Therapeutic effects of deep brain stimulation on antidepressant-link activities in animal models of depression

Abstract

More than 264 million people are being treated for depression, but up to 30% of patients suffer from treatment-resistant depression. Deep Brain Stimulation (DBS) is being investigated as a potential treatment option. It involves the implantation of electrodes to electrically stimulate a brain region. While previous studies have shown its effectiveness in reducing depressive-like behaviors, much is still unknown about the mechanism of DBS. In my thesis, I reviewed the chronic mild stress (CMS) animal model of depression, aiming to address issues with reproducibility and improve reporting protocols. I then discussed clinical and preclinical studies stimulating the subcallosal cingulate, and the rat homolog, medial prefrontal cortex (mPFC), reviewing the mechanisms identified. The role of orexin in depressive-like behaviors is then examined, in both clinical and preclinical studies. I then showed that the environmental effects of light had a significant effect on young rats in certain behavioral tests. I then showed that 1h DBS was able to induce long-term antidepressant effects, and that it was able to increase neurogenesis and neuroplasticity in stressed animals. I then reported that mPFC stimulation at 100 Hz, 200 μA resulted in the strongest antidepressive effect in animals, and showed that stressed animals had reduced orexin levels, and that stimulating the infralimbic or prelimbic (PrL) subregions of the mPFC significantly reduced depressive-like behavior in stressed animals. PrL DBS was able to reverse a knockdown of orexin expression, inducing anti-depressive behavior and rescuing social behavior in rats. Finally, I showed the effects of PrL DBS on orexin was dependent on the dopaminergic circuit in the ventral tegmental area. Taken together, my thesis reports novel mechanisms for DBS and highlights its role in promoting social interaction.