Ablation of the central noradrenergic neurons for unraveling their roles in stress and anxiety
Ablation of the central noradrenergic neurons for unraveling their roles in stress and anxiety
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DOI：
10.1196/annals.1417.012
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发表时间：
2008-01-01
期刊：
影响因子：
--
通讯作者：
Itoi, Keiichi
中科院分区：
文献类型：
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作者：
Itoi, Keiichi
尽管有大量证据表明中枢去甲肾上腺素(NA)系统与恐惧/焦虑状态之间存在联系，但先前的动物研究并未显示蓝斑(LC)完全参与调节恐惧或焦虑。在恐惧条件反射研究中，由于6-羟基多巴胺(6-OHDA)诱导的LC消融的阴性结果，大多数研究人员不敢使用消融策略来解决这个问题。除了Lapiz和他的同事的研究外，后来进行的有限数量的努力所获得的结果也与LC与焦虑有关的想法不一致。鉴于神经毒素诱导的NA消融存在方法学问题，本文建立了一种新的小鼠模型，即通过免疫毒素介导的细胞靶向选择性、彻底地消融LC-NA神经元。这个模型的使用清楚地证明了LC是焦虑回路的一部分。最新的研究与以前的研究不同的原因尚不清楚，但这可能是由于实验范式的不同或LC消融的不同方法所致。无论如何，我们的发现阐明了LC是与焦虑行为有关的基因座，并可能有助于将先前研究中明显不一致的结果联系起来。此外，本文提出的LC细胞靶向的新方法可能为研究LC的生理作用提供一种潜在的手段，包括睡眠/觉醒，以及它可能参与精神障碍的发病机制，包括抑郁、焦虑障碍和注意缺陷/多动障碍。
Despite considerable evidence suggesting the relationship between the central noradrenergic (NA) system and fear/anxiety states, previous animal studies have not demonstrated sheer involvement of the locus coeruleus (LC) in mediating fear or anxiety. Following the negative results of 6-hydroexydopamine (6-OHDA)-induced LC ablation in fear-conditioning studies, most researchers dared not approach this problem using the ablation strategy. The results obtained by a limited number of endeavors, conducted later, were not consistent with the idea of LC being related to anxiety, either, with the exception of the study by Lapiz and colleagues. Since methodological problems were recognized in the neurotoxin-induced NA ablation, employed in previous studies, a novel mouse model was developed in which the LC-NA neurons were ablated selectively and thoroughly by the immunotoxin-mediated cellular targeting. The use of this model clearly demonstrated that the LC was part of the anxiety circuitry. The reason for the discrepancy between the latest study and previous ones is not clear, but it may be due either to the difference in the experimental paradigms or to the different methods for LC ablation. In any case, our findings have shed light on the LC as a locus pertaining to anxiety behavior, and may help link the apparently inconsistent results in previous studies. In addition, the novel method for the LC cell targeting, presented here may provide a potential means for studying the physiological roles of the LC including sleep/wakefulness, as well as its possible involvement in the pathogenesis of psychiatric disorders, including depression, anxiety disorders, and attention deficit/hyperactivity disorder.