
Most writing on sexual differentiation of the mammalian brain (including our own) considers just two organs: the gonads and the brain. This perspective, which leaves out all other body parts, misleads us in several ways. First, there is accumulating evidence that all organs are sexually differentiated, and that sex differences in peripheral organs affect the brain. We demonstrate this by reviewing examples involving sex differences in muscles, adipose tissue, the liver, immune system, gut, kidneys, bladder, and placenta that affect the nervous system and behavior. The second consequence of ignoring other organs when considering neural sex differences is that we are likely to miss the fact that some brain sex differences develop to compensate for differences in the internal environment (i.e., because male and female brains operate in different bodies, sex differences are required to make output/function more similar in the two sexes). We also consider evidence that sex differences in sensory systems cause male and female brains to perceive different information about the world; the two sexes are also perceived by the world differently and therefore exposed to differences in experience via treatment by others. Although the topic of sex differences in the brain is often seen as much more emotionally charged than studies of sex differences in other organs, the dichotomy is largely false. By putting the brain firmly back in the body, sex differences in the brain are predictable and can be more completely understood.
In an effort to increase applicability of preclinical research to both men and women, the National Institute of Health is anticipated to put forth guidelines for the incorporation of sex as a variable in animal studies. Common myths and perceived barriers to the inclusion of females in neuroscience research are discussed and a roadmap for implementation provided. Accounting for sex as a variable does not require studying sex differences and is easier to implement than generally assumed.
© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Neuroimaging (NI) technologies are having increasing impact in the study of complex cognitive and social processes. In this emerging field of social cognitive neuroscience, a central goal should be to increase the understanding of the interaction between the neurobiology of the individual and the environment in which humans develop and function. The study of sex/gender is often a focus for NI research, and may be motivated by a desire to better understand general developmental principles, mental health problems that show female-male disparities, and gendered differences in society. In order to ensure the maximum possible contribution of NI research to these goals, we draw attention to four key principles—overlap, mosaicism, contingency and entanglement—that have emerged from sex/gender research and that should inform NI research design, analysis and interpretation. We discuss the implications of these principles in the form of constructive guidelines and suggestions for researchers, editors, reviewers and science communicators.
Parental care, including feeding and protection of young, is essential for the survival as well as mental and physical well-being
of the offspring. A large variety of parental behaviors has been described across species and sexes, raising fascinating questions
about how animals identify the young and how brain circuits drive and modulate parental displays in males and females. Recent
studies have begun to uncover a striking antagonistic interplay between brain systems underlying parental care and infant-directed
aggression in both males and females, as well as a large range of intrinsic and environmentally driven neural modulation and
plasticity. Improved understanding of the neural control of parental interactions in animals should provide novel insights
into the complex issue of human parental care in both health and disease.
In the process of morphological evolution, the extent to which cryptic, preexisting variation provides a substrate for natural
selection has been controversial. We provide evidence that heat shock protein 90 (HSP90) phenotypically masks standing eye-size
variation in surface populations of the cavefish Astyanax mexicanus. This variation is exposed by HSP90 inhibition and can be selected for, ultimately yielding a reduced-eye phenotype even
in the presence of full HSP90 activity. Raising surface fish under conditions found in caves taxes the HSP90 system, unmasking
the same phenotypic variation as does direct inhibition of HSP90. These results suggest that cryptic variation played a role
in the evolution of eye loss in cavefish and provide the first evidence for HSP90 as a capacitor for morphological evolution
in a natural setting.
The FOXP2 gene is central to acquisition of speech and language in humans and vocal production in birds and mammals. Rodents communicate via ultrasonic vocalizations (USVs) and newborn pups emit distress USVs when separated from their dam, thereby facilitating their retrieval. We observed that isolated male rat pups emitted substantially more USV calls and these were characterized by a significantly lower frequency and amplitude compared with female rat pups. Moreover, the dam was more likely to first retrieve male pups back to the nest, then females. The amount of Foxp2 protein was significantly higher in multiple regions of the developing male brain compared with females and a reduction of brain Foxp2 by siRNA eliminated the sex differences in USVs and altered the order of pup retrieval. Our results implicate Foxp2 as a component of the neurobiological basis of sex differences in vocal communication in mammals. We extended these observations to humans, a species reported to have gender differences in language acquisition, and found the amount of FOXP2 protein in the left hemisphere cortex of 4-year-old boys was significantly lower than in age-matched girls.
