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Synaptic histamine shapes the neurocomputational dynamics of human learning

Colwell, M. J.; van Uum, F.; Cowen, P. J.; Martens, M.; Browning, M.; Barron, H.; Harmer, C. J.; Murphy, S.

2025-10-06 neuroscience
10.1101/2025.10.05.680501 bioRxiv
Show abstract

Histamine was the first canonical monoamine identified in the mammalian brain 1-6, yet arguably remains the least understood in its mechanistic contributions to human behaviour. Using a first-in-class causal probe (H3R inverse agonist pitolisant), we show how increased synaptic histamine shapes offline and online temporal-hippocampal dynamics, sustaining learning-related activity and polarising retrieval computations. At a broader level, elevated histamine adaptively shifts neurocomputational strategy under high cognitive load, while stabilising value updates during aversive reinforcement learning. These findings uncover a mechanistically grounded influence of this underexplored system on human neurocomputation, supporting its therapeutic potential in psychiatry.

Published in Nature Communications (predicted rank #1) · training set

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