Brain pacemaker and molecular signaling: From antidepressant to memory enhancement

Abstract

Background: Major depression is the most common psychiatric disorder and is predicted to become the second leading cause of disability worldwide by 2020. Depression can be treated effectively by medication, usually targeting the serotonergic system, and/or by psychotherapy. Nevertheless, approximately 20% of patients failed to respond to these standard therapies and nearly 60% of patients did not achieve adequate response. In view of patients who remained severely depressed despite trial-and-error combinations of medication and psychotherapy, we investigated the potential role of deep brain stimulation to alleviate depressive-like behaviors and their putative mechanisms in preclinical animal models. Methods: Animals were implanted with platinum-iridium stimulating electrodes in the Prelimbic cortex, and they were behaviorally tested for mood- and anxiety-related, as well as hippocampal-dependent memory tests. For elucidation of antidepressant-like mechanisms, the hippocampal neuroplasticity- and/or orexin-mediated signaling, as well as midbrain monoaminergic effects of stimulation were investigated using a combination of neuromodulation, histochemistry, electrophysiology, and chemogenetics/biochemical approaches. Results: Our results demonstrated that stimulation of the Prelimbic cortex induced significant antidepressant-like activities and memory enhancement in animal models of depression and aged-related dementia, respectively. For hippocampal neuroplasticity, we found a remarkable increase of neural progenitors, surviving BrdU-positive cells, and dendritic arborization after Prelimbic cortical stimulation as compared to the non-stimulated sham. Interestingly, we showed that Prelimbic cortical stimulation rescued the stress-induced dopaminergic neurodegeneration in the ventral tegmental area and dorsal raphe nucleus of animal model with vulnerability to stress-induced depression. To confirm this finding, our reversal experiments with bilateral 6-hydroxydopamine lesions, revealed the specific dopaminergic-dependent and -independent mechanisms of Prelimbic cortical stimulation-induced antidepressant-like effects. Finally, using c-Fos-immunoreactivity and electrophysiological approaches, we showed that stimulation evoked a specific activation pathway within the neurocircuitry of depression that associated with the midbrain monoaminergic system which linked to depression. Conclusion: Our overall findings suggested that the antidepressant-like and memory enhancement mechanisms of Prelimbic cortical stimulation were possibly mediated by the hippocampal neuroplasticity and the midbrain monoaminergic neurotransmission systems in animal models of stress-induced depression and aged-related dementia.