Sepsis-induced morbidity in mice: Effects on body temperature, body weight, cage activity, social behavior and cytokines in brain
Open accessAbstract
Infection negatively impacts mental health, as evidenced by the lethargy, malaise, and cognitive deficits experienced during illness. These changes in central nervous system processes, collectively termed sickness behavior, have been shown in animal models to be mediated primarily by the actions of cytokines in brain. Most studies of sickness behavior to date have used bolus injection of bacterial lipopolysaccharide (LPS) or selective administration of the proinflammatory cytokines interleukin-1β (IL-1β) or IL-6 as the immune challenge. Such models, although useful for determining mechanisms responsible for acute changes in physiology and behavior, do not adequately represent the more complex effects on central nervous system (CNS) processes of a true infection with replicating pathogens. In the present study, we used the cecal ligation and puncture (CLP) model to quantify sepsis-induced alterations in several facets of physiology and behavior of mice. We determined the impact of sepsis on cage activity, body temperature, food and water consumption and body weights of mice. Because cytokines are critical mediators of changes in behavior and temperature regulation during immune challenge, we also quantified sepsis-induced alterations in cytokine mRNA and protein in brain during the acute period of sepsis onset. We now report that cage activity and temperature regulation in mice that survive are altered for up to 23 days after sepsis induction. Food and water consumption are transiently reduced, and body weight is lost during sepsis. Furthermore, sepsis decreases social interactions for 24-48 h. Finally, mRNA and protein for IL-1β, IL-6, and tumor necrosis factor-α (TNFα) are upregulated in the hypothalamus, hippocampus, and brain stem during sepsis onset, from 6h to 72 h post sepsis induction. Collectively, these data indicate that sepsis not only acutely alters physiology, behavior and cytokine profiles in brain, but that some brain functions are impaired for long periods in animals that survive.
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Changes in sleep during sepsis coincide with increased cytokine mRNA and protein in brain.
“These changes in sleep coincide with increased cytokine mRNA and protein in brain (Granger et al, 2013).”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Granger et al, 2013
Effects of sepsis on body temperature and activity rhythms persist long after the animal has recovered and is no longer at risk of dying.
“effects of sepsis on body temperature and activity rhythms persist long after the animal has recovered and is no longer at risk of dying (Granger et al, 2013).”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Granger et al, 2013
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BackgroundInfluentialObesity is associated with hypothalamic injury in rodents and humans.
Thaler, J. P., Yi, C.-X., Schur, E. A., Guyenet, S. J., Hwang, B. H., Dietrich, M. O., Zhao, X., Sarruf, D. A., Izgur, V., Maravilla, K. R., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59660 · Cited by 1,857 · cited 2× · see citing works
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“Clinical studies demonstrate the brain may be one of the first organs affected by sepsis (Freedman et al., 2001), and septic patients often suffer from cognitive impairment and loss of cognitive function after discharge from the hospital (Iwashyna et al.”
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“induced by CLP as previously described (Ebong et al., 1999a; Remick et al., 2000).”
MethodTNF-α suppresses the expression of clock genes by interfering with E-box-mediated transcription
Cavadini, G., Petrzilka, S., Kohler, P. P., Jud, C., Tobler, I., Birchler, T., & Fontana, A. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701466104 · Cited by 421 · cited 2× · see citing works
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“The hippocampus is involved in aspects of cognition, learning and memory (Chen et al., 2008) that may be relevant to altered social exploration, and the brainstem is critical for aspects of autonomic responses to this insult (Kafa et al., 2010).”
BackgroundLeptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei
Elmquist, J. K., Ahima, R. S., Elias, C. F., Flier, J. S., & Saper, C. B. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.2.741 · Cited by 376 · cited 2× · see citing works
“…of body temperature, locomotor activity, feeding, drinking, and energy metabolism (Klir et al., 1993; Myers et al., 1993; Gayle et al., 1999; Elmquist et al., 2000; Gaykema et al., 2008; Szymusiak and McGinty, 2008; Thaler et al., 2012), as well as the timing of when these physiological and…”
Background<i>Hypothalamic Regulation of Sleep and Arousal</i>
Szymusiak, R., & McGinty, D. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1417.027 · Cited by 294 · see citing works
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Role of IL-6 in cytokine-induced sickness behavior: a study with IL-6 deficient mice.
Bluthé, R., Michaud, B., Poli, V., & Dantzer, R. (2000) · Physiology and Behavior · doi:10.1016/s0031-9384(00)00269-9 · Cited by 239 · cited 2× · see citing works
“We adapted the model refined and characterized by Dantzer and colleagues (Bluthé et al., 2000a; 2000b) to determine the impact of sepsis on social exploration.”
