性别差异在神经发育过程中普遍存在,并在自闭症等神经精神疾病中发挥作用,男性比女性更普遍。在人类中,男性的大脑体积比女性大,海马体和杏仁核的发育显示出明显的性别差异。机械上,性类固醇和性染色体驱动大脑发育的这些差异,似乎在产前和青春期达到高峰。动物模型在理解性别差异方面发挥了至关重要的作用,但是对人类性别差异的研究需要一个能够概括复杂遗传性状的实验模型。为了填补这个空白,人类诱导的多能干细胞来源的脑类器官现在被用于研究复杂的遗传特征如何影响产前大脑发育。例如,自闭症患者和X染色体连锁Rett综合征和脆性X综合征患者的脑类器官显示了产前细胞增殖的差异,测量大脑体积差异,和兴奋性抑制失衡。脑类器官还揭示了由于雄激素导致的兴奋性神经元的神经发生增加。然而,尽管人们对使用脑类器官越来越感兴趣,几个关键挑战仍然存在,影响其作为模型系统的有效性。在这次审查中,我们讨论了性类固醇和性染色体是如何导致大脑发育中的性别差异的。然后,我们研究了X染色体失活作为驱动性别差异的一个因素的作用.最后,我们讨论了在研究性别差异时需要考虑的X染色体失活建模和脑类器官局限性的综合挑战。
性别差异是自闭症等神经精神疾病的一个促成因素,这在男性中更为普遍。性别差异是通过雌激素和睾丸激素等性类固醇激素与性染色体(chrX和chrY)之间的相互作用而发生的。人类干细胞衍生的脑类器官是模拟大脑发育的实验室模型。例如,在有神经发育状况的个体中,与神经典型个体相比,脑类器官显示出神经元种群的不平衡。在这次审查中,我们讨论了性类固醇和性染色体对大脑发育的影响,以及研究性别差异时需要考虑的挑战。
Sex differences are widespread during neurodevelopment and play a role in neuropsychiatric conditions such as autism, which is more prevalent in males than females. In humans, males have been shown to have larger brain volumes than females with development of the hippocampus and amygdala showing prominent sex differences. Mechanistically, sex steroids and sex chromosomes drive these differences in brain development, which seem to peak during prenatal and pubertal stages. Animal models have played a crucial role in understanding sex differences, but the study of human sex differences requires an experimental model that can recapitulate complex genetic traits. To fill this gap, human induced pluripotent stem cell-derived brain organoids are now being used to study how complex genetic traits influence prenatal brain development. For example, brain organoids from individuals with autism and individuals with X chromosome-linked Rett syndrome and fragile X syndrome have revealed prenatal differences in cell proliferation, a measure of brain volume differences, and excitatory-inhibitory imbalances. Brain organoids have also revealed increased neurogenesis of excitatory neurons due to androgens. However, despite growing interest in using brain organoids, several key challenges remain that affect its validity as a model system. In this review, we discuss how sex steroids and the sex chromosomes each contribute to sex differences in brain development. Then, we examine the role of X chromosome inactivation as a factor that drives sex differences. Finally, we discuss the combined challenges of modeling X chromosome inactivation and limitations of brain organoids that need to be taken into consideration when studying sex differences.
Sex differences are a contributing factor in neuropsychiatric conditions such as autism, which is more prevalent in males. Sex differences occur through interactions between sex steroid hormones such as estrogen and testosterone and sex chromosomes (chrX and chrY). Human stem cell–derived brain organoids are laboratory models that mimic brain development. For example, in individuals with neurodevelopmental conditions, brain organoids have revealed an imbalance of neuron populations compared with neurotypical individuals. In this review, we discuss sex steroid and sex chromosome influences on brain development and challenges of this model that need to be taken into account when studying sex differences.