Sex Differences In Brain Research Articles

Asymmetry, sex differences and age-related changes in the white matter in the healthy elderly: a tract-based study

BackgroundHemispherical asymmetry, sex differences and age-related changes have been reported for the human brain. Meanwhile it was still unclear the presence of the asymmetry or sex differences in the human brain occurred whether as a normal development or as consequences of any pathological changes. The aim of this study was to investigate hemispherical asymmetry, sex differences and age-related changes by using a tract-based analysis in the nerve bundles.Methods40 healthy elderly subjects underwent magnetic resonance diffusion tensor imaging, and we calculated fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values along the major white matter bundles.ResultsWe identified hemispherical asymmetry in the ADC values for the cingulate fasciculus in the total subject set and in males, and a sex difference in the FA values for the right uncinate fasciculus. For age-related changes, we demonstrated a significant increase in ADC values with advancing age in the right cingulum, left temporal white matter, and a significant decrease in FA values in the right superior longitudinal fasciculus.ConclusionIn this study, we found hemispherical asymmetry, sex differences and age-related changes in particular regions of the white matter in the healthy elderly. Our results suggest considering these differences can be important in imaging studies.

Development of Brain and Behavior in Birds

ABSTRACT Sex differences in brain and behavior are widespread across vertebrates. Birds exhibit remarkable examples of these types of parallels between structure and function. For example, only male zebra finches sing, and the brain areas and muscles controlling the learning and production of these vocalizations are greatly enhanced in males compared to females. These sex differences are permanently established in development. Some songbirds, unlike zebra finches, change their songs seasonally. In a number of these species, the brain regions exhibit changes in neuron loss and incorporation across these periods. The mechanisms involved in these types of sexual differentiation and adult plasticity are described—they likely involve both steroid hormones and genetic (protein) factors. The strength of the relationships between morphology and behavior, as well as many other factors, has made birds outstanding models for the investigation of numerous functions. These include the mechanisms regulating vocal learn...

Gestational Exposure to Low Dose Bisphenol A Alters Social Behavior in Juvenile Mice

Bisphenol A (BPA) is a man-made compound used to make polycarbonate plastics and epoxy resins; public health concerns have been fueled by findings that BPA exposure can reduce sex differences in brain and some behaviors. We asked if a low BPA dose, within the range measured in humans, ingested during pregnancy, would affect social behaviors in prepubertal mice. We noted sex differences in social interactions whereby females spent more time sitting side-by-side, while males engaged in more exploring and sitting alone. In addition BPA increased display of nose-to-nose contacts, play solicitations and approaches in both sexes. Interactions between sex and diet were found for self grooming, social interactions while sitting side-by-side and following the other mouse. In all these cases interactions were produced by differences between control and BPA females. We examined brains from embryos during late gestation to determine if gene expression differences might be correlated with some of the sexually dimorphic or BPA affected behaviors we observed. Because BPA treatments ended at birth we took the brains during embryogenesis to increase the probability of discovering BPA mediated effects. We also selected this embryonic age (E18.5) because it coincides with the onset of sexual differentiation of the brain. Interestingly, mRNA for the glutamate transporter, Slc1a1, was enhanced by exposure to BPA in female brains. Also we noted that BPA changed the expression of two of the three DNA methyltransferase genes, Dnmt1 and Dnmt3a. We propose that BPA affects DNA methylation of Sc1a1 during neural development. Sex differences in juvenile social interactions are affected by BPA and in particular this compound modifies behavior in females.

Gonadal and Nongonadal Regulation of Sex Differences in Hypothalamic Kiss1 Neurones

