Establishing operant conflict tests for the translational study of anxiety in mice

Abstract

Rationale: In conflict-based anxiety tests, rodents decide between actions with simultaneous rewarding and aversive outcomes. In humans, computerised operant conflict tests have identified response choice, latency, and vigour as distinct behavioural components. Animal operant conflict tests for measurement of these components would facilitate translational study.

Objectives: In C57BL/6 mice, two operant conflict tests for measurement of response choice, latency, and vigour were established, and effects of chlordiazepoxide (CDZ) thereon investigated.

Methods: Mice were moderately diet-restricted to increase sucrose reward salience. A 1-lever test required responding under medium-effort reward/threat conditions of variable ratio 2-10 resulting in sucrose at p = 0.7 and footshock at p = 0.3. A 2-lever test mandated a choice between low-effort reward/threat with a fixed-ratio (FR) 2 lever yielding sucrose at p = 0.7 and footshock at p = 0.3 versus high-effort reward/no threat with a FR 20 lever yielding sucrose at p = 1.

Results: In the 1-lever test, CDZ (7.5 or 15 mg/kg i.p.) reduced post-trial pause (response latency) following either sucrose or footshock and reduced inter-response interval (increased response vigour) after footshock. In the 2-lever test, mice favoured the FR2 lever and particularly at post-reward trials. CDZ increased choice of FR2 and FR20 responding after footshock, reduced response latency overall, and increased response vigour at the FR2 lever and after footshock specifically.

Conclusions: Mouse operant conflict tests, especially 2-lever choice, allow for the translational study of distinct anxiety components. CDZ influences each component by ameliorating the impact of both previous punishment and potential future punishment.

Keywords: Anxiety; Anxiolytic; Mouse; Operant choice; Response latency; Response vigour; Reward-aversion conflict; Translational test.