ADIPONECTIN ELICITS RAPID-ANTIDEPRESSANT EFFECTS IN CHRONICALLY STRESSED MICE IN ASSOCIATION WITH INCREASED GLUTAMATERGIC ACTIVITY IN THE MPFC

Abstract Background Depression is a pervasive disease and a worldwide health challenge 1. First-line antidepressants have a delayed therapeutic onset and low remission rates 2,3, while rapid-acting antidepressants (e.g., ketamine) have psychomimetic side effects that hinder their widespread use 4. Adiponectin is an adipocyte-related hormone that has been implicated in depression 5 and is shown to elicit rapid antidepressant effects in pre-clinical studies 6. Despite its promise as a target in depression treatment 7–9, adiponectin antidepressant properties have not been tested in animal models of depression and the mechanisms behind its antidepressant effects remain largely elusive. Objectives Test and characterize the rapid antidepressant effects of central adiponectin administration in a mouse model of depression. Methods Six-week-old mice were exposed to chronic unpredictable stress (CUS) for 21 days once daily to induce depression, whereas controls were briefly handled for the same period. On the 14th day, animals were implanted with intracerebroventricular cannulas. On the 22nd day, one cohort of CUS and control mice received a single infusion of globular adiponectin (1 mg) or vehicle (PBS) and were tested on the open field test (OFT) to examine locomotor activity and anxiety-like behavior, followed by the forced swim test (FST) to examine behavioral despair 30 min post-infusion. Mice then received a second infusion of adiponectin or vehicle 2 h before euthanasia for immunohistochemical analysis. Another cohort of animals was tested on the splash test (ST) for motivation-like behavior, followed by the sucrose preference test (SPT) for anhedonia-like behavior. Results Two-way ANOVA with Tukey post-hoc test indicated that adiponectin treatment reversed the CUS-induced increase in behavioral despair and anhedonia-like behavior, with no significant effects observed in motivation- or anxiety-like behaviors. Locomotor activity was not affected. Immunohistochemical analysis of brain slices from stressed mice showed increased expression of c-Fos in the anterior cingulate cortex (ACC) and prelimbic (PL) subregion of the medial prefrontal cortex (mPFC) in adiponectin-treated when compared to vehicle- treated mice, suggesting an acute increase in mPFC neuronal activation in response to adiponectin treatment. Moreover, the level of c-Fos expression in the ACC and PL subregions presented strong negative correlations with the immobility time in the FST, indicating that increased mPFC activity in response to adiponectin treatment is associated with improvements in depression-like behavior in stressed mice. Co-labeling analysis demonstrated that approximately 83% of c-Fos positive cells in the mPFC were CaMKII positive in adiponectin-treated mice (versus ~58% in vehicle-treated mice), suggesting the rapid antidepressant effects of adiponectin were associated with increased mPFC glutamatergic activity. Conclusion Adiponectin elicits rapid antidepressant effects, which is associated with increased glutamatergic activity in the mPFC of stressed mice. Such findings suggest the central adiponectin signaling system is a potential target for the rapid relief of depression symptoms. References 1. Smith, K. Mental health: a world of depression. Nature 515, 181 (2014). 2. Solomon, D. A. et al. Multiple recurrences of major depressive disorder. Am J Psychiatry 157, 229–33 (2000). 3. Trivedi, M. H. et al. Evaluation of Outcomes With Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. American Journal of Psychiatry 163, 28–40 (2006). 4.Kadriu, B. et al. Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants. Int J Neuropsychopharmacol 24, 8–21 (2021). 5. Vuong, E. et al. Peripheral adiponectin levels in anxiety, mood, trauma- and stressor-related disorders: A systematic review and meta-analysis. J Affect Disord 260, 372–409 (2020). 6.Liu, J. et al. Adiponectin is critical in determining susceptibility to depressive behaviors and has antidepressant-like activity. Proceedings of the National Academy of Sciences 109, 12248–12253 (2012). 7.Formolo, D. A., Lee, T. H.-Y. &Yau, S.-Y. Increasing Adiponergic System Activity as a Potential Treatment for Depressive Disorders. Mol Neurobiol (2019) doi:10.1007/s12035-019-01644-3. 8.Formolo, D. A., Cheng, T., Yu, J., Kranz, G. S. &Yau, S.-Y. Central Adiponectin Signaling – A Metabolic Regulator in Support of Brain Plasticity. Brain Plasticity 8, 79–96 (2022). 9.Formolo, D. A. et al. Increasing Adiponectin Signaling by Sub-Chronic AdipoRon Treatment Elicits Antidepressant- and Anxiolytic-Like Effects Independent of Changes in Hippocampal Plasticity. Biomedicines 11, 249 (2023).