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Sex Differences in the Healthy and Diseased Brain

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A special issue of Brain Sciences (ISSN 2076-3425).

Deadline for manuscript submissions: closed (30 June 2018) | Viewed by 109296

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Special Issue Editors

Dr. Joohyung Lee

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Guest Editor

Brain and Gender laboratory, Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia
Interests: brain sex differences; SRY; Y-chromosome; autism; Parkinson's disease; ADHD; dopamine; sex chromosome

Dr. Rachel Hill

E-Mail Website
Guest Editor

Department of Psychiatry, Monash University, Melbourne, Australia
Interests: brain sex differences; psychiatric disorders; sex steroid hormones; GABAergic interneurons

Special Issue Information

Dear Colleagues,

In 2015, the National Institutes of Health (NIH) mandated the inclusion of both sexes in most research with animals, tissues or cells. This is a welcomed development, as robust sex differences in the anatomy, physiology, and biochemistry of the healthy brain are likely to underlie the inherent sex bias in the diseased brain. For instance, females suffer more from mood disorders, such as depression and anxiety, whereas males are more susceptible to Parkinson's disease (PD), attention-deficit hyperactivity disorder (ADHD), autism, and early-onset schizophrenia. Hence, better understanding of the biology underlying brain sex differences will be vital for designing novel therapeutic agents that will have optimal effectiveness in each sex.

It is well established that many sex differences in both the development and course of neuropsychiatric and neurodegenerative disorders are attributable to sex steroids, in particular, the neuroprotective actions of the sex hormone, estradiol (R.Hill, Neuroscience and Biobehavioural Reviews 2016). However, emerging evidence indicates that the sex chromosome genes (i.e. X- and Y-linked genes) also contribute to sex differences in the health and diseased brain (Lee and Harley, 2012, Bioessays). Taken together, these studies highlight the importance of understanding the interplay between sex hormones and sex-specific genes in healthy and diseased brain.

This Special Issue, covering the influence of sex on brain structure and function in both animals and humans, will discuss the interplay between sex hormones and sex-chromosome genes in regulating brain development and function in both health and disease.

Dr. Joohyung Lee
Dr. Rachel Hill
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Brain Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Brain Sex Differences
Sex hormones
Sex chromosomes
Estrogen
Neurodegenerative disorders
Neuropsychiatric disorders

Published Papers (6 papers)

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Research

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11 pages, 2200 KiB

Open AccessArticle

A Study of Differential Resting-State Brain Functional Activity in Males and Females with Recurrent Depressive Disorder

by Jifei Sun, Shanshan Gao, Yue Ma, Chunlei Guo, Zhongming Du, Yi Luo, Limei Chen, Zhi Wang, Xiaojiao Li, Ke Xu, Yang Hong, Xue Yu, Xue Xiao and Jiliang Fang

Brain Sci. 2022, 12(11), 1508; https://doi.org/10.3390/brainsci12111508 - 06 Nov 2022

Cited by 1 | Viewed by 1371

Abstract

In this study, we observed the sex differences in functional brain activity in patients with recurrent depressive disorder (RDE) and assessed the correlation between abnormal functional brain activity changes and clinical symptoms. A total of 40 patients with RDE (19 male and 21 female) and 42 healthy controls (HCs) (20 male and 22 female) met the inclusion criteria. Analysis of images using regional homogeneity (ReHo) and further analysis of the correlation between abnormal brain areas and clinical symptoms of the different sexes with RDE groups were carried out. For the main effects of sex (male vs. female), there were statistically significant differences in ReHo among the four groups in the right middle temporal gyrus, right thalamus, and left posterior cerebellar lobe. For the effects of the sex-by-group interaction, there were statistically significant differences in ReHo among the four groups in the left middle frontal gyrus, left precentral gyrus, and right insula. Post hoc analyses showed that compared with the female RDE group, the male RDE group had decreased ReHo in the left middle frontal gyrus and right insula. In the female RDE group, the ReHo values of the left middle frontal gyrus were positively correlated with the 17-item Hamilton Rating Scale for Depression (HAMD-17) scores. This study provides new insights into the clinical targeting of different sexes for RDE. Full article

