Quiñones-Labernik Pravda, Blocklinger Kelsey L, Bruce Matthew R, Ferri Sarah L
Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, United States.
Carver College of Medicine, University of Iowa, Iowa City, IA, United States.
bioRxiv. 2025 Jan 21:2023.10.18.562939. doi: 10.1101/2023.10.18.562939.
Neurodevelopmental disorders disproportionately affect males compared to females. The biological mechanisms of this male susceptibility or female protection have not been identified. There is evidence that fetal/neonatal gonadal hormones, which play a pivotal role in many aspects of development, may contribute. Here, we investigate the effects of excess testosterone during a critical period of sex-specific brain organization on social approach and fear learning behaviors in C57BL/6J wild-type mice. Male, but not female, mice treated with testosterone on the day of birth (PN0) exhibited decreased social approach as juveniles and decreased contextual fear memory as adults, compared to vehicle-treated controls. These deficits were not driven by anxiety-like behavior or changes in locomotion or body weight. Mice treated with the same dose of testosterone on postnatal day 18 (PN18), which is outside of the critical period of brain masculinization, did not demonstrate impairments compared to the vehicle group. These findings indicate that excess testosterone during a critical period of early development, but not shortly after, induces long-term deficits relevant to the male sex bias in neurodevelopmental disorders.
与女性相比，神经发育障碍对男性的影响更为严重。这种男性易感性或女性保护性的生物学机制尚未明确。有证据表明，在发育的许多方面起关键作用的胎儿/新生儿性腺激素可能与此有关。在此，我们研究了在性别特异性脑组织结构的关键时期过量睾酮对C57BL/6J野生型小鼠社交趋近和恐惧学习行为的影响。与接受载体处理的对照组相比，出生当天（出生后第0天，PN0）接受睾酮处理的雄性小鼠在幼年时社交趋近减少，成年时情境恐惧记忆减退，而雌性小鼠则没有这种情况。这些缺陷并非由焦虑样行为、运动或体重变化所致。在出生后第18天（PN18）接受相同剂量睾酮处理的小鼠，此时已超出脑男性化的关键时期，与载体组相比未表现出损伤。这些发现表明，在早期发育的关键时期而非之后不久的过量睾酮会导致与神经发育障碍中男性性别偏见相关的长期缺陷。
