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Behavior of dairy calves after a low dose of bacterial endotoxin¹

T. F. Borderas^*,,2, A. M. de Passillé^* and J. Rushen^*

^* Pacific Agri-Food Research Centre, Agriculture and Agri-Food Canada, Agassiz, British Columbia, Canada; and Departamento de Producción Agrícola y Animal, Universidad Autónoma Metropolitana-Xochimilco, Mexico

	Abstract

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The aim of this experiment was to better describe early behavioral responses of calves to illness to help improve early detection. We examined the behavior of calves after injections of very low doses of bacterial lipopolysaccharide (LPS). Fifteen dairy calves of 2 ages (3 and 20 wk), housed in individual pens and fed milk and concentrates with free access to hay and water, were injected i.v. with 1 of 2 low doses (0.025 or 0.05 µg/kg of BW) of LPS before feed delivery with saline injections as a control using a crossover design. Fifteen calves showed an increased body temperature (>39.5°C) lasting 2 to 8 h, with a maximum temperature of 40.59 ± 0.52°C attained 4.62 ± 0.96 h after the LPS injection. Video recordings were used to measure durations of behaviors during a 4-h period when body temperatures were elevated. We found a decreased duration of rumination (LPS vs. saline 6.42 ± 3.69 min vs. 24.57 ± 6.64 min; P = 0.001) and hay eating (23.11 ± 6.93 min vs. 31.52 ± 7.54 min; P = 0.04), a decreased frequency of self-grooming (13.47 ± 1.75 vs. 24.07 ± 3.12; P = 0.008), and an increased duration of lying inactive (132.63 ± 10.60 min vs. 104.39 ± 12.63 min; P = 0.02). There was an increased bout frequency (P = 0.002) and mean bout duration (P = 0.005) of standing inactive. Changes in these behaviors may indicate the beginning of illness. Time spent lying down and amount of concentrate and milk consumed were not affected. There were no differences between the 2 doses and no interactions between LPS and the age of the calves. Very low doses of LPS seem promising to understand early development of sickness behaviors in dairy calves. However, the short duration of the effect and differences between calves in sensitivity to LPS must be considered as limitations to the effectiveness of this model.

Key Words: dairy calf • endotoxin • lipopolysaccharide • sickness behavior • welfare

	INTRODUCTION

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Rates of illness remain high among dairy calves (Losinger and Heinrichs, 1997; USDA, 2002; Svensson et al., 2003). Treatment is more effective if done early, and so there is a need for better early detection of illness.

Animals respond to illness with a consistent pattern of behavioral changes, including reduced feeding and social behavior and increased rest (Johnson, 2002; Dantzer and Kelley, 2007). These behavioral changes occur simultaneously with physiological changes and are adaptive responses helping the animals cope with illness (Owen-Ashley et al., 2006). Veterinary diagnosis involves some assessment of these behaviors (Broom, 2006). A better understanding of which behaviors change as illness develops may help improve the early detection of illness. Research on laboratory animals shows that behavioral responses to illness are stimulated by injections of bacterial lipopolysaccharide (LPS; Wen and Prendergast, 2007), operating through cytokines (Johnson, 1998; Dantzer, 2001; Larson and Dunn, 2001). Some research has examined behavioral responses to LPS in swine (Johnson and von Borell, 1994; Wright et al., 2000). Immune and physiological responses of calves to LPS have been described (Kinsbergen et al., 1994; Elsasser et al., 1996; Deluyker et al., 2004), but no studies have documented behavioral responses to induced sickness in cattle.

To produce an immunological response, high doses of LPS are often used. The effect of low doses of LPS, which might be more typical of the early onset of illness, has been studied only in primates (Krabbe et al., 2005; Willette et al., 2007).

To help understand the early behavioral response of dairy calves to a mild immunological challenge, we examined the effect of low doses of LPS on heart rate, respiratory frequency, and body temperature of calves and examined the behavioral changes that accompanied the presence of fever, which was used as the main indicator of the response.

