The orexin-neuroplasticity mechanisms of deep brain stimulation on depressive-like behaviours in rat models

Abstract

Introduction: Growing evidence has implicated the involvement of orexin in depression. Deep brain stimulation (DBS) has been shown to treat patients with treatment-resistant depression, and preclinical studies have demonstrated that this is mediated through hippocampal neuroplasticity pathways. While orexin has been linked to neuroplasticity, its role in DBS and depression remains unknown. In this study, we investigated the function of orexin on hippocampal neuroplasticity in animal models of depression. Materials and Methods: Bilateral electrodes were implanted in the medial prefrontal cortex (mPFC). Animals were then tested for depressive-like behaviours in naïve and chronic unpredictable stress (CUS) paradigms. To further investigate the role of orexin on neuroplasticity, animals were injected with shOrexin/shControlAAV and temozolomide. Immunohistochemistry, mass spectrometry, and RT-qPCR were conducted to investigate the orexin-neuroplasticity related mechanisms. Results and Discussion: In this study, animals were tested with various stimulation parameters and we have identified that high-frequency stimulation (100 Hz) at 200 μA amplitude produced maximal antidepressant-like effects in both the acute and chronic stimulation paradigms. Chronic DBS treatment continued to exert antidepressive effects, without a refractory response. Notably, we found that preproorexin mRNA was depleted in CUS-treated animals and DBS was able to reverse this condition. Further validating this finding, animals with shOrexin-AAV exhibited depressive-like behaviours, and DBS was shown to rescue these behavioural deficits. With temozolomide treatment, our results show that the antidepressantlike effects of mPFC DBS were dependent on the orexin-neuroplasticity function. Conclusion: Our novel findings demonstrate the important role of orexinneuroplasticity mechanisms in mediating antidepressant-like effects of DBS.