Causal factors of psychiatric diseases are unclear, due to gene × environment interactions. Evaluation of consequences, after a dopamine-transporter (DAT) gene knock-out (DAT-KO), has enhanced our understanding into the pathological dynamics of several brain disorders, such as Attention-Deficit/Hyperactivity and Bipolar-Affective disorders. Recently, our attention has shifted to DAT hypo-functional (heterozygous, HET) rodents: HET dams display less maternal care and HET females display marked hypo-locomotion if cared by HET dams (Mariano et al., 2019). We assessed phenotypes of male DAT-heterozygous rats as a function of their parents: we compared "maternal" origin (MAT-HET, obtained by breeding KO-male rats with WT-female dams) to "mixed" origin (MIX-HET, obtained by classical breeding, both heterozygous parents) of the allele. MAT-HET subjects had significantly longer rhythms of daily locomotor activity than MIX-HET and WT-control subjects. Furthermore, acute methylphenidate (MPH: 0, 1, 2 mg/kg) revealed elevated threshold for locomotor stimulation in MAT-HETs, with no response to the lower dose. Finally, by Porsolt-Test, MAT-HETs showed enhanced escape-seeking (diving) with more transitions towards behavioral despair (floating). When comparing both MAT- and MIX-HET to WT-control rats, decreased levels of DAT and HDAC4 were evident in the ventral-striatum; moreover, with respect to MIX-HET subjects, MAT-HET ones displayed increased DAT density in dorsal-striatum. MAT-HET rats displayed region-specific changes in DAT expression, compared to "classical" MIX-HET subjects: greater DAT availability may elevate threshold for dopamine action. Further behavioral and epigenetic characterizations of MAT-HETs, together with deeper characterization of maternal roles, could help to explore parent-of-origin mechanisms for such a peculiar phenotype.

中文翻译：

---

当非常规KOxWT交配的后代时，杂合DAT大鼠的运动转换的特殊性。

由于基因×环境的相互作用，精神病的病因尚不清楚。在多巴胺转运蛋白（DAT）基因敲除（DAT-KO）后，对后果的评估增强了我们对几种脑部疾病（例如注意力缺陷/多动症和双相情感障碍）的病理动力学的了解。最近，我们的注意力已经转移到DAT功能低下的啮齿类动物（杂合子，HET）上：HET水坝显示较少的孕产妇照料，HET雌性如果受到HET水坝照顾则表现出明显的运动不足（Mariano等人，2019）。我们评估了雄性DAT杂合大鼠的表型作为其父母的功能：我们将“母体”起源（MAT-HET，通过将WT雌性母鼠与KO雄性大鼠进行繁殖获得）与“混合”起源（MIX-HET，通过经典育种获得的，均是等位基因的杂合亲本）。MAT-HET受试者的日常运动节奏比MIX-HET和WT对照受试者更长。此外，急性哌醋甲酯（MPH：0、1、2 mg / kg）显示出MAT-HET中运动刺激的阈值升高，对较低剂量无反应。最后，通过Porsolt-Test，MAT-HETs表现出增强的逃生寻求（跳水）能力，向行为绝望（浮动）的过渡更多。当将MAT-和MIX-HET与WT对照大鼠进行比较时，腹侧纹状体中DAT和HDAC4的水平降低。此外，对于MIX-HET受试者，MAT-HET受试者的背纹状体DAT密度增加。与“经典” MIX-HET受试者相比，MAT-HET大鼠在DAT表达上表现出区域特异性变化：更大的DAT利用率可能会提高多巴胺作用的阈值。