Neonatal Infection-Induced Memory Impairment after Lipopolysaccharide in Adulthood Is Prevented via Caspase-1 Inhibition

“To adjust for variability in tissue sample sizes, total protein concentrations were determined by Coomassie Brilliant Blue AG-250 protein assay (Bradford, 1976).”

“Relative gene expression was determined using the 2 -⌬⌬Ct method (Livak and Schmittgen, 2001; Pfaffl, 2001).”

“Total RNA was isolated from hippocampal tissue based on the TRIzol method of Chomczynski and Sacchi (1987) and has been described in detail previously (Frank et al., 2005).”

“Relative gene expression was determined using the 2 -⌬⌬Ct method (Livak and Schmittgen, 2001; Pfaffl, 2001).”

“, 2001) and represents a time relatively comparable with the third trimester in humans during which significant brain growth occurs (Dobbing and Sands, 1979; Rodier, 1980).”

“Role of IL-1 in memory impairment Patients with acquired immunodeficiency syndrome (AIDS)related dementia, cancer, or chronic inflammatory diseases often exhibit elevated levels of IL-1 co-occurring with cognitive impairment (Gallo et al., 1989; Griffin et al., 1989; Stanley et al., 1994; Meyers, 2000).”

“IL-1 is the most consistently induced cytokine in the brain after peripheral immune stimulation and has a high density of receptors in the hippocampus (Maier and Watkins, 1998).”

“Furthermore, an increasing body of evidence from both animal (Hornig et al., 1999; Shi et al., 2003) and human (Rantakallio et al.”

“However, if a rat is preexposed to the context the day before, immediate shock conditioning will then produce substantial freezing on a subsequent test day (Fanselow, 1990; Westbrook et al., 1994; Rudy and O'Reilly, 2001).”

“Furthermore, cognitive impairment in aged or diseased populations during a subsequent infection or illness is generally more severe or prolonged compared with normal controls with the same infection/ illness (Bodles and Barger, 2004; Perry, 2004).”

“…generated by the maternal or fetal immune system during perinatal infection are important mediators of abnormal brain development and increased risk for neurodevelopmental disorders (Cai et al., 2000; Urakubo et al., 2001; Pang et al., 2003; Richardson-Burns and Tyler, 2004; Yu et al., 2004).”

“Behavioral procedures Memory was tested using a modified version of contextual fear conditioning known as the context preexposure task (Fanselow, 1990; Rudy et al., 2004).”

“Similarly, peripheral LPS increases IL-1 protein within the hippocampus (Nguyen et al., 1998) and interferes with LTP, with this effect depending on hippocampal IL-1 (Vereker et al.”

“Primer specificity (Proligo, Boulder, CO) has been verified previously in our laboratory by melt curve analysis (Johnston et al., 2004).”

“…generated by the maternal or fetal immune system during perinatal infection are important mediators of abnormal brain development and increased risk for neurodevelopmental disorders (Cai et al., 2000; Urakubo et al., 2001; Pang et al., 2003; Richardson-Burns and Tyler, 2004; Yu et al., 2004).”

“For instance, neonatal exposure to bacterial products [lipopolysaccharide (LPS)] in rats influences reactivity to stress, immune regulation, and susceptibility to disease in adulthood (Shanks et al., 2000; Hodgson et al., 2001; Boisse et al., 2004).”

“First, each stage of the procedure critically depends on the hippocampus, and the hippocampus may be particularly vulnerable to immune-related alterations (Barrientos et al., 2002; Rudy et al., 2002; Matus-Amat et al., 2004).”

“Hippocampal long-term potentiation (LTP) is thought to play a major role in the formation of many types of memory (Abraham and Williams, 2003), and exogenous IL-1 inhibits LTP within major hippocampal pathways in a dosedependent manner (Katsuki et al., 1990; Cunningham et al., 1996).”

“Total RNA was isolated from hippocampal tissue based on the TRIzol method of Chomczynski and Sacchi (1987) and has been described in detail previously (Frank et al., 2005).”

