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

[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 signal–regulated 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.This work was supported by grants from the “Ministerio de Economía y Competitividad” (MINECO) co-financed by “Fondo Europeo de Desarrollo Regional” FEDER “A way to build Europe” (SAF2015-68647-R; “Instituto de Salud Carlos III” (PI12/00915; PI16/00287)); the “Centro de Investigacion Biomedica en Red de Salud Mental-CIBERSAM” (Spain; G18, G02); the “Consejería de Economía, Innovacion, Ciencia y Empleo de la Junta de Andalucía ” (Spain; CTS-510 and CTS-7748); a 2015 NARSAD Young Investigator Grant from the Brain Behavior Research Foundation (NARSAD 23982); and a FPI fellowship (2011-145).Peer reviewe