Temporally and anatomically specific contributions of the human amygdala to threat and safety learning

Zhenfu Wen, Candace M. Raio, Edward F. Pace-Schott, Sara W. Lazar, Joseph E. LeDoux, Elizabeth A. Phelps, Mohammed R. Milad

Research output: Contribution to journalArticlepeer-review


Neural plasticity in subareas of the rodent amygdala is widely known to be essential for Pavlovian threat conditioning and safety learning. However, less consistent results have been observed in human neuroimaging studies. Here, we identify and test three important factors that may contribute to these discrepancies: the temporal profile of amygdala response in threat conditioning, the anatomical specificity of amygdala responses during threat conditioning and safety learning, and insufficient power to identify these responses. We combined data across multiple studies using a well-validated human threat conditioning paradigm to examine amygdala involvement during threat conditioning and safety learning. In 601 humans, we show that two amygdala subregions tracked the conditioned stimulus with aversive shock during early conditioning while only one demonstrated delayed responding to a stimulus not paired with shock. Our findings identify cross-species similarities in temporal- and anatomical-specific amygdala contributions to threat and safety learning, affirm human amygdala involvement in associative learning and highlight important factors for future associative learning research in humans.

Original languageEnglish (US)
Article numbere2204066119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number26
StatePublished - Jun 28 2022


  • amygdala
  • fMRI
  • threat conditioning

ASJC Scopus subject areas

  • General


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