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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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Shaker, T., Chattopadhyaya, B., Amilhon, B., Cristo, G. D., & Weil, A. G. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105535 · Cited by 17
Aluminum as a CNS and Immune System Toxin Across the Life Span
Shaw, C. A. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-1370-7_4 · Cited by 17
Prenatal Alcohol Exposure: Impact on Neuroendocrine–Neuroimmune Networks
Bodnar, T. S., & Weinberg, J. (2012) · Springer eBooks · doi:10.1007/978-1-4614-4729-0_10 · Cited by 19
“Reduced birth weight and length, reduced litter size, and increased malformations have been reported in offspring sired by alcohol-consuming males [ 3, 114, 115 ] , although fetal vulnerability to depressed body weight was shown to have a maternal genetic contribution as well [ 116 ] .”
BackgroundMethodFetal inflammation induces acute immune tolerance in the neonatal rat hippocampus
Singh, G., Segura, B. J., Georgieff, M., & Gisslen, T. A. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02119-w · Cited by 15
“Regulation of IL-1β in the hippocampus is important for proper development of learning and memory [53].”
BackgroundGlucocorticoid production in the thymus and brain: Immunosteroids and neurosteroids
Salehzadeh, M., & Soma, K. K. (2021) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2021.100352 · Cited by 15
Topper, L. A., & Valenzuela, C. F. (2014) · Alcohol · doi:10.1016/j.alcohol.2014.09.032 · Cited by 13
“It has been postulated that neonatal infection programs an exaggerated response in the developing neuroimmune system that could result in behavioral alterations such as memory impairment (Bilbo et al., 2005a).”
BackgroundResultInfluentialVelez-Perez, A., Holder, M. K., Fountain, S., & Blaustein, J. D. (2020) · eNeuro · doi:10.1523/eneuro.0505-19.2020 · Cited by 14
“In fact, a bacterial infection or LPS administration to neonatal male rats increases brain cytokines levels, inducing long-term changes in microglial activation and behavior (Bilbo et al., 2005, 2008).”
BackgroundChamniansawat, S., & Chongthammakun, S. (2014) · NeuroToxicology · doi:10.1016/j.neuro.2014.11.005 · Cited by 14
Spann, M. N., Bansal, R., Aydin, E., Pollatou, A., Alleyne, K., Bennett, M., Sawardekar, S., Delapenha, K., Cheng, B., Lee, S., et al. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.08.025 · Cited by 13
Rong, J., Yang, Y., Liang, M., Zhong, H., Li, Y., Zhu, Y., Sha, S., Chen, L., & Zhou, R. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02697-x · Cited by 13
Williamson, L. L., & Bilbo, S. D. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.02.033 · Cited by 13
“a second challenge in adulthood, including aging [18] and endotoxin exposure [13,14,16,17].”
Evaluating different models of maternal stress on stress-responsive systems in prepubertal mice
Sheng, J. A., Handa, R. J., & Tobet, S. A. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1292642 · Cited by 12
Jiao, C., Yuan, L., Yu, S., Gu, B., Luo, Q., Wang, X., Zhao, Y., Gai, C., Li, T., Li, T., et al. (2024) · Behavioural Brain Research · doi:10.1016/j.bbr.2024.115028 · Cited by 14
Swanepoel, T., Harvey, B. H., Harden, L. M., Laburn, H. P., & Mitchell, D. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.05.008 · Cited by 11
Factors in Early-Life Programming of Reproductive Fitness
Sominsky, L., Fuller, E. A., & Hodgson, D. M. (2015) · Neuroendocrinology · doi:10.1159/000431378 · Cited by 12
Li, D., Tomljenovic, L., Li, Y., & Shaw, C. A. (2017) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2017.08.035 · Cited by 11
RetractedBiswas, B., Eapen, V., Morris, M. J., & Jones, N. M. (2024) · Biomolecules · doi:10.3390/biom14020197 · Cited by 11
“Other cognitive domains including working or recognition memory were not explored in this study.”
BackgroundIsoflurane stress induces glucocorticoid production in mouse lymphoid organs
Hamden, J. E., Salehzadeh, M., Gray, K. M., Forys, B. J., & Soma, K. K. (2021) · Journal of Endocrinology · doi:10.1530/joe-21-0154 · Cited by 13
Merrill, L., Naylor, M. F., Dalimonte, M., McLaughlin, S., Merrill, T. E. S., & Grindstaff, J. L. (2017) · Functional Ecology · doi:10.1111/1365-2435.12916 · Cited by 11
“However, it is important to note that rodent studies have demonstrated elevated levels of the pro-inflammatory cytokine IL-1β in the brain after neonatal infection, and elevated levels of IL-6 only in the periphery, not in the brain (Bilbo et al. 2005, Bilbo & Schwarz 2009).”
