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Effect of Deep Brain Stimulation of the ventromedial prefrontal cortex on the noradrenergic system in rats
Authors:Sonia Torres-Sanchez  Laura Perez-Caballero  Juan A. Mico  Pau Celada  Esther Berrocoso
Affiliation:1. Neuropsychopharmacology & Psychobiology Research Group, University of Cádiz, Cádiz, Spain;2. CIBER of Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain;3. Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain;4. Neuropsychopharmacology & Psychobiology Research Group, Department of Psychology, Area of Psychobiology, University of Cádiz, Puerto Real, Cádiz, Spain;5. Neuropsychopharmacology & Psychobiology Research Group, Department of Neuroscience, University of Cádiz, Cádiz, Spain;6. Institut d’Investigacions Biomèdiques August Pi i Sunyer, IDIBAPS, Barcelona, Spain;7. Institut d''Investigacions Biomèdiques de Barcelona IIBB-CSIC, Department of Neurochemistry and Neuropharmacology, Barcelona, Spain
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 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.
Keywords:Deep brain stimulation  Locus coeruleus  Depression  Prefrontal cortex  Local field potential  ANOVA  analysis of variance  AP  anteroposterior  CRF  corticotropin-releasing factor  DBS  deep brain stimulation  DV  dorsoventral  ECoG  electrocorticograms  ECT  electroconvulsive therapy  ERK  extracellular signal-regulated kinase  FFT  Fast Fourier Transformations  FG  Fluoro-Gold  FIR  finite impulse response  LC  locus coeruleus  LFP  local field potentials  ML  midline  NAT  noradrenaline transporter  SCC  subgenual cingulate cortex  TBST  Tris-buffered saline containing Tween-20  TH  tyrosine hydroxylase  vmPFC  ventromedial prefrontal cortex
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