The categorization of individuals as "male" or "female" is based on chromosome complement and gonadal and genital phenotype. This combined genetic-gonadal-genitals sex, here referred to as 3G-sex, is internally consistent in ~99% of humans (i.e., one has either the "female" form at all levels, or the "male" form at all levels). About 1% of the human population is identified as "intersex" because of either having an intermediate form at one or more levels, or having the "male" form at some levels and the "female" form at other levels. These two types of "intersex" reflect the facts, respectively, that the different levels of 3G-sex are not completely dimorphic nor perfectly consistent. Using 3G-sex as a model to understand sex differences in other domains (e.g., brain, behavior) leads to the erroneous assumption that sex differences in these other domains are also highly dimorphic and highly consistent. But parallel lines of research have led to the conclusion that sex differences in the brain and in behavior, cognition, personality, and other gender characteristics are for the most part not dimorphic and not internally consistent (i.e., having one brain/gender characteristic with the "male" form is not a reliable predictor for the form of other brain/gender characteristics). Therefore although only ~1% percent of humans are 3G-"intersex", when it comes to brain and gender, we all have an intersex gender (i.e., an array of masculine and feminine traits) and an intersex brain (a mosaic of "male" and "female" brain characteristics).
The underlying assumption in popular and scientific publications on sex differences in the brain is that human brains can take one of two forms "male" or "female," and that the differences between these two forms underlie differences between men and women in personality, cognition, emotion, and behavior. Documented sex differences in brain structure are typically taken to support this dimorphic view of the brain. However, neuroanatomical data reveal that sex interacts with other factors in utero and throughout life to determine the structure of the brain, and that because these interactions are complex, the result is a multi-morphic, rather than a dimorphic, brain. More specifically, here I argue that human brains are composed of an ever-changing heterogeneous mosaic of "male" and "female" brain characteristics (rather than being all "male" or all "female") that cannot be aligned on a continuum between a "male brain" and a "female brain." I further suggest that sex differences in the direction of change in the brain mosaic following specific environmental events lead to sex differences in neuropsychiatric disorders.
A major impediment to novel drug development has been the paucity of animal models that accurately reflect symptoms of affective disorders. In animal models, prolonged social stress has proven to be useful in understanding the molecular mechanisms underlying affective-like disorders. When considering experimental approaches for studying depression, social defeat stress, in particular, has been shown to have excellent etiological, predictive, discriminative and face validity. Described here is a protocol whereby C57BL/6J mice that are repeatedly subjected to bouts of social defeat by a larger and aggressive CD-1 mouse results in the development of a clear depressive-like syndrome, characterized by enduring deficits in social interactions. Specifically, the protocol consists of three important stages, beginning with the selection of aggressive CD-1 mice, followed by agonistic social confrontations between the CD-1 and C57BL/6J mice, and concluding with the confirmation of social avoidance in subordinate C57BL/6J mice. The automated detection of social avoidance allows a marked increase in throughput, reproducibility and quantitative analysis. This protocol is highly adaptable, but in its most common form it requires 3-4 weeks for completion.
Female mammals have long been neglected in biomedical research. The NIH mandated enrollment of women in human clinical trials in 1993, but no similar initiatives exist to foster research on female animals. We reviewed sex bias in research on mammals in 10 biological fields for 2009 and their historical precedents. Male bias was evident in 8 disciplines and most prominent in neuroscience, with single-sex studies of male animals outnumbering those of females 5.5 to 1. In the past half-century, male bias in non-human studies has increased while declining in human studies. Studies of both sexes frequently fail to analyze results by sex. Underrepresentation of females in animal models of disease is also commonplace, and our understanding of female biology is compromised by these deficiencies. The majority of articles in several journals are conducted on rats and mice to the exclusion of other useful animal models. The belief that non-human female mammals are intrinsically more variable than males and too troublesome for routine inclusion in research protocols is without foundation. We recommend that when only one sex is studied, this should be indicated in article titles, and that funding agencies favor proposals that investigate both sexes and analyze data by sex.