BackgroundInnate Immune Memory: Implications for Microglial Function and Neuroprogression
Salam, A. P., Pariante, C. M., & Zunszain, P. A. (2017) · Modern trends in psychiatry · doi:10.1159/000470808 · Cited by 11
Long-Lasting Impact of Early Life Immune Stress on Neuroimmune Functions
Mouihate, A. (2013) · Medical Principles and Practice · doi:10.1159/000354199 · Cited by 9
Headmasters: Microglial regulation of learning and memory in health and disease
Weinhard, L., d’Errico, P., & Tay, T. L. (2018) · AIMS molecular science · doi:10.3934/molsci.2018.1.63 · Cited by 11
“These effects were likely mediated by microglial IL-1β, as treatment with minocycline or caspase-1, an inhibitor of IL-1β synthesis, prevented the learning deficits [48,102].”
Ceasrine, A. M., Batorsky, R., Shook, L. L., Kışlal, S., Bordt, E. A., Devlin, B. A., Perlis, R. H., Slonim, D. K., Bilbo, S. D., & Edlow, A. G. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.12.03.471177 · Cited by 9
“This programming in turn may contribute to adverse neurodevelopmental and psychiatric outcomes in offspring ranging from autism spectrum disorder/social behavioral deficits, to attention deficit hyperactivity disorder, cognitive deficits, schizophrenia, obsessive compulsive disorder, anxiety, and depression (Bachiller…”
BackgroundNikodémová, M., Oberto, J. R., Kaye, E. L., Berschel, M. R., Michaelson, A. L., Watters, J. J., & Mitchell, G. S. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03245-x · Cited by 9
Isoflurane stress induces region-specific glucocorticoid levels in neonatal mouse brain
Hamden, J. E., Gray, K. M., Salehzadeh, M., & Soma, K. K. (2022) · Journal of Endocrinology · doi:10.1530/joe-22-0049 · Cited by 9
Holder, M. K., & Blaustein, J. D. (2017) · PLoS ONE · doi:10.1371/journal.pone.0171381 · Cited by 9
Perspective on the status of preclinical models for psychiatric disorders
Winsky, L., & Brady, L. S. (2005) · Drug Discovery Today Disease Models · doi:10.1016/j.ddmod.2005.11.007 · Cited by 9
Prenatal immune origins of brain aging differ by sex
Goldstein, J. M., Konishi, K., Aroner, S. A., Lee, H., Remington, A., Chitnis, T., Buka, S. L., Hornig, M., & Tobet, S. A. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02798-w · Cited by 8
Osborne, B. F., Beamish, S. B., & Schwarz, J. M. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.06.004 · Cited by 10
Autism Spectrum Disorders and Aluminum Vaccine Adjuvants
Tomljenovic, L., Blaylock, R. L., & Shaw, C. A. (2013) · Springer eBooks · doi:10.1007/978-1-4614-4788-7_89 · Cited by 8
Factors Controlling Microglial Activation
Hanisch, U. (2012) · Oxford University Press eBooks · doi:10.1093/med/9780199794591.003.0048 · Cited by 7
Portugalov, A., & Akirav, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020730 · Cited by 8
Alteration of Neurodevelopment and behavior by Maternal Immune Activation
Smith, S. E. P., & Patterson, P. H. (2008) · Springer eBooks · doi:10.1007/978-0-387-84851-8_7 · Cited by 7
“In a similar study, rats given a neonatal E. coli infection show impaired memory and increased brain inflammation after a subsequent challenge with LPS as adults ( Bilbo et al., 2005a, b), compared to control rats given only an adult LPS injection.”
BackgroundHamden, J. E., Salehzadeh, M., Bajaj, H., Li, M. X., & Soma, K. K. (2024) · Journal of Neuroendocrinology · doi:10.1111/jne.13481 · Cited by 6
“35,65 There are no sex differences in circulating GC levels in these prepubertal mice within the SHRP, as previously reported.”
Linking the gut microbiome to microglial activation in opioid use disorder
Antoine, D., Venigalla, G., Truitt, B., & Roy, S. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1050661 · Cited by 6
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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