Characterization of Spatial Learning and Sickness Responses in Aging Rats Following Recurrent Lipopolysaccharide Administration

Abstract

Infections in older individuals can result in cognitive function decline, yet research is limited on how recurrent infections affect cognitive responses. Activation of the immune system results in sickness responses mediated by cytokines. This pilot study examined effects of a model of recurrent infection in aged, male Brown Norway rats on sickness responses, including spatial learning, and cytokine levels. To model initial and recurrent infection, 300 μg/kg lipopolysaccharide (LPS) or saline was administered 1/day for 2 consecutive days during 2 weeks separated by 16 days. Testing occurred for 6 days during each LPS injection week using the Morris water maze, a measure used to evaluate spatial learning. Directional heading error (DHE) and swim time latency served as spatial learning indices. Retention tests and probe trials assessed memory. Plasma cytokine levels were assessed 5 and 24 hr after each LPS injection during Week 2. While food intake and weight decreased significantly in LPS-injected rats compared to controls during Week 1, both displayed increased DHE. Despite exhibiting lessened sickness behaviors during Week 2, experimental animals still displayed spatial learning deficits. Probe trials revealed memory deficits in LPS-injected animals. Interleukin 6 level was higher in the experimental group 5 and 24 hr after LPS injection on Day 1 compared to Day 2 and higher in the experimental compared to the control group at 5 hr on Day 1. Cognitive effects were dissociated from metabolic effects in aged rats, with recurring LPS exposure resulting in persistent cognitive impairment despite decreased sickness responses. Further research with older individuals is warranted.

Keywords

aging sickness behavior lipopolysaccharide recurrent infection spatial learning animal model

Get full access to this article

View all access options for this article.

References

Barrientos

R. M.

Higgins

E. A.

Biedenkapp

J. C.

Sprunger

D. B.

Wright-Hardesty

K. J.

Watkins

L. R.

… Maier

S. F

. (2006). Peripheral infection and aging interact to impair hippocampal memory consolidation. Neurobiology of Aging, 27, 723–732. doi:10.1016/j.neurobiolaging.2005.03.010

Barrientos

R. M.

Kitt

M. M.

Watkins

L. R.

Maier

S. F.

(2015). Neuroinflammation in the normal aging hippocampus. Neuroscience, 309, 84–99. doi:10.1016/j.neuroscience.2015.03.007

Barrientos

R. M.

Watkins

L. R.

Rudy

J. W.

Maier

S. F.

(2009). Characterization of the sickness response in young and aging rats following E. Coli infection. Brain, Behavior, and Immunity, 23, 450–454. doi:10.1016/j.bbi.2009.01.016

Biswas

S. K.

Lopez-Collazo

(2009). Endotoxin tolerance: New mechanisms, molecules and clinical significance. Trends in Immunology, 30, 475–487. doi:10.1016/j.it.2009.07.009

Bucks

R. S.

Gidron

Harris

Teeling

Wesnes

K. A.

Perry

V. H.

(2008). Selective effects of upper respiratory tract infection on cognition, mood and emotion processing: A prospective study. Brain, Behavior, and Immunity, 22, 399–407. doi:10.1016/j.bbi.2007.09.005

Chen

Zhou

Beltran

Malellari

Chang

S. L.

(2005). Differential expression of cytokines in the brain and serum during endotoxin tolerance. Journal of Neuroimmunology, 163, 53–72. doi:10.1016/j.jneuroim.2005.02.012

Curns

A. T.

Steiner

C. A.

Sejvar

J. J.

Schonberger

L. B.

(2008). Hospital charges attributable to a primary diagnosis of infectious diseases in older adults in the United States, 1998 to 2004. Journal of the American Geriatrics Society, 56, 969–975. doi:10.1111/j.1532-5415.2008.01712.x

Dang

T. T.

Majumdar

S. R.

Marrie

T. J.

Eurich

D. T.

(2015). Recurrent pneumonia: A review with focus on clinical epidemiology and modifiable risk factors in elderly patients. Drugs & Aging, 32, 13–19. doi:10.1007/s40266-014-0229-6

Davis

R. L.

Therrien

B. A.

West

B. T.

(2008). Cue conditions and wayfinding in older and younger women. Research in Gerontological Nursing, 1, 252–263. doi:10.3928/19404921-20081001-06

10.