The sexually dimorphic population of dopamine neurons in the anteroventral periventricular nucleus of the preoptic region of the hypothalamus (AVPV) develops postnatally under the influence of testosterone, which is aromatized to estrogen. There are fewer dopaminergic neurons labeled with tyrosine hydroxylase (TH) in the male AVPV than the female, and sex steroids determine this sex difference, yet the role of cell death in specifying numbers of dopaminergic neurons in the AVPV is unknown. Estradiol treatment of the AVPV, in vivo and in vitro, was used to manipulate TH-ir cell number. In vitro, concurrent treatment with the estrogen receptor antagonist ICI 182,780 rescued TH-ir cells. Cyclosporin A, an inhibitor of cell death dependent on the opening of a mitochondrial permeability transition pore also blocked TH-ir cell loss. In vivo, estradiol increased the number of apoptotic profiles, both TUNEL and Hoechst labeled nuclei, in the AVPV. This increased apoptosis was also dependent on the presence of the alpha form of the estrogen receptor. To test for caspase dependent TH-ir cell loss, the pancaspase inhibitor ZVAD (N-benzyloxycabonyl-Val-Ala-Asp-fluoromethylketone) was used to rescue TH-ir cells from estradiol-mediated reduction in number. Together, these data suggest that an intrinsic cell death pathway is activated by estrogen to regulate TH-ir cell number. Thus, in contrast to the more widespread neuroprotective actions of sex steroids in the mammalian nervous system, in the AVPV estrogen regulates dopaminergic neuron number through a caspase-dependent mechanism of apoptotic cell death.
Lactating Long-Evans rats were observed to interact differently with male and female pups during the first 18 days postpartum. Differences in the mother's behavior were related to the gender composition of her litter (GHL), to the sex of a single introduced pup, and to the sex of individual pups within her litter. Major differences were the greater time spent in licking the anogenital region of own male pups and the greater stimulation of anogenital licking by male foster pups, an effect that did not interact with GHL or age of pup. The GHL interacted with day of testing to affect nest building and time spent near pups.
We have found that the density of synapses in the stratum radiatum of the hippocampal CA1 region in the adult female rat is sensitive to estradiol manipulation and fluctuates naturally as the levels of ovarian steroids vary during the 5 d estrous cycle. In both cases, low levels of estradiol are correlated with lower synapse density, while high estradiol levels are correlated with a higher density of synapses. These synaptic changes occur very rapidly in that within approximately 24 hr between the proestrus and estrus stages of the estrous cycle, we observe a 32% decrease in the density of hippocampal synapses. Synapse density then appears to cycle back to proestrus values over a period of several days. To our knowledge, this is the first demonstration of such short-term steroid-mediated synaptic plasticity occurring naturally in the adult mammalian brain.
We have used Golgi-impregnated tissue to demonstrate that apical dendritic spine density in CA1 hippocampal pyramidal cells undergoes a cyclic fluctuation as estradiol and progesterone levels vary across the estrous cycle in the adult female rat. We observed a 30% decrease in apical dendritic spine density over the 24-hr period between the late proestrus and the late estrus phases of the cycle. Spine density then appears to cycle back to proestrus values over a period of several days. In contrast, no significant changes in dendritic spine density across the estrous cycle occur in CA3 pyramidal cells or dentate gyrus granule cells. These results demonstrate rapid and ongoing dendritic plasticity in a specific population of hippocampal neurons in experimentally unmanipulated animals.
