title: Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms.
abstract: Deep brain stimulation (DBS) is a promising therapy for patients with refractory depression. However, key questions remain with regard to which brain target(s) should be used for stimulation, and which mechanisms underlie the therapeutic effects. Here, we investigated the effect of DBS, with low- and high-frequency stimulation (LFS, HFS), in different brain regions (ventromedial prefrontal cortex, vmPFC; cingulate cortex, Cg; nucleus accumbens (NAc) core or shell; lateral habenula, LHb; and ventral tegmental area) on a variety of depressive-like behaviors using rat models. In the naive animal study, we found that HFS of the Cg, vmPFC, NAc core and LHb reduced anxiety levels and increased motivation for food. In the chronic unpredictable stress model, there was a robust depressive-like behavioral phenotype. Moreover, vmPFC HFS, in a comparison of all stimulated targets, produced the most profound antidepressant effects with enhanced hedonia, reduced anxiety and decreased forced-swim immobility. In the following set of electrophysiological and histochemical experiments designed to unravel some of the underlying mechanisms, we found that vmPFC HFS evoked a specific modulation of the serotonergic neurons in the dorsal raphe nucleus (DRN), which have long been linked to mood. Finally, using a neuronal mapping approach by means of c-Fos expression, we found that vmPFC HFS modulated a brain circuit linked to the DRN and known to be involved in affect. In conclusion, HFS of the vmPFC produced the most potent antidepressant effects in naive rats and rats subjected to stress by mechanisms also including the DRN.
authors.affiliation: 1] Department of Biological Sciences, Sunway University, Selangor, Malaysia [2] Department of Neuroscience, Maastricht University, Maastricht, The Netherlands [3] Department of Pharmacology, Oxford University, Oxford, UK [4] Department of Neurosurgery, Maastricht University, Maastricht, The Netherlands [5] School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
authors.forename: L W
authors.initials: LW
authors.lastname: Lim
authors.affiliation: Department of Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Prickaerts
authors.affiliation: Department of Biology, Girona University, Girona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Huguet
authors.affiliation: Department of Biology, Girona University, Girona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Kadar
authors.affiliation: Department of Pharmacology, Oxford University, Oxford, UK.
authors.forename: H
authors.initials: H
authors.lastname: Hartung
authors.affiliation: Department of Pharmacology, Oxford University, Oxford, UK.
authors.forename: T
authors.initials: T
authors.lastname: Sharp
authors.affiliation: 1] Department of Neuroscience, Maastricht University, Maastricht, The Netherlands [2] Department of Neurosurgery, Maastricht University, Maastricht, The Netherlands.
authors.forename: Y
authors.initials: Y
authors.lastname: Temel
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D046690:Deep Brain Stimulation / Q000379:methods*; D003863:Depression / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D004195:Disease Models, Animal; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism
chemical_list: D012701:Serotonin
references.citation: Physiol Behav. 1996 Jul;60(1):43-50
references.pmid: 8804641
references.citation: Biol Psychiatry. 2000 Jul 1;48(1):30-42
references.pmid: 10913505
references.citation: J Neurosci. 1992 Oct;12(10):4037-44
references.pmid: 1357117
references.citation: Am J Psychiatry. 1999 May;156(5):675-82
references.pmid: 10327898
references.citation: Int Rev Neurobiol. 2012;107:283-314
