Characterization of Spatial Learning and Sickness Responses in Aging Rats Following Recurrent Lipopolysaccharide Administration.

Infections in older individuals can result in cognitive function decline, yet research is limited on how recurrent infections affect cognitive responses. Activation of the immune system results in sickness responses mediated by cytokines. This pilot study examined effects of a model of recurrent infection in aged, male Brown Norway rats on sickness responses, including spatial learning, and cytokine levels. To model initial and recurrent infection, 300 µg/kg lipopolysaccharide (LPS) or saline was administered 1/day for 2 consecutive days during 2 weeks separated by 16 days. Testing occurred for 6 days during each LPS injection week using the Morris water maze, a measure used to evaluate spatial learning. Directional heading error (DHE) and swim time latency served as spatial learning indices. Retention tests and probe trials assessed memory. Plasma cytokine levels were assessed 5 and 24 hr after each LPS injection during Week 2. While food intake and weight decreased significantly in LPS-injected rats compared to controls during Week 1, both displayed increased DHE. Despite exhibiting lessened sickness behaviors during Week 2, experimental animals still displayed spatial learning deficits. Probe trials revealed memory deficits in LPS-injected animals. Interleukin 6 level was higher in the experimental group 5 and 24 hr after LPS injection on Day 1 compared to Day 2 and higher in the experimental compared to the control group at 5 hr on Day 1. Cognitive effects were dissociated from metabolic effects in aged rats, with recurring LPS exposure resulting in persistent cognitive impairment despite decreased sickness responses. Further research with older individuals is warranted.

Persistent Adult Neuroimmune Activation and Loss of Hippocampal Neurogenesis Following Adolescent Ethanol Exposure: Blockade by Exercise and the Anti-inflammatory Drug Indomethacin.

Alcohol abuse and binge drinking are common during adolescence, a developmental period characterized by heightened neuroplasticity. Animal studies reveal that adolescent ethanol exposure decreases hippocampal neurogenesis that persists into adulthood, but the mechanism remains to be fully elucidated. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-days on/2-days off from postnatal day [P]25 to P55), we tested the hypothesis that AIE-induced upregulation of neuroimmune signaling contributes to the loss of hippocampal neurogenesis in adulthood. We found that AIE caused upregulation of multiple proinflammatory Toll-like receptors (TLRs), increased expression of phosphorylated NF-κB p65 (pNF-κB p65) and the cell death marker cleaved caspase 3, and reduced markers of neurogenesis in the adult (P80) hippocampus, which is consistent with persistently increased neuroimmune signaling reducing neurogenesis. We observed a similar increase of pNF-κB p65-immunoreactive cells in the post-mortem human alcoholic hippocampus, an effect that was negatively correlated with age of drinking onset. Voluntary wheel running from P24 to P80 prevented the AIE-induced loss of neurogenesis markers (i.e., nestin and doublecortin) in the adult hippocampus that was paralleled by blockade of increased expression of the cell death marker cleaved caspase 3. Wheel running also prevented the AIE-induced increase of hippocampal pNF-κB p65 and induction of neuroimmune NF-κB target genes, including TNFα and IκBα in the adult brain. Administration of the anti-inflammatory drug indomethacin during AIE prevented the loss of neurogenesis markers (i.e., nestin and doublecortin) and the concomitant increase of cleaved caspase 3, an effect that was accompanied by blockade of the increase of pNF-κB p65. Similarly, administration of the proinflammatory TLR4 activator lipopolysaccharide resulted in a loss of doublecortin that was paralleled by increased expression of cleaved caspase 3 and pNF-κB p65 in the hippocampal dentate gyrus of CON animals that mimicked the AIE-induced loss of neurogenesis. Taken together, these data suggest that exercise and anti-inflammatory drugs protect against adolescent binge ethanol-induced brain neuroimmune signaling and the loss of neurogenesis in the adult hippocampus.

Different Sickness Responses in Adult and Aged Rats Following Lipopolysaccharide Administration.

OBJECTIVE: Immune challenges result in sickness responses such as decreased activity, fever, and spatial learning deficits. While these responses occur simultaneously, they are not usually evaluated concurrently or for an extended time. The purpose of this study was to examine how an immune challenge affected activity and temperature responses in animals tested concurrently in the Morris water maze (MWM) over 5 days and how aging interacts with such responses. METHOD: An accepted model of aging, adult ( n = 10; 5-6 months) and aged ( n = 7; 22 months) male Brown-Norway rats were implanted with a telemetry device (Mini Mitter, Oakmont, PA) to continuously monitor temperature and activity following an immune challenge. These animals were injected with either 250 µg/kg lipopolysaccharide (LPS) or 0.9% sodium chloride and then assessed in the MWM for 5 days. RESULTS: Temperature responses varied by age. Initial temperatures decreased in both experimental groups followed by an increase (fever) in the adult group, while the temperatures of the aged animals remained decreased. Although both age groups were sedentary at baseline, activity decreased after LPS only in the adult group. CONCLUSION: An LPS immune challenge resulted in age-dependent temperature and activity changes. There was an absence of fever and no effect on activity in aged LPS-treated animals. These results may suggest the need to assess a broader spectrum of sickness responses when monitoring elderly individuals for infection and not rely on the presence of fever. Activity may not be a sensitive indicator of sickness in some aging models.

