与酪氨酸羟化酶 Cre（TH-Cre）小鼠相比，多巴胺转运体 Cre（DAT-Ires-Cre）小鼠的基线和安非他命介导的行为特征发生改变。
Altered baseline and amphetamine-mediated behavioral profiles in dopamine transporter Cre (DAT-Ires-Cre) mice compared to tyrosine hydroxylase Cre (TH-Cre) mice.
机构信息
Department of Psychiatry, Columbia University Medical Center, New York, NY, 10032, USA.
New York State Psychiatric Institute, 1051 Riverside Drive, Mail Unit 78, New York, NY, 10032, USA.
出版信息
Psychopharmacology (Berl). 2020 Dec;237(12):3553-3568. doi: 10.1007/s00213-020-05635-4. Epub 2020 Aug 10.
RATIONALE
Transgenic mouse lines expressing Cre-recombinase under the regulation of either dopamine transporter (DAT) or tyrosine hydroxylase (TH) promoters are commonly used to study the dopamine (DA) system. While use of the TH promoter appears to have less liability to changes in native gene expression, transgene insertion in the DAT locus results in reduced DAT expression and function. This confound is sometimes overlooked in genetically targeted behavioral experiments.
OBJECTIVES
We sought to evaluate the suitability of DAT-Ires-Cre and TH-Cre transgenic lines for behavioral pharmacology experiments with DA agonists. We hypothesized that DAT-Ires-Cre expression would impact DAT-mediated behaviors, but no impact of TH-Cre expression would be observed.
METHODS
DAT-Ires-Cre and TH-Cre mice bred on mixed 129S6/C57BL/6 and pure C57BL/6 backgrounds were evaluated for novelty-induced, baseline, and amphetamine (AMPH)-induced locomotion, and for AMPH and D1 agonist (SKF-38393)-induced preservative behaviors.
RESULTS
DAT-Ires-Cre mice on both mixed 129S6/C57BL/6 and pure C57BL/6 backgrounds displayed increased novelty-induced activity and decreased AMPH-induced locomotion, with mixed results for AMPH-induced stereotypy. TH-Cre mice on both backgrounds showed typical baseline activity and AMPH-induced stereotypy, with a difference in AMPH-induced locomotion observed only on the mixed background. Both transgenic lines displayed unaltered SKF-38393-induced grooming behavior.
CONCLUSIONS
Our findings indicate that the DAT-Ires-Cre transgenic line may lead to confounds for experiments that are dependent on DAT expression. The TH-Cre transgenic line studied here may be a more useful option, depending on background strain, because of its lack of baseline and drug-induced phenotypes. These data highlight the importance of appropriate controls in studies employing transgenic mice.
背景
表达 Cre 重组酶的转基因小鼠品系在多巴胺转运体（DAT）或酪氨酸羟化酶（TH）启动子的调控下表达，常用于研究多巴胺（DA）系统。虽然使用 TH 启动子似乎较少引起内源性基因表达的变化，但 DAT 基因座中的转基因插入会导致 DAT 表达和功能降低。这种混杂因素在基因靶向行为实验中有时会被忽视。
目的
我们旨在评估 DAT-Ires-Cre 和 TH-Cre 转基因品系用于 DA 激动剂的行为药理学实验的适用性。我们假设 DAT-Ires-Cre 表达会影响 DAT 介导的行为，但不会观察到 TH-Cre 表达的影响。
方法
在混合 129S6/C57BL/6 和纯 C57BL/6 背景以及纯 C57BL/6 背景下繁殖 DAT-Ires-Cre 和 TH-Cre 转基因小鼠，评估其对新奇诱导、基线和安非他命（AMPH）诱导的运动，以及 AMPH 和 D1 激动剂（SKF-38393）诱导的保存行为的影响。
结果
混合 129S6/C57BL/6 和纯 C57BL/6 背景下的 DAT-Ires-Cre 小鼠均表现出增加的新奇诱导活动和减少的 AMPH 诱导运动，而 AMPH 诱导刻板行为的结果则不一致。两种背景下的 TH-Cre 小鼠均表现出典型的基线活动和 AMPH 诱导的刻板行为，仅在混合背景下观察到 AMPH 诱导的运动差异。两种转基因品系的 SKF-38393 诱导的梳理行为均未改变。
结论
我们的发现表明，DAT-Ires-Cre 转基因线可能会导致依赖 DAT 表达的实验出现混杂因素。本研究中使用的 TH-Cre 转基因线可能是一种更有用的选择，这取决于背景品系，因为它没有基线和药物诱导的表型。这些数据强调了在使用转基因小鼠进行研究时适当对照的重要性。
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