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.

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.

Spatial Learning Responses to Lipopolysaccharide in Adult and Aged Rats.

Sickness behaviors, adaptive responses to infections, include lethargy, depression, reduced eating and grooming, and concentration problems resulting from interactions between the immune and neuroendocrine systems. Detecting these responses is especially critical in the elderly, as the infections that cause them can lead to cognitive impairment. While deficits in spatial learning, a hippocampal-dependent form of learning, are part of the sickness response, directional heading errors (DHEs; an indicator of spatial-learning deficits) and their time trajectories need further examination. Therefore, we simultaneously investigated the time trajectory of age-dependent sickness responses and spatial learning over 5 days in adult (5-6 months) and aged (22 months) male Brown-Norway rats injected with 250 µg/kg lipopolysaccharide (LPS; experimental group) or 0.9% sodium chloride (control group). LPS administration resulted in pronounced, age-dependent weight loss and decreased food intake that persisted in the aged group. Animals were tested for 5 days (trial) in the Morris water maze. After 7 days of rest, animals were retested for 2 days (retention). Adult and aged LPS-treated animals displayed greater differences in mean DHE than the control groups, indicating that they exhibited more DHE over the trial days. Experimental groups did not show consistent DHE improvement until Day 4 (adult) or 5 (aged). LPS had no effect on probe or retention trials. We conclude that LPS activation of the immune system results in a selective, age-dependent impairment in spatial learning, decreased food intake, and weight loss. All of these results are prolonged in aged animals.

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.