Abstract
Objective. Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (MFB) has provided rapid and dramatic reduction of depressive symptoms in a clinical trial. Early intracranial self-stimulation experiments of the MFB suggested detrimental side effects on the animals' health; therefore, the current study looked at the viability of chronic and continuous MFB-DBS in rodents, with particular attention given to welfare issues and identification of stimulated pathways. Methods. Sprague-Dawley female rats were submitted to stereotactic microelectrode implantation into the MFB. Chronic continuous DBS was applied for 3–6 weeks. Welfare monitoring and behavior changes were assessed. Postmortem histological analysis of c-fos protein expression was carried out. Results. MFB-DBS resulted in mild and temporary weight loss in the animals, which was regained even with continuing stimulation. MFB-DBS led to increased and long-lasting c-fos expression in target regions of the mesolimbic/mesocortical system. Conclusions. Bilateral continuous chronic MFB-DBS is feasible, safe, and without impact on the rodent's health. MFB-DBS results in temporary increase in exploration, which could explain the initial weight loss, and does not produce any apparent behavioral abnormalities. This platform represents a powerful tool for further preclinical investigation of the MFB stimulation in the treatment of depression.
Highlights
Major depressive disorder (MDD) is a debilitating predicament with negative consequences on both the affected individual and those close to the suffering person
Intracranial self-stimulation experiments of the medial forebrain bundle (MFB) suggested detrimental side effects on the animals’ health; the current study looked at the viability of chronic and continuous MFB-Deep brain stimulation (DBS) in rodents, with particular attention given to welfare issues and identification of stimulated pathways
The results suggest that bilateral MFB stimulation has a robust, reproducible, reversible but moderate impact on the animals’ welfare as shown by the cycle of weight decrease, stabilization, return to pre-DBS weight, and the weight gain following the end of stimulation
Summary
Major depressive disorder (MDD) is a debilitating predicament with negative consequences on both the affected individual and those close to the suffering person. The best therapies include psychotherapy, electroconvulsive, and drug treatment ones, together producing remission in 70–90% of sufferers; 10–30% of the patients remain resistant to all currently available treatment combinations. The limited number of clinical studies targeting treatment-resistant MDD by DBS ranges from a case study [5] to small trials [6,7,8,9] and suggests that the approach both is safe and can show long-lasting efficacy in a significant number of patients who have not responded positively to other types of interventions. The stimulation targets selected in these clinical studies included the subcallosal cingulate, nucleus accumbens (NAC), and the habenula. The diversity of targets reflects the characteristics of the network-model of depression that states that aspects of the syndrome (e.g., cognitive, vegetative, and somatic) can arise from dysregulation of neuronal activity at numerous loci on the limbic-cortical circuitry [7, 10]
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