references.pmid: 23206687
references.citation: JAMA. 2003 Jun 18;289(23):3095-105
references.pmid: 12813115
references.citation: Am J Psychiatry. 2011 May;168(5):502-10
references.pmid: 21285143
references.citation: Neuropsychopharmacology. 1999 Sep;21(3):391-8
references.pmid: 10457536
references.citation: Neuron. 2004 Sep 16;43(6):897-905
references.pmid: 15363399
references.citation: Curr Opin Neurobiol. 2006 Dec;16(6):723-7
references.pmid: 17084617
references.citation: Neurosurgery. 2010 Oct;67(4):1073-9; discussion1080
references.pmid: 20881571
references.citation: Neuropharmacology. 2003 Jul;45(1):72-81
references.pmid: 12814660
references.citation: Neuron. 2012 Dec 20;76(6):1057-70
references.pmid: 23259943
references.citation: Brain Struct Funct. 2007 Sep;212(2):149-79
references.pmid: 17717690
references.citation: Neuroscience. 2008 Jul 31;155(1):164-73
references.pmid: 18588948
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2473-8
references.pmid: 10051667
references.citation: Neuron. 2005 Mar 3;45(5):651-60
references.pmid: 15748841
references.citation: Neurosci Biobehav Rev. 2003 Oct;27(6):555-79
references.pmid: 14599436
references.citation: J Psychiatr Res. 2010 Aug;44(11):683-7
references.pmid: 20096858
references.citation: Transl Psychiatry. 2013;3:e210
references.pmid: 23321807
references.citation: Arzneimittelforschung. 2008;58(6):269-76
references.pmid: 18677968
references.citation: Biol Psychiatry. 2009 Feb 15;65(4):267-75
references.pmid: 18842257
references.citation: Exp Neurol. 2010 Dec;226(2):293-300
references.pmid: 20837005
references.citation: Neuropsychopharmacology. 2008 Jan;33(2):368-77
references.pmid: 17429407
references.citation: Neuroscience. 2001;106(4):783-92
references.pmid: 11682163
references.citation: Am J Psychiatry. 2007 Oct;164(10):1476-88
references.pmid: 17898336
references.citation: Curr Opin Neurobiol. 2004 Apr;14(2):198-202
references.pmid: 15082325
references.citation: Physiol Behav. 1996 Dec;60(6):1481-4
references.pmid: 8946494
references.citation: Neuropsychopharmacology. 2009 Mar;34(4):1057-66
references.pmid: 18843267
references.citation: Brain Res Bull. 2007 Mar 30;71(6):601-9
references.pmid: 17292803
references.citation: Biol Psychiatry. 2010 Jan 15;67(2):e9-e11
references.pmid: 19846068
references.citation: Neuron. 2012 Sep 6;75(5):747-61
references.pmid: 22958817
references.citation: Cerebellum. 2011 Mar;10(1):61-9
references.pmid: 21076996
references.citation: Arch Gen Psychiatry. 1983 Jan;40(1):79-84
references.pmid: 6849623
references.citation: J Neurochem. 2012 Dec;123(6):897-903
references.pmid: 23061486
references.citation: Neuropharmacology. 1999 Aug;38(8):1083-152
references.pmid: 10462127
references.citation: Neurosurgery. 2011 Dec;69(6):1281-90
references.pmid: 21566538
references.citation: Behav Brain Res. 2008 Nov 21;193(2):197-203
references.pmid: 18582503
references.citation: Brain Res. 2000 Aug 4;873(1):34-45
references.pmid: 10915808
references.citation: Biol Psychiatry. 2012 Dec 1;72(11):916-23
references.pmid: 22748616
references.citation: Brain Struct Funct. 2008 Sep;213(1-2):93-118
references.pmid: 18704495
references.citation: Soc Cogn Affect Neurosci. 2014 Dec;9(12):2026-33
references.pmid: 24493840
references.citation: Neurobiol Dis. 2014 Nov;71:205-14
references.pmid: 25131446
references.citation: Neuroscience. 2003;122(1):193-204
references.pmid: 14596860
references.citation: Mol Psychiatry. 1998 May;3(3):220-6, 190-1
references.pmid: 9672897
references.citation: Neuron. 2007 Sep 6;55(5):712-25
references.pmid: 17785179
references.citation: Nature. 2013 Apr 18;496(7445):359-62
references.pmid: 23552889
references.citation: Behav Brain Res. 2009 Nov 5;203(2):256-63
