# Vasopressin and angiotensin II pathways differentially modulate human fear response dynamics to looming threats

## TL;DR

This study shows how two neuropeptide systems, vasopressin and angiotensin II, differently affect human fear responses to approaching threats.

## Contribution

The study reveals distinct roles of vasopressin and angiotensin II in modulating human threat processing dynamics.

## Key findings

- Vasopressin induced time overestimation and sustained hypervigilance during threat exposure.
- Losartan reduced anxiety and promoted flexible threat response patterns.
- Pupillometry and computational models showed pathway-specific arousal and response dynamics.

## Abstract

While basal threat processing dynamics (e.g., visual looming) are well characterized in animals, the underlying mechanisms and their modulation by neuropeptide systems with different modulatory roles in threat processing (vasopressin, angiotensin II) remain poorly understood in humans. In a randomized, placebo-controlled eye-tracking study (N = 111), we administered vasopressin (AVP) or an angiotensin II receptor blocker (via Losartan, LT) during a time-to-collision threat paradigm. This study was prospectively registered at ClinicalTrials.gov (NCT06329076, NCT06329063) on April 11, 2024, prior to participant enrollment. Behaviorally, AVP induced a systematic time overestimation while LT induced temporal compression and reduced state anxiety. Pupillometry revealed distinguishable profiles: AVP induced sustained constriction during stimulus approach followed by post-stimulus threat-specific dilation, LT maintained sustained pupillary constriction throughout both approach and occlusion phases yet preserving threat-specificity, while placebo (PLC) showed no threat-specific modulation. A computational framework (combining Functional Principal Component Analysis, clustering, and Markov chain analysis) underscored the distinct modulations: AVP stabilized a high-arousal state characterized by the co-activation of vigilance, threat-proactive preparation and a shift from perception to internal simulation. LT suppressed transitions to high-arousal states and exhibited maximal sequence entropy, reflecting flexible response patterns—contrasting with placebo’s lowest entropy dynamics. These results demonstrate that AVP and LT differentially regulate basal threat processing via separable neuropeptide pathways: AVP sustains hypervigilance while LT promotes anxiolysis and adaptive flexibility. Our findings suggest neuropeptide pathway-specific targets maladaptive threat processing in trauma- or anxiety-related disorders.

Neuromodulatory pathways are involved in threat-processing, but the roles of specific neuropeptides in the human threat response are not clear. This study in humans characterized the distinct impacts of pharmacological manipulation of two neuropeptide pathways on responses to looming stimuli, with implications for understanding trauma- or anxiety-related disorders.