Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviors. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (7 Tesla) fMRI to examine the neural basis of safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat omission when paired with a known threat signal (A+/AX-), and a standard safety signal that generally predicted threat omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation (P_FDR whole-brain corrected). The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular, and dorsolateral PFC compared with the standard safety signal, whereas the latter evoked greater activation of the ventromedial PFC, posterior cingulate, and hippocampus, among other regions. Further analyses of the conditioned inhibitor indicated that its initial learning was characterized by consistent engagement of dorsal striatal, midbrain, thalamic, premotor, and prefrontal subregions. These findings suggest that safety learning via conditioned inhibition involves a distributed cortico-striatal circuitry, separable from broader cortical regions involved with processing standard safety signals (e.g., CS^–). This cortico-striatal system could represent a novel neural substrate of safety learning, underlying the initial generation of "stimulus–safety" associations, distinct from wider cortical correlates of safety processing, which facilitate the behavioral outcomes of learning.

SIGNIFICANCE STATEMENT Identifying safety is critical for maintaining adaptive levels of anxiety, but the neural mechanisms of human safety learning remain unclear. Using 7 Tesla fMRI, we compared learning-related brain activity for a conditioned inhibitor, which actively predicted threat omission, and a standard safety signal (CS^–), which was passively unpaired with threat. The inhibitor engaged an extended circuitry primarily featuring the dorsal striatum, along with thalamic, midbrain, and premotor/PFC regions. The CS^– exclusively involved cortical safety-related regions observed in basic safety conditioning, such as the vmPFC. These findings extend current models to include learning-specific mechanisms for encoding stimulus–safety associations, which might be distinguished from expression-related cortical mechanisms. These insights may suggest novel avenues for targeting dysfunctional safety learning in psychopathology.

安全学习在中性刺激和没有威胁之间产生关联，促进抑制恐惧和寻求安全的行为。安全学习究竟是如何在大脑系统的底层进行调节的，尤其是在人类中，目前尚不清楚。在这里，我们将一种新的巴甫洛夫条件抑制任务与超高场 (7 特斯拉) fMRI 相结合，以检查 49 名健康参与者安全学习的神经基础。在我们的任务中，参与者受到两个安全信号的制约：一种条件抑制物，当与已知威胁信号 (A+/AX-) 配对时预测威胁遗漏，以及一个通常预测威胁遗漏 (BC-) 的标准安全信号。两种安全信号都引起了等效的自主和主观学习反应，但在潜在的大脑激活方面存在很大差异（P _FDR全脑校正）。与标准安全信号相比，条件性抑制剂的特点是背侧纹状体、前岛叶和背外侧 PFC 的激活更显着，而后者引起腹内侧 PFC、后扣带回和海马等区域的更大激活。对条件性抑制剂的进一步分析表明，其初始学习的特点是背侧纹状体、中脑、丘脑、前运动和前额叶亚区的持续参与。这些发现表明，通过条件抑制进行的安全学习涉及分布式皮质-纹状体回路，可与处理标准安全信号（例如，CS ^–). 这种皮质-纹状体系统可以代表一种新的安全学习神经基质，它是最初生成的“刺激-安全”关联的基础，不同于更广泛的安全处理皮质关联，后者促进了学习的行为结果。

意义声明识别安全对于维持适应性焦虑水平至关重要，但人类安全学习的神经机制仍不清楚。使用 7 Tesla fMRI，我们比较了与学习相关的大脑活动的条件抑制剂，它主动预测威胁遗漏，以及标准安全信号 (CS ^– )，它被动地与威胁不配对。该抑制剂参与了一个主要以背侧纹状体为特征的扩展电路，以及丘脑、中脑和运动前/前额叶皮层区域。CS—— ^_专门涉及在基本安全调节中观察到的皮质安全相关区域，例如 vmPFC。这些发现扩展了当前的模型，以包括用于编码刺激-安全关联的学习特定机制，这可能与表达相关的皮层机制不同。这些见解可能会提出针对精神病理学中功能失调的安全学习的新途径。