Cowen, P. J. | Search bioRxiv

bioRxiv2025

Synaptic histamine shapes the neurocomputational dynamics of human learning

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.

neuroscience↗

bioRxiv2023

Direct serotonin release in humans shapes decision computations within aversive environments

The role of serotonin in human behaviour is critically informed by approaches which allow in vivo modification of synaptic serotonin. However, characterising the effects of increased serotonin signalling in human models of behaviour is challenging given the limitations of available experimental probes (e.g., SSRIs). Here we use a now accessible approach to directly increase synaptic serotonin in humans - a selective serotonin releasing agent - and examine its influence on domains of behaviour historically considered core functions of serotonin. Computational techniques including reinforcement learning and drift diffusion modelling were fit to observed behaviour. Reinforcement learning models revealed that increased synaptic serotonin reduced sensitivity specifically for outcomes in aversive but not appetitive contexts. Furthermore, increasing synaptic serotonin enhanced behavioural inhibition, and shifted bias towards impulse control during exposure to aversive emotional probes. These effects were seen in the context of overall improvements in memory for neutral verbal information. Our findings highlight the direct effects of increased synaptic serotonin on human behaviour, underlining its critical role in guiding decision-making within aversive and neutral contexts, and offering broad implications for longstanding theories of central serotonin function.

neuroscience↗