Biology subjects

Cowen, P. J.

Publications and source records attributed to Cowen, P. J..

4 recordsLinked to original sources

bioRxiv2026

Context-dependent effects of ketamine on emotional evidence integration

Understanding others' emotions requires continuously integrating noisy affective information as emotional states change over time. Research on emotion processing, however, has thus far focused on static environments or discrete events. Here, we developed a continuous emotional evidence integration task in which participants had to track the average emotional state in a rapidly changing sequence of faces under different levels of environmental volatility. This allowed us to examine emotion integration in changing environments. In online (n=92) and in-person (n=29) cohorts, participants integrated emotional information over longer timescales in stable environments while relying more strongly on recent evidence under volatility, consistent with principles established in perceptual decision-making. We further examined whether this process was modulated by ketamine, an NMDA receptor antagonist associated with evidence integration in the perceptual domain. We conducted a double-blind, placebo-controlled, within-subject study and probed emotion integration during the post-acute period, approximately 1.5 hours after the infusion. Ketamine modulated the temporal weighting of emotional evidence, shifting the balance between recent and past information depending on environmental volatility. Together, these findings show that emotional evidence integration dynamically adapts to the statistical structure of the environment and that ketamine can further modulate this process, which may have relevance for affective disorders.

neuroscience↗

bioRxiv2026

A hippocampal neuroimaging signature of neurovascular insulin signalling links metabolism to mood

Depression is a leading cause of global disability and is increasingly linked to systemic metabolic dysfunctions, including insulin resistance. However, the biological pathways connecting metabolic state to affective symptoms are unresolved. A growing body of evidence indicates that insulin, beyond its role in systemic glucose homeostasis, supports brain metabolism, synaptic function and cognition, yet its contribution to mood regulation remains unclear. Here, we identify a human hippocampal metabolic signature associated with glycaemic variation in individuals with depression. Using multimodal neuroimaging, we show that hippocampal concentrations of GABA and lactate correlate with HbA1c and with mood severity, while functional connectivity between the hippocampus and the default mode network tracks affective symptoms independently of adiposity. To causally probe these relationships, we generated a mouse model of hippocampus-specific insulin receptor depletion. Unexpectedly, reducing insulin signalling at the blood brain barrier enhanced neuronal metabolism and attenuated anxiety-like behaviour. Notably, hippocampal lactate and GABA levels similarly tracked anxiety-related behaviour in mice, mirroring their association with symptom severity in humans. Together, these findings identify a conserved neurometabolic signature linking hippocampal insulin signalling to affective state, and reveal that brain insulin resistance exerts context- and cell-type-specific effects on behaviour. This work establishes a mechanistic basis for brain insulin resistance in depression and highlights the hippocampus as a critical hub for metabolic modulation of mood.

neuroscience↗

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↗