Sex differences in mechanisms of disease

Nearly every known mental illness and neurological disorder afflicts both men and women, but very few affect them at equal rates. These discrepancies in disease prevalence suggest that biological sex may contribute to a person's risk and etiology of a given disorder, and therefore, understanding the influence of sex on disease mechanisms is critical for preclinical research. The articles in this issue—the second of two G2B Special Issues on sex differences—work toward this exact goal. Covering research in rodents and humans and topics ranging from maternal care, stress, substance abuse and Alzheimer's models, we offer a diverse look at the many ways in which sex, genetics and experience interact to shape brain health. Common to the emergence of many mental illnesses is exposure to stress, and sex differences in how stress impacts the brain likely contribute to sex-dependent outcomes in disease risk, symptoms and recovery. Two reviews on this topic lead the issue. First, Shaw et al examine one of the most stress-sensitive developmental periods, adolescence. They focus on the prefrontal cortex, which continues to mature throughout adolescence, undergoing critical windows of structural plasticity in both gray and white matter. That these key periods of synaptic pruning and myelination coincide with puberty provides a perfect opportunity for stress to elicit long-term, sexually divergent effects on brain structure, function and health. The authors pull from both human and rodent literature to describe the current state of evidence for these sex-dependent outcomes, drawing connections to the development of mental illness and neurological disorders. In the second review, Brivio et al take a brain-wide look at sexual dimorphism in stress-induced gene expression in both clinical populations and animal studies. They discuss the complex factors that can contribute to observed alterations in gene transcription, including stress modality, timing and experimental techniques used. They also provide exceptionally useful tables that outline acute and chronic stress effects on the expression of dozens of genes, broken down by animal sex and strain, brain region and type of stressor—a fantastic resource for our readers. Women are particularly susceptible to mood and anxiety disorders, and several research papers in this issue identify potential mechanisms underlying this imbalance. Kreutzmann et al report that previous exposure to foot shock stress improves safety learning in male mice, but not females, an effect that was dependent on neuropeptide S. In a new mouse model of stress-induced binge eating, females exhibited increased binging after a “frustration stress” experience, while poststress eating in males stayed constant. Stress can also lead to reinstatement of drug-seeking behavior, an effect observed equally in male and female mice. However, Lee et al show that the ability of the drug guanfacine to prevent stress-induced reinstatement of nicotine-seeking behavior in a conditioned place preference test depends on a novel interaction between sex and individual animals' preferred test chamber at baseline, suggesting a role for sexdependent context processing in the likelihood of substance abuse treatments being successful. Other aspects of addiction—such as substance type, age of initiation, and abuse trajectories—have clear sex and gender differences, suggesting a need for sex-specific evaluation of addiction mechanisms. In a thoughtful review of both clinical and preclinical evidence, Datta et al argue that parallel genomic studies in human and model organisms represent a promising investigative strategy toward this end. Finally, a review by Booher et al explores the current literature on exercise as an ameliorative agent in animal models of alcohol use disorder. Although the vast majority of this work has been carried out only in male mice and rats, the studies that were conducted on both sexes suggest that exercise may be even more beneficial to females than it is in males. Two papers in this issue examine factors that can disrupt a behavior that is (at least in most laboratory rodents) uniquely female— maternal care—which can have long-lasting effects on offspring development and mental health. Reshetnikov et al find that prolonged separation from their pups during the first 2 weeks of life causes a robust decrease in pup licking, an effect accompanied by cell loss in the hippocampus and spatial memory deficits. Poor maternal care was also observed in mice with a double knockout (dKO) of two diacylglycerol kinase genes (eta and iota). dKO dams were deficient at pup retrieval and did not appear to feed their pups as often, resulting in only a 30% pup survival rate after postnatal day 3. These rodent papers are complemented by a review of the human literature connecting maternal caregiving behavior to DNA methylation in offspring. Notably, the authors include a discussion of the impact that maternal depression can have on epigenetic outcomes in children, especially in stressand inflammation-related genes. Finally, two articles investigate potential sex differences in the 5xFAD mouse model of Alzheimer's disease (AD). AD is both more prevalent and more severe in women, but as in many fields, relevant preclinical research has been conducted primarily in male animals. Characterization of behavioral phenotypes in female genetic models will, therefore, be a critical step in determining their utility for understanding sex-dependent AD symptoms and disease trajectories. An extensive battery of locomotor behavior across the adult lifespan (age 3-16 months) showed that, despite robust motor deficits in 5xFAD mice of both sexes and a few age-dependent sex differences, very DOI: 10.1111/gbb.12646