Beyond the locus coeruleus: pupil dynamics as a systems-level marker of neuromodulatory influences on hippocampal...

Dopamine and norepinephrine regulate hippocampal plasticity through molecular, cellular and circuit mechanisms that shape which experiences are encoded and later remembered. Translating these mechanisms into human memory research remains challenging because direct measures of endogenous catecholaminergic activity are difficult to obtain during memory formation. This Perspective argues that pupillometry provides a non-invasive, temporally precise biomarker for bridging this translational gap. Rather than treating pupil dynamics as a simple proxy for locus coeruleus activity or general arousal, I consider whether pupil-linked memory effects can be better understood by relating them to concurrent neuromodulatory, autonomic and hippocampal processes. I further propose that dilation- and constriction-linked encoding profiles may be associated with different physiological configurations across encoding contexts, including conditions that favour model updating or integration with existing knowledge. I outline how multimodal approaches combining pupillometry with functional MRI, neuromelanin-sensitive imaging, pharmacology, magnetic resonance spectroscopy and computational modelling can test these hypotheses directly. Reframing pupillometry in this way provides a scalable route for linking dopamine and norepinephrine mechanisms with human hippocampal memory and for advancing translational research across ageing and disease.