MethodResultRole of IL-6 and TNF in thermoregulation and survival during sepsis in mice
Leon, L. R., White, A. A., & Kluger, M. J. (1998) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1998.275.1.r269 · Cited by 236 · cited 2× · see citing works
“It is clear, however, that cytokines are critical mediators of CNS responses to sepsis [e.g., (Gourine et al., 1998; Leon et al., 1998; Figueiredo et al., 2012)].”
BackgroundModeling sepsis in the laboratory: merging sound science with animal well-being.
Nemzek, J. A., Hugunin, K. M. S., & Opp, M. R. (2008) · PubMed Central · Cited by 221 · see citing works
Self-citationImmunopathologic Alterations in Murine Models of Sepsis of Increasing Severity
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“Cecal Ligation and Puncture (CLP)—Polymicrobial intra-abdominal infection was induced by CLP as previously described (Ebong et al., 1999a; Remick et al., 2000).”
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“…behavior (sickness) during an immune challenge are mediated, in part by actions in brain of proinflammatory cytokines such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNFα), (Opp and Krueger, 1991; Bluthé et al., 1994; Kozak et al., 1998; Dantzer, 2001a; Chida and Iwakura, 2007).”
BackgroundMethodTumour necrosis factor-α causes an increase in blood-brain barrier permeability during sepsis
Tsao, N., Hsu, H., Wu, C.-M., Liu, C., & Lei, H. (2001) · Journal of Medical Microbiology · doi:10.1099/0022-1317-50-9-812 · Cited by 190 · cited 2× · see citing works
“However, the underlying pathogenesis of sepsis-induced alterations in CNS processes is not well understood, though several potential mechanisms, such as alterations in the blood—brain barrier, metabolism, and cerebral circulation have been explored (du Moulin et al., 1985; Miller et al., 1987; Koo et al., 2001; Tsao e…”
BackgroundIL‐6 and IL‐1β in Fever: Studies Using Cytokine‐Deficient (Knockout) Mice <sup>a</sup>
KOZAK, W., KLUGER, M. J., SOSZYNSKI, D., CONN, C. A., RUDOLPH, K., LEON, L. R., & ZHENG, H. (1998) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1998.tb08310.x · Cited by 189 · cited 1× · see citing works
“…behavior (sickness) during an immune challenge are mediated, in part by actions in brain of proinflammatory cytokines such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNFα), (Opp and Krueger, 1991; Bluthé et al., 1994; Kozak et al., 1998; Dantzer, 2001a; Chida and Iwakura, 2007).”
BackgroundHypothalamic regulation of sleep and arousal
McGinty, D. (2003) · Frontiers in bioscience · doi:10.2741/1159 · Cited by 178 · cited 2× · see citing works
“…feeding, drinking, and energy metabolism (Klir et al., 1993; Myers et al., 1993; Gayle et al., 1999; Elmquist et al., 2000; Gaykema et al., 2008; Szymusiak and McGinty, 2008; Thaler et al., 2012), as well as the timing of when these physiological and behavioral processes occur (Beynon and…”
BackgroundInterleukin-6 and leptin mediate lipopolysaccharide-induced fever and sickness behavior
Harden, L. M., du Plessis, I., Poole, S., & Laburn, H. P. (2006) · Physiology & Behavior · doi:10.1016/j.physbeh.2006.05.016 · Cited by 155 · cited 2× · see citing works
“The role of cytokines as mediators of sickness has been determined, in part, by using LPS or selected cytokines as a challenge to activate the immune system (Bluthé et al., 1994; Inui, 2001; Harden et al., 2006).”
MethodInterleukin 1-receptor antagonist blocks interleukin 1-induced sleep and fever
Opp, M. R., & Krueger, J. M. (1991) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1991.260.2.r453 · Cited by 152 · cited 2× · see citing works
“Numerous studies demonstrate that these changes in physiology and behavior (sickness) during an immune challenge are mediated, in part by actions in brain of proinflammatory cytokines such as interleukin-1b (IL-1b), IL-6, and tumor necrosis factor-a (TNFa) (Opp and Krueger, 1991; Bluthé et al., 1994; Kozak et al., 199…”
BackgroundSelf-citationKonsman, J. P., Veeneman, J., Combe, C., Poole, S., Luheshi, G. N., & Dantzer, R. (2008) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2008.06549.x · Cited by 132 · cited 1× · see citing works
“Within the context of bacterial infections, lipopolysaccharide (LPS) is frequently used as a stimulus to induce sickness behavior (Konsman et al., 2008)because it is derived from the cell wall of Gramm-negative bacteria.”
BackgroundBlood–Brain Barrier Permeability to Ebiratide and TNF in Acute Spinal Cord Injury
Pan, W., Banks, W. A., & Kastin, A. J. (1997) · Experimental Neurology · doi:10.1006/exnr.1997.6533 · Cited by 106 · cited 15× · see citing works
“Collectively, our data suggest behavioral outcome measures may be used as global indicators of CNS impairment during the development of sepsis.”