references.pmid: 19450624
references.citation: Elife. 2015;4. doi: 10.7554/eLife.04803
references.pmid: 25768425
references.citation: Behav Brain Res. 2015 Feb 15;279:17-21
references.pmid: 25446757
references.citation: Neuroscience. 1998 Nov;87(1):95-108
references.pmid: 9722144
references.citation: Biol Psychiatry. 2012 Jan 1;71(1):30-5
references.pmid: 22000731
references.citation: Trends Pharmacol Sci. 2002 May;23(5):238-45
references.pmid: 12008002
references.citation: Neuropsychopharmacology. 2010 Jan;35(1):192-216
references.pmid: 19693001
references.citation: Brain Stimul. 2013 May;6(3):377-83
references.pmid: 22921765
references.citation: Physiol Behav. 2012 Feb 1;105(3):628-38
references.pmid: 21971366
references.citation: Behav Brain Res. 2014 Oct 15;273:155-65
references.pmid: 25043730
references.citation: J Neurosci. 2010 Feb 10;30(6):2356-64
references.pmid: 20147561
references.citation: Neuroimage. 2009 Jan 15;44(2):489-501
references.pmid: 18835452
references.citation: Eur J Neurosci. 2005 Feb;21(4):945-58
references.pmid: 15787701
references.citation: Nat Rev Neurosci. 2010 Jul;11(7):503-13
references.pmid: 20559337
references.citation: Physiol Rev. 1992 Jan;72(1):165-229
references.pmid: 1731370
references.citation: Exp Neurol. 2010 Oct;225(2):302-9
references.pmid: 20615406
references.citation: Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):18980-4
references.pmid: 23112179
references.citation: Acta Psychiatr Scand Suppl. 2004;(420):21-7
references.pmid: 15128384
references.citation: Exp Neurol. 2012 Jan;233(1):145-53
references.pmid: 21925498
references.citation: Am J Psychiatry. 2000 Apr;157(4 Suppl):1-45
references.pmid: 10767867
references.citation: PLoS One. 2012;7(3):e33455
references.pmid: 22428054
references.citation: Prog Brain Res. 2000;126:413-31
references.pmid: 11105660
references.citation: Biol Psychiatry. 2010 Jan 15;67(2):117-24
references.pmid: 19819426
references.citation: Neuroscience. 2011 Jul 14;186:135-45
references.pmid: 21515342
references.citation: Neurochem Res. 2000 Nov;25(11):1465-73
references.pmid: 11071365
references.citation: Biol Mood Anxiety Disord. 2012 May 18;2:9
references.pmid: 22738125
references.citation: J Neurol Neurosurg Psychiatry. 1992 Sep;55(9):768-73
references.pmid: 1402966
references.citation: Neuroimage. 1999 Aug;10(2):163-72
references.pmid: 10417248
references.citation: J Neurosci. 2006 Dec 13;26(50):12967-76
references.pmid: 17167086
references.citation: Brain Res. 1989 Jul 17;492(1-2):187-202
references.pmid: 2473826
references.citation: J Neuropsychiatry Clin Neurosci. 1997 Summer;9(3):471-81
references.pmid: 9276848
references.citation: Nature. 2011 Feb 24;470(7335):535-9
references.pmid: 21350486
references.citation: Exp Neurol. 1974 Nov;45(2):268-87
references.pmid: 4422320
references.citation: J Psychopharmacol. 2002 Mar;16(1):39-49
references.pmid: 11949770
references.citation: Neurosci Lett. 2010 Apr 5;473(2):136-40
references.pmid: 20178829
references.citation: Nature. 1997 Apr 24;386(6627):824-7
references.pmid: 9126739
references.citation: Neurosci Biobehav Rev. 2005;29(4-5):547-69
references.pmid: 15893822
references.citation: Front Pharmacol. 2013 Aug 02;4:97
references.pmid: 23935583
references.citation: Curr Top Behav Neurosci. 2013;14:327-39
references.pmid: 22865464
references.citation: Front Behav Neurosci. 2013 Aug 08;7:102
references.pmid: 23964215
references.citation: J Neurosci. 1982 Aug;2(8):1062-71
references.pmid: 6180148
references.citation: J Neurosci. 2010 Dec 1;30(48):16082-90
references.pmid: 21123555
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17087-92
references.pmid: 17942692
references.citation: Biol Psychiatry. 2008 Sep 15;64(6):461-7
references.pmid: 18639234