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Neonatal Infection-Induced Memory Impairment after Lipopolysaccharide in Adulthood Is Prevented via Caspase-1 Inhibition
Open accessAbstract
We have reported that neonatal infection leads to memory impairment after an immune challenge in adulthood. Here we explored whether events occurring as a result of early infection alter the response to a subsequent immune challenge in adult rats, which may then impair memory. In experiment 1, peripheral infection with Escherichia coli on postnatal day 4 increased cytokines and corticosterone in the periphery, and cytokine and microglial cell marker gene expression in the hippocampus of neonate pups. Next, rats treated neonatally with E. coli or PBS were injected in adulthood with lipopolysaccharide (LPS) or saline and killed 1-24 h later. Microglial cell marker mRNA was elevated in hippocampus in saline controls infected as neonates. Furthermore, LPS induced a greater increase in glial cell marker mRNA in hippocampus of neonatally infected rats, and this increase remained elevated at 24 h versus controls. After LPS, neonatally infected rats exhibited faster increases in interleukin-1beta (IL-1beta) within the hippocampus and cortex and a prolonged response within the cortex. There were no group differences in peripheral cytokines or corticosterone. In experiment 2, rats treated neonatally with E. coli or PBS received as adults either saline or a centrally administered caspase-1 inhibitor, which specifically prevents the synthesis of IL-1beta, 1 h before a learning event and subsequent LPS challenge. Caspase-1 inhibition completely prevented LPS-induced memory impairment in neonatally infected rats. These data implicate IL-1beta in the set of immune/inflammatory events that occur in the brain as a result of neonatal infection, which likely contribute to cognitive alterations in adulthood.
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“Bilbo et al. revealed that neonatal E. coli infection could impair memory in adult rats (394).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [394]
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Williamson, L. L., McKenney, E. A., Holzknecht, Z. E., Belliveau, C., Rawls, J. F., Poulton, S., Parker, W., & Bilbo, S. D. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.07.006 · Cited by 84
Current understanding and neurobiology of epileptic encephalopathies
Auvin, S., Cilio, M. R., & Vezzani, A. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.03.007 · Cited by 83
“Notably, neonatal rats infected with Escherichia coli exhibit cognitive deficits after a second immune challenge by LPS in adulthood (Bilbo et al., 2005a; Williamson et al., 2011), and P7-P14 offspring of dams injected during gestation with poly I:C (a TLR3 agonist that mimics viral infections), or…”
Innate Immune Regulation by Toll-Like Receptors in the Brain
Mallard, C. E. (2012) · ISRN Neurology · doi:10.5402/2012/701950 · Cited by 82
Li, Z., Ma, L., Kulesskaya, N., Võikar, V., & Tian, L. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.02.008 · Cited by 81
“Neonatal infection attenuated corticosterone response to an acute stressor, impaired cognition, and decreased social interactions in rats (Bilbo et al., 2005; Bilbo and Schwarz, 2012). http://dx.doi.org/10.1016/j.bbi.2014.02.008 0889-1591/ 2014 Elsevier Inc.”
BackgroundInfluentialDoenni, V. M., Gray, J. M., Song, C. M., Patel, S., Hill, M. N., & Pittman, Q. J. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.07.152 · Cited by 80
“Inflammatory insults with live bacteria on postnatal day (P) 4 have been associated with altered fear memory (Bilbo et al., 2005) and motor coordination (Lieblein-Boff et al., 2013), as well as potentiation of glial and cytokine responses in the adult rat (reviewed in Bilbo and Schwarz, 2012),…”
Savi, F. F., de Oliveira, A. L. R., de Medeiros, G. F., Bozza, F. A., Michels, M., Sharshar, T., Dal‐Pizzol, F., & Ritter, C. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.12.005 · Cited by 83
Modulating Neuroinflammation to Treat Neuropsychiatric Disorders
Radtke, F., Chapman, G., Hall, J., & Syed, Y. A. (2017) · BioMed Research International · doi:10.1155/2017/5071786 · Cited by 80
“This observation is further supported by animal studies, where neonatal bacterial infection of rats induces hippocampus-dependent memory deficits in adulthood [77].”
ResultSchwarz, J. M., & Bilbo, S. D. (2011) · Neuroscience Letters · doi:10.1016/j.neulet.2011.04.042 · Cited by 74
“These data confirm previous analyses of cytokines and chemokines within the brain [7], and complement data implicating IL-1β as a critical molecule underlying the adult cognitive impairments [6,7].”
