Stress disrupts hippocampal integration of overlapping events and memory inference in humans
Stress disrupts hippocampal integration of overlapping events and memory inference in humans
KAI A. SCHÜREN HTTPS://ORCID.ORG/0009-0008-4720-9131, NICOLE L. VARGA HTTPS://ORCID.ORG/0000-0002-3972-9187, […] , AND LARS SCHWABE HTTPS://ORCID.ORG/0000-0003-4429-4373+3 authors Authors Info & Affiliations
SCIENCE ADVANCES
22 May 2026
Vol 12, Issue 21
DOI: 10.1126/sciadv.aea5496
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Abstract
Integrating related events in memory is essential for building knowledge that extends beyond direct observation and enables flexible inference. Here, we show that acute stress impairs inference by both reducing the degree to which past memories are reactivated during new learning and leading to their differentiation, rather than integration, in hippocampus. Adults learned A-B associations on day 1 and underwent a stress or control manipulation before learning overlapping B-C associations on day 2, with A-C inference tested thereafter. We demonstrate that stress reduces hippocampal reactivation of A elements during B-C learning, and lower reactivation was directly correlated with impaired A-C inference. Representational similarity analysis revealed that stress increases neural dissimilarity between overlapping A and C elements in the hippocampus, indicating pattern differentiation and a representation as discrete events. Our findings demonstrate that acute stress hampers a key memory integration mechanism, with broad implications for educational, legal, and clinical settings.
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INTRODUCTION
Human memory is remarkably flexible, allowing us to maintain an up-to-date and coherent model of our environment. A key feature of this flexibility is the ability to integrate distinct experiences that share overlapping elements, forming structured knowledge representations that allow inferring novel relationships (1–3). For instance, if a friend shows you their new, light blue Vespa, and you later see the same scooter parked outside the university library, you might infer that your friend is studying inside. This ability to link related memories—a process referred to as memory integration and known to depend on the hippocampus (4, 5)—is a fundamental cognitive mechanism that supports memory inference based on shared information (6, 7). Beyond its fundamental relevance for cognition in general, the accuracy of memory integration has important implications for several applied contexts. In legal settings, the impaired integration of overlapping memories can lead to false inferences and wrongful accusations (8). In education, building cohesive memory structures by combining related information underpins conceptual understanding and predicts long-term academic outcome (1, 9). Furthermore, mnemonic integration is highly relevant to mental health, as impairments in linking related experiences are characteristic of several psychiatric disorders, such as psychosis (10, 11) and anxiety disorders (12, 13). Thus, understanding the factors that influence our capacity to link memories is crucial.
Acute stress is a potent modulator of memory (14–16), with substantial implications for both educational and mental health outcomes (17–20). Decades of research have shown that acute stress can enhance memory consolidation while impairing memory retrieval, and both of these effects appeared to be particularly pronounced for emotionally arousing material (21–24). While most research on stress and memory has focused on consolidation and retrieval processes, initial evidence suggests that acute stress may also influence memory flexibility (25–27). Brain regions that are critical for memory integration—especially the hippocampus (4, 28)—have a particularly high density of receptors for stress mediators such as glucocorticoids and norepinephrine (29, 30). Through the action of these stress mediators, stress can disrupt hippocampal processing (14, 31) and hence interfere with hippocampal reactivation of overlapping memory content during new learning and updating mechanisms that promote integration. However, it remains unknown whether stress affects the integration of events that share overlapping elements, allowing inferences about relationships between events that have not been experienced together, and if so, which neural mechanisms underlie such stress-induced changes in mnemonic integration.
In this preregistered study, we tested the hypothesis that acute psychosocial stress before learning of overlapping mnemonic content affects the ability to integrate memories and, consequently, memory-based inference. Using repeated functional magnetic resonance imaging (fMRI) combined with multivariate decoding and representational similarity analysis (RSA), we further sought to elucidate the neural mechanisms underlying stress effects on memory integration in the human brain. To this end, we used an associative inference task probing memory integration (32). In this task, healthy participants first learned A-B image associations (e.g., a friend and a light blue Vespa) on day 1. On the following day, they underwent either a psychosocial stressor [Trier Social Stress Test (TSST); (33)] or a control manipulation immediately before encoding B-C image associations (e.g., the same Vespa and the university library), thus testing whether stress may interfere with A element reactivation during B-C encoding. Approximately 1 hour later, we assessed participants’ inference ability by testing A-C associations (e.g., friend and library). Given that stress effects on memory are typically stronger for emotionally salient material (21, 22, 34), A images were drawn from emotionally arousing (e.g., fear or threat related) or neutral categories, and emotional valence was rated by the participants at the end of the experiment. We predicted that acute stress before B-C learning would impair mnemonic integration and inference. This impairment could potentially stem from difficulties retrieving A-B and B-C pairs, which we therefore evaluated following the A-C inference test.
However, we assumed that a mere stress-induced retrieval deficit would not fully account for the predicted inference impairment. Instead, we proposed that stress would affect how new experiences are organized relative to prior, related memories. Specifically, we hypothesized that stress would disrupt reactivation of A elements during B-C learning, thereby hindering the integration of A, B, and C elements into a coherent memory trace. To test this hypothesis, A stimuli were drawn from two categories (i.e., faces and scenes) that are known to have distinct neural underpinnings (35, 36). We trained a classifier on a separate task to identify these category-specific neural signatures and applied it to the B-C learning phase to quantify A element reactivation. In addition, we considered a complementary mechanism involving pattern integration or differentiation processes reflected in representational changes of individual memory elements A and C, which shared an overlapping association (B). To assess this, we presented all A and C stimuli individually on day 1 (preexposure) and again on day 2 (postexposure). Increases in representational similarity after learning would indicate memory integration, whereas decreases in representational similarity would point to memory differentiation [or repulsion; (2, 3, 32)]. This analysis of neural A and C element representations provides also important insights into how acute stress affects memory, either by increasing integration, thus leading to overgeneralization, or by decreasing it, thus reducing memory flexibility. By combining measures of representational change and memory reactivation, our experimental design extends our understanding of how stress influences the neural organization of overlapping events.
RESULTS
To unravel the impact of acute stress on memory integration of overlapping events and the underlying neural mechanisms, 121 healthy participants completed an associative inference task (32) within a 2-day fMRI design (Fig. 1). On day 1, participants completed a category localizer and afterward an item-level preexposure task in the MRI scanner, in which they saw all stimuli that were subsequently used as A and C elements. Thereafter, they learned 24 A-B associations as part of the associative inference task outside the scanner. On day 2, ~24 hours later, participants underwent either the TSST—a mock job interview widely regarded as a gold standard in experimental stress research (33)—or a control manipulation, immediately before learning 24 B-C associations that overlapped with previously learned A-B pairs and 12 nonoverlapping X-Y associations. They then completed a postexposure task, assessing learning-related representational changes of A and C elements, and a surprise A-C inference test inside the scanner. At the end of the experiment, participants rated the emotionality of the stimuli used in the task.