The brains of males and females differ anatomically and physiologically, including sex differences in neurone size or number, synapse morphology and specific patterns of gene expression. Brain sex differences may underlie critical sex differences in physiology or behaviour, including several aspects of reproduction, such as the timing of sexual maturation (earlier in females than males) and the ability to generate a preovulatory gonadotrophin surge (in females only). The reproductive axis is controlled by afferent pathways that converge upon forebrain gonadotrophin-releasing hormone (GnRH) neurones, but GnRH neurones are not sexually dimorphic. Although most reproductive sex differences probably reflect sex differences in the upstream circuits and factors that regulate GnRH secretion, the key sexually-dimorphic factors that influence reproductive status have remained poorly defined. The recently-identified neuropeptide kisspeptin, encoded by the Kiss1 gene, is an important regulator of GnRH secretion, and Kiss1 neurones in rodents are sexually dimorphic in specific hypothalamic populations, including the anteroventral periventricular nucleus-periventricular nucleus continuum (AVPV/PeN) and the arcuate nucleus (ARC). In the adult AVPV/PeN, Kiss1 neurones are more abundant in females than males, representing a sex difference that is regulated by oestradiol signalling during critical periods of postnatal and pubertal development. By contrast, Kiss1 neurones in the ARC are not sexually differentiated in adult rodents but, in mice, the regulation of ARC Kiss1 cells by gonadal hormone-independent factors is sexually dimorphic during prepubertal development. These various sex differences in hypothalamic Kiss1 neurones may relate to known sex differences in reproductive physiology, such as puberty onset and positive feedback.

Sex Differences in Epigenetic Regulation of the Estrogen Receptor-α Promoter within the Developing Preoptic Area

Sex differences in the brain are largely organized by a testicular hormone surge that occurs in males shortly after birth. Although this hormone surge is transient, sex differences in brain and behavior are lasting. Here we describe a sex difference in DNA methylation of the estrogen receptor-alpha (ERalpha) promoter region within the developing rat preoptic area, with males exhibiting more DNA methylation within the ERalpha promoter than females. More importantly, we report that simulating maternal grooming, a form of maternal interaction that is sexually dimorphic with males experiencing more than females during the neonatal period, effectively masculinizes female ERalpha promoter methylation and gene expression. This suggests natural variations in maternal care that are directed differentially at males vs. females can influence sex differences in the brain by creating sexually dimorphic DNA methylation patterns. We also find that the early estradiol exposure may contribute to sex differences in DNA methylation patterns. This suggests that early social interaction and estradiol exposure may converge at the genome to organize lasting sex differences in the brain via epigenetic differentiation.

Hormonal effects on the plasticity of cognitive brain functions.

Sex hormones have powerful neuronal actions in the brain and affect the interaction between functionally linked cortical areas within and across cerebral hemispheres, probably via their neuromodulatory properties on gamma-aminobutyric acid and glutamate receptors. Menstrual cycle-related dynamic fluctuations in functional cerebral asymmetries and interhemispheric crosstalk have been shown to be a useful experimental model to investigate the activating effects of sex hormones on cognitive brain functions, particularly those of estradiol and progesterone. Besides a better understanding of sex hormonal effects on cognitive brain functions, this research may significantly contribute to addressing the question of whether sex differences in cognitive brain functioning truly exist and where they originate from. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website.

Sex differences and neuroethics

Discussions in neuroethics to date have ignored an ever-increasing neuroscientific lilterature on sex differences in brains. If, indeed, there are significant differences in the brains of men versus women and in the brains of boys versus girls, the ethical and social implications loom very large. I argue that recent neuroscientific findings on sex-based brain differences have significant implications for theories of morality and for our understandings of the neuroscience of moral cognition and behavior.

Digital morphometric study of the extrasulcal surface of the cingulate gyrus in man

The frequency of different morphological types and extrasulcal (visible) surface area of the cingulate gyrus, were measured and analysed in order to obtain more precise data about morphology, right/left and sex differences in the human brain. The study included 42 brains (84 hemispheres) from persons of both sexes and of different age (26 males, 16 females, 20-65 years old), without neuropathological changes. After fixation in 10% formaline (3-4 weeks) and removal of meninges the brains were photographed under standard conditions by digital camera. Following determination of morphological type, regions of interest of cingulate gyrus were determined in stereotactic system system of coordinates and the extrasulcal surface was measured by digital AutoCAD planimetry. Three basic morphological types of cingulate gyrus were found: the continuous type (34.5%), segmented type (35.7%) and double paralel type (29.8%). There was no statistically significant difference in the frequency of morphological types related to the side (right/left) or sex (p 0.05). The area of extrasulcal cortex of cingulate gyrus was statistically significantly (p < 0.05) larger on the left hemispheres (for 1.13 cm) than on the right (left: 14.58 cm; right: 13.45 cnm. 7he extrasulcal surface of the left cingulate gyrus was significantly larger (p 0 .05) in males (males 15.9 cm; females - 13.6 cm), while for the right cingulate gyrus this difference was not significant. Morphometry indicated sex and right/left differences of extrasulcal surface area of the human cingulate gyrus. However, the morphological analysis itself did not indicate corresponding differences, suggesting complexity of the problem of sex dimorphism and of right/left asymmetries in the domain of limbic cortex.