(This article belongs to the Special Issue Sex Differences in the Healthy and Diseased Brain)

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15 pages, 938 KiB

Open AccessArticle

Reelin Haploinsufficiency and Late-Adolescent Corticosterone Treatment Induce Long-Lasting and Female-Specific Molecular Changes in the Dorsal Hippocampus

by Anna Schroeder, Maarten Van den Buuse and Rachel A. Hill

Brain Sci. 2018, 8(7), 118; https://doi.org/10.3390/brainsci8070118 - 25 Jun 2018

Cited by 5 | Viewed by 4503

Abstract

Reelin depletion and stress seem to affect similar pathways including GABAergic and glutamatergic signaling and both are implicated in psychiatric disorders in late adolescence/early adulthood. The interaction between reelin depletion and stress, however, remains unclear. To investigate this, male and female heterozygous reelin mice (HRM) and wildtype (WT) controls were treated with the stress hormone, corticosterone (CORT), during late adolescence to simulate chronic stress. Glucocorticoid receptors (GR), N-methyl-d-aspartate receptor (NMDAr) subunits, glutamic acid decarboxylase (GAD₆₇) and parvalbumin (PV) were measured in the hippocampus and the prefrontal cortex (PFC) in adulthood. While no changes were seen in male mice, female HRM showed a significant reduction in GR expression in the dorsal hippocampus. In addition, CORT reduced GR levels as well as GluN2B and GluN2C subunits of NMDAr in the dorsal hippocampus in female mice only. CORT furthermore reduced GluN1 levels in the PFC of female mice. The combined effect of HRM and CORT treatment appeared to be additive in terms of GR expression in the dorsal hippocampus. Female-specific CORT-induced changes were associated with overall higher circulating CORT levels in female compared to male mice. This study shows differential effects of reelin depletion and CORT treatment on GR and NMDAr protein expression in male and female mice, suggesting that females are more susceptible to reelin haploinsufficiency as well as late-adolescent stress. These findings shed more light on female-specific vulnerability to stress and have implications for stress-associated mental illnesses with a female bias including anxiety and major depression. Full article

(This article belongs to the Special Issue Sex Differences in the Healthy and Diseased Brain)

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15 pages, 1625 KiB

Open AccessArticle

Sex Specific Alterations in α4*Nicotinic Receptor Expression in the Nucleus Accumbens

by Joan Y. Holgate, Josephine R. Tarren and Selena E. Bartlett

Brain Sci. 2018, 8(4), 70; https://doi.org/10.3390/brainsci8040070 - 19 Apr 2018

Cited by 3 | Viewed by 5074

Abstract

Background: The mechanisms leading from traumatic stress to social, emotional and cognitive impairment and the development of mental illnesses are still undetermined and consequently there remains a critical need to develop therapies for preventing the adverse consequences of traumatic stress. Research indicates nicotinic acetylcholine receptors containing α4 subunits (α4*nAChRs) are both impacted by stress and capable of modulating the stress response. In this study, we investigated whether varenicline, a partial α4β2*nAChR agonist which reduces nicotine, alcohol and sucrose consumption, can reduce stress, a driving factor in substance use disorders. We also examined the effect of stress on nucleus accumbens (NAc) α4*nAChR expression. Methods: Transgenic mice with fluorescent tags attached to α4*nAChRs were administered varenicline and/or yohimbine (a pharmacological stressor) and plasma corticosterone and NAc α4*nAChR expression were measured. A separated group of mice were exposed to maternal separation (MS) during post-natal day (P) 2–14, then restraint stressed (30 min) at six weeks of age. Body weight, anxiety-like behaviours (elevated plus maze), plasma corticosterone and NAc α4*nAChR levels were measured. Results: Varenicline attenuated yohimbine-induced plasma corticosterone increases with no effect on NAc α4*nAChR expression. MS reduced unrestrained plasma corticosterone levels in both sexes. In females, MS increased body weight and NAc α4*nAChR expression, whereas, in males, MS and restraint caused a greater change in anxiety-like behaviours and plasma corticosterone levels. Restraint altered NAc α4*nAChR expression in both male and female MS mice. Conclusions: The effects of stress on NAc α4*nAChR are sex-dependent. While varenicline attenuated acute stress-induced rises in corticosterone levels, future studies are required to determine whether varenicline is effective for relieving the effects of stress. Full article

