691. DIFFERENTIAL STRIATAL GENE EXPRESSION PROFILES UNDERLYING THE PROPENSITY FOR DEPRESSION-LIKE BEHAVIOUR IN A MOUSE MODEL OF VERTICAL SLEEVE GASTRECTOMY

Abstract Background Bariatric surgery is the most effective long-term obesity treatment, reducing appetite and improving glycaemic control. These benefits are due to profound changes to the gut-brain axis. However, a small patient subset experiences adverse mental health outcomes post-surgery, such as depression and suicidality. While longitudinal studies begin to explore this, research exploring how gut-brain axis alterations could mechanistically contribute to these adverse mental health outcomes post-surgery is lacking. Aims & Objectives This study aimed to investigate individual differences in the effect of bariatric surgery on depressive-like behaviour using a mouse model of vertical sleeve gastrectomy (VSG). It was hypothesized that while VSG generally improves metabolic outcomes, a subset of mice would exhibit increased susceptibility to depressive-like behaviour, accompanied by distinct transcriptional changes in reward-related brain regions. Method Male and female C57BL/6 mice (n=57) were fed a high-fat, high-sugar diet (11 weeks) before VSG or sham surgery. Depression-like behaviour was assessed pre- and post-surgery. VSG mice were stratified post hoc into tertiles based on changes in depressive-like behaviour; the top and bottom tertiles were classified as ‘depression-susceptible’ and ‘depression-resilient’, respectively. From these subgroups, RNA was extracted from tissue punches of the dorsal striatum and nucleus accumbens, key components of brain circuitry known to be dysregulated in major depressive disorder. These punches were then subjected to bulk RNA-sequencing to identify differential gene expression patterns associated with post-surgical vulnerability to depression-like behaviour. Results VSG resulted in significant and sustained weight loss and reduced food intake compared to sham controls. Differential gene expression analysis revealed downregulated neuroinflammation and tight junction-related genes. Further gene set enrichment analysis shows depression-susceptible VSG mice display an upregulation of TNF-α-NF-κB and PI3K-AKT/mTOR pathways. Additional chow-diet cohort data and further RNA-seq validation are ongoing, and preliminary findings will be presented. Discussion & Conclusions These findings, although preliminary, suggest that individual variability in depressive outcomes following bariatric surgery may be underpinned by differential activation of inflammatory and metabolic signalling pathways in key brain regions. This study provides foundational insight into the neurobiological mechanisms underlying post-surgical affective vulnerability and may inform future clinical screening and intervention strategies in bariatric populations.