TRANSLATIONAL ANIMAL MODELS OF ANTIDEPRESSANT EFFECTS, LONGITUDINAL BIOMARKER MONITORING IN RESPONDER/ NON RESPONDER MALE AND FEMALE MICE

Abstract Background Predictive biomarkers of antidepressant (AD) response, as well as ADs with novel mechanisms of action are an unmet medical need. Translational models that encompass both sexes, multiple ADs, and longitudinal monitoring are urgently needed to identify biomarkers that could inform new AD mechanisms and allow to test pharmacological hypotheses. Here we present two such models in male (M) and female (F) mice. Aim and Objectives We have previously shown that the transcription factor Elk1 is a mediator of the stress response in M mice. We expand these findings in F and test Elk1 expression as a novel biomarker differentiating ad hoc responders from non responders in both sexes. Methods We use M and F C57Bl6 mice in the unpredictable chronic mild stress (UCMS; n=107M, 113F) and the vicarious social defeat (vSD; n=60M, 60F) to longitudinally assess stress and fluoxetine (FL) or desipramine (DM) effects. We determine responders (R) and non-responders (NR) with principal component analysis across multiple behavioral tests. We perform transcriptomics in whole blood (sampled longitudinally) and RT-qPCR to validate candidate blood biomarkers (including Elk1) translated from previous and current (ANTaRES; ERANET Neuron) clinical trials. Results UCMS and vSD precipitate a depressive-like phenotype in both sexes with different trajectories in M and F (interaction p=0.016 UCMS; p=0.007 vSD). In R (which account for approximately 30% of AD treated M and F mice) AD treatment overall reverses this phenotype with effects varying across behavioral test, sex and drug. RT-qPCR confirms Elk1 as a blood biomarker for stress and AD also in females (main effect p=0.003). Conclusions We validate two mouse models of AD action in M and F mice. Longitudinal behavioral and molecular (biomarker) monitoring reveals sex-dependent differences in stress and AD effects over time. We confirm Elk1 as a novel target and putative blood biomarker in both sexes.