Histamine shapes the neurocomputational dynamics of human learning.

Colwell, Michael J; van Uum, Fin J E; Cowen, Philip J; Martens, Marieke A G; Browning, Michael; Barron, Helen C; Harmer, Catherine J; Murphy, Susannah E · Nat Commun · 2026

basic_science · Level V

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Abstract

Histamine was the first canonical monoamine identified in the mammalian brain, yet arguably remains the least understood in its mechanistic contributions to human behaviour. Using a first-in-class causal probe (H<sub>3</sub>R inverse agonist pitolisant), we show how elevating histamine shapes offline and online temporal-hippocampal dynamics - sustaining episodic learning-related activity and polarising retrieval computations. Beyond this, histamine adaptively shifts neurocomputational strategy under high working memory 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.