Sex differences in rats' performance on a stationary hidden-platform task (spatial task) in the Morris water maze and the effects of initial nonstationary hidden platform training (NSP training) were examined. The NSP training was designed to familiarize rats with the general requirements of the water-maze task without providing spatial information. NSP training led to faster acquisition and improved retention of the subsequent spatial task in both males and females. There was a sex difference favoring males on acquisition and retention of the spatial task only in rats that had not received previous NSP training. Moreover, there was an apparent reversed sex difference favoring females on some measures of spatial performance in NSP-trained rats. These results suggest that performance on the water-maze task, including the expression of sex differences, can be altered by previous familiarization with nonspatial aspects of the task.
Gonadal steroids have remarkable developmental effects on sex-dependent brain organization and behavior in animals. Presumably, fetal or neonatal gonadal steroids are also responsible for sexual differentiation of the human brain. A limbic structure of special interest in this regard is the sexually dimorphic central subdivision of the bed nucleus of the stria terminalis (BSTc), because its size has been related to the gender identity disorder transsexuality. To determine at what age the BSTc becomes sexually dimorphic, the BSTc volume in males and females was studied from midgestation into adulthood. Using vasoactive intestinal polypeptide and somatostatin immunocytochemical staining as markers, we found that the BSTc was larger and contains more neurons in men than in women. However, this difference became significant only in adulthood, showing that sexual differentiation of the human brain may extend into the adulthood. The unexpectedly late sexual differentiation of the BSTc is discussed in relation to sex differences in developmental, adolescent, and adult gonadal steroid levels.
Despite decades of research, we do not know the functional significance of most sex differences in the brain. We are heavily invested in the idea that sex differences in brain structure cause sex differences in behavior. We rarely consider the possibility that sex differences in brain structure may also prevent sex differences in overt functions and behavior, by compensating for sex differences in physiological conditions, e.g. gonadal hormone levels that may generate undesirable sex differences if left unchecked. Such a dual function for sex differences is unlikely to be restricted to adult brains. This review will entertain the possibility that transient sex differences in gene expression in developing brains may cause permanent differences in brain structure but prevent them as well, by compensating for potentially differentiating effects of sex differences in gonadal hormone levels and sex chromosomal gene expression. Consistent application of this dual-function hypothesis will make the search for the functional significance of sex differences more productive.
Significance
Sex/gender differences in the brain are of high social interest because their presence is typically assumed to prove that humans belong to two distinct categories not only in terms of their genitalia, and thus justify differential treatment of males and females. Here we show that, although there are sex/gender differences in brain and behavior, humans and human 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 results demonstrate that regardless of the cause of observed sex/gender differences in brain and behavior (nature or nurture), human brains cannot be categorized into two distinct classes: male brain/female brain.
Discerning the biologic origins of neuroanatomical sex differences has been of interest since they were first reported in the late 60's and early 70's. The centrality of gonadal hormone exposure during a developmental critical window cannot be denied but hormones are indirect agents of change, acting to induce gene transcription or modulate membrane bound signaling cascades. Sex differences in the brain include regional volume differences due to differential cell death, neuronal and glial genesis, dendritic branching and synaptic patterning. Early emphasis on mechanism therefore focused on neurotransmitters and neural growth factors, but by and large these endpoints failed to explain the origins of neural sex differences. More recently evidence has accumulated in favor of inflammatory mediators and immune cells as principle regulators of brain sexual differentiation and reveal that the establishment of dimorphic circuits is not cell autonomous but instead requires extensive cell-to-cell communication including cells of non-neuronal origin. Despite the multiplicity of cells involved the nature of the sex differences in the neuroanatomical endpoints suggests canalization, a process that explains the robustness of individuals in the face of intrinsic and extrinsic variability. We propose that some neuroanatomical endpoints are canalized to enhance sex differences in the brain by reducing variability within one sex while also preventing the sexes from diverging too greatly. We further propose mechanisms by which such canalization could occur and discuss what relevance this may have to sex differences in behavior.
Copyright © 2015. Published by Elsevier Inc.