BackgroundInfluentialAmino acid imbalance early in septic encephalopathy
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“However, the underlying pathogenesis of sepsis-induced alterations in CNS processes is not well understood, though several potential mechanisms, such as alterations in the blood-brain barrier, metabolism, and cerebral circulation have been explored (du Moulin et al., 1985; Miller et al., 1987; Koo et al., 2001; Tsao e…”
BackgroundIMMUNOPATHOLOGIC RESPONSES TO NON-LETHAL SEPSIS
Ebong, S., Call, D. R., Bolgos, G. L., Newcomb, D. E., Granger, J. I., O’Reilly, M., & Remick, D. G. (1999) · Shock · doi:10.1097/00024382-199908000-00005 · Cited by 96 · cited 5× · see citing works
“Cecal Ligation and Puncture (CLP)—Polymicrobial intra-abdominal infection was induced by CLP as previously described (Ebong et al., 1999a; Remick et al., 2000).”
BackgroundMethodResultInfluentialSelf-citationANTIBIOTIC TREATMENT INFLUENCES OUTCOME IN MURINE SEPSIS
Newcomb, D. E., Bolgos, G. L., Green, L. B., & Remick, D. G. (1998) · Shock · doi:10.1097/00024382-199808000-00005 · Cited by 92 · cited 2× · see citing works
“…because it a) elicits dynamic changes in cardiovascular function that are similar to those observed in septic patients, b) induces the progressive release of inflammatory mediators, and c) is sensitive to antibiotic treatment and fluid resuscitation (Newcomb et al. 1998; Ebong et al. 1999a;1999b).”
BackgroundMethodAn evaluation of analgesic regimens for abdominal surgery in mice.
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Role of hypothalamic interleukin-6 and tumor necrosis factor-alpha in LPS fever in rat
Klir, J. J., Roth, J., Szelenyi, Z., McClellan, J. L., & Kluger, M. J. (1993) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1993.265.3.r512 · Cited by 83 · cited 2× · see citing works
“For example, within the context of sickness the hypothalamus is critical for the regulation of body temperature, locomotor activity, feeding, drinking, and energy metabolism (Klir et al., 1993; Myers et al., 1993; Gayle et al., 1999; Elmquist et al., 2000; Gaykema et al., 2008; Szymusiak and McGinty, 2008; Thaler et a…”
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“Collectively, our data suggest behavioral outcome measures may be used as global indicators of CNS impairment during the development of sepsis.”
BackgroundInfluentialSepsis induces apoptotic cell death in different regions of the brain in a rat model of sepsis
Kafa, İ. M., Uysal, M., Bakırcı, S., & Kurt, M. A. (2010) · Acta Neurobiologiae Experimentalis · doi:10.55782/ane-2010-1796 · Cited by 69 · cited 2× · see citing works
“The hippocampus is involved in aspects of cognition, learning and memory (Chen et al., 2008) that may be relevant to altered social exploration, and the brainstem is critical for aspects of autonomic responses to this insult (Kafa et al., 2010).”
BackgroundVyas, D., Javadi, P., DiPasco, P. J., Buchman, T. G., Hotchkiss, R. S., & Coopersmith, C. M. (2005) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00312.2005 · Cited by 69 · cited 1× · see citing works
“Furthermore, human patients who become septic are treated with antibiotics, and CLP has been used as a model to determine the effectiveness of antibiotics as a therapeutic intervention (Vyas et al., 2005).”
BackgroundE. coli peritonitis and bacteremia cause increased blood-brain barrier permeability
du Moulin, G. C., Paterson, D., Hedley‐Whyte, J., & Broitman, S. A. (1985) · Brain Research · doi:10.1016/0006-8993(85)90922-9 · Cited by 60 · cited 1× · see citing works
“…alterations in CNS processes is not well understood, though several potential mechanisms, such as alterations in the blood-brain barrier, metabolism, and cerebral circulation have been explored (du Moulin et al., 1985; Miller et al., 1987; Koo et al., 2001; Tsao et al., 2001; Basler et al., 2002).”
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“0 pg/ml for IL-1b based upon assessment of the linear portion of the standard curves (Datta and Opp, 2008).”
BackgroundMethodInfluentialSelf-citationCytokines and sickness behavior: implications from knockout animal models
Inui, A. (2001) · Trends in Immunology · doi:10.1016/s1471-4906(01)01981-0 · Cited by 59 · cited 2× · see citing works
“The role of cytokines as mediators of sickness has been determined, in part, by using LPS or selected cytokines as a challenge to activate the immune system (Bluthé et al., 1994; Inui, 2001; Harden et al., 2006).”
