Can we model anxio-depressive states through auditory-driven escape behaviour in mice

Anxiety and depression are highly prevalent psychiatric conditions that frequently co-occur, affecting approximately 25% of the population. The development of novel and effective therapeutic strategies for these disorders depends on the availability of robust preclinical models that can reliably capture their underlying behavioural and affective components. In particular, there is a growing need for non-invasive, repeatable, and longitudinal behavioural assays capable of monitoring anxio-depressive symptoms over time within the same subjects. Such approaches would improve translational validity and allow for more precise evaluation of treatment effects and disease progression.

The present study aimed to validate a novel behavioural paradigm designed to assess emotional distress in mice using an operant escape task driven by aversive, yet non-painful, auditory stimuli. In this task, mice were trained to terminate an ongoing tone by performing a simple operant response i.e., nose-poking into a tunnel. This design allows for the quantification of escape behaviour as a proxy for aversion and emotional distress while minimizing confounds associated with physical pain.

To establish the aversive nature of the auditory stimulus and confirm its independence from nociceptive processing, we conducted pharmacological validation using two distinct classes of analgesics: buprenorphine, an opioid with both analgesic and affective-modulating properties, and meloxicam, a nonsteroidal anti-inflammatory drug primarily targeting peripheral inflammation. Escape behaviour was significantly attenuated following administration of buprenorphine, suggesting modulation of affective processing, whereas meloxicam had no significant effect. These findings support the interpretation that the task is driven by psychological distress rather than physical pain.

To further evaluate the predictive validity of the operant escape paradigm for anxio-depressive-like states, we assessed its sensitivity to a range of pharmacological and stress-related manipulations. Acute administration of ethanol at anxiolytic doses produced a mild reduction in escape frequency, indicating partial sensitivity of the task to anxiolytic interventions. In contrast, chronic exposure to corticosterone, a commonly used model of stress-induced depression, did not significantly alter escape behaviour, suggesting that the task may capture a specific dimension of affective processing that is not directly influenced by this form of endocrine stress manipulation. Ongoing studies are examining the effects of additional pharmacological agents, including diazepam, fluoxetine, and ketamine, to further characterize the behavioural and neuropharmacological profile of the assay.

Overall, these findings provide preliminary evidence that escape from aversive auditory stimuli reflects an affective state driven by psychological distress rather than nociceptive input. The operant nature of the task, combined with its non-invasive and repeatable design, makes it particularly well-suited for longitudinal studies of emotional behaviour. Although the paradigm demonstrates moderate sensitivity to certain anxiolytic agents, its lack of responsiveness to corticosterone highlights the possibility that it isolates a distinct behavioural phenotype within the broader spectrum of anxio-depressive symptoms. Collectively, this work underscores the potential utility of auditory-driven operant escape tasks as a novel tool for dissecting the affective components of aversive processing and advancing preclinical research in mood disorders.

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