A common genetic variant in fatty acid amide hydrolase is linked to alterations in fear extinction neural circuitry in a racially diverse, nonclinical sample of adults.
A common genetic variant in fatty acid amide hydrolase is linked to alterations in fear extinction neural circuitry in a racially diverse, nonclinical sample of adults.
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DOI：
10.1002/jnr.24860
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发表时间：
2022-03
影响因子：
4.2
通讯作者：
Rabinak CA
中科院分区：
文献类型：
--
作者：
Zabik NL;Iadipaolo AS;Marusak HA;Peters C;Burghardt K;Rabinak CA
恐惧消退学习和回忆能力差与基于恐惧的疾病（如创伤后应激障碍）的发展有关，并与恐惧相关神经回路的异常激活有关。这包括在消退学习过程中杏仁核的激活程度更高，而在回忆过程中海马和腹内侧前额叶皮层（vmPFC）的激活程度更低。新出现的数据表明，脂肪酸酰胺水解酶（FAAH C385 A; rs324420）的遗传变异与外周内源性大麻素（eCB）水平增加和与威胁相关的杏仁核反应性降低有关。临床前研究将增加的eCB信号传导与更好的消退学习和回忆联系起来，因此FAAH C385 A可以通过促进消退学习来防止创伤相关精神病理学的发展。然而，这种FAAH变体如何影响恐惧消退神经回路仍然未知。在本研究中，我们使用了一种新的，沉浸式现实的恐惧消退范式与功能性神经影像学相结合，以评估FAAH C385 A对来自城市地区（底特律，MI; N = 59; C/C = 35，A-载体= 24）的健康成年人的恐惧相关神经回路和条件性恐惧反应（美国预期评级，痛苦的主观单位和皮肤电导反应）的影响。我们发现，与C/C纯合子相比，A等位基因携带者在早期灭绝回忆过程中杏仁核激活较少。同样，我们发现较少的背侧前扣带皮层和更大的海马激活在早期灭绝学习的A-携带者相比，C/C纯合子。我们发现FAAH C385 A对vmPFC激活或行为恐惧指数没有影响。这些数据支持并扩展了先前的发现，即FAAH遗传变异与eCB信号的增加和随后的恐惧消退增强相关，可以预测成功的恐惧学习的个体差异。
Poor fear extinction learning and recall are linked to the development of fear-based disorders, like posttraumatic stress disorder, and are associated with aberrant activation of fear-related neural circuitry. This includes greater amygdala activation during extinction learning and lesser hippocampal and ventromedial prefrontal cortex (vmPFC) activation during recall. Emerging data indicate that genetic variation in fatty acid amide hydrolase (FAAH C385A; rs324420) is associated with increased peripheral endocannabinoid (eCB) levels and lesser threat-related amygdala reactivity. Preclinical studies link increased eCB signaling to better extinction learning and recall, thus FAAH C385A may protect against the development of trauma-related psychopathology by facilitating extinction learning. However, how this FAAH variant affects fear extinction neural circuitry remains unknown. In the present study, we used a novel, immersive-reality fear extinction paradigm paired with functional neuroimaging to assess FAAH C385A effects on fear-related neural circuitry and conditioned fear responding (US expectancy ratings, subjective units of distress, and skin conductance responding) in healthy adults from an urban area (Detroit, MI; N = 59; C/C = 35, A-carrier = 24). We found lesser amygdala activation in A-allele carriers, compared to C/C homozygotes, during early extinction recall. Likewise, we found lesser dorsal anterior cingulate cortex and greater hippocampus activation in early extinction learning in A-carriers compared to C/C homozygotes. We found no effects of FAAH C385A on vmPFC activation or behavioral fear indices. These data support and extend previous findings that FAAH genetic variation, associated with increased eCB signaling and subsequent enhanced fear extinction, may predict individual differences in successful fear learning.