LAUSR

&NA; Prior knowledge, represented as a schema, facilitates memory encoding. This schema‐related learning is assumed to rely on the medial prefrontal cortex (mPFC) that rapidly integrates new information into the schema, whereas schema‐incongruent or novel information is encoded by the hippocampus. Stress is a powerful modulator of prefrontal and hippocampal functioning and first studies suggest a stress‐induced deficit of schema‐related learning. However, the underlying neural mechanism is currently unknown. To investigate the neural basis of a stress‐induced schema‐related learning impairment, participants first acquired a schema. One day later, they underwent a stress induction or a control procedure before learning schema‐related and novel information in the MRI scanner. In line with previous studies, learning schema‐related compared to novel information activated the mPFC, angular gyrus, and precuneus. Stress, however, affected the neural ensemble activated during learning. Whereas the control group distinguished between sets of brain regions for related and novel information, stressed individuals engaged the hippocampus even when a relevant schema was present. Additionally, stressed participants displayed aberrant functional connectivity between brain regions involved in schema processing when encoding novel information. The failure to segregate functional connectivity patterns depending on the presence of prior knowledge was linked to impaired performance after stress. Our results show that stress affects the neural ensemble underlying the efficient use of schemas during learning. These findings may have relevant implications for clinical and educational settings. HighlightsThe ability to use prior knowledge (schemas) enhances new learning.Acute stress interferes with the neural ensemble supporting schema‐related learning.Stress reduces the separation of brain regions involved in schema‐related and novel learning.This reduced segregation between neural ensembles is associated with impaired performance.