Robustness is a fundamental property of biological systems. The type of robustness that ensures uniform phenotypic outcomes in the face of variation during an organism's development is called canalization. Here, we discuss the roles that microRNAs play in providing canalization to animal development, citing recent theoretical and experimental advances. MicroRNAs repress protein expression, and they do this in ways that create thresholds in expression and provide adaptation to regulatory networks. Numerous examples have now been described where the developmental impact of environmental variation is suppressed by individual microRNAs. A recent paper has found that the impact of genomic variation between individuals is similarly suppressed by a microRNA operating in a developmental network. Thus, genetic variability is held in check, which is potentially important for both animal evolution and manifestation of disease.
PRENDERGAST, B.J., K.G. Onishi and I. Zucker. Female mice liberated for inclusion in neuroscience and biomedical research. NEUROSCI BIOBEHAV REV 37(X) XXX-XXX, 2013.- The underrepresentation of female mice in neuroscience and biomedical research is based on the assumption that females are intrinsically more variable than males and must be tested at each of four stages of the estrous cycle to generate reliable data. Neither belief is empirically based. In a meta-analysis of 293 articles, behavioral, morphological, physiological, and molecular traits were monitored in male mice and females tested without regard to estrous cycle stage; variability was not significantly greater in females than males for any endpoint and was substantially greater in males for several traits. Group housing of mice increased variability in both males and females by 37%. Utilization of female mice in neuroscience research does not require monitoring of the estrous cycle. The prevalence of sex differences at all levels of biological organization, and limitations in generalizing findings obtained with males to females, argue for the routine inclusion of female rodents in most research protocols.
Testosterone (T) and other androgens are incorporated into an increasingly wide array of human sexuality research, but there are a number of issues that can affect or confound research outcomes. This review addresses various methodological issues relevant to research design in human studies with T; unaddressed, these issues may introduce unwanted noise, error, or conceptual barriers to interpreting results. Topics covered are (1) social and demographic factors (gender and sex; sexual orientations and sexual diversity; social/familial connections and processes; social location variables), (2) biological rhythms (diurnal variation; seasonality; menstrual cycles; aging and menopause), (3) sample collection, handling, and storage (saliva vs. blood; sialogogues, saliva, and tubes; sampling frequency, timing, and context; shipping samples), (4) health, medical issues, and the body (hormonal contraceptives; medications and nicotine; health conditions and stress; body composition, weight, and exercise), and (5) incorporating multiple hormones. Detailing a comprehensive set of important issues and relevant empirical evidence, this review provides a starting point for best practices in human sexuality research with T and other androgens that may be especially useful for those new to hormone research.
Background:
The classic model of sex determination in mammals states that the sex of the individual is determined by the type of gonad that develops, which in turn determines the gonadal hormonal milieu that creates sex differences outside of the gonads. However, XX and XY cells are intrinsically different because of the cell-autonomous sex-biasing action of X and Y genes.
Results:
Recent studies of mice, in which sex chromosome complement is independent of gonadal sex, reveal that sex chromosome complement has strong effects contributing to sex differences in phenotypes such as metabolism. Adult mice with two X chromosomes (relative to mice with one X chromosome) show dramatically greater increases in body weight and adiposity after gonadectomy, irrespective of their gonadal sex. When fed a high-fat diet, XX mice develop striking hyperinsulinemia and fatty liver, relative to XY mice. The sex chromosome effects are modulated by the presence of gonadal hormones, indicating an interaction of the sex-biasing effects of gonadal hormones and sex chromosome genes.
Conclusions:
Other cell-autonomous sex chromosome effects are detected in mice in many phenotypes. Birds (relative to eutherian mammals) are expected to show more widespread cell-autonomous sex determination in non-gonadal tissues, because of ineffective sex chromosome dosage compensation mechanisms.
During the intrauterine period a testosterone surge masculinizes the fetal brain, whereas the absence of such a surge results in a feminine brain. As sexual differentiation of the brain takes place at a much later stage in development than sexual differentiation of the genitals, these two processes can be influenced independently of each other. Sex differences in cognition, gender identity (an individual's perception of their own sexual identity), sexual orientation (heterosexuality, homosexuality or bisexuality), and the risks of developing neuropsychiatric disorders are programmed into our brain during early development. There is no evidence that one's postnatal social environment plays a crucial role in gender identity or sexual orientation. We discuss the relationships between structural and functional sex differences of various brain areas and the way they change along with any changes in the supply of sex hormones on the one hand and sex differences in behavior in health and disease on the other.