MethodAdrenal insufficiency during the late stage of polymicrobial sepsis
Koo, D. J., Jackman, D. M., Chaudry, I. H., & Wang, P. (2001) · Critical Care Medicine · doi:10.1097/00003246-200103000-00026 · Cited by 57 · see citing works
Feeding status and bacterial LPS-induced cytokine and neuropeptide gene expression in hypothalamus
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“…for the regulation of body temperature, locomotor activity, feeding, drinking, and energy metabolism (Klir et al., 1993; Myers et al., 1993; Gayle et al., 1999; Elmquist et al., 2000; Gaykema et al., 2008; Szymusiak and McGinty, 2008; Thaler et al., 2012), as well as the timing of when…”
BackgroundOlivadoti, M. D., & Opp, M. R. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.02.008 · Cited by 53 · cited 1× · see citing works
“Cage activity was determined using infrared sensors [BioBserv, BmgH, Bonn, Germany (Olivadoti and Opp, 2008)].”
MethodSelf-citationBeynon, A. L., & Coogan, A. N. (2010) · Chronobiology International · doi:10.3109/07420528.2010.501927 · Cited by 52 · cited 2× · see citing works
“IL-1β and TNF modulate the expression of various clock genes (Cavadini et al., 2007; Beynon and Coogan, 2010), and signaling receptors for IL-1β and TNFα are found throughout the brain, including the hypothalamus and the suprachiasmatic nucleus [SCN; (Beynon and Coogan, 2010)].”
BackgroundToxicity evaluation of prophylactic treatments for mites and pinworms in mice.
Toth, L. A., Oberbeck, C., Straign, C. M., Frazier, S. J., & Rehg, J. E. (2000) · PubMed · Cited by 47 · see citing works
Cognitive Impairment in the Septic Brain
Comim, C. M., Constantino, L. C., Barichello, T., STRECK, E. L., Quevedo, J., & Dal‐Pizzol, F. (2009) · Current Neurovascular Research · doi:10.2174/156720209788970045 · Cited by 45 · cited 1× · see citing works
“Patients who survive sepsis often suffer from cognitive impairment long after hospital discharge (Comim et al., 2009; Iwashyna et al., 2010), suggesting that the effects of sepsis on the brain are not limited to the acute period during active infection.”
BackgroundGaykema, R. P. A., Park, S.-M., McKibbin, C. R., & Goehler, L. E. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.10.042 · Cited by 42 · cited 2× · see citing works
“…locomotor activity, feeding, drinking, and energy metabolism (Klir et al., 1993; Myers et al., 1993; Gayle et al., 1999; Elmquist et al., 2000; Gaykema et al., 2008; Szymusiak and McGinty, 2008; Thaler et al., 2012), as well as the timing of when these physiological and behavioral processes…”
BackgroundSepsis-induced alterations in sleep of rats
Baracchi, F., Ingiosi, A. M., Raymond, R. M., & Opp, M. R. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00354.2011 · Cited by 42 · cited 3× · see citing works
“We have demonstrated that sepsis alters sleep and EEG parameters in rats (Baracchi et al., 2011).”
BackgroundInfluentialSelf-citationMyers, R. D., Páez, X., Roscoe, A. K., Sherry, B. A., & Cerami, A. (1993) · Neurochemical Research · doi:10.1007/bf00966780 · Cited by 36 · cited 2× · see citing works
“…hypothalamus is critical for the regulation of body temperature, locomotor activity, feeding, drinking, and energy metabolism (Klir et al., 1993; Myers et al., 1993; Gayle et al., 1999; Elmquist et al., 2000; Gaykema et al., 2008; Szymusiak and McGinty, 2008; Thaler et al., 2012), as well as…”
BackgroundRole of hypothalamic interleukin-1β in fever induced by cecal ligation and puncture in rats
Gourine, A. V., Rudolph, K., Tesfaigzi, Y., & Kluger, M. J. (1998) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1998.275.3.r754 · Cited by 36 · cited 1× · see citing works
“It is clear, however, that cytokines are critical mediators of CNS responses to sepsis [e.g., (Gourine et al., 1998; Leon et al., 1998; Figueiredo et al., 2012)].”
BackgroundBluthé, R.-M., Layé, S., Michaud, B., Combe, C., Dantzer, R., & Parnet, P. (2000) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2000.01348.x · Cited by 26 · cited 2× · see citing works
“We adapted the model refined and characterized by Dantzer and colleagues (Bluthé et al., 2000a; 2000b) to determine the impact of sepsis on social exploration.”
MethodResultFigueiredo, M. J., Soares, D. D. M., Martins, J. M., Machado, R. R., Sorgi, C. A., Faccioli, L. H., Melo, M. C. C., Malvar, D. D. C., & de Souza, G. E. P. (2011) · Medical Microbiology and Immunology · doi:10.1007/s00430-011-0225-y · Cited by 24 · cited 2× · see citing works
“These findings of an early increase in cytokine protein in mouse brain are consistent with those of a recent study demonstrating increased IL-1β, IL-6 and TNF in hypothalamus of rats as early as 3 – 6 h post CLP (Figueiredo et al. 2012).”
