Copy number variants (CNVs) are robustly associated with psychiatric disorders and changes in brain structures. However, because CNVs contain many genes, the precise gene-phenotype relationship remains unclear. Although various volumetric alterations in the brains of 22q11.2 CNV carriers have been identified in humans and mouse models, it is unknown how each gene encoded in the 22q11.2 region contributes to structural alterations, associated mental illnesses, and their dimensions. Our previous studies identified Tbx1, a T-box family transcription factor encoded in the 22q11.2 CNV, as a driver gene for social interaction and communication, spatial and working memory, and cognitive flexibility. However, it remains unclear how TBX1 impacts the volumes of various brain regions and their functionally linked behavioral dimensions. In this study, we used volumetric magnetic resonance imaging analysis to comprehensively evaluate brain region volumes and behavioral alterations relevant to affected structures in congenic Tbx1 heterozygous mice. Our data showed that the volumes of the anterior and posterior portions of the amygdaloid complex and its surrounding cortical regions were most robustly reduced in Tbx1 heterozygous mice. In an amygdala-dependent task, Tbx1 heterozygous mice were impaired in their ability to learn the incentive value of a social partner. The volumes of the primary and secondary auditory cortexes were increased, and acoustic, but not non-acoustic, sensorimotor gating was impaired in Tbx1 heterozygous mice. Our findings identify the brain’s regional volume alterations and their relevant behavioral dimensions associated with Tbx1 heterozygosity.

拷贝数变异 （CNV） 与精神疾病和大脑结构变化密切相关。然而，由于 CNV 包含许多基因，确切的基因-表型关系仍不清楚。尽管已在人类和小鼠模型中鉴定出 22q11.2 CNV 携带者大脑中的各种体积改变，但尚不清楚编码在 22q11.2 区域的每个基因如何导致结构改变、相关的精神疾病及其尺寸。我们之前的研究发现 Tbx1 是一种编码在 22q11.2 CNV 中的 T 盒家族转录因子，是社交互动和交流、空间和工作记忆以及认知灵活性的驱动基因。然而，目前尚不清楚 TBX1 如何影响各种大脑区域的体积及其功能相关的行为维度。在这项研究中，我们使用体积磁共振成像分析来全面评估同源 Tbx1 杂合子小鼠与受影响结构相关的脑区体积和行为改变。我们的数据显示，在 Tbx1 杂合子小鼠中，杏仁核复合体的前部和后部及其周围皮质区域的体积最强烈地减少。在杏仁核依赖性任务中，Tbx1 杂合子小鼠学习社交伙伴激励价值的能力受损。Tbx1 杂合子小鼠的初级和次级听觉皮层的体积增加，声学但不是非声学的感觉运动门控受损。我们的研究结果确定了大脑的区域体积改变及其与 Tbx1 杂合性相关的相关行为维度。