Andrew J. Tarr

The effects of age on lipopolysaccharide-induced cognitive deficits and interleukin-1β expression.

An acute LPS challenge immediately following day 1 of shuttlebox training triggered exacerbated central IL-1β production and disrupted memory consolidation and/or further acquisition of the task in 18-month-old mice, compared to 4-month-old controls. These deficits cannot be attributed to alterations in sickness behavior. The findings suggest that age and immune activation combine to impair learning and memory consolidation processes, and that increased central IL-1β production may play a role.

Influence of prenatal stress on behavioral, endocrine, and cytokine responses to adulthood bacterial endotoxin exposure

Prior research suggests that prenatal stress, among other effects, can lead to hyper-reactivity of the offsprings hypothalamic-pituitary-adrenal (HPA) axis and alterations in immune function. These stress-induced changes have been linked to a greater propensity to develop depression or anxiety disorders. Furthermore, prenatally stressed offspring may be more susceptible to certain diseases. The immune alterations induced by prenatal stress exposure may disrupt the normal communication between the immune system, endocrine system, and central nervous system, potentially making prenatally stressed individuals more vulnerable to the negative aspects of immune activation, including cytokine-induced cognitive deficits and anxiety. The present study investigated whether prenatal stress would exaggerate these detrimental effects of peripheral immune activation. We hypothesized that prenatally stressed subjects would be hypersensitive to endotoxin administration and would therefore show exaggerated learning deficits, increased anxiety-like behavior, and increased peripheral and central interleukin-1beta (IL-1beta) levels. The observed results only partially supported our hypotheses, as prenatally stressed subjects showed evidence, albeit modest, of increased anxiety-like behavior following endotoxin administration relative to non-stressed controls. While prenatal stress exposure or lipopolysaccharide (LPS) administration independently impaired learning, the data failed to support the hypothesis that prenatally stressed subjects would show exaggerated cognitive deficits, engendered via enhanced peripheral and central IL-1beta levels, following immune activation. Collectively, the data suggest that although prenatal stress exposure led to increases in anxiety-like behavior following endotoxin exposure, it did not appear to increase susceptibility to LPS-induced cognitive decline or elevations in proinflammatory cytokine production.

Neonatal endotoxin exposure impairs avoidance learning and attenuates endotoxin-induced sickness behavior and central IL-1β gene transcription in adulthood

Infection during infancy, a time of critical neural development, may have long-term implications. Infection or exposure to an immune stimulus such as lipopolysaccharide (LPS) early in life leads to alterations in the reactivity of the hypothalamic-pituitary-adrenal axis (HPA) and febrile response in adulthood. Relatively few studies have assessed the behavioral and cognitive alterations induced by perinatal immune challenge. The data indicate that neonatal immune activation may alter adulthood behavior with, or sometimes without, subsequent adulthood exposure, depending on the study. The current study investigated the behavioral effects and IL-1beta transcription following intraperitoneal LPS administration on postnatal days (PNDs) 4 and 5, and subsequent LPS or saline administration in adulthood. Alterations in anxiety, motor behavior, and learning were assessed in male and female subjects. The results indicate that neonatal endotoxin exposure attenuated the LPS-induced decrease in motor behavior in female, but not male, subjects. Furthermore, perinatal immune activation disrupted avoidance learning in male, but not female, subjects in the absence of adulthood LPS administration. In addition, for male subjects, neonatal LPS exposure diminished central IL-1beta gene transcription following adulthood LPS administration. These findings indicate that perinatal endotoxin exposure may lead to alterations in the behavioral response to adulthood LPS administration, and provide evidence that early immune activation alone may trigger alterations in adulthood learning ability.

Age increases vulnerability to bacterial endotoxin-induced behavioral decrements

Peripheral lipopolysaccharide (LPS) or proinflammatory cytokines produce alterations in learning, memory, and other behaviors. Additionally, research has demonstrated that factors such as dose, route of administration, species, strain, gender, and age are important modulatory factors in the effects of endotoxin exposure. Previous research from our laboratory and others indicate that LPS-induced behavioral deficits are greater in older subjects. The current study examined avoidance learning in a negatively reinforced operant procedure (i.e., two-way active avoidance conditioning) following single or repeated intraperitoneal LPS injections in 2- and 12-month-old male C57BL/6J mice. LPS-treated subjects show impaired acquisition of the task regardless of the age of the subject, as these animals performed significantly fewer avoidance responses than controls. However, the effects of LPS administration were more pronounced in the 12-month-old animals, particularly for the subjects given repeated LPS injections. These results support the hypothesis that endotoxin exposure is capable of altering performance in this task in a way that may reflect deficits in learning, and provide evidence that increased age may exacerbate these deleterious behavioral effects.

Systemic lipopolysaccharide plus MPTP as a model of dopamine loss and gait instability in C57Bl/6J mice

In most environmental models of Parkinsons disease (PD), a single neurodegenerative agent is introduced to cause nigrostriatal dopamine depletion. However, cell loss in human PD often might derive, at least in part, from multiple toxins or vulnerabilities, any one of which alone does not inevitably lead to chronic dopamine depletion. In the present research, male C57BL/6J mice were systemically administered the inflammatory bacterial endotoxin, lipopolysaccharide (LPS) and the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) alone or in combination and the behavior as well as striatal dopamine levels were compared to saline-treated mice. Mice in the combination (LPS+MPTP) group, but not in the single-factor groups, showed both dopamine depletion and parkinsonian symptoms, i.e., reduced stride length, at 4 months post-injection. MPTP alone acutely reduced striatal dopamine levels but this effect was transient as striatal dopamine recovered to normal levels after time (4 months). The LPS-only group showed no dopamine depletion or reduced stride length. These data are consistent with the view that nigrostriatal dopamine neurons might succumb after time to multiple toxic agents that independently may have only a transient, adverse effect.

96. Influence of prenatal stress on behavioral, endocrine, and cytokine responses to adulthood endotoxin exposure

of sleep symptoms. Dependent measures included C-reactive protein (CRP) and interleukin (IL)-6, fasting insulin and glucose, estimated IR and fibrinogen. In multivariate-adjusted models, overall poor sleep quality, more frequent problems falling asleep (>2 night/week) and longer periods of time to fall asleep (>30 min) were associated with higher levels of fasting insulin, (p < 0.001), fibrinogen (p < 0.01) and inflammatory biomarkers (p < 0.02), but only for women. Thus, subjective ratings of poor sleep quality, greater frequency of sleeprelated symptoms, and longer periods of time to fall asleep were associated with a mosaic of biobehavioral mechanisms implicated in both CHD and Type 2 diabetes and these associations were more prominent in women. These data are consistent with recent observations suggesting gender-specific differences in the association between symptoms of poor sleep and cardiovascular disease.

The effects of immediate and delayed peripheral LPS administration on contextual fear memory consolidation, BDNF MRNA, and brain/serum expression of cytokines/chemokines in mice

319 No effect of dietary yeast beta-glucan on antibody or cell-mediated response to influenza virus vaccine D. Pence, S.N. Hester, S.A. Martin, S.M. Donovan, J.A. Woods University of Illinois at Urbana-Champaign, Urbana, IL 61801, United

#77 Age affects sensitivity to LPS-induced decrements in shuttlebox learning

murine microglia. Additionally, increased GRK2 levels in astrocytes resulted in a decreased GPCR sensitivity for the chemokine MCP-1. Functional consequences of the increased GRK2 expression in neuronal cells are under current investigation. These data suggest that a short-lasting interaction of IL-1b with cells of the spinal cord may contribute to decreased GPCR receptor function during acute neuro-inflammatory conditions.