Sexually dimorphic brain nuclei underlie gender-specific neural functions and susceptibility to disease, but the developmental basis of dimorphisms is poorly understood. In these studies, we focused on the anteroventral periventricular nucleus (AVPV), a nucleus that is larger in females and critical for the female-typical cyclic surge pattern of luteinizing hormone (LH) release. Sex differences in the size and function of the AVPV result from apoptosis that occurs preferentially in the developing male. To identify upstream pathways responsible for sexual differentiation of the AVPV, we used targeted apoptosis microarrays and in vivo and in vitro follow-up studies. We found that the tumor necrosis factor alpha (TNFalpha)-TNF receptor 2 (TNFR2)-NFkappaB cell survival pathway is active in postnatal day 2 (PND2) female AVPV and repressed in male counterparts. Genes encoding key members of this pathway were expressed exclusively in GABAergic neurons. One gene in particular, TNF receptor-associated factor 2 (TRAF2)-inhibiting protein (trip), was higher in males and it inhibited both TNFalpha-dependent NFkappaB activation and bcl-2 gene expression. The male AVPV also had higher levels of bax and bad mRNA, but neither of these genes was regulated by either TNFalpha or TRIP. Finally, the trip gene was not expressed in the sexually dimorphic nucleus of the preoptic area (SDN-POA), a nucleus in which apoptosis is higher in females than males. These findings form the basis of a new model of sexual differentiation of the AVPV that may also apply to the development of other sexually dimorphic nuclei.
The volume of an intensely staining component of the preoptic area of the male rat is markedly larger than that of the female. Moreover, its volume in both sexes is altered by perinatal hormone exposure consistent with the view that this brain region undergoes hormone dependent sexual differentiation. The present study was carried out to determine if this sexually dimorphic area of the brain has a greater cell density than that of the surround, and if a unique population or distribution of cells, either within one sex or between males and females, characterized this region. A single coronal paraffin section (10 micrometer) through the approximate center of this sexually dimorphic area in four adult gonadectomized rats of each sex was evaluated systematically. Each cell was labelled as being inside or outside of the sexually dimorphic area. In addition to cell density per unit area the following parameters were evaluated through a closed-circuit video system: cell size, staining intensity, shape, and the presence of processes and of a nucleolus. The presence of a nucleolus was further used to identify neurons within the total population of almost 5000 cells that was evaluated. In both sexes, the sexually dimorphic area was characterized by a significantly increased cell density per unit area compared to that of the surround. On this basis, the term, the Sexually Dimorphic Nucleus of the Preoptic Area (SDN-POA) is proposed, for this region. Moreover, the SDN-POA of the male was characterized by increased neuronal density per unit area. The SDN-POA in the male was also found to contain larger cells and neurons, as determined by direct measurement of their greatest diameter, as well as a greater percentage of cells and neurons rated large on a three-point scale (small, medium, and large). No consistent differences in frequency distribution by stain intensity, shape, or the presence of cell processes were found to characterize the SDN-POA or contribute to the sexual dimorphism. It is concluded that the marked sex difference in the volume of the SDN-POA is due principally to an increase in the male of the total area of higher cell and neuronal density. However, the present results do not eliminate the possibility that more subtle differences in neuronal characteristics may exist in the SDN-POA.
