Sex chromosomes and hormones independently influence healthy brain development but act similarly after cranial radiation

• 成果类型: Article
• 署名作者: Yeung, Jonas; Deyoung, Taylor; Spring, Shoshana; Guzman, A. Elizabeth de; Elder, Madeline W.; Beauchamp, Antoine; Wong, C. Shun; Palmert, Mark R.; Lerch, Jason P.; Nieman, Brian J.
• 署名单位: University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; Istituto Italiano di Tecnologia - IIT; University of Toronto; Sunnybrook Research Institute; Sunnybrook Health Science Center; University of Toronto; University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; University of Toronto; University of Toronto; Hospital for Sick Children (SickKids); University of Oxford; University of Oxford; Ontario Institute for Cancer Research; University of Toronto
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13911
• DOI: 10.1073/pnas.2404042121
• 发表日期: 2024-09-03
• 关键词: attention-deficit/hyperactivity disorder; stria terminalis; gene-expression; mouse models; bed nucleus; adult; ccl2; testosterone; complement; dimorphism

摘要

The course of normal development and response to pathology are strongly influenced by biological sex. For instance, female childhood cancer survivors who have undergone cranial radiation therapy (CRT) tend to display more pronounced cognitive deficits than their male counterparts. Sex effects can be the result of sex chromosome complement (XX vs. XY) and/or gonadal hormone influence. The contributions of each can be separated using the four- core genotype mouse model (FCG), where sex chromosome complement and gonadal sex are decoupled. While studies of FCG mice have evaluated brain differences in adulthood, it is still unclear how sex chromosome and sex hormone effects emerge through development in both healthy and pathological contexts. Our study utilizes longitudinal MRI with the FCG model to investigate sex effects in healthy development and after CRT in wildtype and immune- modified Ccl2- knockout mice. Our findings in normally developing mice reveal a relatively prominent chromosome effect prepubertally, compared to sex hormone effects which largely emerge later. Spatially, sex chromosome and hormone influences were independent of one another. After CRT in Ccl2- knockout mice, both male chromosomes and male hormones similarly improved brain outcomes but did so more separately than in combination. Our findings highlight the crucial role of sex chromosomes in early development and identify roles for sex chromosomes and hormones after CRT- induced inflammation, highlighting the influences of biological sex in both normal brain development and pathology.