BackgroundResultChida, D., & Iwakura, Y. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.10.033 · Cited by 15 · cited 2× · see citing works
“Numerous studies demonstrate that these changes in physiology and behavior (sickness) during an immune challenge are mediated, in part by actions in brain of proinflammatory cytokines such as interleukin-1b (IL-1b), IL-6, and tumor necrosis factor-a (TNFa) (Opp and Krueger, 1991; Bluthé et al., 1994; Kozak et al., 199…”
BackgroundRole of hypotension in decreasing cerebral blood flow in porcine endotoxemia
Miller, C. F., Breslow, M. J., Shapiro, R. M., & Traystman, R. J. (1987) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1987.253.4.h956 · Cited by 13 · cited 2× · see citing works
“However, the underlying pathogenesis of sepsis-induced alterations in CNS processes is not well understood, though several potential mechanisms, such as alterations in the blood-brain barrier, metabolism, and cerebral circulation have been explored (du Moulin et al., 1985; Miller et al., 1987; Koo et al., 2001; Tsao e…”
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Sleep and inflammation: partners in sickness and in health
Irwin, M. R. (2019) · Nature reviews. Immunology · doi:10.1038/s41577-019-0190-z · Cited by 1,090 · see citing works
Sleep health: Reciprocal regulation of sleep and innate immunity
Irwin, M. R., & Opp, M. R. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.148 · Cited by 624 · see citing works
Self-citationFu, Q., Wu, J., Zhou, X.-Y., Ji, M.-H., Mao, Q.-H., Li, Q., Zong, M.-M., Zhou, Z.-Q., & Yang, J.-J. (2019) · Inflammation · doi:10.1007/s10753-018-0894-4 · Cited by 232 · see citing works
“CLP appears to be a suitable clinical sepsis model and is an important tool by which to study cognitive impairment and its mechanism after sepsis [30].”
BackgroundBrain Barrier Breakdown as a Cause and Consequence of Neuroinflammation in Sepsis
Danielski, L. G., Giustina, A. D., Badawy, M., Barichello, T., Quevedo, J., Dal-Pizzol, F., & Petronilho, F. (2018) · Molecular Neurobiology · doi:10.1007/s12035-016-0356-7 · Cited by 182 · see citing works
Lipocalin-2 protects the brain during inflammatory conditions
Kang, S. S., Ren, Y., Liu, C.-C., Kurti, A., Baker, K. E., Bu, G., Asmann, Y., & Fryer, J. D. (2018) · Molecular Psychiatry · doi:10.1038/mp.2016.243 · Cited by 162 · see citing works
“Animal models of sepsis have demonstrated that systemic challenge can lead to CNS inflammation and behavioral and cognitive dysfunction(13,14,23).”
Synthetic bacterial vesicles combined with tumour extracellular vesicles as cancer immunotherapy
Park, K., Svennerholm, K., Crescitelli, R., Lässer, C., Gribonika, I., & Lötvall, J. O. (2021) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12120 · Cited by 158 · see citing works
“No statistical differences in body temperature were observed in the SyBV-treated groups versus non-treated mice, while OMV provoked hypothermia, a commonly observed feature in this sepsis model (Granger et al., 2013) (Figure 2c).”
BackgroundLiu, Y., Peng, Y., Liu, L., Wu, T., Zhang, Y., Lian, Y., Yang, Y., Kelley, K. W., Jiang, C., & Wang, Y. (2015) · European Cytokine Network · doi:10.1684/ecn.2015.0362 · Cited by 126 · see citing works
“6 ml beads) are internally dyed with different ratios of fluorophores conjugated to different capture probes (cytokine-specific antibodies), which have been validated in blood, brain and CSF [32, 33].”
InfluentialKrueger, J. M., & Opp, M. R. (2016) · International Review of Neurobiology · doi:10.1016/bs.irn.2016.07.003 · Cited by 120 · see citing works
“Of interest, effects of sepsis on body temperature and activity rhythms of animals that survive persist long after recovery when the subject is no longer at risk of dying (Granger et al., 2013).”
Self-citationLong-Term Cognitive Outcomes After Sepsis: a Translational Systematic Review
Barichello, T., Sayana, P., Giridharan, V. V., Arumanayagam, A. S., Narendran, B., Giustina, A. D., Petronilho, F. C., Quevedo, J., & Dal‐Pizzol, F. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1048-2 · Cited by 112 · see citing works
Zhao, Z., Wang, Y., Zhou, R., Li, Y., Gao, Y., Tu, D., Wilson, B., Song, S., Feng, J., Hong, J.-S., et al. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-1728-5 · Cited by 109 · see citing works
Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects
Cardoso, F. L., Herz, J., Fernandes, A., Rocha, J., Sepodes, B., Brito, M. A., McGavern, D. B., & Brites, D. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0299-3 · Cited by 103 · see citing works
“A sustained glial response to LPS was recently described in the hippocampus and brainstem of adult mice following induction of sepsis [100].”
