A PRECLINICAL MODEL OF COMORBID ANXIETY AND MAJOR DEPRESSIVE DISORDER REVEALS SHARED HIPPOCAMPAL MOLECULAR PATHWAYS IN MALE AND FEMALE MICE

Major depressive disorder (MDD) is a heterogeneous condition with 227 symptom combinations leading to diagnosis. To address this complexity, stratification strategies considering comorbidities, like comorbidity with anxiety disorders, have become increasingly common in clinical research. These reveal that patients with comorbid anxiety and major depressive disorder (CAD) may represent a subgroup with distinct clinical needs compared with MDD alone, as CAD is associated with more severe symptoms and poorer pharmacotherapy response, highlighting the need for deeper insight into its molecular neurobiological background. To address this, we have developed a mouse model of CAD through measuring multiple anxiety- and depression-like traits in male and female mice. Anxious and stress-coping traits were measured based on our previous work, using multiple test repetitions and averaging results of the light-dark (LD) and forced swim (FST) tests. Depression susceptibility was investigated using the learned helplessness test (LH). Consistent with human findings, our results showed that male and female mice with high trait anxiety displayed passive coping and enhanced susceptibility to learned helplessness. Compared to resilient animals, this “comorbid” subpopulation also showed impaired spatial learning and cognitive inflexibility in the Intellicage. Finally, RNAseq of the ventral hippocampus of male and female mice revealed hundreds of different molecular pathways between comorbid and resilient animals, many showing concordant changes in both males and females (e.g. plasticity and cognition), alongside sex-specific differences (e.g. mitochondrial pathways). We aim to investigate the causal role of these pathways in disease susceptibility, ultimately leading to more effective pharmacotherapy in CAD patients.