Department of Psychology, Yale University, New Haven, CT, USA.
Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT, USA.
J Neurosci Res. 2022 Mar;100(3):731-743. doi: 10.1002/jnr.24946. Epub 2021 Sep 8.
The endocannabinoid system is an important regulator of emotional responses such as fear, and a number of studies have implicated endocannabinoid signaling in anxiety. The fatty acid amide hydrolase (FAAH) C385A polymorphism, which is associated with enhanced endocannabinoid signaling in the brain, has been identified across species as a potential protective factor from anxiety. In particular, adults with the variant FAAH 385A allele have greater fronto-amygdala connectivity and lower anxiety symptoms. Whether broader network-level differences in connectivity exist, and when during development this neural phenotype emerges, remains unknown and represents an important next step in understanding how the FAAH C385A polymorphism impacts neurodevelopment and risk for anxiety disorders. Here, we leveraged data from 3,109 participants in the nationwide Adolescent Brain Cognitive Development Study℠ (10.04 ± 0.62 years old; 44.23% female, 55.77% male) and a cross-validated, data-driven approach to examine associations between genetic variation and large-scale resting-state brain networks. Our findings revealed a distributed brain network, comprising functional connections that were both significantly greater (95% CI for p values = [<0.001, <0.001]) and lesser (95% CI for p values = [0.006, <0.001]) in A-allele carriers relative to non-carriers. Furthermore, there was a significant interaction between genotype and the summarized connectivity of functional connections that were greater in A-allele carriers, such that non-carriers with connectivity more similar to A-allele carriers (i.e., greater connectivity) had lower anxiety symptoms (β = -0.041, p = 0.030). These findings provide novel evidence of network-level changes in neural connectivity associated with genetic variation in endocannabinoid signaling and suggest that genotype-associated neural differences may emerge at a younger age than genotype-associated differences in anxiety.
内源性大麻素系统是情绪反应（如恐惧）的重要调节者，许多研究表明内源性大麻素信号与焦虑有关。脂肪酸酰胺水解酶 (FAAH) C385A 多态性与大脑中的内源性大麻素信号增强有关，已在不同物种中被确定为焦虑的潜在保护因素。特别是，具有变异 FAAH 385A 等位基因的成年人具有更大的额-杏仁核连接和更低的焦虑症状。是否存在更广泛的连接网络水平差异，以及这种神经表型何时出现，目前尚不清楚，这是理解 FAAH C385A 多态性如何影响神经发育和焦虑障碍风险的重要下一步。在这里，我们利用来自全国青少年大脑认知发展研究（Adolescent Brain Cognitive Development Study℠）的 3109 名参与者的数据（年龄 10.04±0.62 岁；44.23%女性，55.77%男性）和一种经过交叉验证的数据驱动方法，来研究遗传变异与大规模静息状态大脑网络之间的关联。我们的研究结果揭示了一个分布式大脑网络，包括功能连接，这些连接在 A 等位基因携带者中显著更大（95%置信区间的 p 值 = [<0.001，<0.001]）和更小（95%置信区间的 p 值 = [0.006，<0.001]）。此外，基因型与功能连接的综合连接之间存在显著的相互作用，在 A 等位基因携带者中更大，因此与 A 等位基因携带者连接更相似（即更大的连接）的非携带者具有更低的焦虑症状（β=-0.041，p=0.030）。这些发现为与内源性大麻素信号遗传变异相关的神经连接的网络水平变化提供了新的证据，并表明与基因型相关的神经差异可能出现在比与基因型相关的焦虑差异更早的年龄。