A developmental sex difference in hippocampal neurogenesis is mediated by endogenous oestradiol

BackgroundOestradiol is a steroid hormone that exerts extensive influence on brain development and is a powerful modulator of hippocampal structure and function. The hippocampus is a critical brain region regulating complex cognitive and emotional responses and is implicated in the aetiology of several mental health disorders, many of which exhibit some degree of sex difference. Many sex differences in the adult rat brain are determined by oestradiol action during a sensitive period of development. We had previously reported a sex difference in rates of cell genesis in the developing hippocampus of the laboratory rat. Males generate more new cells on average than females. The current study explored the effects of both exogenous and endogenous oestradiol on this sex difference.MethodsNew born male and female rat pups were injected with the mitotic marker 5-bromo-2-deoxyuridine (BrdU) and oestradiol or agents that antagonize oestradiol action. The effects on cell number, proliferation, differentiation and survival were assessed at several time points. Significant differences between groups were determined by two- or thee-Way ANOVA.ResultsNewborn males had higher rates of cell proliferation than females. Oestradiol treatment increased cell proliferation in neonatal females, but not males, and in the CA1 region many of these cells differentiated into neurons. The increased rate of proliferation induced by neonatal oestradiol persisted until at least 3 weeks of age, suggesting an organizational effect. Administering the aromatase inhibitor, formestane, or the oestrogen receptor antagonist, tamoxifen, significantly decreased the number of new cells in males but not females.ConclusionEndogenous oestradiol increased the rate of cell proliferation observed in newborn males compared to females. This sex difference in neonatal neurogenesis may have implications for adult differences in learning strategy, stress responsivity or vulnerability to damage or disease.

Prenatal sex differences in the human brain

In recent times, major advances have been made towards understanding sexual dimorphism in the brain on a molecular basis. This thesis summarises my modest contributions to these endeavours. Sexual dimorphisms are manifested throughout the spectrum of biological complexity, and can be studied by numerous approaches. The approach of this thesis is to explore sex-biased gene expression in mammalian somatic tissues. Paper I describes an evolutionarily conserved sexual gene expression pattern in the primate brain. Conserved sex-biased genes may underlie important sex differences in neurobiology. In Paper II, Y-chromosome genes expressed across several regions of the human male brain during mid-gestation are identified. Such genes may play male-specific roles during brain development. The studies of Papers III and IV explore sex-biased gene expression in several somatic tissues from mouse. The amount of genes with sex-biased expression varied in different brain regions. The striatum was particularly interesting, with an order of magnitude increase in the number of sex-biased genes as compared to the other included brain regions. Of potentially wider significance are my observations regarding the transcriptional regulation of domains that escape X-chromosome inactivation (XCI). Specifically, I provide the first evidence that long non-coding RNAs (lncRNAs) transcribe together with protein-coding genes in XCI-escaping domains. This raises the possibility that lncRNAs mediate the transcriptional regulation of XCI-escaping domains. I also present evidence that the mouse X-chromosome has undergone both feminisation and de-masculinisation during evolution, as indicated by the sex-skewed regulation of genes on this chromosome. This finding is relevant for understanding the selective forces that shaped the mammalian X-chromosome. In the final chapter, Paper V, the generation of a novel transgenic mouse line, Gpr101-Cre, is described. Its progeny can be used for functional studies of striatum, a brain structure with major sexual dimorphism, as is further demonstrated in the Papers of this thesis.

The Epigenetics of Sex Differences in the Brain: Figure 1.

