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Deja-vu? Neural and behavioural effects of the 5-HT₄ receptor agonist, prucalopride, in a hippocampal-dependent memory task.

ABSTRACT: Cognitive deficits commonly accompany psychiatric disorders but are often underrecognised, and difficult to treat. The 5-HT₄ receptor is a promising potential treatment target for cognitive impairment because in animal studies 5-HT₄ receptor agonists enhance hippocampal-dependent memory processes. To date, there has been little work translating these effects to humans. We tested whether short-term administration of the 5-HT₄ partial agonist, prucalopride, modified behavioural and neural (fMRI) memory processing in 44 healthy human volunteers using an experimental medicine model. We found that participants who had received six days of prucalopride treatment were significantly better at recalling previously seen neutral images and distinguishing them from new images. At a neural level, prucalopride bilaterally increased hippocampal activity and activity in the right angular gyrus compared with placebo. Taken together, these findings demonstrate the potential of 5-HT₄-receptor activation for cognitive enhancement in humans, and support the potential of this receptor as a treatment target for cognitive impairment.

SUBMITTER: de Cates AN

PROVIDER: S-EPMC8488034 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Evolutionary innovation in eukaryotes and especially animals is at least partially driven by genome rearrangements and the resulting emergence of proteins with new domain combinations, and thus potentially novel functionality. Given the random nature of such rearrangements, one could expect that proteins with particularly useful multidomain combinations may have been rediscovered multiple times by parallel evolution. However, existing reports suggest a minimal role of this phenomenon in the overall evolution of eukaryotic proteomes. We assembled a collection of 172 complete eukaryotic genomes that is not only the largest, but also the most phylogenetically complete set of genomes analyzed so far. By employing a maximum parsimony approach to compare repertoires of Pfam domains and their combinations, we show that independent evolution of domain combinations is significantly more prevalent than previously thought. Our results indicate that about 25% of all currently observed domain combinations have evolved multiple times. Interestingly, this percentage is even higher for sets of domain combinations in individual species, with, for instance, 70% of the domain combinations found in the human genome having evolved independently at least once in other species. We also show that previous, much lower estimates of this rate are most likely due to the small number and biased phylogenetic distribution of the genomes analyzed. The process of independent emergence of identical domain combination is widespread, not limited to domains with specific functional categories. Besides data from large-scale analyses, we also present individual examples of independent domain combination evolution. The surprisingly large contribution of parallel evolution to the development of the domain combination repertoire in extant genomes has profound consequences for our understanding of the evolution of pathways and cellular processes in eukaryotes and for comparative functional genomics.

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Deja-vu? Neural and behavioural effects of the 5-HT₄ receptor agonist, prucalopride, in a hippocampal-dependent memory task.

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Deja-vu? Neural and behavioural effects of the 5-HT₄ receptor agonist, prucalopride, in a hippocampal-dependent memory task.