title: Cognitive impairment in pain through amygdala-driven prefrontal cortical deactivation.
abstract: Cognitive deficits such as impaired decision-making can be a consequence of persistent pain. Normal functions of the intact amygdala and prefrontal cortex are required for emotion-based decision-making that relies on the ability to assess risk, attribute value, and identify advantageous strategies. We tested the hypothesis that pain-related cognitive deficits result from amygdala-driven impairment of medial prefrontal cortical (mPFC) function. To do this, we used electrophysiological single-unit recordings in vivo, patch clamp in brain slices, and various behavioral assays to show that increased neuronal activity in the amygdala in an animal model of arthritis pain was accompanied by decreased mPFC activation and impaired decision-making. Furthermore, pharmacologic inhibition (with a corticotropin-releasing factor 1 receptor antagonist) of pain-related hyperactivity in the basolateral amygdala (BLA), but not central amygdala (CeA), reversed deactivation of mPFC pyramidal cells and improved decision-making deficits. Pain-related cortical deactivation resulted from a shift of balance between inhibitory and excitatory synaptic transmission. Direct excitatory transmission to mPFC pyramidal cells did not change in the pain model, whereas polysynaptic inhibitory transmission increased. GABAergic transmission was reduced by non-NMDA receptor antagonists, suggesting that synaptic inhibition was glutamate driven. The results are consistent with a model of BLA-driven feedforward inhibition of mPFC neurons. In contrast to the differential effects of BLA versus CeA hyperactivity on cortical-cognitive functions, both amygdala nuclei modulate emotional-affective pain behavior. Thus, this study shows that the amygdala contributes not only to emotional-affective but also cognitive effects of pain. The novel amygdalo-cortical pain mechanism has important implications for our understanding of amygdala functions and amygdalo-cortical interactions.
authors.affiliation: Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas 77555-1069, USA.
authors.forename: Guangchen
authors.initials: G
authors.lastname: Ji
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Miguel
authors.initials: M
authors.lastname: Pais-Vieira
authors.forename: Vasco
authors.initials: V
authors.lastname: Galhardo
authors.forename: Volker
authors.initials: V
authors.lastname: Neugebauer
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology*; D000818:Animals; D001168:Arthritis / Q000150:complications / Q000503:physiopathology; D003072:Cognition Disorders / Q000150:complications / Q000503:physiopathology*; D003657:Decision Making / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D005680:gamma-Aminobutyric Acid; D000099052:CRF Receptor, Type 1
references.citation: Annu Rev Neurosci. 2004;27:1-28
references.pmid: 15217324
references.citation: Acta Endocrinol (Copenh). 1983 Apr;102(4):583-8
references.pmid: 6303034
references.citation: J Neurosci. 2006 Aug 9;26(32):8360-7
references.pmid: 16899731
references.citation: Nat Protoc. 2007;2(2):322-8
references.pmid: 17406592
references.citation: Nat Rev Neurosci. 2004 Oct;5(10):793-807
references.pmid: 15378039
references.citation: Mol Pain. 2007 Jun 05;3:13
references.pmid: 17550594
references.citation: J Neurosci. 2007 Feb 14;27(7):1543-51
references.pmid: 17301163
references.citation: Neuron. 2001 May;30(2):619-39
references.pmid: 11395019
references.citation: J Neurosci. 2006 Apr 12;26(15):4063-70
references.pmid: 16611823
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2423-8
references.pmid: 19171885
references.citation: Neuron. 2009 Jun 25;62(6):757-71
references.pmid: 19555645
references.citation: Nature. 1999 Nov 18;402(6759):294-6
references.pmid: 10580500
references.citation: Nat Neurosci. 2007 Aug;10(8):949-51
references.pmid: 17603478
references.citation: Neuron. 2008 Jun 12;58(5):662-71
references.pmid: 18549779
references.citation: J Neurophysiol. 2009 Oct;102(4):2253-64
references.pmid: 19625541
references.citation: Trends Neurosci. 2006 May;29(5):272-9
references.pmid: 16545468
references.citation: J Neurosci Methods. 2006 Mar 15;151(2):148-58
references.pmid: 16154203
references.citation: Nature. 2003 Jul 17;424(6946):316-20
references.pmid: 12867983
references.citation: Nat Neurosci. 2009 Jul;12(7):939-45
references.pmid: 19503087
references.citation: Neuron. 2009 Mar 12;61(5):774-85
references.pmid: 19285473
references.citation: J Neurophysiol. 2002 Dec;88(6):3487-97
references.pmid: 12466463
references.citation: Neuroscience. 2006;139(3):1039-48
references.pmid: 16527423
