Kristina A. McLinden

Prolonged elevation in hippocampal Aβ and cognitive deficits following repeated endotoxin exposure in the mouse.

Alzheimers disease (AD) is characterized by neuronal cell death and atrophy in regions of the adult brain, including the hippocampus and cortex, due to formation of amyloid beta (Aβ) plaques and neurofibrillary tangles. The presence of these pathologies can limit normal signaling properties and ultimately lead to learning and memory deficits. Chronic inflammation has been implicated in the onset and progression of these AD-related pathologies. Our study was designed to assess the effects of peripheral inflammation on pathologies associated with AD by using the bacterial endotoxin lipopolysaccharide (LPS). C57BL/6J mice were given intraperitoneal injections of LPS or saline for 1, 3, or 7 consecutive days. Hippocampal tissue from animals receiving LPS contained significantly higher levels of Aβ1-42, a peptide component of AD plaques, than did those from saline control animals. Central and peripheral pro-inflammatory cytokine levels were increased following a single injection of LPS, but retuned to baseline levels before cognitive testing began. We show that one injection of LPS leads to sickness behavior, but 7 consecutive days does not, indicating tolerance to the endotoxin. Cognitive testing was then conducted to determine if whether deficits from increased Aβ1-42 was evident. Results from both Morris water maze and contextual fear conditioning revealed cognitive deficits in LPS-treated mice. In summary, multiple injections of LPS resulted in increased Aβ1-42 in the hippocampus and cognitive deficits in mice.

Peripheral bacterial endotoxin administration triggers both memory consolidation and reconsolidation deficits in mice

Peripherally administered inflammatory stimuli, such as lipopolysaccharide (LPS), induce the synthesis and release of proinflammatory cytokines and chemokines in the periphery and the central nervous system, and trigger a variety of neurobiological responses. Indeed, prior reports indicate that peripheral LPS administration in rats disrupts contextual fear memory consolidation processes, potentially due to elevated cytokine expression. We used a similar, but partially olfaction-based, contextual fear conditioning paradigm to examine the effects of LPS on memory consolidation and reconsolidation in mice. Additionally, interleukin-1β (IL-1β), brain-derived neurotrophic factor (BDNF), and zinc finger (Zif)-268 mRNA expression in the hippocampus and the cortex, along with peripheral cytokines and chemokines, were assessed. As hypothesized, LPS administered immediately or 2 h, but not 12 h, post-training impaired memory consolidation processes that support the storage of the conditioned contextual fear memory. Additionally, as hypothesized, LPS administered immediately following the fear memory trace reactivation session impaired memory reconsolidation processes. Four hours post-injection, both central cytokine and peripheral cytokine and chemokine levels were heightened in LPS-treated animals, with a simultaneous decrease in BDNF, but not Zif-268, mRNA. Collectively, these data reinforce prior work showing LPS- and cytokine-related effects on memory consolidation, and extend this work to memory reconsolidation.

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.

Age exacerbates sickness behavior following exposure to a viral mimetic

Poly I:C, a viral mimetic, is a synthetic double-stranded RNA that is known to cause activation of the innate immune system, resulting in the emergence of sickness behaviors in otherwise healthy adult mice. However, the way in which such effects of poly I:C manifest themselves in aged mice are not currently known. We hypothesized that poly I:C administration would lead to burrowing deficits, but that these deficits would be exaggerated in aged subjects (19-months old) compared to young subjects (4-months old) that received the same dose. In order to associate these behavioral decrements with inflammatory factors, we measured mRNA expression of IL-1β and IL-6 in the hippocampus and parietal cortex and peripheral protein expression of IL-6, TNF-α, MCP-1, MIP-1α, and IL-1β in the serum. After exposure to poly I:C, aged subjects demonstrated significant impairments in their burrowing behavior, compared to younger subjects administered the same dose. These behavioral decrements coincided with increased expression of IL-6 among animals exposed to poly I:C and increased expression of IL-1β among aged animals in the hippocampus and cortex. Furthermore, we observed an increase in peripheral poly I:C-induced IL-6, TNF-α, MCP-1, and MIP-1α, but not IL-1β. These results indicate that virus-mediated immune activation in the aging body can lead to increased sickness behavior. Furthermore, these data indicated a possible dissociation between the effects of poly I:C on sickness behaviors in aged mice, with central expression of IL-1β potentially playing a role in age-related impairments.

Peripheral administration of poly I:C disrupts contextual fear memory consolidation and BDNF expression in mice.

In the current study, administration of poly I:C induced a deficit in contextual, but not auditory-cue, fear memory consolidation. This memory deficit coincided with a decrease in hippocampal and cortical BDNF mRNA expression. These results extend prior work, and suggest that a single peripheral injection of poly I:C disrupts contextual fear memory consolidation processes in adult mice, and that these deficits may potentially be mediated by diminished BDNF expression.

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