Bravo Paloma, Marlow Florence L
bioRxiv. 2025 Aug 21:2025.08.15.670359. doi: 10.1101/2025.08.15.670359.
Sex specific differences in size and distribution of cell types have been observed in mammalian brains. How sex-specific differences in the brain are established and to what extent sexual dimorphism contributes to sex-biased neurodevelopment and neurological disorders is not well understood. Microglia are the resident immune cells of the nervous system and have been implicated in masculinizing the mammalian brain and refining neural connections to promote remodeling of neural circuitry, yet their contributions to developmental brain patterning and plasticity in zebrafish remains unclear. Here, we report anatomical and cellular differences between juvenile brains and adult female and male brains. Leveraging the plasticity of the zebrafish female brain and genetic models lacking microglia and tumor suppressor factors, we provide insight into the mechanisms that establish sex-specific brain dimorphism in zebrafish. Specifically, we identified sexually dimorphic features in the adult zebrafish brain that depend on microglia and Chek2, which may have broader implications and represent therapeutic targets for sex-biased neurological disorders.
Males and females of species can have significant differences in appearance, including differences in size, color, or sex specific anatomical structures. In addition to overt morphological differences, sex specific differences in size and distribution of cell types have been observed in mammalian brains. How these sex-specific differences in the brain are established and to what extent these differences contribute to sex-specific neurodevelopment and neurological disorders that differentially impact males and females is not well understood. Despite an incomplete picture of the mechanisms regulating sex-specific development, some of the cell types involved include microglia. Microglia are the resident immune cells of the nervous system and have been implicated in promoting features that are typical in the male mammalian brain. Specifically, microglia may refine neural connections and promote remodeling of neural circuitry and influence sex-specific behaviors. The contributions of microglia to developmental brain patterning and plasticity in zebrafish remain unclear. Here, we report anatomical and cellular differences between juvenile brains and adult female and male brains. Leveraging zebrafish genetic models lacking microglia and tumor suppressor factors, and the unique plasticity of the zebrafish female brain, we investigated and provide insight into the mechanisms that establish sex-specific brain differences in zebrafish. Specifically, we identified sexually distinct features in the adult zebrafish brain that depend on microglia and the tumor suppressor Chek2. If these or similar mechanisms operate in other species, our findings may have broader implications for sex-specific brain development and represent therapeutic targets for sex-biased neurological disorders.
Tissue clearing and immunostaining of juvenile and adult whole-mount zebrafish brains allows analysis of sex differences.Anatomical and cellular sexual dimorphism in the adult vertebrate brain appears after gonadal sex differentiation.Sexual dimorphism in the adult brain is driven by differences in cell death regulation.Microglia colonization of brain areas involved in courtship is sexually dimorphic.Microglia involvement in establishing sex-specific differences in the adult brain.
在哺乳动物大脑中已观察到细胞类型的大小和分布存在性别特异性差异。大脑中的性别特异性差异是如何形成的，以及性二态性在多大程度上导致了性别偏向的神经发育和神经系统疾病，目前尚不清楚。小胶质细胞是神经系统的常驻免疫细胞，与哺乳动物大脑的雄性化以及优化神经连接以促进神经回路重塑有关，但其对斑马鱼发育性脑模式形成和可塑性的贡献仍不清楚。在这里，我们报告了幼年斑马鱼大脑与成年雌性和雄性斑马鱼大脑之间的解剖学和细胞差异。利用斑马鱼雌性大脑的可塑性以及缺乏小胶质细胞和肿瘤抑制因子的遗传模型，我们深入了解了斑马鱼中建立性别特异性脑二态性的机制。具体而言，我们在成年斑马鱼大脑中发现了依赖于小胶质细胞和Chek2的性别二态性特征，这可能具有更广泛的意义，并代表了性别偏向性神经系统疾病的治疗靶点。
物种的雄性和雌性在外观上可能存在显著差异，包括大小、颜色或性别特异性解剖结构的差异。除了明显的形态差异外，在哺乳动物大脑中还观察到细胞类型的大小和分布存在性别特异性差异。大脑中的这些性别特异性差异是如何形成的，以及这些差异在多大程度上导致了对雄性和雌性有不同影响的性别特异性神经发育和神经系统疾病，目前尚不清楚。尽管调节性别特异性发育的机制尚不完全清楚，但其中涉及的一些细胞类型包括小胶质细胞。小胶质细胞是神经系统的常驻免疫细胞，与促进雄性哺乳动物大脑中的典型特征有关。具体而言，小胶质细胞可能优化神经连接并促进神经回路重塑，并影响性别特异性行为。小胶质细胞对斑马鱼发育性脑模式形成和可塑性的贡献仍不清楚。在这里，我们报告了幼年斑马鱼大脑与成年雌性和雄性斑马鱼大脑之间的解剖学和细胞差异。利用缺乏小胶质细胞和肿瘤抑制因子的斑马鱼遗传模型，以及斑马鱼雌性大脑独特的可塑性，我们研究并深入了解了斑马鱼中建立性别特异性脑差异的机制。具体而言，我们在成年斑马鱼大脑中发现了依赖于小胶质细胞和肿瘤抑制因子Chek2的性别特异性特征。如果这些或类似机制在其他物种中起作用，我们的发现可能对性别特异性脑发育具有更广泛的意义，并代表了性别偏向性神经系统疾病的治疗靶点。
对幼年和成年斑马鱼全脑进行组织透明化和免疫染色，可分析性别差异。成年脊椎动物大脑中的解剖学和细胞性二态性在性腺性别分化后出现。成年大脑中的性二态性由细胞死亡调节的差异驱动。参与求偶的脑区的小胶质细胞定植存在性别二态性。小胶质细胞参与成年大脑中性别特异性差异的确立。