“, 2001) and represents a time relatively comparable with the third trimester in humans during which significant brain growth occurs (Dobbing and Sands, 1979; Rodier, 1980).”

“This finding is of particular interest, because memory consolidation is generally considered to occur in two stages: an early short-term memory stage and a later long-term memory stage (Igaz et al., 2002).”

“First, each stage of the procedure critically depends on the hippocampus, and the hippocampus may be particularly vulnerable to immune-related alterations (Barrientos et al., 2002; Rudy et al., 2002; Matus-Amat et al., 2004).”

“, 2003) and human (Rantakallio et al., 1997; Nelson and Willoughby, 2000) studies suggests that perinatal events involving the immune system may contribute to the development of behavioral or neuropsychiatric disorders, including schizophrenia, autism, and cerebral palsy.”

“Furthermore, an increasing body of evidence from both animal (Hornig et al., 1999; Shi et al., 2003) and human (Rantakallio et al., 1997; Nelson and Willoughby , 2000) studies suggests that perinatal events involving the immune system may contribute to the development of behavioral or…”

“Rats injected with pathological doses of IL-1 either intracerebroventricularly or directly into the dorsal hippocampus display memory impairments (Pugh et al., 1999; Barrientos et al., 2002).”

“Role of IL-1 in memory impairment Patients with acquired immunodeficiency syndrome (AIDS)related dementia, cancer, or chronic inflammatory diseases often exhibit elevated levels of IL-1 co-occurring with cognitive impairment (Gallo et al., 1989; Griffin et al., 1989; Stanley et al., 1994; Meyers, 2000).”

“For example, perinatal endotoxin administration induces cytokine expression, apoptosis, and glial activation in the immature rat brain, factors that have been linked to white matter injury (Cai et al., 2003; Golan et al., 2005).”

“Rats injected with pathological doses of IL-1 either intracerebroventricularly or directly into the dorsal hippocampus display memory impairments (Pugh et al., 1999; Barrientos et al., 2002).”

“…generated by the maternal or fetal immune system during perinatal infection are important mediators of abnormal brain development and increased risk for neurodevelopmental disorders (Cai et al., 2000; Urakubo et al., 2001; Pang et al., 2003; Richardson-Burns and Tyler, 2004; Yu et al., 2004).”

“Preexposure should facilitate the amount of conditioning produced by the immediate shock because it allows the rat to have established a memory of the context before the immediate shock; it is this retrieved memory representation of the context that is then associated with the immediate shock (Rudy and O’Reilly, 2001;…”

“Evidence from animal models suggests that cytokine actions within the brain, in particular IL-1␤, may influence cognitive processes (Banks et al., 2002).”

“Furthermore, we observed no group differences in corticosterone within the serum, a finding consistent with our previous study (Bilbo et al., 2005) but in contrast to several reports that neonatal LPS exposure potentiates hypothalamic-pituitary-adrenal (HPA) activity in adult rodents (Shanks et al.”

“There is also evidence that IL-1 contributes to demyelination and blood– brain barrier breakdown, processes that can disrupt communication among brain regions (Ferrari et al., 2004).”

“YVAD-cmk administration induces neuroprotection after cerebral ischemia, an effect that is attributed to decreases in both apoptotic mechanisms and IL-1 production (Rabuffetti et al., 2000).”

“Hippocampal long-term potentiation (LTP) is thought to play a major role in the formation of many types of memory (Abraham and Williams, 2003), and exogenous IL-1 inhibits LTP within major hippocampal pathways in a dosedependent manner (Katsuki et al.”

“, 2003) and human (Rantakallio et al., 1997; Nelson and Willoughby, 2000) studies suggests that perinatal events involving the immune system may contribute to the development of behavioral or neuropsychiatric disorders, including schizophrenia, autism, and cerebral palsy.”

“, 1998) and interferes with LTP, with this effect depending on hippocampal IL-1 (Vereker et al., 2000).”

“For example, perinatal endotoxin administration induces cytokine expression, apoptosis, and glial activation in the immature rat brain, factors that have been linked to white matter injury (Cai et al., 2003; Golan et al., 2005).”