Gale

S. D.

Erickson

L. D.

Berrett

Brown

B. L.

Hedges

D. W.

(2016). Infectious disease burden and cognitive function in young to middle-aged adults. Brain, Behavior, and Immunity, 52, 161–168. doi:10.1016/j.bbi.2015.10.014

11.

Godbout

J. P.

Chen

Abraham

Richwine

A. F.

Berg

B. M.

Kelley

K. W.

Johnson

R. W.

(2005). Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. The FASEB Journal, 19, 1329–1331. doi:10.1096/fj.05-3776fje

12.

Hauss-Wegrzyniak

Dobrzanski

Stoehr

J. D.

Wenk

G. L.

(1998). Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer’s disease. Brain Research, 780, 294–303.

13.

Hauss-Wegrzyniak

Vraniak

Wenk

G. L.

(1999). The effects of a novel NSAID on chronic neuroinflammation are age dependent. Neurobiology of Aging, 20, 305–313. doi:10.1016/S0197-4580(99)00028-7

14.

Hauss-Wegrzyniak

Vraniak

P. D.

Wenk

G. L.

(2000). LPS-induced neuroinflammatory effects do not recover with time. Neuroreport, 11, 1759–1763. doi:10.1097/00001756-200006050-00032

15.

Hebda-Bauer

E. K.

Morano

M. I.

Therrien

(1999). Aging and corticosterone injections affect spatial learning in Fischer-344 x Brown Norway rats. Brain Research, 827, 93–103. doi:10.1016/S0006-8993(99)01310-4

16.

Huang

Henry

C. J.

Dantzer

Johnson

R. W.

Godbout

J. P.

(2008). Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide. Neurobiology of Aging, 29, 1744–1753. doi:10.1016/j.neurobiolaging.2007.04.012

17.

Iwashyna

T. J.

Ely

E. W.

Smith

D. M.

Langa

K. M.

(2010). Long-term cognitive impairment and functional disability among survivors of severe sepsis. Journal of the American Medical Association, 304, 1787–1794. doi:10.1001/jama.2010.1553

18.

Joëls

Wiegert

Oitzl

M. S.

Krugers

H. J

. (2006). Learning under stress: How does it work? Trends in Cognitive Sciences, 10, 152–158. doi:10.1016/j.tics.2006.02.002

19.

Kahn

M. S.

Kranjac

Alonzo

C. A.

Haase

J. H.

Cedillos

R. O.

McLinden

K. A.

… Chumley

M. J

. (2012). Prolonged elevation in hippocampal Aβ and cognitive deficits following repeated endotoxin exposure in the mouse. Behavioural Brain Research, 229, 176–184. doi:10.1016/j.bbr.2012.01.010

20.

Katan

Moon

Y. P.

Paik

M. C.

Sacco

R. L.

Wright

C. B.

Elkind

M. S.

(2013). Infectious burden and cognitive function: The Northern Manhattan Study. Neurology, 80, 1209–1215. doi:10.1212/WNL.0b013e3182896e79

21.

Kim

S. E.

I. G.

Shin

M. S.

Kim

C. J.

Jin

B. K.

Hong

H. P.

Jee

Y. S.

(2013). Treadmill exercise and wheel exercise enhance expressions of neutrophic factors in the hippocampus of lipopolysaccharide-injected rats. Neuroscience Letters, 538, 54–59. doi:10.1016/j.neulet.2013.01.039

22.

Kupferschmid

B. J.

Therrien

B. A.

(2018). Spatial learning responses to lipopolysaccharide in adult and aged rats. Biological Research for Nursing, 20, 32–39. doi:10.1177/1099800417726875

23.

Kupferschmid

B. J.

Therrien

Rowsey

P. J.

(2017). Effects of low-dose lipopolysaccharide and age on spatial learning in different Morris water maze protocols. SAGE Open Medicine, 5. doi:10.1177/2050312117729112

24.

Kupferschmid

B. J.

Therrien

Rowsey

P. J.

(2018). Different sickness responses in adult and aged rats following lipopolysaccharide administration. Biological Research for Nursing, 20, 335–342. doi:10.1177/1099800418759599

25.

Langhans

Balkowski

Savoldelli

(1991). Differential feeding responses to bacterial lipopolysaccharide and muramyl dipeptide. The American Journal of Physiology, 261, R659–R664.

