Lombardo Michael V, Auyeung Bonnie, Pramparo Tiziano, Quartier Angélique, Courraud Jérémie, Holt Rosemary J, Waldman Jack, Ruigrok Amber N V, Mooney Natasha, Bethlehem Richard A I, Lai Meng-Chuan, Kundu Prantik, Bullmore Edward T, Mandel Jean-Louis, Piton Amélie, Baron-Cohen Simon
Center for Applied Neuroscience, Department of Psychology, University of Cyprus, Nicosia, Cyprus.
Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.
Mol Psychiatry. 2020 Sep;25(9):2175-2188. doi: 10.1038/s41380-018-0198-y. Epub 2018 Aug 13.
Early-onset neurodevelopmental conditions (e.g., autism) affect males more frequently than females. Androgens may play a role in this male-bias by sex-differentially impacting early prenatal brain development, particularly neural circuits that later develop specialized roles in social cognition. Here, we find that increasing prenatal testosterone in humans is associated with later reduction of functional connectivity between social brain default mode (DMN) subsystems in adolescent males, but has no effect in females. Since testosterone can work directly via the androgen receptor (AR) or indirectly via the estrogen receptor through aromatase conversion to estradiol, we further examined how a potent non-aromatizable androgen, dihydrotestosterone (DHT), acts via the AR to influence gene expression in human neural stem cells (hNSC)-particularly for genes of high-relevance for DMN circuitry. DHT dysregulates a number of genes enriched for syndromic causes of autism and intellectual disability and for genes that in later development are expressed in anatomical patterns that highly correspond to the cortical midline DMN subsystem. DMN-related and DHT-affected genes (e.g., MEF2C) are involved in a number of synaptic processes, many of which impact excitation-inhibition balance. Androgens have male-specific prenatal influence over social brain circuitry in humans and may be relevant towards explaining some component of male-bias in early-onset neurodevelopmental conditions.
早发性神经发育疾病（如自闭症）在男性中比女性更常见。雄激素可能通过对早期产前大脑发育产生性别差异影响，特别是对后来在社会认知中发挥特殊作用的神经回路，从而在这种男性偏向中发挥作用。在这里，我们发现，人类产前睾酮水平的升高与青少年男性社交大脑默认模式（DMN）子系统之间功能连接的后期减少有关，但对女性没有影响。由于睾酮可以直接通过雄激素受体（AR）起作用，也可以通过芳香化酶转化为雌二醇间接通过雌激素受体起作用，我们进一步研究了一种强效的不可芳香化雄激素双氢睾酮（DHT）如何通过AR影响人类神经干细胞（hNSC）中的基因表达——特别是对与DMN回路高度相关的基因。DHT会失调一些因自闭症和智力残疾的综合征病因以及在后期发育中以与皮质中线DMN子系统高度对应的解剖模式表达的基因而富集的基因。与DMN相关且受DHT影响的基因（如MEF2C）参与了许多突触过程，其中许多过程会影响兴奋抑制平衡。雄激素在人类中对社交大脑回路有特定于男性的产前影响，可能与解释早发性神经发育疾病中男性偏向的某些因素有关。
