Modelling depression-related behaviours in mice

Abstract

Major depressive disorder (MDD) is a globally prevalent, complex disorder with a wide range of symptoms. Current-line antidepressants are only effective in minority of patients and do not seem to provide a long-term solution since relapses are also frequent. To develop better antidepressant agents, novel and improved animal models are needed. The research presented here is comprises of 3 studies. Each study investigated a different murine model for studying depression-related behaviours. In our first study we examined a touchscreen-based judgement bias task, since a tone-based rat version of the task displayed sensitivity to rapid-acting antidepressants. Animals were trained to associate 2 distinct cues with either high or low reward and were then tested in probe sessions where midpoint ambiguous cues were presented. Baseline judgement bias was then evaluated by calculating cognitive bias index (CBI). Pharmacological manipulations with amphetamine and ketamine revealed that neither drug induced a significant judgement bias shift, unlike results found in rats. The second study explored whether a rat affective bias task (ABT) can be adapted for murine use. During pairing sessions, mice were trained to associate 2 digging substrates with either small or large reward in a proof-of-concept reward assay. Then a choice test was conducted where both substrates were presented and choices over 30 trials were recorded. Effects of chronic restraint stress and venlafaxine were then tested, equal reward values for both substrates were used. Despite the ABT demonstrating good predictive validity in rats, mice seemed to do the task differently, unable to replicate rat findings. Finally, a systematic review with meta-analysis was conducted on 66 studies investigating the effects of rapid acting antidepressant ketamine and other NMDAR antagonists on the immobility times in the FST and TST in mice. Our research emphasises the need for more ecologically relevant, clinically translatable mouse models.

Date of Award	21 Jun 2022
Original language	English
Awarding Institution	University of Bristol
Supervisor	Emma S J Robinson (Supervisor)