(This article belongs to the Special Issue Sex Differences in the Healthy and Diseased Brain)

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Review

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14 pages, 235 KiB

Open AccessReview

Sex Differences and the Influence of Sex Hormones on Cognition through Adulthood and the Aging Process

by Caroline Gurvich, Kate Hoy, Natalie Thomas and Jayashri Kulkarni

Brain Sci. 2018, 8(9), 163; https://doi.org/10.3390/brainsci8090163 - 28 Aug 2018

Cited by 76 | Viewed by 9603

Abstract

Hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function have multiple effects on the development, maintenance and function of the brain. Sex differences in cognitive functioning have been reported in both health and disease, which may be partly attributed to sex hormones. The aim of the current paper was to provide a theoretical review of how sex hormones influence cognitive functioning across the lifespan as well as provide an overview of the literature on sex differences and the role of sex hormones in cognitive decline, specifically in relation to Alzheimer’s disease (AD). A summary of current hormone and sex-based interventions for enhancing cognitive functioning and/or reducing the risk of Alzheimer’s disease is also provided. Full article

(This article belongs to the Special Issue Sex Differences in the Healthy and Diseased Brain)

27 pages, 542 KiB

Open AccessReview

Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders

by Paulo Pinares-Garcia, Marielle Stratikopoulos, Alice Zagato, Hannah Loke and Joohyung Lee

Brain Sci. 2018, 8(8), 154; https://doi.org/10.3390/brainsci8080154 - 13 Aug 2018

Cited by 125 | Viewed by 81465

Abstract

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. Full article

(This article belongs to the Special Issue Sex Differences in the Healthy and Diseased Brain)

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29 pages, 738 KiB

Open AccessReview

On the Developmental Timing of Stress: Delineating Sex-Specific Effects of Stress across Development on Adult Behavior

by Anna Schroeder, Michael Notaras, Xin Du and Rachel A. Hill

Brain Sci. 2018, 8(7), 121; https://doi.org/10.3390/brainsci8070121 - 29 Jun 2018

Cited by 36 | Viewed by 6295

Abstract

Stress, and the chronic overactivation of major stress hormones, is associated with several neuropsychiatric disorders. However, clinical literature on the exact role of stress either as a causative, triggering, or modulatory factor to mental illness remains unclear. We suggest that the impact of stress on the brain and behavior is heavily dependent on the developmental timing at which the stress has occurred, and as such, this may contribute to the overall variability reported on the association of stress and mental illness. Here, animal models provide a way to comprehensively assess the temporal impact of stress on behavior in a controlled manner. This review particularly focuses on the long-term impact of stress on behavior in various rodent stress models at three major developmental time points: early life, adolescence, and adulthood. We characterize the various stressor paradigms into physical, social, and pharmacological, and discuss commonalities and differences observed across these various stress-inducing methods. In addition, we discuss here how sex can influence the impact of stress at various developmental time points. We conclude here that early postnatal life and adolescence represent particular periods of vulnerability, but that stress exposure during early life can sometimes lead to resilience, particularly to fear-potentiated memories. In the adult brain, while shorter periods of stress tended to enhance spatial memory, longer periods caused impairments. Overall, males tended to be more vulnerable to the long-term effects of early life and adolescent stress, albeit very few studies incorporate both sexes, and further well-powered sex comparisons are needed. Full article

(This article belongs to the Special Issue Sex Differences in the Healthy and Diseased Brain)

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