Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA.
Medical Scientist Training Program, University of Minnesota, Minneapolis, MN, USA.
Psychopharmacology (Berl). 2024 Dec;241(12):2431-2440. doi: 10.1007/s00213-024-06660-3. Epub 2024 Jul 31.
Sex has a strong influence on the prevalence and course of brain conditions, including autism spectrum disorders. The mechanistic basis for these sex differences remains poorly understood, due in part to historical bias in biomedical research favoring analysis of male subjects, and the exclusion of female subjects. For example, studies of male mice carrying autism-associated mutations in neuroligin-3 are over-represented in the literature, including our own prior work showing diminished responses to chronic morphine exposure in male neuroligin-3 knockout mice. We therefore studied how constitutive and conditional genetic knockout of neuroligin-3 affects morphine sensitivity of female mice, using locomotor activity as a proxy for differences in opioid sensitivity that may be related to the pathophysiology and treatment of autism spectrum disorders. In contrast to male mice, female neuroligin-3 knockout mice showed normal psychomotor sensitization after chronic morphine exposure. However, in the absence of neuroligin-3 expression, both female and male mice show a similar change in the topography of locomotor stimulation produced by morphine. Conditional genetic deletion of neuroligin-3 from dopamine neurons increased the locomotor response of female mice to high doses of morphine, contrasting with the decrease in psychomotor sensitization caused by the same manipulation in male mice. Together, our data reveal that knockout of neuroligin-3 has both common and distinct effects on morphine sensitivity in female and male mice. These results also support the notion that female sex can confer resilience against the impact of autism-associated gene variants.
性别对大脑疾病的流行和病程有很强的影响，包括自闭症谱系障碍。由于历史上生物医学研究偏向于分析雄性对象，以及排除雌性对象，这些性别差异的机制基础仍未被很好地理解。例如，在神经连接蛋白-3（neuroligin-3）携带自闭症相关突变的雄性小鼠的研究中，文献中过度代表了这种情况，包括我们之前的工作表明，雄性 neuroligin-3 基因敲除小鼠对慢性吗啡暴露的反应减弱。因此，我们研究了神经连接蛋白-3 的组成型和条件性基因敲除如何影响雌性小鼠对吗啡的敏感性，以运动活动作为对阿片类药物敏感性差异的替代指标，这种差异可能与自闭症谱系障碍的病理生理学和治疗有关。与雄性小鼠不同，雌性 neuroligin-3 基因敲除小鼠在慢性吗啡暴露后表现出正常的精神运动敏感化。然而，在没有神经连接蛋白-3 表达的情况下，雌性和雄性小鼠对吗啡产生的运动刺激的地形都发生了类似的变化。从多巴胺神经元中条件性基因删除神经连接蛋白-3会增加雌性小鼠对高剂量吗啡的运动反应，这与同一操作在雄性小鼠中引起的精神运动敏感化下降形成对比。总之，我们的数据揭示了神经连接蛋白-3 的敲除对雌性和雄性小鼠对吗啡敏感性有共同和不同的影响。这些结果还支持了这样一种观点，即女性性别可以赋予对自闭症相关基因变异影响的抵抗力。
