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"Brain -- Sex differences"
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Man and woman : an inside story
\"The saga of sex differences in brain and behavior begins with a tiny sperm swimming toward a huge egg, to contribute its tiny Y chromosome plus its copies of the other chromosomes. Genetic, anatomic and physiologic alterations in the male ensue, making his brain and behavior different in specific respects from his sister. Brain-wise, specific cell groups develop differently in males compared to females, in some cases right after birth and in other cases at puberty. But genetics and neuroanatomy do not dominate the scene. Prenatal stress, postnatal stress and lousy treatment at puberty all can affect males and females in different ways. The upshot of all these genetic and environmental factors produces small sex differences in certain abilities and huge sex differences in feelings, in pain and in suffering. Put this all together and the reader will see that biological and cultural influences on gender roles operate at so many different levels to influence behavioral mechanisms that gender role choices are flexible, reversible and non-dichotomous, especially in modern societies.\"--Book jacket.
Book
Sex differences in the brain : from genes to behavior
Sex is a fundamentally important biological variable. Recent years have seen significant progress in the integration of sex in many aspects of basic and clinical research, including analyses of sex differences in brain function. Significant advances in the technology available for studying the endocrine and nervous systems are now coupled with a more sophisticated awareness of the interconnections of these two communication systems of the body. A thorough understanding of the current knowledge, conceptual approaches, methodological capabilities, and challenges is a prerequisite to continued progress in research and therapeutics in this interdisciplinary area. This book provides scientists with the basic tools for investigating sex differences in brain and behavior, and insight into areas where important progress in understanding physiologically relevant sex differences has already been made. The book is arranged in three parts. The first part of the book introduces the study of sex differences in the brain, with an overview of how the brain, stress systems, and pharmacogenetics differ in males and females and how this information is important for the study of behavior and neurobiology of both genders. The second part presents examples of sex differences in neurobiology and behavior from both basic and clinical research perspectives, covering both humans and nonhuman animals. The final part discusses sex differences in the neurobiology of disease and neurological disorders.
eBook
Gender identification based on human brain structural MRI with a multi-layer 3D convolution extreme learning machine
Previous group-level neuroimaging studies have shown significant gender differences in the human brain. Research on sex-specific brain differences in healthy individuals is an important base for understanding sex-specific expression in psychiatric disorders. This study proposes a multi-layer 3D convolution extreme learning machine (MCN-ELM) to classify male and female brains based on structural MRI (sMRI) grey matter (GM) data scans from human connectome projects (HCP) of 876 healthy adults (491 females). First, the authors extracted multi-scale features by three-scale multi-layer 3D convolution neural networks (CNNs) without fine-tuning the parameters of convolution kernels. Then, they pulled the network output feature maps into a vector as separate ELMs. By voting on the three-scale networks, the MCN-ELM algorithm classifies male and female brains with an accuracy of 98.06% through a 10-fold cross-validation strategy, outperforming other state-of-the-art algorithms. The proposed method may be used to understand other brain diseases. Additionally, the results show that the human brain can be categorised into two distinct classes, male and female brains, suggesting it is better to treat men and women separately when researching psychiatric disorders.
Journal Article
Sex-specific neuroprotection by inhibition of the Y-chromosome gene, SRY, in experimental Parkinson’s disease
Parkinson’s disease (PD) is a debilitating neurodegenerative disorder caused by the loss of midbrain dopamine (DA) neurons. While the cause of DA cell loss in PD is unknown, male sex is a strong risk factor. Aside from the protective actions of sex hormones in females, emerging evidence suggests that sex-chromosome genes contribute to the male bias in PD. We previously showed that the Y-chromosome gene, SRY, directly regulates adult brain function in males independent of gonadal hormone influence. SRY protein colocalizes with DA neurons in the male substantia nigra, where it regulates DA biosynthesis and voluntary movement. Here we demonstrate that nigral SRY expression is highly and persistently up-regulated in animal and human cell culture models of PD. Remarkably, lowering nigral SRY expression with antisense oligonucleotides in male rats diminished motor deficits and nigral DA cell loss in 6-hydroxydopamine (6-OHDA)-induced and rotenone-induced rat models of PD. The protective effect of the SRY antisense oligonucleotides was associated with male-specific attenuation of DNA damage, mitochondrial degradation, and neuroinflammation in the toxin-induced rat models of PD. Moreover, reducing nigral SRY expression diminished or removed the male bias in nigrostriatal degeneration, mitochondrial degradation, DNA damage, and neuroinflammation in the 6-OHDA rat model of PD, suggesting that SRY directly contributes to the sex differences in PD. These findings demonstrate that SRY directs a previously unrecognized male-specific mechanism of DA cell death and suggests that suppressing nigral Sry synthesis represents a sex-specific strategy to slow or prevent DA cell loss in PD.