	MATERIALS AND METHODS

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This study was conducted at the Dairy and Swine Research and Development Center at Lennoxville, Quebec, Canada. The institutional animal care committee (monitored by the Canadian Council for Animal Care) approved all procedures described in this study.

Seven young [(mean ± SD) age = 22.83 ± 3.6 d; BW = 51.92 ± 4.5 kg] and 8 older (153.92 ± 8.1 d; 181.08 ± 14.8 kg) Holstein calves (2 males, both young, and 13 females: 5 young and 8 old) were housed in individual pens (2.15 m x 1.7 m) with free access to water through an automatic water bowl. All animals were kept in the same heated room with an average temperature of 18°C and 12 h/d light (0700 to 1900 h). Normal feeding management consisted of younger calves being bucket fed 4 kg of milk replacer (CP = 18.5%; Violac, Coopérative Féderée de Québec, Montreal, Canada) and 0.250 kg of concentrate (CP = 22.0%; Goliath XLR, Coopérative Féderée de Québec, Montreal, Canada) twice a day (at 0800 and 1500 h) and older calves bucket fed 0.5 kg of concentrate at the same times. All animals had free access to hay in a hayrack freshly filled twice a day shortly after concentrate was offered. Because the aim of the project was to examine behavioral and physiological changes associated with induced fever in otherwise healthy calves, we used only calves that showed no signs of illness during the experiment. The health check performed by a qualified veterinarian of all calves included assessment of body temperature, respiratory and cardiac rates and sounds, presence of diarrhea, presence of nasal and ocular discharges, general state of the coat, and dehydration (tent test and muzzle humidity).

All calves of both ages were fitted with an indwelling jugular catheter 3 d before the start of the experiment, and one-half of the calves of each age group were assigned randomly to receive either a low (0.025 µg/kg, iv) or high (0.05 µg/kg, iv) dose of bacterial LPS (Escherichia coli O55:B5, L6529; Sigma, St. Louis, MO) in 50-mL volume. These doses were established through a previous pilot study, which showed that both of these doses induced fever in young and old calves but were mild enough to not cause prostration, severe pathological consequences, or preshock state.

A crossover design was used in which each calf was used as its own control. Treatment consisted of injections of LPS with injections of physiological saline (SAL) administered as a control on a separate day. One half of the calves received LPS on d 1 through the jugular catheter just before to the morning feeding at 0800 h, whereas the other one half received SAL by the same procedure. The volume infused in both treatments was 50 mL per calf. After 7 d, the treatments were reversed and calves that had received LPS previously were injected with SAL, whereas calves that had received SAL previously were injected with LPS. The order of treatment and control days were balanced across age groups and doses.

A health check that included rectal body temperature (RT), heart rate (HR), and respiratory frequency (RF), as well as eye and nose secretions, state of coat, and humidity of the muzzle, was performed on each calf before the initial injection. Calves were observed directly for the following 60 min to ensure no septic shock resulted as a consequence of LPS injection.

To determine the effectiveness of the low doses of endotoxin, RT, HR, and RF were recorded by a qualified veterinarian before injections, at 1-h intervals during the first 4 h, and at 6, 8, 10, 12, and 24 h after first injection. To measure RT, a digital thermometer was fully inserted into the rectum and temperature was recorded to the nearest 0.1°C. Heart rate was measured by applying a stethoscope to the seventh left intercostal space near the sternum and counting heartbeats during a 20-s period. After assessing HR, RF was measured by counting the number of expansions of the thoracic wall during a 30-s period.

Video cameras were placed 2 m in front of and 2.5 m above the pen walls to record the behavior of each animal. Recordings began 24 h before injection of LPS or SAL and ended 24 h after. Differences in body temperature between treatment and control days were observed 2 to 6 h after the start of the experiment for both age groups. Because the maximum rectal body temperature occurred 4 h after LPS injection, the behavior of the calves was observed during the 2 h before and 2 h after the maximum rectal body temperature was reached (fever peak) and during the same period of time during the control days. A single observer scored the calves following the behavioral definitions in Table 1 and using the Observer program (2003, Noldus Information Technology, Wageningen, the Netherlands). Milk and concentrate intake were monitored by weighing refusals in the milk or concentrate buckets during the experimental day at 8 and 12 h after the initial injection.

