Fever and sickness behaviours in rats following central administration of interleukin-1B

Abstract

Upon entry into the central nervous system different pathogens are recognized by different pathogen receptors (e.g. Escherichia coli (E. coli) is recognized by Toll like receptor 4) present on the surface of innate immune cells. Once recognized, pathogens activate the innate immune system of the host which ultimately results in the synthesis and release of pro-inflammatory cytokines (e.g. Interleukin-1β (IL-1β)). Pro-inflammatory cytokines are the primary mediators of the acute phase response which consists of a suite of physiological and behavioural changes which include fever, lethargy, anorexia and in some cases memory impairment. Clinical cases of central bacterial infections (e.g. meningitis and brain abscesses) have shown that in addition to developing fever, lethargy and anorexia, one third of patients also present with cognitive deficits. Laboratory based studies simulating central bacterial infections using Lipopolysaccharide (LPS), the active fragment of E. coli, and IL-1β have well documented their effects on fever, anorexia, and lethargy. In addition centrally administered IL-1β has also been demonstrated to effect on memory, however no studies have examined the effect of centrally administered LPS on memory. Furthermore, to my knowledge, no studies have concurrently examined the impact of a simulated central bacterial infection using LPS or IL-1β on a suite of sickness responses including body temperature, activity, food intake, body mass and memory. Therefore I set out to concurrently examine body temperature, voluntary activity, food intake, body mass and memory after the central administration of either LPS or IL-1β and their appropriate vehicles. Materials and methods Male Sprague-Dawley rats (~200g) were anaesthetised and had radiotelemeters implanted intra-abdominally, which measured abdominal temperature and cage activity. Body mass and food intake were measured daily. The contextual and auditory fear conditioning paradigm was used to assess memory in rats. Fear conditioning entails conditioning/training of rats and performing two memory (hippocampal and amygdala dependent) tests. Rats were randomly assigned to receive a single intra-cisterna magna (ICM) injection of either LPS (10 μg or 100 μg), IL-1β (100 ng) or vehicle (phosphate buffered saline or 0.1% bovine serum albumin) in a total volume of 5 μl. Rats set to receive LPS and PBS were assigned to a protocol in which they were conditioned/trained, followed by an immediate ICM injection of either LPS or PBS. Rats set to receive IL-1β or BSA were assigned to one of two protocols: a) a protocol in which rats were conditioned/trained, followed by an immediate ICM injection of either IL-1β or BSA; b) a protocol in which rats first received an ICM injection of either IL-1β or BSA and then were conditioned/trained 2 h later. Sickness responses were measured for 7 days following injection and memory was assessed on day 7. In addition, hypothalamic and hippocampal concentrations of IL-1β for rats that received IL-1β and BSA were measured at several time points following injection. Results Following the administration of LPS, rats showed a dose-dependent hypothermia which preceded a fever, as well as a dose-dependent decrease in nocturnal activity, food intake and body mass (P < 0.05). However, regardless of dose, LPS administered immediately after conditioning had no effect on hippocampal-dependent memory assessed 7 days after LPS administration (P > 0.05). Moreover, following IL-1β administration, rats showed an increase in body temperature, a decrease in activity and food intake and had significantly increased concentrations of IL-1β in the hippocampus and hypothalamus (P < 0.05). Furthermore, rats that received IL-1β immediately after conditioning had no effect on hippocampal-dependent memory (P > 0.05) however, rats that received IL-1β 2 h before being conditioned showed both hippocampal and amygdala-dependent memory impairment (P < 0.05). Discussion and conclusion The results of the present study suggest that a central infection severe enough to induce a suite of sickness responses including fever, anorexia and lethargy may occur without incurring memory impairment in rats. However, rats that received IL-1β 2 h before being conditioned were conditioned at a time when brain IL-1β concentrations were raised and whilst they were febrile, which suggests that memory impairment may occur, concurrently with other sickness behaviours, only when learning takes place during an immune challenge within the brain.