“Primer sequences used for amplification of rat cDNAs via the ICM have demonstrated a pattern of labeling throughout the brain within 1.5 h (Proescholdt et al., 2000).”

“For this reason, the hippocampus is thought to be particularly vulnerable to immune-related alterations (Lynch et al., 2004).”

“Role of IL-1 in memory impairment Patients with acquired immunodeficiency syndrome (AIDS)related dementia, cancer, or chronic inflammatory diseases often exhibit elevated levels of IL-1 co-occurring with cognitive impairment (Gallo et al., 1989; Griffin et al., 1989; Stanley et al., 1994; Meyers, 2000).”

“Microglia and astrocytes are resident immunocompetent cells of the CNS and, in addition to providing support to neurons, play a vital role in the brain response to infection as a major source of cytokines (Benveniste, 1997; Streit, 2002).”

“For instance, neonatal exposure to bacterial products [lipopolysaccharide (LPS)] in rats influences reactivity to stress, immune regulation, and susceptibility to disease in adulthood (Shanks et al., 2000; Hodgson et al., 2001; Boisse et al., 2004).”

“Furthermore, cognitive impairment in aged or diseased populations during a subsequent infection or illness is generally more severe or prolonged compared with normal controls with the same infection/ illness (Bodles and Barger, 2004; Perry, 2004).”

“, Alzheimer’s disease and AIDS-related dementia), and astrocyte reactivity in aged rats is positively correlated with cognitive impairment (Sugaya et al., 1996).”

“, 2001; Hodgson and Knott, 2002), and yet others report no change (Granger et al., 1996; Breivik et al., 2002), consistent with our own findings.”

“For instance, neonatal exposure to bacterial products [lipopolysaccharide (LPS)] in rats influences reactivity to stress, immune regulation, and susceptibility to disease in adulthood (Shanks et al., 2000; Hodgson et al., 2001; Boisse et al., 2004).”

“Early exposure to infectious agents may have significant consequences for the development and function of physiological systems throughout an individual's lifespan, a phenomenon termed " perinatal programming " (Barker et al., 1995).”

“YVAD-cmk reduces death from sepsis after a lethal dose of LPS, independent of serum reductions in IL-1 (Mathiak et al., 2000).”

“, 2001; Hodgson and Knott, 2002), and yet others report no change (Granger et al., 1996; Breivik et al., 2002), consistent with our own findings.”

“…generated by the maternal or fetal immune system during perinatal infection are important mediators of abnormal brain development and increased risk for neurodevelopmental disorders (Cai et al., 2000; Urakubo et al., 2001; Pang et al., 2003; Richardson-Burns and Tyler, 2004; Yu et al., 2004).”

“…generated by the maternal or fetal immune system during perinatal infection are important mediators of abnormal brain development and increased risk for neurodevelopmental disorders (Cai et al., 2000; Urakubo et al., 2001; Pang et al., 2003; Richardson-Burns and Tyler, 2004; Yu et al., 2004).”

“, 2002), some report altered stress-induced activity only (Hodgson et al., 2001; Hodgson and Knott, 2002), and yet others report no change (Granger et al.”

“YVAD-cmk also prevents peroxynitrite-induced neurotoxicity in neuronal cultures, a metabolite of nitric oxide and strong oxidizing agent thought to be involved in sepsis, inflammation, and apoptosis (Zhang and Rosenberg, 2004).”

“Specifically, peripheral infection with Escherichia coli on postnatal day 4 in rats resulted in markedly impaired learning and memory due to an inflammatory (LPS) challenge in adulthood (Bilbo et al., 2008, 2005a,b, 2007).”

“coli challenge showed no differences in TNF-α concentration as compared to the control group, independent of whether or not microglia were activated [37].”

“In contrast, expression levels of the astrocyte cell marker glial-fi brillary acidic protein (GFAP) did not change, suggesting a selective change in microglial activation after neonatal infection (Bilbo et al., 2005a).”