The effect of LPS on RT, HR, and RF of all calves was analyzed using the MIXED procedure (SAS Institute Inc., Cary, NC). The model included treatment (LPS or SAL), age (young or old), dose (high or low), and time as factors, with calf nested within age and dose. The interactions between treatment, age, and dose were also included. Physiological variables were analyzed for the 24-h period after treatments with baseline values (0 h) as covariates. Behavioral data from calves during the period of peak fever were analyzed using the MIXED procedure with a model that included the same factors and interactions described previously for the physiological variables. Variables in this model included total duration, bout frequency, and mean bout duration of behaviors. Because bouts of self-grooming were very short, we analyzed only the frequency of the bouts. Natural logarithm transformations (ln x + 1) were used when variables did not show normal distribution. Transformed variables included time spent eating hay and time spent ruminating.

	RESULTS

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Figures 1, 2, and 3 show the time course of changes in RT, HR, and RF after LPS and SAL injections. Table 2 shows the mean (±SE) values of the physiological variables (n = 15). Administration of LPS increased RT and RF in all calves. During the 4-h period of fever peak, the average maximum RT for the calves was 40.55 ± 0.13°C during the treatment day. This temperature was reached 4.80 ± 0.32 h after the LPS injection. The average temperature at this time on the control day was 39.16 ± 0.05°C. Heart rate was not affected by LPS treatment. An effect of age (P = 0.001) on RF was observed, with older calves showing a greater RF (44.60 ± 0.88 bouts/min for all calves) than younger calves (37.87 ± 0.69 bouts/min for all calves). No significant effects of dose (P = 0.78) or interactions between age and dose (P = 0.48) were reported.

View larger version (12K): [in this window] [in a new window]   Figure 1. Mean (±SE) rectal temperature of calves at each sampling time after injections of either lipopolysaccharide (LPS) or saline (SAL; n = 15). A low dose (0.025 mg·kg–1) and a high dose (0.05 mg·kg–1) of LPS were used. No statistical differences were found due to the dose (P > 0.10); therefore, the results from the 2 doses were combined. A volume of 50 mL of saline or LPS solution was injected (n = 15).

View larger version (13K): [in this window] [in a new window]   Figure 2. Mean (±SE) heart rate of calves at each sampling time after injections of either lipopolysaccharide (LPS) or saline (SAL; n = 15). A low dose (0.025 mg·kg–1) and a high dose (0.05 mg·kg–1) of LPS were used. No statistical differences were found due to the dose (P > 0.10); therefore, the results from the 2 doses were combined. A volume of 50 mL of saline or LPS solution was injected (n = 15).

View larger version (13K): [in this window] [in a new window]   Figure 3. Mean (±SE) respiratory frequency of calves at each sampling time after injections of either lipopolysaccharide (LPS) or saline (SAL; n = 15). A low dose (0.025 mg·kg–1) and a high dose (0.05 mg·kg–1) of LPS were used. No statistical differences were found due to the dose (P > 0.10); therefore, the results from the 2 doses were combined. A volume of 50 mL of saline or LPS solution was injected (n = 15).

Tables 3 and 4 show the effects of treatment on behavioral variables and postures of calves during the 4-h period of fever peak. Treatment with LPS resulted in a decreased duration of rumination, which was due to a reduction in both the frequency of bouts (P = 0.002) and the mean bout duration (P = 0.01); LPS also reduced the total duration of time spent eating hay and increased the total duration of lying inactive. There was a trend for longer bouts for lying inactive with LPS. Although calves tended to spend more time standing inactive after LPS, this effect was not statistically significant due to the large SE after LPS. However, LPS increased the frequency of bouts and the mean bout duration of standing inactive. No differences between treatments were found for time spent eating concentrate, drinking water, and time spent standing up or lying down on the side or sternum. There was a decreased frequency of bouts of self-grooming (LPS vs. SAL: 13.47 ± 1.75 vs. 24.07 ± 3.12, P = 0.008).

