Early-Life Immune Challenge: Defining a Critical Window for Effects on Adult Responses to Immune Challenge

Spencer, Sarah J.; Martin, Sheilagh; Mouihate, Abdeslam; Pittman, Quentin J.

doi:10.1038/sj.npp.1301004

Cited by 100 publications

(95 citation statements)

References 38 publications

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“…This time window is similar to the period we previously observed for other physiological changes caused by postnatal LPS (Spencer et al, 2006b). Interestingly, this is also the time when long-term potentiation-induced plasticity first becomes apparent (e.g., P7) and shows maximum responsivity (e.g., P15) (Harris and Teyler, 1984).…”

Section: Discussionsupporting

confidence: 53%

Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats

Galic¹,

Riazi²,

Heida³

et al. 2008

Journal of Neuroscience

262

211

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There are critical postnatal periods during which even subtle interventions can have long-lasting effects on adult physiology. We asked whether an immune challenge during early postnatal development can alter neuronal excitability and seizure susceptibility in adults. Postnatal day 14 (P14) male Sprague Dawley rats were injected with the bacterial endotoxin lipopolysaccharide (LPS), and control animals received sterile saline. Three weeks later, extracellular recordings from hippocampal slices revealed enhanced field EPSP slopes after Schaffer collateral stimulation and increased epileptiform burst-firing activity in CA1 after 4-aminopyridine application. Six to 8 weeks after postnatal LPS injection, seizure susceptibility was assessed in response to lithium-pilocarpine, kainic acid, and pentylenetetrazol. Rats treated with LPS showed significantly greater adult seizure susceptibility to all convulsants, as well as increased cytokine release and enhanced neuronal degeneration within the hippocampus after limbic seizures. These persistent increases in seizure susceptibility occurred only when LPS was given during a critical postnatal period (P7 and P14) and not before (P1) or after (P20). This early effect of LPS on adult seizures was blocked by concurrent intracerebroventricular administration of a tumor necrosis factor ␣ (TNF␣) antibody and mimicked by intracerebroventricular injection of rat recombinant TNF␣. Postnatal LPS injection did not result in permanent changes in microglial (Iba1) activity or hippocampal cytokine [IL-1␤ (interleukin-1␤) and TNF␣] levels, but caused a slight increase in astrocyte (GFAP) numbers. These novel results indicate that a single LPS injection during a critical postnatal period causes a longlasting increase in seizure susceptibility that is strongly dependent on TNF␣.

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Section: Discussionsupporting

confidence: 53%

Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats

Galic¹,

Riazi²,

Heida³

et al. 2008

Journal of Neuroscience

262

211

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“…In this laboratory, we have observed body weight changes under the condition of experimental colitis, where P14 LPS-treated rats, as adults, lost considerably more of their body weight than did neonatally saline-treated controls in response to trinitrobenzene sulfonic acid (TNBS)-colitis (56). However, we have not seen similar changes with a P14 immune challenge under other experimental conditions (57). These observations leave some important questions unanswered.…”