We studied the extent of sex-typing across different areas of child functioning (personality, interests, activities) in middle childhood as a function of the traditionality of parents' gender role attitudes and the sex composition of the sibling dyad. Participants included 200 firstborn children (mean = 10.4 years old), their secondborn siblings (mean = 7.7 years old) and their mothers and fathers. Family members were interviewed in their homes about their attitudes and personal characteristics and completed a series of seven evening telephone interviews about their daily activities. We measured children's attitudes, personality characteristics, and interests in sex-typed leisure activities (e.g., sports, handicrafts) as well as time spent in sex-typed leisure activities and household tasks (e.g., washing dishes, home repairs) and with same and opposite sex companions (i.e., parents, peers). Analyses revealed that sex-typing was most evident in children's interests and activities. Further, comparisons of girls versus boys and sisters versus brothers revealed that differences in children's sex-typing as a function of fathers' attitudes and sibling sex constellation were most apparent for children's activities. A notable exception was sex-typed peer involvement; time spent with same versus opposite sex peers was impervious to context effects. Analyses focused on children's sex-typing as a function of mothers' attitudes generally were nonsignificant.
Dendritic spines are postsynaptic sites of excitatory input in the mammalian nervous system. Despite much information about their structure, their functional significance remains unknown. It has been reported that females in proestrus, when estrogen levels are elevated, have a greater density of apical dendritic spines on pyramidal neurons in area CA1 of the hippocampus than females in other stages of estrous (Woolley et al., 1990). Here we replicate these findings and in addition, show that females in proestrus have a greater density of spines in area CA1 of the hippocampus than males. Moreover, this sex difference in spine density is affected in opposite directions by stressful experience. In response to one acute stressful event of intermittent tailshocks, spine density was enhanced in the male hippocampus but reduced in the female hippocampus. The decrease in the female was observed for those that were stressed during diestrus 2 and perfused 24 hr later during proestrus. The opposing effects of stress were not evident immediately after the stressor but rather occurred within 24 hr and were evident on apical and to a lesser extent on basal dendrites of pyramidal cells in area CA1. Neither sex nor stress affected spine density on pyramidal neurons in somatosensory cortex. Sex differences in hippocampal spine density correlated with sex hormones, estradiol and testosterone, whereas stress effects on spine density were not directly associated with differences in the stress hormones, glucocorticoids. In summary, males and females have different levels of dendritic spine density in the hippocampus under unstressed conditions, and their neuronal anatomy can respond in opposite directions to the same stressful event.
Mammalian reproduction depends on the coordinated expression of behavior with precisely timed physiological events that are fundamentally different in males and females. An improved understanding of the neuroanatomical relationships between sexually dimorphic parts of the forebrain has contributed to a significant paradigm shift in how functional neural systems are approached experimentally. This review focuses on the organization of interconnected limbic-hypothalamic pathways that participate in the neural control of reproduction and summarizes what is known about the developmental neurobiology of these pathways. Sex steroid hormones such as estrogen and testosterone have much in common with neurotrophins and regulate cell death, neuronal migration, neurogenesis, and neurotransmitter plasticity. In addition, these hormones direct formation of sexually dimorphic circuits by influencing axonal guidance and synaptogenesis. The signaling events underlying the developmental activities of sex steroids involve interactions between nuclear hormone receptors and other transcriptional regulators, as well as interactions at multiple levels with neurotrophin and neurotransmitter signal transduction pathways.
Conrad Waddington published an influential model for evolution in his 1942 paper, Canalization of Development and Inheritance of Acquired Characters. In this classic, albeit controversial, paper, he proposed that an unknown mechanism exists that conceals phenotypic variation until the organism is stressed. Recent studies have proposed that the highly conserved chaperone Hsp90 could function as a "capacitor," or an "adaptively inducible canalizer," that masks silent phenotypic variation of either genetic or epigenetic origin. This review will discuss evidence for, and arguments against, the role of Hsp90 as a capacitor for morphological evolution, and as a key component of what we call "Waddington's widget."