BackgroundMethodResultInfluentialZiko, I., Luca, S. N. D., Dinan, T., Barwood, J. M., Sominsky, L., Cai, G., Kenny, R., Stokes, L., Jenkins, T. A., & Spencer, S. J. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.06.014 · Cited by 73
for the ELGAN Study Investigators, Yanni, D., Korzeniewski, S. J., Allred, E. N., Fichorova, R. N., O’Shea, T. M., Kuban, K., Dammann, O., & Leviton, A. (2017) · Pediatric Research · doi:10.1038/pr.2017.128 · Cited by 73
Ellis, S. L., Mouihate, A., & Pittman, Q. J. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2005.102939 · Cited by 72
“Additionally, it has been shown that neonatal immune challenges alter memory, cognitive ability and pain sensitivity as adults (Gilmore et al. 2003, 2005; Zuckerman & Weiner, 2005; Bilbo et al. 2005; Boisse et al. 2005).”
BackgroundKuijer, E. J., & Steenbergen, L. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105296 · Cited by 76
Tsakiri, N., Kimber, I., Rothwell, N. J., & Pinteaux, E. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707610 · Cited by 70
“, 2003), as well as host defence responses, such as fever and sickness behaviour (Takahashi et al., 1996; Dantzer et al., 1998; Schneider et al., 1998; Rachal et al., 2001; Watkins et al., 2001; Ross et al., 2003; Bilbo et al., 2005).”
BackgroundBilbo, S. D., Yirmiya, R., Amat, J., Paul, E. D., Watkins, L. R., & Maier, S. F. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2007.11.008 · Cited by 75
“…stage relatively comparable to the third trimester in humans during which significant brain growth occurs (Dobbing and Sands, 1979; Rodier, 1980), increases both peripheral and brain cytokines, as well as corticosterone for several hours (>48) following the infection (Bilbo et al., 2005a).”
BackgroundResultInfluentialMakinson, R., Lloyd, K., Rayasam, A., McKee, S., Brown, A., Barila, G., Grissom, N., George, R., Marini, M., Fabry, Z., et al. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.07.016 · Cited by 67
Increased microglial activation in the rat brain following neonatal exposure to a bacterial mimetic
Sominsky, L., Walker, A. K., Ong, L. K., Tynan, R. J., Walker, F. R., & Hodgson, D. M. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.08.038 · Cited by 67
Walker, A. K., Hawkins, G. E., Sominsky, L., & Hodgson, D. M. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.01.005 · Cited by 67
The impact of inflammation on respiratory plasticity
Hocker, A. D., Stokes, J. A., Powell, F. L., & Huxtable, A. G. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.07.022 · Cited by 63
“In contrast, low-dose, neonatal LPS alters future immune responses and causes memory impairment in adults (Bilbo et al., 2005).”
Sex Differences in Neurodevelopmental Disorders: A Key Role for the Immune System
Breach, M. R., & Lenz, K. M. (2022) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2022_308 · Cited by 62
Lasheras, I., Seral, P., Latorre, E., Barroso, E., Gracia‐García, P., & Santabárbara, J. (2019) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2019.101874 · Cited by 66
Harden, L. M., du Plessis, I., Roth, J., Loram, L. C., Poole, S., & Laburn, H. P. (2010) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2010.09.003 · Cited by 64
Stolp, H. B., Johansson, P. A., Habgood, M. D., Dzięgielewska, K. M., Saunders, N. R., & Ek, C. J. (2011) · Cardiovascular Psychiatry and Neurology · doi:10.1155/2011/469046 · Cited by 63
“In addition, in animals exposed to inflammation in utero or during early postnatal life, long-term behavioural alterations such as deficits in prepulse inhibition test [17, 18], motor behaviour [19], and learning and memory [19, 20] have also been reported.”
Gene–environment interactions in severe intraventricular hemorrhage of preterm neonates
; for the Gene Targets for IVH Study Group, Ment, L. R., Ådén, U., Lin, A., Kwon, S. H., Choi, M., Hallman, M., Lifton, R. P., Zhang, H., & Bauer, C. R. (2013) · Pediatric Research · doi:10.1038/pr.2013.195 · Cited by 63
“Such perinatal immune activation has been associated not only with change in behavior in neonatal animals but also disrupted avoidance learning in male, but not female subjects in adulthood (69).”
BackgroundNeuroprotective Role of Lactoferrin during Early Brain Development and Injury through Lifespan
Schirmbeck, G. H., Sizonenko, S. V., & Sanches, E. F. (2022) · Nutrients · doi:10.3390/nu14142923 · Cited by 68
Hennessy, M. B., Deak, T., & Schiml‐Webb, P. A. (2009) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2009.03.012 · Cited by 61
“These effects include an enhanced febrile response, elevated central and peripheral cytokine activity, and increased central COX-2 levels and glia activity, and appear in large part to reflect reduced tolerance to later immunological challenges (Bilbo et al., 2005a,2007a,2008a).”
