Journal of Neuroimmune Pharmacology

, Volume 7, Issue 1, pp 145–155 | Cite as

Behavioral, Structural and Molecular Changes following Long-term Hippocampal IL-1β Overexpression in Transgenic Mice

  • Amy M. Hein
  • Troy J. Zarcone
  • David B. Parfitt
  • Sarah B. Matousek
  • Dena M. Carbonari
  • John A. Olschowka
  • M. Kerry O’Banion
ORIGINAL ARTICLE

Abstract

Chronic neuroinflammation is associated with many neurodegenerative and neurocognitive disorders, yet few animal models exist to study the behavioral effects of prolonged neuroinflammation. Therefore, we recently developed a transgenic mouse model harboring an interleukin-1β excisional activation transgene (IL-1βXAT). These mice display localized IL-1β overexpression and resultant neuroinflammation for up to 1 year following transgene induction. Initial behavioral studies demonstrated long-term memory deficits after 2 weeks of hippocampal IL-1β overexpression. In the present studies, we extend these behavioral studies both in scope and timing. We find long-term contextual but not auditory fear memory impairments following 3 months of IL-1β overexpression. On a battery of other behavioral tests, IL-1β overexpression in IL-1βXAT mice increased locomotor activity, especially in female mice, and had slight anxiolytic effects. No differences were found in operant conditioning or in basal or stress-induced CORT levels, despite profound hippocampal glial activation. Interestingly, the volume of discrete hippocampal cell layers was reduced after 6 but not 3 months of IL-1β overexpression. Therefore, this animal model provides a novel tool for examining the effects of chronic inflammation on discrete brain regions.