Brain sexual differentiation in mammals requires activity of gonadal hormones; organizational effects of these steroids on brain development occur early in life while activational ones in adulthood ensure appropriate and timely sex-specific behaviors. This traditional view has long served as a reliable model for sexual differentiation of reproductively relevant brain structures. Here, we take a fresh look at this model but refocused in the context of sexual differentiation of non-reproductive parameters and with an emphasis on the hippocampus, a telencephalic brain structure predominantly involved in cognition and stress regulation. We explore sex differences in morphology, neurochemistry, and hippocampal-dependent behaviors to propose a new prototype that can be used to explain and further investigate the effects of steroid hormones, those synthesized gonadally or intracerebrally, on hippocampal development and function. We also propose that a new vernacular be employed, one that distinguishes hormonally modulated responses from sex differences, and argue these are mechanistically and functionally distinct. Understanding when and how the sexes are different is as important as understanding when and how they are the same, at the biological, social, and cultural level.
Early life experiences can shape brain function and behavior in adulthood. The present study sought to elucidate the effects of repetitive, predictable vs. varied, unpredictable prenatal stress on sexually dichotomous neuroendocrine and anxiety-related behavioral responses in adult offspring. Rat dams were exposed repeatedly during the last week of pregnancy to no stress, only restraint stress [prenatal stress (PS)-restraint], or a randomized sequence of varied stressors (PS-random), and several behavioral and endocrine measures were assessed in adult male and female offspring. Repeated exposure to the same stressor (restraint) generated the most robust changes, including increased anxiety-related behaviors (both passive, measured on the elevated plus maze, and active, measured using defensive burying tests), a delayed and prolonged hypothalamic-pituitary-adrenal (HPA) axis response to stress in female offspring. Conversely, PS-restraint males showed no changes in anxiety-like behavior and had elevated basal ACTH and a blunted HPA response to stress; consistent with attenuated HPA responsivity was an increase in glucocorticoid receptor immunoreactivity in the hippocampus, suggesting increased negative feedback on the HPA axis in these animals. Prenatal exposure to a varied, unpredictable pattern of stressors did not have as much effect on HPA function, with most neuroendocrine measures residing intermediate to PS-restraint and control animals within each sex. Gonadal steroids were altered independent of the type of prenatal stress, but changes were measurable only in males (lower testosterone). The present data exemplify the differential sensitivity of the developing nervous and endocrine systems to stress, depending on not only gender but also the nature of the stressful experience endured by the mother during pregnancy.
Numerous studies have documented the consequences of exposure to anesthesia in models of term and post-term infants, evaluating the incidence of cell loss, physiological alterations and cognitive dysfunction. However, surprisingly few studies have investigated the effect of anesthetic exposure on outcomes in newborn rodents, the developmental equivalent of premature human infants. This is critical given that one out of every eight babies born in the United States is premature, with an increased prevalence of surgical procedures required in these individuals. Also, no studies have investigated if the genetic sex of the individual influences the response to neonatal anesthesia. Using the newborn rat as the developmental equivalent of the premature human, we documented the effect of a single bout of exposure to either the inhalant isoflurane or the injectable barbiturate phenobarbital on hippocampal anatomy, hippocampal dependent behavioral performance and normal developmental endpoints in male and female rats. While both forms of anesthesia led to significant decrements in cognitive abilities, along with a significant reduction in volume and neuron number in the hippocampus in adulthood, the decrements were significantly greater in males than in females. Interestingly, the deleterious effects of anesthesia were manifest on developmental measures including surface righting and forelimb grasp, but were not evident on basic physiological parameters including body weight or suckling. These findings point to the hazardous effects of exposure to anesthesia on the developing CNS and the particular sensitivity of males to deficits.
- Gruene TM
Sexually divergent expression of active and passive conditioned fear responses in rats
- T M Gruene
- K Flick
- A Stefano
- S D Shea
- R M Shansky
- TM Gruene
Gruene TM, Flick K, Stefano A, Shea SD, Shansky RM (2015).
Sexually divergent expression of active and passive conditioned
fear responses in rats. eLife 4: e11352.
Knobil & Neill's Physiology of Reproduction
- M M Mccarthy
- E F Rissman
McCarthy MM, Rissman EF (2014). Epigenetics of reproduction. In:
Plant TM and Zeleznik AJ (eds). Knobil & Neill's Physiology of
Reproduction, 4th edn. New York: Academic Press, pp 2439-2501.