Kuhn Manuel, Haaker Jan, Glotzbach-Schoon Evelyn, Schümann Dirk, Andreatta Marta, Mechias Marie-Luise, Raczka Karolina, Gartmann Nina, Büchel Christian, Mühlberger Andreas, Pauli Paul, Reif Andreas, Kalisch Raffael, Lonsdorf Tina B
Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,
Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Soc Cogn Affect Neurosci. 2016 May;11(5):803-12. doi: 10.1093/scan/nsv151. Epub 2016 Jan 8.
Being a complex phenotype with substantial heritability, anxiety and related phenotypes are characterized by a complex polygenic basis. Thereby, one candidate pathway is neuronal nitric oxide (NO) signaling, and accordingly, rodent studies have identified NO synthase (NOS-I), encoded by NOS1, as a strong molecular candidate for modulating anxiety and hippocampus-dependent learning processes. Using a multi-dimensional and -methodological replication approach, we investigated the impact of a functional promoter polymorphism (NOS1-ex1f-VNTR) on human anxiety-related phenotypes in a total of 1019 healthy controls in five different studies. Homozygous carriers of the NOS1-ex1f short-allele displayed enhanced trait anxiety, worrying and depression scores. Furthermore, short-allele carriers were characterized by increased anxious apprehension during contextual fear conditioning. While autonomous measures (fear-potentiated startle) provided only suggestive evidence for a modulatory role of NOS1-ex1f-VNTR on (contextual) fear conditioning processes, neural activation at the amygdala/anterior hippocampus junction was significantly increased in short-allele carriers during context conditioning. Notably, this could not be attributed to morphological differences. In accordance with data from a plethora of rodent studies, we here provide converging evidence from behavioral, subjective, psychophysiological and neuroimaging studies in large human cohorts that NOS-I plays an important role in anxious apprehension but provide only limited evidence for a role in (contextual) fear conditioning.
焦虑及相关表型是具有高度遗传性的复杂表型，其特征在于复杂的多基因基础。因此，一个候选途径是神经元一氧化氮（NO）信号传导，相应地，啮齿动物研究已将由NOS1编码的一氧化氮合酶（NOS-I）确定为调节焦虑和海马依赖性学习过程的强有力分子候选物。我们采用多维度和多方法的重复研究方法，在五项不同研究中，对总共1019名健康对照者，研究了功能性启动子多态性（NOS1-ex1f-VNTR）对人类焦虑相关表型的影响。NOS1-ex1f短等位基因的纯合携带者表现出更高的特质焦虑、担忧和抑郁得分。此外，短等位基因携带者在情境恐惧条件反射过程中表现出焦虑性担忧增加。虽然自主测量（恐惧增强惊吓）仅为NOS1-ex1f-VNTR对（情境）恐惧条件反射过程的调节作用提供了提示性证据，但在情境条件反射过程中，短等位基因携带者杏仁核/前海马交界处的神经激活显著增加。值得注意的是，这不能归因于形态学差异。根据大量啮齿动物研究的数据，我们在此提供了来自大型人类队列的行为、主观、心理生理和神经影像学研究的汇聚证据，表明NOS-I在焦虑性担忧中起重要作用，但仅为其在（情境）恐惧条件反射中的作用提供了有限证据。