Journal Article
Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders
Males and females sometimes significantly differ in their propensity to develop neurological disorders. Females suffer more from mood disorders such as depression and anxiety, whereas males are more susceptible to deficits in the dopamine system including Parkinson’s disease (PD), attention-deficit hyperactivity disorder (ADHD) and autism. Despite this, biological sex is rarely considered when making treatment decisions in neurological disorders. A better understanding of the molecular mechanism(s) underlying sex differences in the healthy and diseased brain will help to devise diagnostic and therapeutic strategies optimal for each sex. Thus, the aim of this review is to discuss the available evidence on sex differences in neuropsychiatric and neurodegenerative disorders regarding prevalence, progression, symptoms and response to therapy. We also discuss the sex-related factors such as gonadal sex hormones and sex chromosome genes and how these might help to explain some of the clinically observed sex differences in these disorders. In particular, we highlight the emerging role of the Y-chromosome gene, SRY, in the male brain and its potential role as a male-specific risk factor for disorders such as PD, autism, and ADHD in many individuals.
Journal Article
Microglia Activation in the Midbrain of the Human Neonate: The Effect of Perinatal Hypoxic-Ischemic Injury
Abstract
Perinatal hypoxia-ischemia (PHI) is a major risk factor for the development of neuropsychiatric deficits later in life. We previously reported that after prolonged PHI, the dopaminergic neurons of the human neonate showed a dramatic reduction of tyrosine hydroxylase (TH) in the substantia nigra, without important signs of neuronal degeneration despite the significant reduction in their cell size. Since microglia activation could precede neuronal death, we now investigated 2 microglia activation markers, ionized calcium-binding adapter molecule 1 (Iba1), and the phagocytosis marker Cd68. The highest Iba1 immunoreactivity was found in neonates with neuropathological lesions of severe/abrupt PHI, while the lowest in subjects with moderate/prolonged or older PHI. Subjects with very severe/prolonged or chronic PHI showed an increased Iba1 expression and very activated microglial morphology. Heavy attachment of microglia on TH neurons and remarkable expression of Cd68 were also observed indicating phagocytosis in this group. Females appear to express more Iba1 than males, suggesting a gender difference in microglia maturation and immune reactivity after PHI insult. PHI-induced microglial “priming” during the sensitive for brain development perinatal/neonatal period, in combination with genetic or other epigenetic factors, could predispose the survivors to neuropsychiatric disorders later in life, possibly through a sexually dimorphic way.
Journal Article
Prediction of brain sex from EEG: using large-scale heterogeneous dataset for developing a highly accurate and interpretable ML model
•The deep convolutional neural networks (DCNN) outperform all previous results in the sex prediction task from EEG data•With DCNN, the accuracy of sex prediction from EEG can match the level of sex prediction from fMRI•There is a need for continued improvement in DCNN-based feature interpretation.