26.

Howell

E. A.

Lagoo

A. S.

Kuchibhatla

Pan

Cohen

H. J.

Lagoo

S. A.

(2009). Differential gene expression of interleukin-1 receptor associated kinase-1 and interleukin-1 receptor associated kinase-M in peripheral blood mononuclear cells of young and aged rats following preconditioning with endotoxin. Shock, 31, 55–63. doi:10.1097/SHK.0b013e3181778ab2

27.

Liang

S. Y.

(2016). Sepsis and other infectious disease emergencies in the elderly. Emergency Medicine Clinics of North America, 34, 501–522. doi:10.1016/j.emc.2016.04.005

28.

McCusker

R. H.

Kelley

K. W.

(2013). Immune-neural connections: how the immune system’s response to infectious agents influences behavior. Journal of Experimental Biology, 216, 84–98. doi:10.1242/jeb.073411

29.

Moffat

S. D.

Zonderman

A. B.

Resnick

S. M.

(2001). Age differences in spatial memory in a virtual environment navigation task. Neurobiology of Aging, 22, 787–796. doi:10.1016/S0197-4580(01)00251-2

30.

Schneeberger

Stolk

R. P.

Devries

J. H.

Schneeberger

P. M.

Herings

R. M.

Geerlings

S. E.

(2008). Differences in the pattern of antibiotic prescription profile and recurrence rate for possible urinary tract infections in women with and without diabetes. Diabetes Care, 31, 1380–1385. doi:10.2337/dc07-2188

31.

Shaw

K. N.

Commins

O’Mara

S. M.

(2001). Lipopolysaccharide causes deficits in spatial learning in the watermaze but not in BDNF expression in the rat dentate gyrus. Behavioural Brain Research, 124, 47–54. doi:10.1016/S0166-4328(01)00232-7

32.

Smith

A. P.

(2012). Effects of the common cold on mood, psychomotor performance, the encoding of new information, speed of working memory and semantic processing. Brain, Behavior, and Immunity, 26, 1072–1076. doi:10.1016/j.bbi.2012.06.012

33.

Sparkman

N. L.

Kohman

R. A.

Scott

V. J.

Boehm

G. W.

(2005). Bacterial endotoxin-induced behavioral alterations in two variations of the Morris water maze. Physiology & Behavior, 86, 244–251. doi:10.1016/j.physbeh.2005.07.016

34.

Sparkman

N. L.

Martin

L. A.

Calvert

W. S.

Boehm

G. W.

(2005). Effects of intraperitoneal lipopolysaccharide on Morris maze performance in year-old and 2-month-old female C57BL/6J mice. Behavioural Brain Research, 159, 145–151. doi:10.1016/j.bbr.2004.10.011

35.

Swanepoel

Harvey

B. H.

Harden

L. M.

Laburn

H. P.

Mitchell

(2012). Simulated systemic recurrent Mycoplasma infection in rats induces recurrent sickness responses without residual impairment in spatial learning and memory. Physiology & Behavior, 105, 800–808. doi:10.1016/j.physbeh.2011.10.010

36.

Therrien

B. A.

(1982). Sex differences in the effects of hippocampal lesions on place navigation (Doctoral dissertation). The University of Michigan, Ann Arbor.

37.

Vorhees

C. V.

Williams

M. T.

(2014). Value of water mazes for assessing spatial and egocentric learning and memory in rodent basic research and regulatory studies. Neurotoxicology and Teratology, 45, 75–90. doi:10.1016/j.ntt.2014.07.003

38.

Wolden-Hanson

(2006). Mechanisms of the anorexia of aging in the Brown Norway rat. Physiology & Behavior, 88, 267–276. doi:10.1016/j.physbeh.2006.05.032

39.

Wright

C. B.

Gardener

Dong

Yoshita

DeCarli

Sacco

R. L.

… Elkind

M. S

. (2015). Infectious burden and cognitive decline in the Northern Manhattan study. Journal of the American Geriatrics Society, 63, 1540–1545. doi:10.1111/jgs.13557

40.

Zelinski

E. L.

Deibel

S. H.

McDonald

R. J.

(2014). The trouble with circadian clock dysfunction: Multiple deleterious effects on the brain and body. Neuroscience and Biobehavioral Reviews, 40, 80–101. doi:10.1016/j.neubiorev.2014.01.007