Sannino Sara, Gozzi Alessandro, Cerasa Antonio, Piras Fabrizio, Scheggia Diego, Managò Francesca, Damiano Mario, Galbusera Alberto, Erickson Lucy C, De Pietri Tonelli Davide, Bifone Angelo, Tsaftaris Sotirios A, Caltagirone Carlo, Weinberger Daniel R, Spalletta Gianfranco, Papaleo Francesco
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Science @UNITN, 38068, Rovereto, Italy.
Cereb Cortex. 2015 Sep;25(9):2529-41. doi: 10.1093/cercor/bhu053. Epub 2014 Mar 21.
Genetic variations in catechol-O-methyltransferase (COMT) that modulate cortical dopamine have been associated with pleiotropic behavioral effects in humans and mice. Recent data suggest that some of these effects may vary among sexes. However, the specific brain substrates underlying COMT sexual dimorphisms remain unknown. Here, we report that genetically driven reduction in COMT enzyme activity increased cortical thickness in the prefrontal cortex (PFC) and postero-parieto-temporal cortex of male, but not female adult mice and humans. Dichotomous changes in PFC cytoarchitecture were also observed: reduced COMT increased a measure of neuronal density in males, while reducing it in female mice. Consistent with the neuroanatomical findings, COMT-dependent sex-specific morphological brain changes were paralleled by divergent effects on PFC-dependent working memory in both mice and humans. These findings emphasize a specific sex-gene interaction that can modulate brain morphological substrates with influence on behavioral outcomes in healthy subjects and, potentially, in neuropsychiatric populations.
儿茶酚-O-甲基转移酶（COMT）的基因变异可调节皮质多巴胺，这种变异与人类和小鼠的多效性行为效应有关。最近的数据表明，其中一些效应可能存在性别差异。然而，COMT性别二态性背后的具体脑底物仍不清楚。在此，我们报告，基因驱动的COMT酶活性降低增加了成年雄性小鼠和人类前额叶皮质（PFC）以及后顶叶颞叶皮质的皮质厚度，但对成年雌性小鼠和人类没有影响。我们还观察到PFC细胞结构的二分变化：COMT降低增加了雄性小鼠的神经元密度指标，而在雌性小鼠中则降低了该指标。与神经解剖学结果一致，COMT依赖的性别特异性脑形态变化在小鼠和人类中均与对PFC依赖的工作记忆的不同影响平行。这些发现强调了一种特定的性别-基因相互作用，这种相互作用可以调节脑形态底物，从而影响健康受试者以及潜在的神经精神疾病人群的行为结果。