references.citation: J Neurosci. 2004 Apr 7;24(14):3471-9
references.pmid: 15071094
references.citation: Eur J Neurosci. 2003 Oct;18(8):2343-50
references.pmid: 14622196
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):18004-9
references.pmid: 19815518
references.citation: Neuron. 2005 Oct 20;48(2):175-87
references.pmid: 16242399
references.citation: Brain Res Rev. 2009 Apr;60(1):226-42
references.pmid: 19162070
references.citation: J Neurophysiol. 1995 Dec;74(6):2329-35
references.pmid: 8747195
references.citation: Nat Rev Neurosci. 2004 Nov;5(11):844-52
references.pmid: 15496862
references.citation: Pain. 2007 Jan;127(1-2):161-72
references.pmid: 17055162
references.citation: Nature. 2006 Jun 15;441(7095):876-9
references.pmid: 16778890
references.citation: J Neurosci. 2008 Apr 9;28(15):3861-76
references.pmid: 18400885
references.citation: Nat Neurosci. 2007 Apr;10(4):462-8
references.pmid: 17334362
references.citation: J Physiol. 2005 May 1;564(Pt 3):907-21
references.pmid: 15760935
references.citation: Neuron. 2007 Apr 5;54(1):51-8
references.pmid: 17408577
references.citation: Brain Res. 1996 May 13;720(1-2):211-9
references.pmid: 8782914
references.citation: Neuroscience. 2008 Aug 26;155(3):573-84
references.pmid: 18640246
references.citation: J Neurosci. 2006 Jun 14;26(24):6458-68
references.pmid: 16775133
references.citation: J Neurosci. 1997 Feb 1;17(3):983-95
references.pmid: 8994053
references.citation: Physiol Rev. 2003 Jul;83(3):803-34
references.pmid: 12843409
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1622-9
references.pmid: 17347454
references.citation: J Neurosci. 2006 Apr 19;26(16):4415-25
references.pmid: 16624961
references.citation: J Neurophysiol. 1999 Jul;82(1):272-82
references.pmid: 10400956
references.citation: Curr Opin Neurobiol. 2004 Apr;14(2):148-55
references.pmid: 15082318
references.citation: J Neurosci. 1995 Dec;15(12):8199-213
references.pmid: 8613754
references.citation: Pain. 2002 Mar;96(1-2):153-62
references.pmid: 11932071
references.citation: Neuroscience. 2006 Sep 29;142(1):1-20
references.pmid: 16887277
references.citation: J Neurosci. 2004 Nov 17;24(46):10410-5
references.pmid: 15548656
references.citation: Endocr Res. 2004 Nov;30(4):661-6
references.pmid: 15666809
references.citation: Annu Rev Pharmacol Toxicol. 1998;38:201-27
references.pmid: 9597154
references.citation: Neuroscientist. 2004 Jun;10(3):221-34
references.pmid: 15155061
references.citation: Mol Pain. 2007 Mar 28;3:8
references.pmid: 17391515
references.citation: J Neurophysiol. 2000 Aug;84(2):759-70
references.pmid: 10938303
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8351-6
references.pmid: 15928095
references.citation: Pain. 1992 Jan;48(1):89-99
references.pmid: 1738579
references.citation: J Neurophysiol. 2007 Jun;97(6):3893-904
references.pmid: 17392412
references.citation: Ann N Y Acad Sci. 2003 Apr;985:356-69
references.pmid: 12724171
references.citation: Nature. 2008 Jul 31;454(7204):600-6
references.pmid: 18615015
references.citation: Nat Rev Neurosci. 2009 Jun;10(6):423-33
references.pmid: 19469026
references.citation: J Comp Neurol. 1990 Aug 1;298(1):40-9
references.pmid: 1698828
references.citation: Neuron. 2007 Mar 1;53(5):735-46
references.pmid: 17329212
references.citation: Neuroscience. 1991;44(1):1-14
references.pmid: 1722886
references.citation: J Neurosci. 1999 Jul 1;19(13):5473-81
references.pmid: 10377356
references.citation: Pain. 2004 Mar;108(1-2):129-36
references.pmid: 15109516
references.citation: Neuroscience. 2007 Mar 2;145(1):225-31
references.pmid: 17204373
references.citation: J Neurophysiol. 2003 Feb;89(2):716-27
references.pmid: 12574449
references.citation: Science. 2007 Oct 26;318(5850):602-6
references.pmid: 17962553
references.citation: Biol Psychiatry. 2007 Sep 1;62(5):446-54
references.pmid: 17217927
references.citation: Neuron. 2008 Sep 11;59(5):829-38
references.pmid: 18786365
references.citation: J Neurosci. 2003 Jan 1;23(1):52-63
references.pmid: 12514201
references.citation: J Neurosci. 2009 Jul 15;29(28):8991-5
references.pmid: 19605636
references.citation: Neuroscience. 2007 Sep 7;148(3):737-43
references.pmid: 17706366
references.citation: Neuroscience. 2009 Jul 7;161(3):671-9
references.pmid: 19362121
references.citation: J Neurophysiol. 2001 May;85(5):2213-23
references.pmid: 11353036
references.citation: Genes Brain Behav. 2003 Oct;2(5):295-302
references.pmid: 14606694
references.citation: J Neurosci. 1992 Oct;12(10):4066-79
references.pmid: 1403101
references.citation: Brain Res. 1998 Oct 12;808(1):101-5
references.pmid: 9795166
references.citation: Science. 2007 May 4;316(5825):758-61
references.pmid: 17478724