Epigenetic changes in the nervous system are emerging as a critical component of enduring effects induced by early life experience, hormonal exposure, trauma and injury, or learning and memory. Sex differences in the brain are largely determined by steroid hormone exposure during a perinatal sensitive period that alters subsequent hormonal and nonhormonal responses throughout the lifespan. Steroid receptors are members of a nuclear receptor transcription factor superfamily and recruit multiple proteins that possess enzymatic activity relevant to epigenetic changes such as acetylation and methylation. Thus steroid hormones are uniquely poised to exert epigenetic effects on the developing nervous system to dictate adult sex differences in brain and behavior. Sex differences in the methylation pattern in the promoter of estrogen and progesterone receptor genes are evident in newborns and persist in adults but with a different pattern. Changes in response to injury and in methyl-binding proteins and steroid receptor coregulatory proteins are also reported. Many steroid-induced epigenetic changes are opportunistic and restricted to a single lifespan, but new evidence suggests endocrine-disrupting compounds can exert multigenerational effects. Similarly, maternal diet also induces transgenerational effects, but the impact is sex specific. The study of epigenetics of sex differences is in its earliest stages, with needed advances in understanding of the hormonal regulation of enzymes controlling acetylation and methylation, coregulatory proteins, transient versus stable DNA methylation patterns, and sex differences across the epigenome to fully understand sex differences in brain and behavior.

Sexual Dimorphism of the Human Brain: Myth and Reality

Many neuroanatomical sex differences have been identified in both animals and humans, which may form the neural bases for sex-specific behavior and reproductive as well as non-reproductive functions. The present essay gives a brief review of the findings on sex differences in the human brain. Our observations on the human hypothalamus revealed that the shape of the suprachiasmatic nucleus (SCN)--a structure involved in the regulation of circadian rhythms and reproductive cycles--is elongated in females and more spherical in males. In addition, an extremely large SCN was observed in the brains of homosexual men who died from AIDS. Both the volume of the SCN and the number of vasopressin neurons were about twice as large as in a male reference group. In contrast to the SCN, in which only shape differences were found in relation to gender, the volume and cell number of the sexually dimorphic nucleus of the preoptic area (SDN-POA) showed a marked sexual dimorphism. The mean volume of the SDN-POA was 2.2 times larger in males than in females and contained about twice as many cells. The function of this sexually dimorphic area in humans is not known, but presumably it is involved in the control of male sexual behavior. The fact that no differences in either volume or cell number were observed between the SDN-POAs of homo- and heterosexual men indicates a selectivity of the SCN in this respect and contradicts the view that male homosexuals have a 'female' hypothalamus.

Brain Sex Differences and the Organisation of Juvenile Social Play Behaviour

Juvenile social play behaviour is one of the earliest forms of non-mother directed social behaviour in rodents. Juvenile social play behaviour is sexually dimorphic, with males exhibiting higher levels compared to females, making it a useful model to study both social development and sexual differentiation of the brain. As with most sexually dimorphic behaviour, juvenile play behaviour is organised by neonatal steroid hormone exposure. The developmental organisation of juvenile play behaviour also appears to be influenced by the early maternal environment. This review will focus briefly on why and how rats play, some brain regions controlling play behaviour, and how neurotransmitters and the social environment converge within the developing brain to influence sexual differentiation of juvenile play behaviour.

Back to the future: The organizational–activational hypothesis adapted to puberty and adolescence

Phoenix, Goy, Gerall, and Young first proposed in 1959 the organizational–activational hypothesis of hormone-driven sex differences in brain and behavior. The original hypothesis posited that exposure to steroid hormones early in development masculinizes and defeminizes neural circuits, programming behavioral responses to hormones in adulthood. This hypothesis has inspired a multitude of experiments demonstrating that the perinatal period is a time of maximal sensitivity to gonadal steroid hormones. However, recent work from our laboratory and others demonstrates that steroid-dependent organization of behavior also occurs during adolescence, prompting a reassessment of the developmental time-frame within which organizational effects are possible. In addition, we present evidence that adolescence is part of a single protracted postnatal sensitive period for steroid-dependent organization of male mating behavior that begins perinatally and ends in late adolescence. These findings are consistent with the original formulation of the organizational/activational hypothesis, but extend our notions of what constitutes “early” development considerably. Finally, we present evidence that female behaviors also undergo steroid-dependent organization during adolescence, and that social experience modulates steroid-dependent adolescent brain and behavioral development. The implications for human adolescent development are also discussed, especially with respect to how animal models can help to elucidate the factors underlying the association between pubertal timing and adult psychopathology in humans.

