Systemic inflammation induces acute working memory deficits in the primed brain: relevance for delirium.
Delirium is an acute, severe neuropsychiatric syndrome, characterized by cognitive deficits, that is highly prevalent in aging and dementia and is frequently precipitated by peripheral infections. Delirium is poorly understood and the lack of biologically relevant animal models has limited basic research. Here we hypothesized that synaptic loss and accompanying microglial priming during chronic neurodegeneration in the ME7 mouse model of prion disease predisposes these animals to acute dysfunction in the region of prior pathology upon systemic inflammatory activation. Lipopolysaccharide (LPS; 100 μg/kg) induced acute and transient working memory deficits in ME7 animals on a novel T-maze task, but did not do so in normal animals. LPS-treated ME7 animals showed heightened and prolonged transcription of inflammatory mediators in the central nervous system (CNS), compared with LPS-treated normal animals, despite having equivalent levels of circulating cytokines. The demonstration that prior synaptic loss and microglial priming are predisposing factors for acute cognitive impairments induced by systemic inflammation suggests an important animal model with which to study aspects of delirium during dementia.
Murray
Carol
C
Trinity College Institute of Neuroscience, School of Biochemistry & Immunology, Trinity College Dublin, Dublin, Ireland.
Sanderson
David J
DJ
Barkus
Chris
C
Deacon
Robert M J
RM
Rawlins
J Nicholas P
JN
Bannerman
David M
DM
Cunningham
Colm
C
D000208:Acute Disease; D000818:Animals; D003693:Delirium / Q000473:pathology / Q000503:physiopathology; D003704:Dementia / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000150:complications / Q000473:pathology; D018836:Inflammation Mediators / Q000008:administration & dosage; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008569:Memory Disorders / Q000473:pathology* / Q000503:physiopathology; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL
D018836:Inflammation Mediators; D008070:Lipopolysaccharides
FASEB J. 2005 Aug;19(10):1329-31
15919760
J Am Geriatr Soc. 2008 Sep;56(9):1704-9
18691278
Brain Res. 2006 Oct 18;1115(1):194-9
16938281
J Neuropsychiatry Clin Neurosci. 1994 Summer;6(3):279-84
7950352
Q J Exp Psychol B. 1988 Aug;40(3):243-58
3175038
J Neurol Neurosurg Psychiatry. 2000 Oct;69(4):519-21
10990515
J Gen Intern Med. 1998 Mar;13(3):204-12
9541379
Psychosomatics. 1999 Sep-Oct;40(5):428-35
10479948
Nat Rev Neurol. 2009 Apr;5(4):210-20
19347026
Nat Rev Immunol. 2006 Sep;6(9):644-58
16932750
Behav Brain Res. 2006 Jun 30;170(2):302-7
16621055
J Neurosci. 2006 Oct 18;26(42):10709-16
17050710
Int Rev Psychiatry. 2009 Feb;21(1):30-42
19219711
Brain Behav Immun. 2008 Mar;22(3):301-11
17951027
Brain Behav Immun. 1998 Sep;12(3):212-29
9769157
J Am Geriatr Soc. 2002 Oct;50(10):1723-32
12366629
Eur J Neurosci. 2003 May;17(10):2147-55
12786981
CMAJ. 2001 Sep 4;165(5):575-83
11563209
Int J Geriatr Psychiatry. 2001 Apr;16(4):415-21
11333430
J Neurosci. 2005 Oct 5;25(40):9275-84
16207887
Alzheimer Dis Assoc Disord. 1997 Mar;11(1):16-20
9071440
Neurobiol Dis. 2008 Apr;30(1):19-29
18255301
Int Rev Psychiatry. 2009 Feb;21(1):1-3
19219706
J Mol Neurosci. 2003;21(3):199-212
14645987
Int J Geriatr Psychiatry. 2008 Sep;23(9):943-8
18481319
Neuropsychopharmacology. 2003 Jul;28(7):1235-46
12700710
J Neurooncol. 1988 Dec;6(4):355-9
2464673
J Biol Chem. 2001 Dec 7;276(49):45564-72
11581275
Neuroscience. 2002;112(1):7-11
12044467
J Psychosom Res. 2007 May;62(5):521-5
17467406
Glia. 2009 Dec;57(16):1802-14
19459212
Neurobiol Aging. 2006 May;27(5):723-32
15893410
Brain Behav Immun. 2005 Sep;19(5):453-60
15963684
Nat Rev Immunol. 2007 Feb;7(2):161-7
17220915
Behav Neural Biol. 1988 May;49(3):332-43
3408445
Crit Care Clin. 2008 Jan;24(1):45-65, viii
18241778
Age Ageing. 1999 Oct;28(6):551-6
10604507
J Neurosci. 2005 Feb 16;25(7):1788-96
15716415
Anticancer Res. 2001 Sep-Oct;21(5):3699-700
11848546
Arch Gen Psychiatry. 2001 May;58(5):445-52
11343523
Ann Neurol. 1990 May;27(5):457-64
2360787
Behav Brain Res. 2002 Jun 15;133(1):57-68
12048174
Neurology. 2009 May 5;72(18):1570-5
19414723
Brain Res Bull. 2005 Sep 30;67(1-2):24-9
16140159
J Gerontol. 1993 Sep;48(5):M181-6
8366260
Neuropharmacology. 2004 Jun;46(8):1195-200
15111026
J Neurol Neurosurg Psychiatry. 2004 Mar;75(3):362-7
14966146
J Neurochem. 2010 Feb;112(4):1054-64
19968753
Biol Psychiatry. 2009 Feb 15;65(4):304-12
18801476
Curr Opin Neurobiol. 1997 Apr;7(2):164-9
9142761
Age Ageing. 2009 Jul;38(4):368-73
19297372
Eur J Neurosci. 2006 May;23(10):2723-30
16817875
Immunity. 2002 Sep;17(3):251-63
12354379
J Biol Chem. 2002 Nov 22;277(47):45129-40
12221085
Neurobiol Learn Mem. 1995 May;63(3):269-76
7670840
Neuroscience. 2007 Dec 19;150(4):754-63
18035502
J Gerontol A Biol Sci Med Sci. 2007 Apr;62(4):420-6
17452737
Brain Behav Immun. 2007 May;21(4):490-502
17321719
Dement Geriatr Cogn Disord. 2005;19(2-3):158-63
15627764
Exp Brain Res. 1981;41(3-4):380-9
7215498
Psychosomatics. 1996 Nov-Dec;37(6):533-46
8942204
J Psychosom Res. 1997 Oct;43(4):417-23
9330241
Mol Psychiatry. 2008 May;13(5):480-97
18180766
Psychoneuroendocrinology. 2008 Nov;33(10):1369-77
18805643
Brain Behav Immun. 2008 Nov;22(8):1117-27
18640811