InfluentialLieblein‐Boff, J. C., McKim, D. B., Shea, D. T., Wei, P. Y., Deng, Z., Sawicki, C. M., Quan, N., Bilbo, S. D., Bailey, M. T., McTigue, D. M., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0708-13.2013 · Cited by 57
“Some studies have linked poor cognitive performance following neonatal challenge with LPS (Harré et al., 2008) or IL-1 (Favrais et al., 2011), whereas other studies have not (Bilbo et al., 2005a,b, 2006).”
BackgroundResultDoosti, M.-H., Bakhtiari, A., Zare, P., Amani, M., Zolbanin, N. M., Babri, S., & Salari, A. (2012) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2012.12.003 · Cited by 57
Fan, L., Tien, L., Mitchell, H. J., Rhodes, P. G., & Cai, Z. (2008) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2008.06121.x · Cited by 56
“It is also known that the HP is vulnerable to immune-related alterations and important to the pathology of behavioral and cognitive disorders (Lynch et al., 2004; Bilbo et al., 2005).”
InfluentialQi, F., Zuo, Z., Yang, J., Hu, S., Yang, Y., Yuan, Q., Zou, J., Guo, K., & Yao, Z. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0808-7 · Cited by 51
“impairment after a subsequent immune challenge later in life [1].”
Pourganji, M., Hosseini, M., Soukhtanloo, M., Zabihi, H., & Hadjzadeh, M. A.-R. (2014) · Iranian Red Crescent Medical Journal · doi:10.5812/ircmj.13954 · Cited by 53
“The results of present study confirmed LPS-induced learning and memory impairments which had been repeatedly reported (63-65).”
ResultDo Epigenetic Pathways Initiate Late Onset Alzheimer Disease (LOAD): Towards a New Paradigm
Bihaqi, S. W., Schumacher, A., Maloney, B., Lahiri, D. K., & Zawia, N. H. (2012) · Current Alzheimer Research · doi:10.2174/156720512800617982 · Cited by 52
“Diseases such as SZ have also been linked to infection, fetal malnutrition, or hypoxia in early life [107-110], thus suggesting a role for environmental factors acting in the pre–conceptual, fetal, and infantile phases of life [111].”
BackgroundComparison of anorexia, lethargy, and fever induced by bacterial and viral mimetics in rats
Hopwood, N., Maswanganyi, T., & Harden, L. M. (2009) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y09-003 · Cited by 50
“As with IL-6 production, LPS is more potent than poly I:C at inducing an increase in the concentration of IL-1b in the circulation (Fortier et al. 2004; Bilbo et al. 2005).”
BackgroundNeonatal BCG vaccination of mice improves neurogenesis and behavior in early life
Yang, J., Qi, F., Gu, H., Zou, J., Yang, Y., Yuan, Q., & Yao, Z. (2015) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2015.10.012 · Cited by 48
Saavedra, L. M., Navarro, B. F., & Torner, L. (2017) · NeuroImmunoModulation · doi:10.1159/000485383 · Cited by 56
Frost, P. S., Barros‐Aragão, F. G. Q., da Silva, R. T., Venancio, A. M., Matias, I. C. P., Silva, N. M. L. E., Kincheski, G. C., Pimentel‐Coelho, P. M., Felice, F. G. D., Gomes, F. C. A., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1529-x · Cited by 51
Metadata
- Authors
- Bilbo, S. D., Biedenkapp, J. C., Der-Avakian, A., Watkins, L. R., Rudy, J. W., & Maier, S. F.
- Affiliations
- University of Colorado Boulder (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-08-31
- Volume
- 25
- Issue
- 35
- Pages
- 8000-8009
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725459
- OpenAlex
- W2042311033
- Cited by
- 251
- References
- 71
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 9 · 2023: 9 · 2022: 6 · 2021: 18 · 2020: 10 · 2019: 15 · 2018: 10 · 2017: 28 · 2016: 9 · 2015: 17 · 2014: 20 · 2013: 24 · 2012: 12
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (R01MH065656, R01-MH065656-02)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- neonatal infection, lipopolysaccharide, memory impairment, caspase-1 inhibition, IL-1β, hippocampus, microglia, neuroinflammation, Escherichia coli, corticosterone, cytokines, learning, neuroimmune interactions
- MeSH terms
- Age Factors, Animals, Animals, Newborn, Enzyme Inhibitors, Escherichia coli Infections, Female, Hippocampus, Interleukin-1, Lipopolysaccharides, Male, Memory Disorders, Pregnancy, Rats, Sprague-Dawley, Caspase 1, Rats, Caspase Inhibitors
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