Genetic Variation of the Serotonin 2a Receptor Affects Hippocampal Novelty Processing in Humans

Serotonin (5-hydroxytryptamine, 5-HT) is an important neuromodulator in learning and memory processes. A functional genetic polymorphism of the 5-HT 2a receptor (5-HTR2a His452Tyr), which leads to blunted intracellular signaling, has previously been associated with explicit memory performance in several independent cohorts, but the underlying neural mechanisms are thus far unclear. The human hippocampus plays a critical role in memory, particularly in the detection and encoding of novel information. Here we investigated the relationship of 5-HTR2a His452Tyr and hippocampal novelty processing in 41 young, healthy subjects using functional magnetic resonance imaging (fMRI). Participants performed a novelty/familiarity task with complex scene stimuli, which was followed by a delayed recognition memory test 24 hours later. Compared to His homozygotes, Tyr carriers exhibited a diminished hippocampal response to novel stimuli and a higher tendency to judge novel stimuli as familiar during delayed recognition. Across the cohort, the false alarm rate during delayed recognition correlated negatively with the hippocampal novelty response. Our results suggest that previously reported effects of 5-HTR2a on explicit memory performance may, at least in part, be mediated by alterations of hippocampal novelty processing

Retrieval of bindings between task-irrelevant stimuli and responses can facilitate behaviour under conditions of high response certainty

Repetition priming can be driven by the encoding and retrieval of stimulus-response (S-R) bindings. When a previously encoded S-R binding is retrieved, and is congruent with the response currently required, it can bias response-selection processes towards selecting the retrieved response, resulting in facilitation. Previous studies have used classification tasks at retrieval. Here, two (or more) response options are competing, and it is likely that any evidence (e.g., an S-R binding) in favour of one option will be utilized to effect a decision. Thus, S-R effects are likely to be seen when using such a task. It is unclear whether such effects can be seen under conditions of higher response certainty, when participants are explicitly cued to make a response. Across two experiments, evidence for a modulating influence of S-R bindings is seen despite using a response cueing method at retrieval to minimize response uncertainty and despite stimuli being task irrelevant. Finally, the results suggest that responses within these S-R bindings are coded at the level of left versus right hand, and not a more fine-grained within-hand thumb versus index finger. The results underline the resilience of S-R effects, suggesting that they are present even under conditions where no explicit object-oriented decision is required