Altered Baseline and Nicotine-Mediated Behavioral and Cholinergic Profiles in ChAT-Cre Mouse Lines
Altered Baseline and Nicotine-Mediated Behavioral and Cholinergic Profiles in ChAT-Cre Mouse Lines
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DOI：
10.1523/jneurosci.1433-17.2018
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发表时间：
2018-02-28
影响因子：
5.3
通讯作者：
Fowler, Christie D.
中科院分区：
文献类型：
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作者：
Chen, Edison;Lallai, Valeria;Fowler, Christie D.
最近发展的转基因啮齿动物线表达cre重组酶在细胞特异性的方式，沿着在工程病毒载体的进展，允许深入调查电路功能。然而，新出现的证据已经开始表明，基因改造可能会带来意想不到的警告。在目前的研究中，我们试图广泛表征雄性和雌性小鼠的ChAT（（BAC））-Cremouseline，创建与细菌人工染色体（BAC）的方法，和ChAT（IRES）-Cre小鼠系，产生与内部核糖体进入位点（IRES）的方法。ChAT（（BAC））-Cre转基因小鼠和野生型小鼠在一般运动行为、焦虑测量、药物诱导的紧张性昏厥、尼古丁介导的运动功能减退或操作性食物训练方面没有差异。然而，ChAT（（BAC））-Cre转基因小鼠在静脉内尼古丁自我给药中确实表现出明显的缺陷，这导致囊泡乙酰胆碱转运蛋白和胆碱乙酰转移酶（ChAT）海马表达的增加。对于ChAT（（IRES））-Cre系，与野生型和半合子同窝出生的小鼠相比，转基因小鼠在基线运动、尼古丁介导的低运动和操作性食物训练方面表现出缺陷。ChAT（（IRES））-Cre野生型，半合子，和转基因同窝仔之间没有差异，发现焦虑措施，药物诱导的catabalism，尼古丁自我管理。鉴于ChAT（（IRES））-Cre转基因小鼠中存在cre表达增加，以及海马中ChAT表达减少，神经元功能改变可能是行为表型的基础。相比之下，ChAT（（IRES））-Cre半合子小鼠在蛋白质表达和大多数行为评估方面与野生型小鼠更相似。因此，对来自ChAT-Cre啮齿动物的数据的解释必须考虑潜在的局限性，这取决于研究调查中使用的品系和/或基因型。
The recent development of transgenic rodent lines expressing cre recombinase in a cell-specific manner, along with advances in engineered viral vectors, has permitted in-depth investigations into circuit function. However, emerging evidence has begun to suggest that genetic modifications may introduce unexpected caveats. In the current studies, we sought to extensively characterize male and female mice from both the ChAT((BAC))-Cremouseline, created with the bacterial artificial chromosome (BAC) method, and ChAT(IRES)-Cre mouse line, generated with the internal ribosome entry site (IRES) method. ChAT((BAC))-Cre transgenic and wild-type mice did not differ in general locomotor behavior, anxiety measures, drug-induced cataplexy, nicotine-mediated hypolocomotion, or operant food training. However, ChAT((BAC))-Cre transgenic mice did exhibit significant deficits in intravenous nicotine self-administration, which paralleled an increase in vesicular acetylcholine transporter and choline acetyltransferase (ChAT) hippocampal expression. For the ChAT((IRES))-Cre line, transgenic mice exhibited deficits in baseline locomotor, nicotine-mediated hypolocomotion, and operant food training compared with wild-type and hemizygous littermates. No differences among ChAT((IRES))-Cre wild-type, hemizygous, and transgenic littermates were found in anxiety measures, drug-induced cataplexy, and nicotine self-administration. Given that increased cre expression was present in the ChAT((IRES))-Cre transgenic mice, as well as a decrease in ChAT expression in the hippocampus, altered neuronal function may underlie behavioral phenotypes. In contrast, ChAT((IRES))-Cre hemizygous mice were more similar to wild-type mice in both protein expression and the majority of behavioral assessments. As such, interpretation of data derived from ChAT-Cre rodents must consider potential limitations dependent on the line and/or genotype used in research investigations.