Brain Sex Differences and Hormone Influences: A Moving Experience?

Sex differences in the nervous system come in many forms. Although a majority of sexually dimorphic characteristics in the brain have been described in older animals, mechanisms that determine sexually differentiated brain characteristics often operate during critical perinatal periods. Both genetic and hormonal factors likely contribute to physiological mechanisms in development to generate the ontogeny of sexual dimorphisms in brain. Relevant mechanisms may include neurogenesis, cell migration, cell differentiation, cell death, axon guidance and synaptogenesis. On a molecular level, there are several ways to categorize factors that drive brain development. These range from the actions of transcription factors in cell nuclei that regulate the expression of genes that control cell development and differentiation, to effector molecules that directly contribute to signalling from one cell to another. In addition, several peptides or proteins in these and other categories might be referred to as 'biomarkers' of sexual differentiation with undetermined functions in development or adulthood. Although a majority of sex differences are revealed as a direct consequence of hormone actions, some may only be revealed after genetic or environmental disruption. Sex differences in cell positions in the developing hypothalamus, and steroid hormone influences on cell movements in vitro, suggest that cell migration may be one target for early molecular actions that impact brain development and sexual differentiation.

Sexual differentiation of the zebra finch song system: potential roles for sex chromosome genes

BackgroundRecent evidence suggests that some sex differences in brain and behavior might result from direct genetic effects, and not solely the result of the organizational effects of steroid hormones. The present study examined the potential role for sex-biased gene expression during development of sexually dimorphic singing behavior and associated song nuclei in juvenile zebra finches.ResultsA microarray screen revealed more than 2400 putative genes (with a false discovery rate less than 0.05) exhibiting sex differences in the telencephalon of developing zebra finches. Increased expression in males was confirmed in 12 of 20 by qPCR using cDNA from the whole telencephalon; all of these appeared to be located on the Z sex chromosome. Six of the genes also showed increased expression in one or more of the song control nuclei of males at post-hatching day 25. Although the function of half of the genes is presently unknown, we have identified three as: 17-beta-hydroxysteroid dehydrogenase type IV, methylcrotonyl-CoA carboxylase, and sorting nexin 2.ConclusionThe data suggest potential influences of these genes in song learning and/or masculinization of song system morphology, both of which are occurring at this developmental stage.

Sex Differences in Brain and Plasma β-Endorphin Content following Testosterone, Dihydrotestosterone and Estradiol Administration to Gonadectomized Rats

Aims: The present study aims at evaluating the effect of a 2-week treatment with testosterone (T), dihydrotestosterone (DHT) and estradiol valerate (E₂V) on brain and plasma β-endorphin (β-END) concentrations in gonadectomized rats of both sexes. Methods: Eight groups of female and 8 groups of male Wistar rats were included. For each sex, 1 group of gonad-intact and 1 group of gonadectomized rats were employed as controls (placebo). The other groups received subcutaneous T at the doses of 10 and 100 μg/kg/day (female rats) or 1 and 5 mg/kg/day (male rats). Subcutaneous DHT was administered at the doses of 1, 10, 100 μg/kg/day (female rats) or 0.1, 1 and 5 mg/kg/day (male rats). E₂V was administered subcutaneously at 0.05 mg/kg/day. β-END levels were measured in different brain areas and plasma. Results: Ovariectomy (OVX) induced a significant decrease in β-END in all brain areas analyzed as well as in plasma. Orchidectomy (OCX) reduced opioid concentration in the hypothalamus, anterior pituitary and neurointermediate lobe. In OVX rats, T replacement as well as E₂V significantly increased β-END concentration in all brain areas and in plasma. In the OCX group, T and E₂V did not influence β-END concentrations in different hypothalamic areas. However, they produced a significant rise in β-END levels in the hypothalamus, neurointermediate lobe, anterior pituitary and plasma. Conversely, DHT replacement did not affect β-END levels at any dose administered, either in males or females. Conclusions: The sensitivity of the endogenous opiatergic system to T administration seems to be sex-related. This effect is particularly evident in the brains of female animals where this endogenous endorphin elicits a much greater response than it does in males that have undergone gonadal steroid depletion and subsequent T replacement.

