title: Heterogeneous organization of the locus coeruleus projections to prefrontal and motor cortices.
abstract: The brainstem nucleus locus coeruleus (LC) is the primary source of norepinephrine (NE) to the mammalian neocortex. It is believed to operate as a homogeneous syncytium of transmitter-specific cells that regulate brain function and behavior via an extensive network of axonal projections and global transmitter-mediated modulatory influences on a diverse assembly of neural targets within the CNS. The data presented here challenge this longstanding notion and argue instead for segregated operation of the LC-NE system with respect to the functions of the circuits within its efferent domain. Anatomical, molecular, and electrophysiological approaches were used in conjunction with a rat model to show that LC cells innervating discrete cortical regions are biochemically and electrophysiologically distinct from one another so as to elicit greater release of norepinephrine in prefrontal versus motor cortex. These findings challenge the consensus view of LC as a relatively homogeneous modulator of forebrain activity and have important implications for understanding the impact of the system on the generation and maintenance of adaptive and maladaptive behaviors.
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Chandler
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Gao
authors.forename: Barry D
authors.initials: BD
authors.lastname: Waterhouse
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004525:Efferent Pathways / Q000033:anatomy & histology / Q000502:physiology; D008125:Locus Coeruleus / Q000033:anatomy & histology* / Q000502:physiology*; D008297:Male; D009044:Motor Cortex / Q000033:anatomy & histology* / Q000502:physiology*; D009638:Norepinephrine / Q000502:physiology; D017397:Prefrontal Cortex / Q000033:anatomy & histology* / Q000502:physiology*; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics; D062549:Voltage-Gated Sodium Channel beta-3 Subunit / Q000235:genetics; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
chemical_list: D009638:Norepinephrine; D012333:RNA, Messenger; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D014446:Tyrosine 3-Monooxygenase; D050493:Vesicular Monoamine Transport Proteins; D062549:Voltage-Gated Sodium Channel beta-3 Subunit; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C409466:NR1 NMDA receptor; C493454:Slc18a2 protein, rat
references.citation: Biol Psychiatry. 2006 Nov 15;60(10):1111-20
references.pmid: 16806100
references.citation: Isr J Psychiatry Relat Sci. 2009;46(3):213-20
references.pmid: 20039523
references.citation: CNS Drugs. 2009;23 Suppl 1:33-41
references.pmid: 19621976
references.citation: J Neurosci. 1996 Aug 15;16(16):5196-204
references.pmid: 8756448
references.citation: Neurosci Biobehav Rev. 2004 Nov;28(7):771-84
references.pmid: 15555683
references.citation: Neuroscience. 1986 Jun;18(2):307-19
references.pmid: 3736861
references.citation: Front Behav Neurosci. 2012 May 21;6:20
references.pmid: 22661934
references.citation: Biol Psychiatry. 2008 Oct 1;64(7):626-35
references.pmid: 18585681
references.citation: Neuroscience. 2008 Apr 22;153(1):63-71
references.pmid: 18355972
references.citation: Neuroscience. 1999;93(4):1263-70
references.pmid: 10501450
references.citation: Neuroscience. 1986 Jun;18(2):291-306
references.pmid: 3736860
references.citation: J Child Psychol Psychiatry. 2004 Feb;45(2):293-305
references.pmid: 14982243
references.citation: Brain Res Bull. 1982 Jul-Dec;9(1-6):287-94
references.pmid: 7172032
references.citation: Nature. 2012 Nov 8;491(7423):212-7
references.pmid: 23064228
references.citation: J Neurosci. 2004 Dec 1;24(48):10773-85
references.pmid: 15574728
references.citation: Neural Plast. 2000;7(1-2):133-46
references.pmid: 10709220
references.citation: IEEE Trans Pattern Anal Mach Intell. 1979 Feb;1(2):224-7
references.pmid: 21868852
references.citation: Nat Neurosci. 2013 Aug;16(8):1016-23
references.pmid: 23852112
references.citation: Pharmacol Ther. 2007 Mar;113(3):523-36
references.pmid: 17303246
references.citation: Psychopharmacology (Berl). 2008 Sep;200(1):39-50
references.pmid: 18568443
references.citation: Dev Cogn Neurosci. 2011 Oct;1(4):552-9
references.pmid: 21927630
references.citation: Neurosci Biobehav Rev. 2000 Jan;24(1):31-9
references.pmid: 10654658
references.citation: J Comp Neurol. 1983 Jul 10;217(4):418-31
references.pmid: 6886061
references.citation: Nat Rev Neurosci. 2009 Mar;10(3):211-23
references.pmid: 19190638
references.citation: Brain Res Brain Res Rev. 2003 Apr;42(1):33-84
references.pmid: 12668290
references.citation: Nat Rev Neurosci. 2009 Jun;10(6):410-22
references.pmid: 19455173
references.citation: Synapse. 2000 Sep 15;37(4):273-82
references.pmid: 10891864
references.citation: Neuroscience. 2006 Feb;137(3):1039-49
references.pmid: 16298081
references.citation: J Comp Neurol. 1993 Oct 15;336(3):345-61
references.pmid: 8263226
references.citation: Neuroscience. 1984 Sep;13(1):137-56
references.pmid: 6493483
references.citation: Nat Neurosci. 2008 Feb;11(2):178-86
references.pmid: 18204443
references.citation: Psychopharmacology (Berl). 2009 Jan;202(1-3):505-19
references.pmid: 18604598
references.citation: Biol Psychiatry. 2012 Mar 1;71(5):467-73
references.pmid: 21890109
references.citation: Behav Brain Res. 1998 Jul;94(1):163-71
references.pmid: 9708847
references.citation: Prog Neurobiol. 1977;9(3):147-96
references.pmid: 202996
references.citation: J Comp Neurol. 2005 Dec 5;493(1):99-110
references.pmid: 16254995
references.citation: Brain Res. 2013 Jul 19;1522:38-58
references.pmid: 23665053
references.citation: J Neurosci. 2006 Sep 27;26(39):9860-72
references.pmid: 17005850
references.citation: Brain Res Bull. 1982 Jul-Dec;9(1-6):295-307
references.pmid: 6129040
references.citation: Behav Brain Res. 2002 Mar 10;130(1-2):191-6
references.pmid: 11864734
references.citation: J Pharmacol Exp Ther. 2006 Dec;319(3):1327-35
references.pmid: 16980569
references.citation: Neurosci Lett. 1981 May 6;23(2):117-23
references.pmid: 7254696
references.citation: Biol Psychiatry. 2005 Jun 1;57(11):1239-47
references.pmid: 15949994
references.citation: Neuron. 2008 Mar 13;57(5):760-73
references.pmid: 18341995
references.citation: Brain Res. 2007 May 25;1147:105-23
references.pmid: 17368434