	DISCUSSION

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After a mild dose of LPS, calves showed increased RT and RF, indicative of a fever response. During the 4-h period that preceded and followed the peak in body temperature, LPS injections also reduced the time spent ruminating, grooming, eating hay, and increased the time spent lying and standing inactive. These behavioral changes may therefore be early indicators of developing illness in calves. However, there was no change in the overall time spent standing or lying, or in the amount of milk or concentrate eaten.

Most studies report a decrease in food intake after an endotoxin challenge (Wright et al., 2000; Elander et al., 2007; Kim et al., 2007). Steiger et al. (1999) found a significant decrease in food intake 4 h after infusing Holstein x Jersey heifers with 2 µg/kg of LPS during 100 min, with the difference in food intake between control and treated animals still evident 24 h after the infusion. In our experiment, milk and concentrate intake were not affected during fever peak. Although we did not measure actual hay intake, the time spent by the calves at the hayrack was decreased during fever peak. The lack of an effect on milk and concentrate intake may be due to the mild doses used. Johnson and von Borell (1994) reported that the reduction of food intake by LPS administration was dose-dependent and short-lived. Pigs receiving the lowest dose in their experiment (0.5 µg/kg of BW) even showed a compensatory increase in feed intake, masking the anorexic effect of LPS shown by male pigs challenged with larger doses (50 µg/kg of BW). Alternatively, the high feeding motivation of the calves may have limited the effect of LPS on milk intake, given that the commercial quantities of milk fed to calves, which we used, are well below ad libitum intake levels (Jasper and Weary, 2002). The small amount of time needed by the calves to consume their portion of milk and concentrate may also have masked any effect. In contrast, hay intake might have been affected due to the low nutritional value of this component of the diet compared with the high nutritional value of the milk and concentrate. Aubert and Dantzer (2005) reported that rats challenged with LPS showed no difference in the frequency of hedonic responses to a sucrose solution compared with controls injected with a saline solution. Those results showed that sickness does not interfere with the hedonic value of sucrose, suggesting that sick animals can still ingest highly nutritious food.

We noticed a marked reduction in the total duration of rumination during the period of peak fever due to both a reduced bout frequency and a reduced bout duration. The observed reduction of rumination could be caused by decrease in hay intake, depression of the gastric centers causing stasis (Leek, 2001), or a combination of both factors. Takeuchi and Mori (1995) also found a reduction in rumination in goats challenged with LPS. A reduction in rumination time is considered as an indicator of anxiety in cattle. For example, Bristow and Holmes (2007) reported reduction in rumination time associated with increases in cortisol under stressful situations.

Previous research has indicated an increased time spent lying down in other species after LPS (Johnson and von Borell, 1994). However, some studies report a decrease in lying time (Tuchscherer et al., 2006). We found no change in overall time spent standing or lying during the period of peak fever. These results are consistent with a lack of an effect reported in goats (Takeuchi and Mori, 1995). Lying on the side is thought to be a form of thermoregulatory behavior increasing heat loss, whereas resting with the neck relaxed has been proposed as an indicator of REM sleep (Hänninen, 2007; Hänninen et al., 2008). We did not observe any change in the amount of time that calves spent resting in these positions. However, the calves spent more time lying inactive when challenged with LPS. The LPS also reduced the frequency and duration of bouts of standing inactive. Owen-Ashley et al. (2006) reported reductions in activity of LPS-challenged sparrows. Reduced activity linked to fever may be an energy-conserving mechanism, but it may also be related to the depression that is reported to occur after challenge with LPS (Königsson et al., 2002). It is now accepted that a link exists between depression and the activation of immune system by means of cytokine action in the brain (Dantzer and Kelley, 2007). Immobility has been reported in mice challenged with LPS in highly stressful situations, such as forced swimming tests, and this is blocked by use of an anti-depressant (Renault and Aubert, 2006). Harden et al. (2006) found that the reduction of voluntary wheel running in rats challenged with LPS was reversed by administration of specific antibodies to an LPS-elicited cytokine (IL-6). Injections of LPS also reduced the frequency of self-grooming events, as has been previously reported in LPS-challenged rats (Yirmiya et al., 1994), mice (Hollis et al., 2006), and goats (Takeuchi and Mori, 1995).