Keywords

Interleukin-1β Hippocampus Neuroinflammation Learning Memory Sickness behavior 

References

  1. Allan SM, Tyrrell PJ, Rothwell NJ (2005) Interleukin-1 and neuronal injury. Nat Rev Immunol 5:629–640PubMedCrossRefGoogle Scholar
  2. Barrientos RM, Higgins EA, Sprunger DB, Watkins LR, Rudy JW, Maier SF (2002) Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus. Behav Brain Res 134:291–298PubMedCrossRefGoogle Scholar
  3. Bretdibat J, Bluthe R, Kent S, Kelley K, Dantzer R (1995) Lipopolysaccharide and interleukin-1 depress food-motivated behavior in mice by a vagal-mediated mechanism. Brain Behav Immun 9:242–246CrossRefGoogle Scholar
  4. Chao CC, Hu S, Ehrlich L, Peterson PK (1995) Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptors. Brain Behav Immun 9:355–365PubMedCrossRefGoogle Scholar
  5. De La Garza 2nd, Asnis GM, Fabrizio KR, Pedrosa E (2005) Acute diclofenac treatment attenuates lipopolysaccharide-induced alterations to basic reward behavior and HPA axis activation in rats. Psychopharmacology 179:356–365Google Scholar
  6. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL (2010) A meta-analysis of cytokines in major depression. Biol Psychiatry 67:446–457PubMedCrossRefGoogle Scholar
  7. Draper K, Ponsford J (2008) Cognitive functioning ten years following traumatic brain injury and rehabilitation. Neuropsychology 22:618–625PubMedCrossRefGoogle Scholar
  8. Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O (2003) Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci USA 100:13632–13637PubMedCrossRefGoogle Scholar
  9. Gibertini M, Newton C, Friedman H, Klein T (1995) Spatial learning impairment in mice infected with legionella pneumophila or administered exogenous interleukin-1-ß. Brain Behav Immun 9:113–128PubMedCrossRefGoogle Scholar
  10. Goshen I, Kreisel T, Ounallah-Saad H, Renbaum P, Zalzstein Y, Ben-Hur T, Levy-Lahad E, Yirmiya R (2007) A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology 32:1106–1115PubMedCrossRefGoogle Scholar
  11. Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL 3rd, Araoz C (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA 86:7611–7615PubMedCrossRefGoogle Scholar
  12. Griffin DE, Wesselingh SL, McArthur JC (1994) Elevated central nervous system prostaglandins in human immunodeficiency virus-associated dementia. Ann Neurol 35:592–597PubMedCrossRefGoogle Scholar
  13. Gundersen HJ, Jensen EB (1987) The efficiency of systematic sampling in stereology and its prediction. J Microsc 147:229–263PubMedCrossRefGoogle Scholar
  14. Hauss-Wegrzyniak B, Dobrzanski P, Stoehr JD, Wenk GL (1998) Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer's disease. Brain Res 780:294–303PubMedCrossRefGoogle Scholar
  15. Hauss-Wegrzyniak B, Vraniak PD, Wenk GL (2000a) LPS-induced neuroinflammatory effects do not recover with time. Neuroreport 11:1759–1763PubMedCrossRefGoogle Scholar
  16. Hauss-Wegrzyniak B, Vannucchi MG, Wenk GL (2000b) Behavioral and ultrastructural changes induced by chronic neuroinflammation in young rats. Brain Res 859:157–166PubMedCrossRefGoogle Scholar
  17. Hein AM, Stutzman DL, Bland ST, Barrientos RM, Watkins LR, Rudy JW, Maier SF (2007) Prostaglandins are necessary and sufficient to induce contextual fear learning impairments after interleukin-1 beta injections into the dorsal hippocampus. Neuroscience 150:754–763PubMedCrossRefGoogle Scholar
  18. Hein AM, Stasko MR, Matousek SB, Scott-McKean JJ, Maier SF, Olschowka JA, Costa AC, O'Banion MK (2010) Sustained hippocampal IL-1beta overexpression impairs contextual and spatial memory in transgenic mice. Brain Behav Immun 24:243–253PubMedCrossRefGoogle Scholar
  19. Hutchinson PJ, O'Connell MT, Rothwell NJ, Hopkins SJ, Nortje J, Carpenter KL, Timofeev I, Al-Rawi PG, Menon DK, Pickard JD (2007) Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous inhibitor IL-1ra. J Neurotrauma 24:1545–1557PubMedCrossRefGoogle Scholar
  20. Kent S, Rodriguez F, Kelley KW, Dantzer R (1994) Reduction in food and water intake induced by microinjection of interleukin-1 beta in the ventromedial hypothalamus of the rat. Physiol Behav 56:1031–1036PubMedCrossRefGoogle Scholar
  21. Kent S, Bret-Dibat JL, Kelley KW, Dantzer R (1996) Mechanisms of sickness-induced decreases in food-motivated behavior. Neurosci Biobehav Rev 20:171–175PubMedCrossRefGoogle Scholar
  22. Kostulas N, Pelidou SH, Kivisakk P, Kostulas V, Link H (1999) Increased IL-1beta, IL-8, and IL-17 mRNA expression in blood mononuclear cells observed in a prospective ischemic stroke study. Stroke 30:2174–2179PubMedCrossRefGoogle Scholar
