SummaryAnimal models of human anxiety often invoke a conflict between approach and avoidance [1, 2]. In these, a key behavioral assay comprises passive avoidance of potential threat and inhibition, both thought to be controlled by ventral hippocampus [2–6]. Efforts to translate these approaches to clinical contexts [7, 8] are hampered by the fact that it is not known whether humans manifest analogous approach-avoidance dispositions and, if so, whether they share a homologous neurobiological substrate [9]. Here, we developed a paradigm to investigate the role of human hippocampus in arbitrating an approach-avoidance conflict under varying levels of potential threat. Across four experiments, subjects showed analogous behavior by adapting both passive avoidance behavior and behavioral inhibition to threat level. Using functional magnetic resonance imaging (fMRI), we observe that threat level engages the anterior hippocampus, the human homolog of rodent ventral hippocampus [10]. Testing patients with selective hippocampal lesions, we demonstrate a causal role for the hippocampus with patients showing reduced passive avoidance behavior and inhibition across all threat levels. Our data provide the first human assay for approach-avoidance conflict akin to that of animal anxiety models. The findings bridge rodent and human research on passive avoidance and behavioral inhibition and furnish a framework for addressing the neuronal underpinnings of human anxiety disorders, where our data indicate a major role for the hippocampus.

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Long-term memory can improve when incoming information is congruent with known semantic information. This so-called congruence effect has widely been shown in younger adults, but age-related changes and neural mechanisms remain unclear. Here, congruence improved recognition memory in younger and older adults (i.e. congruence effect), with only weak evidence for age-related decline in one behavioral study. In an EEG study, however, no significant behavioral differences in the congruence effect could be observed between age-groups. In line with this observation, electroencephalography data show that, in both groups, congruence led to widespread differences in Event-Related Potentials (ERPs), starting at around 400 ms after stimulus onset, and theta, alpha and beta oscillations (4-20 Hz). importantly, these congruence-related eRps were associated to increases in memory performance for congruent items, in both age groups. finally, the described eRps and neural oscillations in the theta-alpha range (5-13 Hz) were less pronounced in the elderly despite a preserved congruence effect. together, semantic congruence increases long-term memory across the lifespan, and, at the neural level, this could be linked to neural oscillations in the theta, alpha and beta range, as well as eRps that were previously associated with semantic processing.

As the stream of experience unfolds, our memory system rapidly transforms current inputs into long-lasting meaningful memories. A putative neural mechanism that strongly influences how input elements are transformed into meaningful memory codes relies on the ability to integrate them with existing structures of knowledge or schemas. However, it is not yet clear whether schema-related integration neural mechanisms occur during online encoding. In the current investigation, we examined the encoding-dependent nature of this phenomenon in humans. We showed that actively integrating words with congruent semantic information provided by a category cue enhances memory for words and increases false recall. The memory effect of such active integration with congruent information was robust, even with an interference task occurring right after each encoding word list. In addition, via electroencephalography, we show in 2 separate studies that the onset of the neural signals of successful encoding appeared early (ϳ400 ms) during the encoding of congruent words. That the neural signals of successful encoding of congruent and incongruent information followed similarly ϳ200 ms later suggests that this earlier neural response contributed to memory formation. We propose that the encoding of events that are congruent with readily available contextual semantics can trigger an accelerated onset of the neural mechanisms, supporting the integration of semantic information with the event input. This faster onset would result in a long-lasting and meaningful memory trace for the event but, at the same time, make it difficult to distinguish it from plausible but never encoded events (i.e., related false memories).