Effects of low-dose lipopolysaccharide and age on spatial learning in different Morris water maze protocols.

OBJECTIVES: Animals administered lipopolysaccharide exhibit dose-related sickness behaviors (decreased food intake, weight loss, and cognitive changes). While research has demonstrated that spatial learning is impaired following a lipopolysaccharide immune challenge, the results differ depending on the methodology used to evaluate spatial learning. Additionally, few studies have evaluated the effects of low-dose lipopolysaccharide on spatial learning. Therefore, we assessed spatial learning, food intake, and weight changes in adult and aged rats after a low-dose lipopolysaccharide immune challenge in the Morris water maze using two water temperatures. METHODS: Adult (5-6 months) and aged (22 months) male Brown-Norway rats were administered either 50 or 100 µg/kg lipopolysaccharide or saline, and then tested in the Morris water maze for 5 days, rested for 7 days, and later underwent 2 days of retention tests. Probe trials were conducted at the end of initial and retention testing. RESULTS: Low-dose lipopolysaccharide administration did not result in food intake or weight changes. While the aged experimental group took longest to improve directional heading error in both cold and warm water, heading error was greater in cold water. Behavioral testing revealed an apparent age and water temperature effect on swim time. Retention and probe trial results showed that aged experimental animals had the worst performance in cold water. CONCLUSION: We conclude that while low-dose lipopolysaccharide did not result in typical sickness behaviors (decreased food intake or weight), spatial learning and memory were impaired in the aged experimental group. These results have important implications for the care of elderly individuals experiencing mild to moderate infections.

Countering the influence of cultural hegemony on choosing a nursing career: a group-mentoring approach for student recruitment.

Extensive literature exists that demonstrates the influence of social cues and interpersonal interactions with influential others on student career choices. This article applies Gramsci's political views of hegemony and counterhegemony to situate student descriptions of their experiences and the goals of a group-mentoring session designed to address the culturally hegemonic symbolic cues and interpersonal interactions that can negatively influence a student's desire to select a career in nursing. Specifics around the development, implementation, and evaluation of the group-mentoring session, as part of a broader school-wide culture to promote diversity and as a larger program to increase the diversity of the nursing workforce, are described.

Psychological stress and arterial stiffness in Korean Americans.

OBJECTIVE: Arterial stiffness is identified as a causative factor for hypertension. The purpose of this study was to explore the relationship between psychological stress and arterial stiffness in Korean Americans. METHODS: A convenience sample of 102 Korean Americans (aged 21-60 years, 60% women) was recruited from North Carolina. Psychological stress was measured by the Perceived Stress Scale, the Social, Attitudinal, Familiar, and Environmental (SAFE) Acculturative Stress Scale, and the Spielberger's State-Trait Anxiety Inventory. Arterial stiffness was measured by carotid-femoral pulse wave velocity (cfPWV) using the SphygmoCor system (AtCor Medical, Australia). RESULTS: This study shows that the emotional stress response, measured by anxiety, significantly predicted arterial stiffness (ß=.25, p=.008), independently of such confounding factors as age, mean arterial pressure (MAP), gender, body mass index, smoking, education, and income. Anxiety was neither related to age (r=.12, p=.212) nor MAP (r=.14, p=.151). Additionally, this sample of Korean Americans had higher levels of psychological stress when compared to previous findings from studies of other racial/ethnic groups in the U.S. CONCLUSION: Findings demonstrate that anxiety is a significant and independent determinant of arterial stiffness. Given that anxiety was not related to MAP, these findings suggest that arterial stiffness may be a pathway to explain the connection between anxiety and hypertension risk. Studies that scrutinize the relationship between anxiety and arterial stiffness are an important next step for future research. Further studies are also recommended to explore cultural factors and individual characteristics that may affect anxiety in Korean Americans.

Serum biomarkers of aging in the Brown Norway rat.

Serum biomarkers to identify susceptibility to disease in aged humans are well researched. On the other hand, our understanding of biomarkers in animal models of aging is limited. Hence, we applied a commercially available panel of 58 serum analytes to screen for possible biomarkers of aging in 4, 12, and 24 month old Brown Norway rats. We found that serum levels of 5 of the 58 analytes were significantly affected by age: C-reactive protein (CRP), myoglobin, macrophage derived chemokine-2 (MDC), fibroblast growth factor-basic, and vascular cell adhesion molecule-1. Among these analytes, CRP was the only one that increased with aging. The variability of CRP and MDC-2 was relatively low compared to the other analytes of the panel. It is concluded that CRP and possibly MDC-2 are candidates for biomarkers of aging in the BN rat.