mentioning

confidence: 46%

Neonatal immune challenge does not affect body weight regulation in rats

Spencer¹,

Mouihate²,

Galic³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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The perinatal environment plays a crucial role in programming many aspects of adult physiology. Myriad stressors during pregnancy, from maternal immune challenge to nutritional deficiency, can alter longterm body weight set points of the offspring. In light of the increasing concern over body weight issues, such as obesity and anorexia, in modern societies and accumulating evidence that developmental stressors have long-lasting effects on other aspects of physiology (e.g., fever, pain), we explored the role of immune system activation during neonatal development and its impact on body weight regulation in adulthood. Here we present a thorough evaluation of the effects of immune system activation (LPS, 100 g/kg ip) at postnatal days 3, 7, or 14 on long-term body weight, adiposity, and body weight regulation after a further LPS injection (50 g/kg ip) or fasting and basal and LPS-induced circulating levels of the appetite-regulating proinflammatory cytokine leptin. We show that neonatal exposure to LPS at various times during the neonatal period has no long-term effects on growth, body weight, or adiposity. We also observed no effects on body weight regulation in response to a short fasting period or a further exposure to LPS. Despite reductions in circulating leptin levels in response to LPS during the neonatal period, no long-term effects on leptin were seen. These results convincingly demonstrate that adult body weight and weight regulation are, unlike many other aspects of adult physiology, resistant to programming by a febrile-dose neonatal immune challenge.gender; leptin; lipopolysaccharide; obesity THE PERINATAL ENVIRONMENT is known to play a crucial role in programming body weight. In humans, low birth weight and malnutrition during gestation have been linked with abdominal obesity in adulthood (31,45,46). Similarly, a variety of behavioral, physiological (including dietary manipulations), and immune stressors given to pregnant experimental animals have been reported to alter the body weight of adult offspring (4,15,27,36,40,63). It appears, however, that the timing of perinatal stress is critical in programming many aspects of adult physiology (35) and relatively little is known regarding the influence of postnatal stress on adult body weight regulation.The long-term physiological consequences of a neonatal immune challenge with LPS have been extensively described by our laboratory and others. For example, we have shown attenuated febrile and associated host defense responses in adulthood to an immune challenge of the same type as that experienced at postnatal day (P) 14 (9,17,18). Changes have also been demonstrated in memory processing (7), hypothalamic-pituitary-adrenal axis activation (51, 52), and susceptibility to pathological insults in adulthood (10, 55, 56). However, the long-term effects of a neonatal immune challenge on body weight regulation are less clear, and given the concern over the current obesity epidemic in modern society [e.g., (29)], demand further investigation. For instance, Walker ...

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“…Ears were clipped for identification and the pups were returned to the dam. We have previously shown that both saline-and LPS-injected pups receive similar maternal attention (Spencer et al, 2006b), thus minimizing the possibility that maternal care is the basis for differences between LPS-and salinetreated animals. At P21, male rats were selected, weaned, and housed four per cage until they reached 2 months of age, at which time they were housed two per cage for the remainder of the experiments.…”

Section: Methodsmentioning

confidence: 99%

Early Life Activation of Toll-Like Receptor 4 Reprograms Neural Anti-Inflammatory Pathways

Mouihate¹,

Galic²,

Ellis³

et al. 2010

Journal of Neuroscience

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A single postnatal exposure to the bacterial endotoxin, lipopolysaccharide (LPS), reduces the neuroimmune response to a subsequent LPS exposure in the adult rat. The attenuated fever and proinflammatory response is caused by a paradoxical, amplified, early corticosterone response to LPS. Here we identify the mechanisms underlying the heightened corticosterone response to LPS in adults after early life exposure to LPS. In postnatal LPS-treated rats, hypothalamic corticotrophin-releasing hormone mRNA, pituitary proopiomelanocortin mRNA, and circulating adrenocorticotrophic hormone were all increased after adult exposure to LPS without significant modification to hippocampal or hypothalamic glucocorticoid receptor mRNA or protein or vagally mediated afferent signaling to the brain. Postnatal LPS administration did cause a persistent upregulation of the LPS Toll-like receptor-4 (TLR4) mRNA in liver and spleen, but not in brain, pituitary, or adrenal gland. In addition, cyclooxygenase-2 (COX-2), which is a prostaglandin biosynthetic enzyme and is normally undetectable in most peripheral tissue, was constitutively expressed in the liver. Adult immune activation of the upregulated TLR4 and COX-2 caused a rapid, amplified rise in circulating, but not brain, prostaglandin E 2 that induced an early, enhanced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Thus, postnatal LPS reprograms the neuroimmune axis by priming peripheral tissues to create a novel, prostaglandin-mediated activation of the HPA axis brought about by increased constitutive expression of TLR4 and COX-2.

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Early-Life Immune Challenge: Defining a Critical Window for Effects on Adult Responses to Immune Challenge

Cited by 100 publications

References 38 publications

Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats

Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats

Neonatal immune challenge does not affect body weight regulation in rats

Early Life Activation of Toll-Like Receptor 4 Reprograms Neural Anti-Inflammatory Pathways

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