BackgroundGlucocorticoid resistance as a major drive in sepsis pathology
Dendoncker, K., & Libert, C. (2017) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2017.04.002 · Cited by 85 · see citing works
“thermoregulation [79, 80], metabolism [81-84], microbiome changes [85, 86] and even circadian”
BackgroundHydrogen Gas Presents a Promising Therapeutic Strategy for Sepsis
Xie, K., Liu, L., Yu, Y., & Wang, G. (2014) · BioMed Research International · doi:10.1155/2014/807635 · Cited by 79 · see citing works
Wu, J., Dong, L., Zhang, M., Jia, M., Zhang, G., Qiu, L., Ji, M., & Yang, J. (2013) · Neurochemical Research · doi:10.1007/s11064-013-1159-0 · Cited by 73 · see citing works
“CLP model appears to be a suitable model of clinical sepsis and thus could be a great tool to study cognitive impairment and the mechanisms associated with the recovery of these functions after sepsis [4].”
MethodKadier, K., Dilixiati, D., Ainiwaer, A., Liu, X., Lu, J.-D., Liu, P., Ainiwan, M., Yesitayi, G., Ma, X., & Ma, Y.-T. (2023) · BMC Psychiatry · doi:10.1186/s12888-023-05286-7 · Cited by 70 · see citing works
“In a sepsis model characterized by significant systemic inflammation, sleep in rats exhibited a fragmented pattern, which was found to be influenced by elevated mRNA and protein levels of cytokines, including IL-1β, IL-6, and TNF-α, in the nervous system [41].”
BackgroundLibert, C., Ayala, A., Bauer, M. W., Cavaillon, J., Deutschman, C. S., FROSTELL, C. G., Knapp, S., Kozlov, A. V., Wang, P., Osuchowski, M. F., et al. (2018) · Shock · doi:10.1097/shk.0000000000001242 · Cited by 67 · see citing works
“Cage activity, body weight, and rectal temperature, for example, can be easily obtained and prior studies show that these correlate with hypothalamic levels of proinflammatory cytokines (83).”
ResultP2X7 Receptor Signaling Contributes to Sepsis-Associated Brain Dysfunction
Savio, L. E. B., Andrade, M. G. J., de Andrade Mello, P., Santana, P. T., Moreira-Souza, A. C. A., Kolling, J., Longoni, A., Feldbrügge, L., Wu, Y., Wyse, A. T. S., et al. (2017) · Molecular Neurobiology · doi:10.1007/s12035-016-0168-9 · Cited by 64 · see citing works
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The Gut Microbiome Modulates Body Temperature Both in Sepsis and Health
Bongers, K. S., Chanderraj, R., Woods, R. J., McDonald, R. A., Adame, M. D., Falkowski, N. R., Brown, C. A., Baker, J. M., Winner, K. M., Fergle, D. J., et al. (2022) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202201-0161oc · Cited by 48 · see citing works
Jenniskens, M., Weckx, R., Dufour, T., Perre, S. V., Pauwels, L., Derde, S., Téblick, A., Güiza, F., den Berghe, G. V., & Langouche, L. (2018) · Endocrinology · doi:10.1210/en.2018-00344 · Cited by 46 · see citing works
Guha, S. K., Tillu, R., Sood, A., Patgaonkar, M. S., Nanavaty, I. N., Sengupta, A., Sharma, S., Vaidya, V. A., & Pathak, S. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.06.009 · Cited by 45 · see citing works
“Experimental models of infection (Jurgens et al., 2012; Calsavara et al., 2013; Lieblein-Boff et al., 2013; Buenz et al., 2006; Granger et al., 2013; Evans et al., 2014; Vyas, 2013), including exposure to non-neurotropic infectious agents, have been linked to cognitive dysfunction and mood-related abnormalities, with…”
BackgroundSialic acid-conjugate modified doxorubicin nanoplatform for treating neutrophil-related inflammation
Wang, S., Lai, X., Li, C., Chen, M., Hu, M., Liu, X., Song, Y., & Deng, Y. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.07.044 · Cited by 45 · see citing works
Lewis, A., Yuan, D., Zhang, X., Angus, D. C., Rosengart, M. R., & Seymour, C. W. (2016) · Critical Care Medicine · doi:10.1097/ccm.0000000000001615 · Cited by 43 · see citing works
Ingiosi, A. M., Raymond, R. M., Pavlova, M. N., & Opp, M. R. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.03.014 · Cited by 39 · see citing works
Self-citationChannabasappa, S., Durgaiah, M., Chikkamadaiah, R., Kumar, S., Joshi, A. A., & Sriram, B. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01358-17 · Cited by 36 · see citing works
Fedele, M. L. M., Aiello, I., Caldart, C. S., Golombek, D. A., Marpegán, L., & Paladino, N. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00100 · Cited by 36 · see citing works
“One characteristic of septic shock is the loss of appetite or anorexia (Granger et al., 2013).”