This study presents a comprehensive examination of sex-related differences in resting-state electroencephalogram (EEG) data, leveraging two different types of machine learning models to predict an individual's sex. We utilized data from the Two Decades-Brainclinics Research Archive for Insights in Neurophysiology (TDBRAIN) EEG study, affirming that gender prediction can be attained with noteworthy accuracy. The best performing model achieved an accuracy of 85% and an ROC AUC of 89%, surpassing all prior benchmarks set using EEG data and rivaling the top-tier results derived from fMRI studies. A comparative analysis of LightGBM and Deep Convolutional Neural Network (DCNN) models revealed DCNN's superior performance, attributed to its ability to learn complex spatial-temporal patterns in the EEG data and handle large volumes of data effectively. Despite this, interpretability remained a challenge for the DCNN model. The LightGBM interpretability analysis revealed that the most important EEG features for accurate sex prediction were related to left fronto-central and parietal EEG connectivity. We also showed the role of both low (delta and theta) and high (beta and gamma) activity in the accurate sex prediction. These results, however, have to be approached with caution, because it was obtained from a dataset comprised largely of participants with various mental health conditions, which limits the generalizability of the results and necessitates further validation in future studies. . Overall, the study illuminates the potential of interpretable machine learning for sex prediction, alongside highlighting the importance of considering individual differences in prediction sex from brain activity.
Journal Article
Therapeutic Potential of Edaravone for Neuroprotection Following Global Cerebral Hypoxia
Global cerebral hypoxia triggers (mal-)adaptive responses that can lead to neuronal damage. This study evaluated edaravone’s neuroprotective effects in a rat hypoxia model, focusing on sex differences, treatment durations, and behavioral outcomes. Male and female rats underwent global cerebral hypoxia induced by rocuronium, with post-hypoxia edaravone treatment. Motor coordination and activity were assessed through exploratory behavior tests. Histological analyses evaluated neuronal integrity and apoptosis, while microglial activity and gene expression were analyzed via immunofluorescence and qPCR. Edaravone showed transient neuroprotective effects on motor behavior and early immune responses, particularly in the cerebellum and hippocampus. No gross morphological damage was observed, though functional impairments occurred despite preserved cytoarchitecture. Microglial activity was initially suppressed in treated and later activated in untreated hypoxic brains, suggesting modulating immune responses. Gene expression analysis revealed region-specific, time-dependent, and sex-specific changes, including early upregulation of CCR7, S100B, and NSE in treated animals. Males were more susceptible to hypoxic damage, while females showed higher baseline resistance and better functional recovery. Seven-day edaravone treatment increased apoptotic markers in male cerebellum, indicating sex-specific differences in cell death mechanisms. These findings highlight the potential for personalized therapy and underscore the importance of considering sex differences in both research and clinical practice.
Journal Article
Perils and pitfalls of reporting sex differences
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.
Journal Article
Endogenous Sex Steroids Dampen Neuroinflammation and Improve Outcome of Traumatic Brain Injury in Mice
The role of biological sex in short-term and long-term outcome after traumatic brain injury (TBI) remains controversial. The observation that exogenous female sex steroids (progesterone and estrogen) reduce brain injury coupled with a small number of clinical studies showing smaller injury in women suggest that sex steroids may play a role in outcome from TBI. We used the controlled cortical impact (CCI) model of TBI in mice to test the hypothesis that after CCI, female mice would demonstrate less injury than male mice, related to the protective role of endogenous steroids. Indeed, adult females exhibit histological protection (3.7 ± 0.5 mm3) compared to adult male mice (6.8 ± 0.6 mm3), and females that lacked sex steroids (ovex) showed increased injury compared to intact females. Consistent with histology, sensorimotor deficits measured as reduced contralateral limb use were most pronounced in male mice (31.9 ± 6.9% reduced limb use) compared to a 12.7 ± 3.8% reduction in female mice. Ovex mice exhibited behavioral deficits similar to males (31.5 ± 3.9% reduced limb use). Ovex females demonstrated increased microglial activation relative to intact females in both the peri-injury cortex and the reticular thalamic nucleus. Ovex females also demonstrated increased astrogliosis in comparison to both females and males in the peri-injury cortex. These data indicate that female sex steroids reduce brain sensitivity to TBI and that reduced acute neuroinflammation may contribute to the relative protection observed in females.
Journal Article