  23. Lai YC, Shaftel SS, Miller JN, Tallents RH, Chang Y, Pinkert CA, Olschowka JA, Dickerson IM, Puzas JE, O'Banion MK, Kyrkanides S (2006) Intraarticular induction of interleukin-1beta expression in the adult mouse, with resultant temporomandibular joint pathologic changes, dysfunction, and pain. Arthritis Rheum 54:1184–1197PubMedCrossRefGoogle Scholar
  24. Matousek SB, Hein AM, Shaftel SS, Olschowka JA, Kyrkanides S, O'Banion MK (2010) Cyclooxygenase-1 mediates prostaglandin E(2) elevation and contextual memory impairment in a model of sustained hippocampal interleukin-1beta expression. J Neurochem 114:247–258PubMedGoogle Scholar
  25. Min SS, Quan HY, Ma J, Han JS, Jeon BH, Seol GH (2009) Chronic brain inflammation impairs two forms of long-term potentiation in the rat hippocampal CA1 area. Neurosci Lett 456:20–24PubMedCrossRefGoogle Scholar
  26. Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765PubMedCrossRefGoogle Scholar
  27. Moore AH, Wu M, Shaftel SS, Graham KA, O'Banion MK (2009) Sustained expression of interleukin-1beta in mouse hippocampus impairs spatial memory. Neuroscience 164:1484–1495PubMedCrossRefGoogle Scholar
  28. Oitzl M, Van Oers H, Schobitz B, Ron de Kloet E (1993) Interleukin-1 ß, but not interleukin-6, impairs spatial navigation learning. Brain Res 613:160–163PubMedCrossRefGoogle Scholar
  29. Piletz JE, Halaris A, Iqbal O, Hoppensteadt D, Fareed J, Zhu H, Sinacore J, Devane CL (2009) Pro-inflammatory biomakers in depression: treatment with venlafaxine. World J Biol Psychiatry 10:313–323PubMedCrossRefGoogle Scholar
  30. Reale M, Iarlori C, Thomas A, Gambi D, Perfetti B, Di Nicola M, Onofrj M (2009) Peripheral cytokines profile in Parkinson's disease. Brain Behav Immun 23:55–63PubMedCrossRefGoogle Scholar
  31. Sachdev PS, Brodaty H, Valenzuela MJ, Lorentz LM, Koschera A (2004) Progression of cognitive impairment in stroke patients. Neurology 63:1618–1623PubMedGoogle Scholar
  32. Sairanen T, Ristimaki A, Karjalainen-Lindsberg ML, Paetau A, Kaste M, Lindsberg PJ (1998) Cyclooxygenase-2 is induced globally in infarcted human brain. Ann Neurol 43:738–747PubMedCrossRefGoogle Scholar
  33. Shaftel SS, Kyrkanides S, Olschowka JA, Miller JN, Johnson RE, O'Banion MK (2007a) Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest 117:1595–1604PubMedCrossRefGoogle Scholar
  34. Shaftel SS, Carlson TJ, Olschowka JA, Kyrkanides S, Matousek SB, O'Banion MK (2007b) Chronic interleukin-1beta expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood brain barrier permeability without overt neurodegeneration. J Neurosci 27:9301–9309PubMedCrossRefGoogle Scholar
  35. Song C, Li X, Leonard BE, Horrobin DF (2003) Effects of dietary n-3 or n-6 fatty acids on interleukin-1beta-induced anxiety, stress, and inflammatory responses in rats. J Lipid Res 44:1984–1991PubMedCrossRefGoogle Scholar
  36. Song C, Leonard BE, Horrobin DF (2004) Dietary ethyl-eicosapentaenoic acid but not soybean oil reverses central interleukin-1-induced changes in behavior, corticosterone and immune response in rats. Stress 7:43–54PubMedCrossRefGoogle Scholar
  37. Song C, Horrobin DF, Leonard BE (2006) The comparison of changes in behavior, neurochemistry, endocrine, and immune functions after different routes, doses and durations of administrations of IL-1beta in rats. Pharmacopsychiatry 39:88–99PubMedCrossRefGoogle Scholar
  38. Swiergiel AH, Dunn AJ (2007) Effects of interleukin-1beta and lipopolysaccharide on behavior of mice in the elevated plus-maze and open field tests. Pharmacol Biochem Behav 86:651–659PubMedCrossRefGoogle Scholar
  39. Tham W, Auchus AP, Thong M, Goh ML, Chang HM, Wong MC, Chen CP (2002) Progression of cognitive impairment after stroke: one year results from a longitudinal study of Singaporean stroke patients. J Neurol Sci 203–204:49–52PubMedCrossRefGoogle Scholar
  40. Trendelenburg G (2008) Acute neurodegeneration and the inflammasome: central processor for danger signals and the inflammatory response? J Cereb Blood Flow Metab 28:867–881PubMedCrossRefGoogle Scholar
  41. Wu MD, Hein AM, Moravan M, Olschowka JA, O’Banion MK (2010) Sustained interleukin-1beta expression ablates adult subgranular zone neurogenesis while sparing subventricular zone neurogenesis. Proc Soc Neurosci 879.21Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Amy M. Hein
    • 1
  • Troy J. Zarcone
    • 2
  • David B. Parfitt
    • 3
  • Sarah B. Matousek
    • 4
  • Dena M. Carbonari
    • 1
  • John A. Olschowka
    • 1
  • M. Kerry O’Banion
    • 1
    • 5
  1. 1.Department of Neurobiology and AnatomyUniversity of Rochester School of Medicine and DentistryRochesterUSA
  2. 2.National Institute on Alcohol Abuse and AlcoholismBethesdaUSA
  3. 3.State University of New YorkGeneseoUSA
  4. 4.Brigham and Women’s HospitalBostonUSA
  5. 5.University of Rochester Medical CenterRochesterUSA

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