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bioRxiv · 10.1101/2025.10.05.680501

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.
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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.

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Colwell, M. J., van Uum, F., Cowen, P. J., Martens, M., Browning, M., Barron, H., Harmer, C. J., Murphy, S.. 2025-10-06. Synaptic histamine shapes the neurocomputational dynamics of human learning. https://doi.org/10.1101/2025.10.05.680501

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