Renee Papaluca1,2, Eva Guerrero-Hreins1,2, Aneta Stefanidis4, Claire Foldi4, Brian Oldfield4, Priya Sumithran*3, Robyn Brown*1

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 experience adverse mental health outcomes post-surgery, such as depression. 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. Therefore, this study investigates individual differences in depressive-like behaviour after vertical sleeve gastrectomy (VSG) in mice. Methods: 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. Based on test performance, VSG mice were then separated into tertiles and the upper and lower tertiles were used as ‘depression-susceptible and ‘depressionprone’ mice respectively. From these subgroups, RNA was extracted from tissue punches of the dorsal striatum and nucleus accumbens, key regions implicated in major depressive disorder and subjected to bulk RNA-sequencing. Results: VSG led to significant, sustained weight loss and reduced food intake. Differential gene expression analysis revealed downregulated neuroinflammation and tight junction-related genes in VSG depression-susceptible mice. Further gene set enrichment analysis displays an upregulation of TNF-α-NF-κB and PI3K-AKT/mTOR pathways. Additional chow-diet cohort data is pending, with preliminary findings to be presented at the meeting. Conclusion: This study provides insight into the possible neurobiological mechanisms underlying post-bariatric surgery mental health outcomes, shedding light on potential new biomarkers for depression risk associated with this common weight-loss procedure.

1University of Melbourne, School of Biomedical Sciences, Department of Biochemistry and Pharmacology, 2Florey Institute of Neuroscience and Mental Health, 3Department of Surgery, School of Translational Medicine, Monash University, 4Department of Physiology, Monash University.

*equal contribution Introduction:

mmanuel S. Onaivi1 , Anna Bukiya2 , Venkat Sharma1 , Shilpa Buch3

There is an explosion of new knowledge that the effect of cannabis is encoded in our genome on chromosomes 1 and 6, and the biological effects is mediated by action on human endocannabinoid system (ECS) that are involved in reproduction and implantation of fertilized egg in the uterus. The identification of additional lipid mediators, enzymes and receptors is expanding the ECS, to endocannabinoidome (eCBome). Together with the ECS, eCBome are composed of genes coding for CB1 and CB2 cannabinoid receptors (CB1Rs, CB2Rs), endocannabinoids (eCBs), and their metabolic enzyme machinery for their biosynthesis and catabolism. The remarkable progress and new understanding are unravelling the role of the eCBome genetics, influence on behavior and providing deeper insights on the biological actions of cannabinoids in many disorders. CB2R conditional knockout (cKO) mice with deletion of CB2Rs from dopamine neurons, DAT-Cnr2 and those with deletion from microglia Cx3Cr1- Cnr2 were used and they displayed differential phenotypes. CB2Rs in dopamine neurons and microglia upregulated the expression of NLRP3 inflammasome pathway including NLRP3, and increased expression of proinflammatory cytokines, TNF-α, IL-6, IL-1α and IL-1β in the frontal cortices of the cKO mice following subacute treatment with 8% alcohol. The molecular pathways of fetal damage by alcohol, from cerebral artery to developmental delay highlights the functional presence and interaction of the ECS in baboons at different stages of development, including the effects of simultaneous alcohol and tetrahydrocannabinol on cerebral artery. An insight into the emerging eCBome genetics and neuroimmune crosstalk offers opportunities for continued preclinical and clinical studies.

1Biology department, College of Science and Health, William Paterson University, Wayne NJ, 2University of Tennessee Health Science Center, Memphis, TN, 3University of Nebraska Medical Center, Omaha, Nebraska.