BackgroundDichloroacetate improves systemic energy balance and feeding behavior during sepsis
Oh, T. S., Zabalawi, M., Jain, S., Long, D. L., Stacpoole, P. W., McCall, C. E., & Quinn, M. A. (2022) · JCI Insight · doi:10.1172/jci.insight.153944 · Cited by 32 · see citing works
Opp, M. R., George, A. M., Ringgold, K. M., Hansen, K. M., Bullock, K. M., & Banks, W. A. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.07.023 · Cited by 32 · see citing works
“Acute responses to sepsis induction in this model manifest during the first 1–3 days after CLP surgery, with 30–40% mortality occurring 3–4 days post CLP (Granger et al., 2013).”
BackgroundSelf-citationLéger, T., Azarnoush, K., Traoré, A. S., Cassagnes, L., Rigaudière, J., Jouve, C., Pagés, G., Bouvier, D., Sapin, V., Pereira, B., et al. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/9710352 · Cited by 30 · see citing works
“CLP in the rodent is known to decrease body temperature [42].”
BackgroundMicroglial activation and neuroinflammation in acute and chronic cognitive deficits in sepsis
Denver, P., & Cunningham, C. M. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110285 · Cited by 27 · see citing works
Ren, C., Tong, Y., Li, J., Dong, N., Hao, J.-W., Zhang, Q., & Yao, Y.-M. (2017) · Oncotarget · doi:10.18632/oncotarget.21502 · Cited by 27 · see citing works
Park, K., Svennerholm, K., Crescitelli, R., Lässer, C., Gribonika, I., Andersson, M., Boström, J., Alalam, H., Harandi, A. M., Farewell, A., et al. (2023) · Journal of Nanobiotechnology · doi:10.1186/s12951-023-01928-w · Cited by 26 · see citing works
“OMV caused hypothermia, a characteristic feature of the mouse sepsis model [15], whereas no significant difference in body temperature was observed in the SyBV-treated group compared to the phosphate-buffered saline (PBS)-treated group (Fig.”
ResultIngiosi, A. M., & Opp, M. R. (2016) · Glia · doi:10.1002/glia.22961 · Cited by 26 · see citing works
“Protein was extracted from tissue and quantified as previously described (Datta and Opp, 2008; Granger et al., 2013; Ingiosi et al., 2015; Sutton and Opp, 2015).”
BackgroundMethodInfluentialSelf-citationOu, H., Zhao, S., Peng, Y., Xiao, X., Wang, Q., Liu, H., Xiao, X., & Yang, M. (2016) · Molecular Medicine Reports · doi:10.3892/mmr.2016.5694 · Cited by 26 · see citing works
“In a cecal ligation and puncture model of sepsis, Granger et al (36) also found that body temperature was significantly reduced in the first few hours prior to increasing.”
Goldim, M. P. D. S., Giustina, A. D., Mathias, K., de Oliveira, A., Fileti, M. E., Carli, R. J. D., Zarbato, G. F., Garbossa, L., da Rosa, N., de Oliveira, J. M., et al. (2020) · Inflammation · doi:10.1007/s10753-020-01187-z · Cited by 24 · see citing works
Microglia Are Necessary to Regulate Sleep after an Immune Challenge
Rowe, R. K., Green, T. R. F., Giordano, K. R., Ortiz, J. B., Murphy, S. M., & Opp, M. R. (2022) · Biology · doi:10.3390/biology11081241 · Cited by 23 · see citing works
Self-citationBi, W., Lan, X., Zhang, J., Xiao, S., Cheng, X., Wang, H., Lu, D., & Zhu, L. (2019) · Brain Research · doi:10.1016/j.brainres.2019.05.009 · Cited by 22 · see citing works
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“Importantly, although mice models are frequently used in critical care research, translation to the human setting should be done with caution, as the murine metabolic response to severe stress and illness can be quite different (42, 43).”
BackgroundYe, H., Li, P., Zhai, Q., Yang, S., Yang, S., Sun, Y., Wu, S., Huang, R., 陈齐兴, & Fang, X. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111178 · Cited by 20 · see citing works
Lai, J. C. Y., Svedin, P., Ek, C. J., Mottahedin, A., Wang, X., Levy, O., Currie, A. J., Strunk, T., & Mallard, C. E. (2019) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02003-19 · Cited by 19 · see citing works
“The observed significant weight loss in our infected animals could be correlated with temporary loss of appetite and feeding (37), which also could partly explain the transient hypoglycemia observed in infected mice.”
