Department of Psychiatry, Addiction Research Center, and Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan 48109.
J Neurosci. 2014 Mar 12;34(11):4099-107. doi: 10.1523/JNEUROSCI.3672-13.2014.
Variations in the corticotropin-releasing hormone receptor 1 (CRHR1) gene have been found to interact with stress in modulating excessive alcohol consumption. However, the neural mechanisms through which CRHR1 influences this risk in humans is largely unknown. This study examined the influence of an intronic CRHR1 gene variant, rs110402, on brain responses to negative emotional words, negative emotional traits, and alcohol use in adolescents and young adults at high risk for alcoholism. Childhood stress was investigated as a potential moderator. Using functional magnetic resonance imaging, we found that a region in the right ventrolateral prefrontal cortex (rVLPFC) was more engaged during negative emotional word processing in G homozygotes than in A allele carriers (p(FWE corrected) < 0.01, N = 77). Moreover, an indirect effect of genotype on negative emotionality via rVLPFC activation (p < 0.05, N = 69) was observed, which was further moderated by childhood stress (p < 0.05, N = 63). Specifically, with low childhood stress, G homozygotes exhibited lower levels of negative emotionality associated with greater rVLPFC activation, suggesting that the rVLPFC is involved in reappraisal that neutralizes negative emotional responses. In addition, we found that genotype indirectly modulated excessive alcohol consumption (p < 0.05, N = 69). Specifically, G homozygotes showed greater rVLPFC activation and had lower levels of negative emotionality, which were associated with fewer binge-drinking days and fewer alcohol related problems. This work provides support for a model in which CRHR1 gene variation modulates the risk of problem drinking via an internalizing/negative affect pathway involving rVLPFC and reappraisal of negative emotion.
促肾上腺皮质激素释放激素受体 1（CRHR1）基因的变异已被发现与应激相互作用，调节过度饮酒。然而，CRHR1 影响人类这种风险的神经机制在很大程度上尚不清楚。本研究探讨了内含子 CRHR1 基因变异 rs110402 对青少年和年轻成人酗酒风险的大脑对负面情绪词、负面情绪特质和酒精使用的反应的影响，同时研究了童年压力作为潜在的调节因素。使用功能磁共振成像，我们发现右外侧前额叶皮层（rVLPFC）的一个区域在 G 纯合子处理负面情绪词时比 A 等位基因携带者更活跃（校正 FWE 后 p < 0.01，N = 77）。此外，还观察到基因型通过 rVLPFC 激活对负面情绪的间接影响（p < 0.05，N = 69），这受到童年压力的进一步调节（p < 0.05，N = 63）。具体来说，在童年压力低的情况下，G 纯合子表现出与更大的 rVLPFC 激活相关的较低水平的负面情绪，这表明 rVLPFC 参与了重新评估，从而中和了负面情绪反应。此外，我们发现基因型间接地调节了过量饮酒（p < 0.05，N = 69）。具体来说，G 纯合子表现出更大的 rVLPFC 激活和较低的负面情绪水平，这与更少的狂饮日和更少的酒精相关问题有关。这项工作为 CRHR1 基因变异通过涉及 rVLPFC 和负面情绪重新评估的内化/负面情绪途径调节问题饮酒风险的模型提供了支持。