The physiological measures were recorded to assess whether or not the very low doses of LPS used were stimulating a fever response. The effects of LPS on body temperature and RF agree with those reported previously for calves injected with LPS (Hüsler and Blum, 2001) and calves experimentally infected with bovine viral diarrhea virus, Mannheimia hemolytica (Ganheim et al., 2003). Steiger et al. (1999) found a very mild increase in RT (to 39.4°C) after an endotoxin dose of 2 µg/kg infused during 100 min into Holstein x Jersey heifers with a BW of 311 kg. This dose is 4 times greater than the dose used in our study, but we found a similar increase in body temperature. No differences were found between high and low doses of LPS. This could be related to the fact that both doses are already very mild for calves. Heart rate did not increase in our study, although increased HR after LPS has been observed previously for calves (Königsson et al., 2002) and other species (Albertini et al., 2002). Possibly the responses of the calves to the handling involved in measuring HR may have masked any effects of LPS.

Injections of LPS have often been used to study sickness behavior (Dantzer, 2004), but there are limitations with using LPS to model behavioral responses to illness. Most obviously, injections of LPS help us understand the behavioral correlates of the activation of the immune system, rather than behavioral consequences of a full infection. A major problem in studying the initial behavioral responses to spontaneously occurring illness is the difficulty in establishing the time at which the illness begins. One of the main advantages of using mild doses of LPS to model early sickness behavior is that it does provide a clear starting point. However, it is unlikely that the time course of the changes in LPS concentrations in the blood after injection would model the time course after naturally occurring illness. Thus, LPS injections may not be a good model for studying the full time course of the behavioral responses to illness. However, this disadvantage is reduced when using low doses of LPS to mimic the beginning of illness. At the doses used in this experiment, the main disadvantage of the LPS model for early signs of sickness is the immediate presence of clinical signs after LPS injection and its short duration compared with naturally acquired diseases. In general, there is a lack of knowledge of how behavior is affected during the incubation period of a viral or bacterial disease. The utilization of even lesser doses could be explored because it has been reported that very low doses of LPS do not elicit fever or other major sickness signs, but affect the cognitive process in chickens (Sell et al., 2001) and cognitive and emotional variables in humans (Krabbe et al., 2005). Further research is needed on the effect of nonfebrigenic doses and their effects on behavior in cattle. Despite the limitations with the procedure, we maintain that injections of low doses of LPS can help us understand the behavioral correlates of the beginning of illness.

In summary, low doses of LPS may mimic low concentrations of circulating bacterial endotoxin during the beginning of acute gram-negative infections. Therefore, behavioral changes of calves after being exposed to mild doses of LPS could be matched to the changes associated with the beginning of some infectious diseases. Behaviors such as self-grooming, rumination, and ingestion of hay are reduced, whereas time spent lying and standing inactive is increased. In spite of fever, ingestion of milk and concentrate remained unchanged. However, the lack of an incubation period, the short duration of the effect, and individual differences between calves in sensitivity to LPS are factors that must be considered as limitations of this model for early detection of illness.

	Footnotes

 
¹ The authors acknowledge Isabelle Blanchet, Marjolaine St.-Louis, Keith Carter, and the staff of the Lennoxville dairy barn for their help. Funding was provided by a Discovery grant to A. M. de Passillé from the Natural Sciences and Engineering Research Council of Canada.

² Corresponding author: borderas{at}interchange.ubc.ca

Received for publication February 4, 2008. Accepted for publication June 9, 2008.

	LITERATURE CITED

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