A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction
A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction
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DOI：
10.1073/pnas.1004745107
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发表时间：
2010-07-27
影响因子：
11.1
通讯作者：
Stein, Elliot A.
中科院分区：
文献类型：
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作者：
Hong, L. Elliot;Hodgkinson, Colin A.;Stein, Elliot A.
全基因组搜索已经确定了与吸烟有关的烟碱乙酰胆碱受体α 5- α 3- β 4亚基基因变异。基因是如何通过其在大脑中的表达来支持这种成瘾和高风险行为的，目前仍知之甚少。在这里，我们发现一个关键的α 5基因变异Asp398Asn与背侧前扣带-腹侧纹状体/扩展杏仁核回路相关，因此“风险等位基因”降低了该回路中固有的静息功能连接强度。重要的是，这种效应是在非吸烟者和吸烟者中独立观察到的，尽管电路强度区分吸烟者和非吸烟者，预测吸烟者的成瘾严重程度，并且不是吸烟本身的继发性，因此代表了一种类似特征的电路生物标志物。同样的神经回路在患有精神疾病的人群中进一步受损，他们的吸烟率最高。确定大脑回路在哪里以及如何将基因与吸烟联系起来，为开发新的治疗方法提供了实用的神经回路目标。
Whole-genome searches have identified nicotinic acetylcholine receptor alpha 5-alpha 3-beta 4 subunit gene variants that are associated with smoking. How genes support this addictive and high-risk behavior through their expression in the brain remains poorly understood. Here we show that a key alpha 5 gene variant Asp398Asn is associated with a dorsal anterior cingulate-ventral striatum/extended amygdala circuit, such that the "risk allele" decreases the intrinsic resting functional connectivity strength in this circuit. Importantly, this effect is observed independently in nonsmokers and smokers, although the circuit strength distinguishes smokers from nonsmokers, predicts addiction severity in smokers, and is not secondary to smoking per se, thus representing a trait-like circuitry biomarker. This same circuit is further impaired in people with mental illnesses, who have the highest rate of smoking. Identifying where and how brain circuits link genes to smoking provides practical neural circuitry targets for new treatment development.