Epigenetic mechanisms underlying sex differences in the brain and behavior

• Published in: Trends in neurosciences (Regular ed.) 2024-01, Vol.47 (1), p.18-35
• Main Authors: Kundakovic, Marija, Tickerhoof, Maria
• Format: Article
• Language: English
• Subjects: brain structure and function; chromatin; epigenetics; gonadal hormones; sex chromosomes; sex difference
• ISSN: 0166-2236; 1878-108X
• DOI: 10.1016/j.tins.2023.09.007

Sex differences in the brain are reflected at the molecular, structural, and behavioral levels, and are observed across brain disorders.Brain sexual differentiation is a dynamic process that takes place throughout life under the influence of interactions between gonadal hormones, sex chromosomes, and the environment.Studies of sex-specific factors, such as perinatal testosterone exposure in males and the estrous cycle in females, show clear evidence that epigenetic mechanisms drive sex differences in the brain and behavior.Studies of environmental impact on the brain epigenome across the lifespan have revealed important sex differences but only limited mechanistic insights.Future neuroepigenetic studies incorporating sex-specific variables and better-targeted, higher-resolution approaches are hoped to maximize the benefit of insights gained from basic research for people across genders. Sex differences are found across brain regions, behaviors, and brain diseases. Sexual differentiation of the brain is initiated prenatally but continues throughout life as a result of the interaction of three major factors: gonadal hormones, sex chromosomes, and the environment. These factors are thought to act, in part, via epigenetic mechanisms which control chromatin and transcriptional states in brain cells. In this review we discuss evidence that epigenetic mechanisms underlie sex-specific neurobehavioral changes during critical organizational periods, across the estrous cycle, and in response to diverse environments throughout life. We further identify future directions for the field that will provide novel mechanistic insights into brain sex differences, inform brain disease treatments and women's brain health in particular, and apply to people across genders. Sex differences are found across brain regions, behaviors, and brain diseases. Sexual differentiation of the brain is initiated prenatally but continues throughout life as a result of the interaction of three major factors: gonadal hormones, sex chromosomes, and the environment. These factors are thought to act, in part, via epigenetic mechanisms which control chromatin and transcriptional states in brain cells. In this review we discuss evidence that epigenetic mechanisms underlie sex-specific neurobehavioral changes during critical organizational periods, across the estrous cycle, and in response to diverse environments throughout life. We further identify future directions for the field that will provide nov