title: Noradrenergic control of cortico-striato-thalamic and mesolimbic cross-structural synchrony.
abstract: Although normal dopaminergic tone has been shown to be essential for the induction of cortico-striatal and mesolimbic theta oscillatory activity, the influence of norepinephrine on these brain networks remains relatively unknown. To address this question, we simultaneously recorded local field potentials and single-neuron activity across 10 interconnected brain areas (ventral striatum, frontal association cortex, hippocampus, primary motor cortex, orbital frontal cortex, prelimbic cortex, dorsal lateral striatum, medial dorsal nucleus of thalamus, substantia nigra pars reticularis, and ventral tegmental area) in a combined genetically and pharmacologically induced mouse model of hyponoradrenergia. Our results show that norepinephrine (NE) depletion induces a novel state in male mice characterized by a profound disruption of coherence across multiple cortico-striatal circuits and an increase in mesolimbic cross-structural coherence. Moreover, this brain state is accompanied by a complex behavioral phenotype consisting of transient hyperactivity, stereotypic behaviors, and an acute 12-fold increase in grooming. Notably, treatment with a norepinephrine precursors (l-3,4-dihydroxyphenylalanine at 100 mg/kg or l-threo-dihydroxyphenylserine at 5 mg/kg) or a selective serotonin reuptake inhibitor (fluoxetine at 20 mg/kg) attenuates the abnormal behaviors and selectively reverses the circuit changes observed in NE-depleted mice. Together, our results demonstrate that norepinephrine modulates the dynamic tuning of coherence across cortico-striato-thalamic circuits, and they suggest that changes in coherence across these circuits mediate the abnormal generation of hyperactivity and repetitive behaviors.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA. dzira001@mc.duke.edu
authors.forename: Kafui
authors.initials: K
authors.lastname: Dzirasa
authors.forename: H Westley
authors.initials: HW
authors.lastname: Phillips
authors.forename: Tatyana D
authors.initials: TD
authors.lastname: Sotnikova
authors.forename: Ali
authors.initials: A
authors.lastname: Salahpour
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.forename: Miguel A L
authors.initials: MA
authors.lastname: Nicolelis
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D003700:Delta Rhythm / Q000187:drug effects; D004295:Dihydroxyphenylalanine / Q000494:pharmacology; D015103:Droxidopa / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009434:Neural Pathways / Q000502:physiology*; D009638:Norepinephrine / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics; D013826:Theta Rhythm / Q000187:drug effects
chemical_list: D050484:Norepinephrine Plasma Membrane Transport Proteins; D005473:Fluoxetine; D004295:Dihydroxyphenylalanine; D015103:Droxidopa; D009638:Norepinephrine
references.citation: PLoS Biol. 2005 Dec;3(12):e402
references.pmid: 16279838
references.citation: Neurology. 2006 Nov 14;67(9):1695-7
references.pmid: 17101911
references.citation: Electroencephalogr Clin Neurophysiol. 1969 Apr;26(4):407-18
references.pmid: 4183562
references.citation: J Neurochem. 1998 Jun;70(6):2468-76
references.pmid: 9603211
references.citation: Prog Neurobiol. 2004 Feb;72(3):195-221
references.pmid: 15130710
references.citation: Ann N Y Acad Sci. 2006 Jul;1071:521-4
references.pmid: 16891611
references.citation: J Psychopharmacol. 1999 Dec;13(4):358-71
references.pmid: 10667612
references.citation: Neuron. 2008 Nov 26;60(4):683-97
references.pmid: 19038224
references.citation: Neuron. 1997 Dec;19(6):1285-96
references.pmid: 9427251
references.citation: J Clin Psychiatry. 1998;59 Suppl 14:11-4
references.pmid: 9818625
references.citation: Biol Psychiatry. 2005 Feb 1;57(3):229-38
references.pmid: 15691523
references.citation: Science. 2003 Aug 8;301(5634):846-50
references.pmid: 12907806
references.citation: J Neurosci. 2006 Oct 11;26(41):10577-89
references.pmid: 17035544
references.citation: Nature. 2007 Aug 23;448(7156):894-900
references.pmid: 17713528
references.citation: Mol Psychiatry. 2005 Dec;10(12):1104-9
references.pmid: 16103889
references.citation: Mol Psychiatry. 2010 Jan;15(1):64-79
references.pmid: 18490925
references.citation: Neuron. 2000 Nov;28(2):343-7
references.pmid: 11144344
references.citation: Science. 2008 Jul 18;321(5887):421-2
references.pmid: 18635808
references.citation: Behav Brain Res. 1990 Dec 14;41(2):81-94
references.pmid: 2288668
references.citation: Neuron. 2006 May 4;50(3):507-17
references.pmid: 16675403
references.citation: J Neurosci Methods. 2008 Mar 30;169(1):141-57
references.pmid: 18242715
references.citation: Behav Brain Res. 2001 Nov 1;125(1-2):279-84
references.pmid: 11682119
references.citation: Psychopharmacology (Berl). 2006 Jun;186(2):246-54
references.pmid: 16583235
references.citation: PLoS Biol. 2005 Aug;3(8):e271
references.pmid: 16050778
references.citation: Science. 2009 Mar 20;323(5921):1578-82
references.pmid: 19299613
references.citation: J Neurosci. 2009 Jun 24;29(25):8215-24
references.pmid: 19553461
references.citation: Electroencephalogr Clin Neurophysiol. 1974 Mar;36(3):291-301
references.pmid: 4130608
references.citation: Aust N Z J Psychiatry. 2008 Sep;42(9):807-13
references.pmid: 18696285
references.citation: Neuron. 2006 Oct 19;52(2):359-69
references.pmid: 17046697
references.citation: Pediatr Neurol. 2009 Jun;40(6):420-5
references.pmid: 19433274
references.citation: Brain Res. 2009 Sep 29;1291:21-31
references.pmid: 19632210
references.citation: Annu Rev Pharmacol Toxicol. 2003;43:261-84
references.pmid: 12359863
references.citation: Acta Neurol Scand Suppl. 1972;51:11-42
references.pmid: 4351191
references.citation: Nat Neurosci. 2000 May;3(5):465-71
references.pmid: 10769386
references.citation: Neurosci Lett. 1980 May 15;18(1):67-72
references.pmid: 6820484