Viral rescue of magnocellular vasopressin cells in adolescent Brattleboro rats ameliorates diabetes insipidus, but not the hypoaroused phenotype
Viral rescue of magnocellular vasopressin cells in adolescent Brattleboro rats ameliorates diabetes insipidus, but not the hypoaroused phenotype
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DOI：
10.1038/s41598-019-44776-1
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发表时间：
2019-06-03
影响因子：
4.6
通讯作者：
Paul, M. J.
中科院分区：
文献类型：
--
作者：
Schatz, K. C.;Brown, L. M.;Paul, M. J.
失调的觉醒通常伴随着神经发育障碍，如注意缺陷多动障碍和自闭症谱系障碍。最近，我们在野外试验中发现，含有精氨酸抗利尿激素（AVP）基因突变的青春期纯合子伯氏大鼠（Hom）表现出比杂合子（Het）幼鼠更低的行为唤醒。这种低激发的表型可能是由于AVP在大细胞中的丢失，大细胞向外周循环提供AVP，并投射到边缘结构或调节应激轴和其他中心靶点的旁细胞。另一种可能是，低觉醒可能是尿囊症的副作用——在大鼠中发现的多饮和多尿，这是由于AVP的丧失促进了肾脏水分的再吸收。我们开发了一种病毒拯救方法来“治愈”巨细胞AVP细胞的Brattleboro突变。注入含有功能性Avp基因和启动子的重组腺相关病毒（rAAV- Avp）可挽救青春期雄性和雌性大鼠下丘脑室旁核（PVN）的大细胞和纤维突起内的Avp。此外，水的摄入量明显减少，改善尿崩症的症状。相比之下，露天油田的活动不受影响。这些研究结果表明，青春期大鼠的低觉醒表型不是由于大细胞AVP功能的丧失或尿囊症的副作用，而是支持了一种假设，即中枢、旁细胞AVP机制是青春期觉醒调节的基础。
Dysregulated arousal often accompanies neurodevelopmental disorders such as attention deficit hyperactivity disorder and autism spectrum disorder. Recently, we have found that adolescent homozygous Brattleboro (Hom) rats, which contain a mutation in the arginine vasopressin (AVP) gene, exhibit lower behavioral arousal than their heterozygous (Het) littermates in the open field test. This hypoaroused phenotype could be due to loss of AVP in magnocellular cells that supply AVP to the peripheral circulation and project to limbic structures or parvocellular cells that regulate the stress axis and other central targets. Alternatively, hypoarousal could be a side effect of diabetes insipidus - polydipsia and polyuria seen in Hom rats due to loss of AVP facilitation of water reabsorption in the kidney. We developed a viral-rescue approach to "cure" magnocellular AVP cells of their Brattleboro mutation. Infusion of a recombinant adeno-associated virus (rAAV) containing a functional Avp gene and promoter (rAAV-AVP) rescued AVP within magnocellular cells and fiber projections of the paraventricular nucleus of the hypothalamus (PVN) of male and female adolescent Hom rats. Furthermore, water intake was markedly reduced, ameliorating the symptoms of diabetes insipidus. In contrast, open field activity was unaffected. These findings indicate that the hyporaoused phenotype of adolescent Hom rats is not due to the loss of AVP function in magnocellular cells or a side effect of diabetes insipidus, but favors the hypothesis that central, parvocellular AVP mechanisms underlie the regulation of arousal during adolescence.