Spatial working memory in Wistar rats: Brain sex differences in metabolic activity

Several works have shown that males and females differ in the ability to learn spatial locations in mazes. In this study, we used the Morris water maze to assess the acquisition of a spatial working memory (WM) task in adult male and female Wistar rats. The task consisted of a paired sample procedure made up of two daily identical trials, sample and retention. To study the oxidative metabolic activity of some brain limbic system regions after the WM task, we applied the cytochrome oxidase (COx) histochemistry. In addition to the experimental groups, free swimming control groups and untrained naïve groups were added to explore the COx changes not specific to the learning process. Similar spatial performances were found between sexes as only one more sample and retention trials were needed in males to reduce the escape latencies significantly. Males showed decreased COx activity as compared to control groups in the medial prefrontal cortex (prelimbic and infralimbic regions) as well as in the lateral septum and dentate gyrus. Regarding females, an increase in COx activity was found in nucleus accumbens, ventral tegmental area and supramammillary region in relation to control groups. Overall, these findings suggest that the acquisition of the spatial WM task is mediated by different subsystems in a sex-dependent manner that points to the hippocampus as the central structure in males whereas other structures would be central in females.

Regulation of progestin receptors in medial amygdala: Estradiol, phytoestrogens and sex

Exposure to estrogens during critical developmental periods and in adulthood affects sex differences in the brain. We examined the roles of estradiol (E2) and phytoestrogens, and their interactions, on potential sex differences in brain. We used aromatase knockout (ArKO) mice, which cannot produce endogenous estrogens, along with wild type (WT) littermates. Mice were gestated, raised and maintained on a diet either rich in phytoestrogens or a diet virtually void of soy-derived phytoestrogens. Adult males and females were gonadectomized and received implants filled with 17-β-estradiol to induce progestin receptors (PR), while controls received empty implants. Mice were sacrificed five days later and brain sections containing the posterodorsal medial amygdala (MePD) were processed for PR immunoreactivity. Activation of sex differences in PR required adult E2 treatment. A diet high in phytoestrogens was required for expression of sex differences in PR after E2 treatment. Our data underscore the important contribution of dietary phytoestrogens for the development of sex differences in PR-ir in the adult mouse medial amygdala. We hypothesize that both aromatization of androgens to estrogens and dietary sources of additional estrogens are part of the normal requirement for sex differences in the rodent brain.

Associative learning enhances the survival of new neurons in the male and female hippocampus

Event Abstract Back to Event Associative learning enhances the survival of new neurons in the male and female hippocampus Christina Dalla1, 2* and Tracey J. Shors2 1 Medical School, University of Athens, Department of Pharmacology, Greece 2 Rutgers University, Department of Psychology and Centre for Neurosciences, United States Two decades ago, it was discovered that certain areas of the adult brain give birth to new neurons, a phenomenon called adult neurogenesis. Research in animals has shown that many of these new cells die within a few weeks, unless the animals learn certain types of complex tasks or are living in an enriched environment. Studies from our lab have shown that new cells in the hippocampus, a brain region involved in learning and memory, are more likely to survive if the animals learn a type of task that is difficult to learn. Specifically, learning during an associative task, which depends on the hippocampus (i.e. trace eyeblink conditioning), increases the survival of new cells that were generated in the hippocampus one week before the training experience [1, 2]. On the other hand, training with delay conditioning, which does not depend on the hippocampus and it is easier to learn, does not enhance the survival of the new cells. This phenomenon was first described for male rats, but it was recently confirmed in females [3]. Interestingly, females learn better than males when they are trained to associate stimuli across time, such as during the trace eyeblink conditioning task. As a consequence, more new neurons per unit volume remain in their hippocampus than in males. Furthermore, in individual animals of both sexes, the number of surviving cells correlates positively with asymptotic performance; those that express more learned responses retain more new neurons. However, animals that learn very well retain even more new cells if they require many trials to do so. Once rescued from death, most of the new cells differentiate into neurons, which become functionally integrated into the existing circuitry of the hippocampus. These new cells might be important for new learning experience or for memory. Furthermore, data on males and females suggest that sex differences in learning can contribute to structural sex differences in the adult brain. This work was supported by National Institutes of Health and National Science Foundation grants to T. J. Shors and a Marie Curie International Fellowship to C. Dalla, within the 6th European Community Framework Programme.