Cre recombinase-mediated restoration of nigrostriatal dopamine in dopamine-deficient mice reverses hypophagia and bradykinesia
Cre recombinase-mediated restoration of nigrostriatal dopamine in dopamine-deficient mice reverses hypophagia and bradykinesia
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DOI：
10.1073/pnas.0603081103
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发表时间：
2006-06-06
影响因子：
11.1
通讯作者：
Palmiter, Richard D.
中科院分区：
文献类型：
--
作者：
Hnasko, Thomas S.;Perez, Francisco A.;Palmiter, Richard D.
产生多巴胺缺陷（DID）小鼠系，以允许选择性恢复正常多巴胺信号传导至特定脑区域。这些DD floxed stop（DDfs）小鼠具有非功能性酪氨酸羟化酶（Th）基因，因为插入了Neo（R）基因，所述Neo（R）基因侧翼为靶向Th基因的第一内含子的lox P位点。DDfs小鼠有微量的脑多巴胺含量，严重的活动减退和食欲不振，它们在没有干预的情况下死亡。然而，它们可以通过每天用L-3，4-二羟基苯丙氨酸（L-dopa）治疗来维持。注射犬腺病毒（CAV-2）工程表达Cre重组酶到中央尾壳核恢复正常的Th基因表达中脑多巴胺神经元的项目，因为CAV-2有效地转导轴突终末和逆行运输到神经元细胞体。双侧注射Cre重组酶到中央尾壳核中恢复DDfs小鼠的进食和正常化运动。通过使用lickometer笼进行的摄食行为分析显示，与对照小鼠相比，病毒拯救的DDfs小鼠是摄食过多的，并且具有改变的膳食结构。与对照组相比，病毒拯救的DDfs小鼠在夜间也过度活跃，运动协调性降低，并且是趋触性的。这些结果强调了背侧纹状体中多巴胺信号对大多数多巴胺依赖行为的关键作用，但表明其他大脑区域中的多巴胺信号对微调这些行为很重要。这种方法提供了许多优势相比，以前的模型，旨在研究离散多巴胺能电路中的多巴胺信号。
A line of dopamine-deficient (DID) mice was generated to allow selective restoration of normal dopamine signaling to specific brain regions. These DD floxed stop (DDfs) mice have a nonfunctional Tyrosine hydroxylase (Th) gene because of insertion of a Neo(R) gene flanked by lox P sites targeted to the first intron of the Th gene. DDfs mice have trace brain dopamine content, severe hypoactivity, and aphagia, and they die without intervention. However, they can be maintained by daily treatment with L-3,4-dihydroxyphenylalanine (L-dopa). Injection of a canine adenovirus (CAV-2) engineered to express Cre recombinase into the central caudate putamen restores normal Th gene expression to the midbrain dopamine neurons that project there because CAV-2 efficiently transduces axon terminals and is retrogradely transported to neuronal cell bodies. Bilateral injection of Cre recombinase into the central caudate putamen restores feeding and normalizes locomotion in DDfs mice. Analysis of feeding behavior by using lickometer cages revealed that virally rescued DDfs mice are hyperphagic and have modified meal structures compared with control mice. The virally rescued DDfs mice are also hyperactive at night, have reduced motor coordination, and are thigmotactic compared with controls. These results highlight the critical role for dopamine signaling in the dorsal striatum for most dopamine-dependent behaviors but suggest that dopamine signaling in other brain regions is important to fine-tune these behaviors. This approach offers numerous advantages compared with previous models aimed at examining dopamine signaling in discrete dopaminergic circuits.