BackgroundProton-mediated burst of dual-drug loaded liposomes for biofilm dispersal and bacterial killing
Wang, D., Yang, G., Zhang, X., van der Mei, H. C., Ren, Y., Busscher, H. J., & Shi, L. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.10.049 · Cited by 18 · see citing works
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Opp, M. R., & Krueger, J. M. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-24288-2.00019-2 · Cited by 18 · see citing works
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“As suggested in previous studies [18,19], significant weight loss occurred in all LPS-challenged mice within 24 h, possibly as a result of the decreased water and food intake (Figure 2).”
ResultNegrin, L. L., Jahn, A., & van Griensven, M. (2017) · Shock · doi:10.1097/shk.0000000000000837 · Cited by 15 · see citing works
Effects of buprenorphine and estrous cycle in a murine model of cecal ligation and puncture.
Kennedy, L. H., Hwang, H., Wolfe, A., Hauptman, J. G., & Nemzek, J. A. (2014) · PubMed Central · Cited by 13 · see citing works
Sex differences in hippocampal cytokine networks after systemic immune challengePreprint
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A Novel Scoring System for Humane Endpoints in Mice with Cecal Ligation and Puncture-Induced Sepsis
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“…in guineapigs, appearing at 2 h and remaining until 7 days after endotoxemia, similar to previous studies using other types of behaviour and also excluding the depressed locomotor activity as a possible bias (Barichello et al. 2005, Granger et al. 2013, Anderson et al. 2015, Kozlowska et al. 2015).”
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Interactions between remote ischemic conditioning and post-stroke sleep regulation
Wang, X., & Ji, X. (2021) · Frontiers of Medicine · doi:10.1007/s11684-021-0887-9 · Cited by 8 · see citing works
“The mild inflammatory reaction triggered by low doses of endotoxin would enhance NREM sleep [48], whereas the proinflammatory response induced by severe infection would aggravate sleep fragmentation [49].”
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“Body temperature was accessed in previous studies using the CLP method and both fever [21–23] and hypothermia [24–26] were observed, but none of these publications focused on the intrinsic body mechanisms associated with the changes in Tb and their relation with Ta.”
MethodDidari, T., Hassani, S., Baeeri, M., Nigjeh, M. N., Rahimifard, M., Haghi‐Aminjan, H., Gholami, M., Nejad, S. M., Hassan, F. I., Mojtahedzadeh, M., et al. (2020) · Drug Research · doi:10.1055/a-1322-7478 · Cited by 7 · see citing works
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“Other authors have reported longterm brain dysfunction in surviving animals using the CLP model [14, 30, 55].”
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Characterization of fever and sickness behavior regulated by cytokines during infection
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Effects of 9-t-butyl doxycycline on the innate immune response to CNS ischemia-reperfusion injury
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Pioglitazone ameliorates sepsis-associated encephalopathy through SIRT1 signaling pathway
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Immune-to-brain signaling and substrates of altered behavior during inflammation
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Functional Characterization of Neutrophils Allows Source Control Evaluation in a Murine Sepsis Model
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Contactless body temperature assessment for signalling humane endpoints in a mouse model of sepsis
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“This is consistent with the literature reporting hypothermia observed 4 to 32 h after induction of CLP (Granger et al. 2013; Li et al. 2018; Mai et al. 2018).”
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“The low food and water intake accompanied with weight loss is one of the determinants for murine sepsis, along with stationary behavior and physical activity [74].”
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- Authors
- Granger, J. I., Ratti, P.-L., Datta, S. C., Raymond, R. M., & Opp, M. R.
- Affiliations
- University of Michigan (US)
- Université Toulouse III - Paul Sabatier (FR)
- Corresponding author
- Opp, Mark R.
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 38
- Issue
- 7
- Pages
- 1047-1057
- ISSN
- 0306-4530 (ISSN-L)
- PMC
- PMC3707484
- OpenAlex
- W2110300086
- Cited by
- 82
- References
- 57
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 7 · 2023: 10 · 2022: 9 · 2021: 8 · 2020: 7 · 2019: 4 · 2018: 5 · 2017: 8 · 2016: 9 · 2015: 5 · 2014: 3 · 2013: 2
- FWCI
- 0.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Michigan
- National Heart, Lung, and Blood Institute (R01HL080972, HL080972)
- National Institute of General Medical Sciences (P01GM067189, GM067189)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- sepsis, sickness behavior, cecal ligation and puncture, thermoregulation, social behavior, food and water intake, weight loss, inflammatory cytokines, IL-1β, interleukin-6, TNF-α, hypothalamus, hippocampus, brainstem
- MeSH terms
- Animals, Body Temperature, Body Weight, Brain, Motor Activity, Social Behavior, Tumor Necrosis Factor-alpha, Interleukin-6, Up-Regulation, Cytokines, Sepsis, Mice, Interleukin-1beta, Illness Behavior
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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