Effect of Deep Brain Stimulation of the ventromedial prefrontal cortex on the noradrenergic system in rats

Abstract

Background: Deep Brain Stimulation (DBS) of the subgenual cingulate cortex (SCC) is a promising therapeutic alternative to treat resistant major depressive disorder. In preclinical studies, DBS of the ventromedial prefrontal cortex (vmPFC, the rodent SCC correlate) provokes an antidepressant-like effect, along with changes in noradrenaline levels at the site of stimulation. Hence, DBS appears to activate the noradrenergic-locus coeruleus (LC) system.Objective/Hypothesis: The aim of this study was to evaluate the effect of vmPFC DBS on the electrical activity of noradrenergic LC neurons, cortical oscillations and coherence between both brain areas in male rats.Methods: The antidepressant-like effect of vmPFC DBS was evaluated through the forced swimming test. Tonic and evoked activity of LC neurons, LC activity of alpha2-adrenoceptors, local field potentials from LC and electrocorticogram signals were studied after DBS by electrophysiological recordings in anaesthetized rats. The effect of DBS on tyrosine hydroxylase (TH), noradrenaline transporters (NAT), phosphorylation of the extracellular signaleregulated kinase (ERK) and corticotropin releasing factor (CRF) expression in the LC were measured by western blot assays.Results: DBS induced an antidepressant-like effect increasing climbing behaviour in the FST that was accompanied by a robust increase of TH expression in the rat LC. The tonic and evoked activity of LC neurons was enhanced by DBS, which impaired alpha2-adrenoceptors activity. DBS also promoted an increase in slow LC oscillations, as well as a shift in LC-cortical coherence.Conclusion: DBS of the vmPFC appears to affect the LC, producing changes that may underlie its antidepressant-like effects.