Peripheral lipopolysaccharide administration impairs two-way active avoidance conditioning in C57BL/6J mice.
ABSTRACT Peripheral administration of lipopolysaccharide (LPS) or interleukin-1 (IL-1) may lead to alterations of CNS function and behavioral changes designated "sickness behavior." Further, some experiments show evidence of LPS- and cytokine-mediated alterations in learning and memory. The current series of experiments examined the effects of a single or repeated intraperitoneal LPS injections, at a number of doses and time points before or after test sessions, on behavior in a two-way active avoidance conditioning paradigm. Subjects were able to avoid the mild shock stimulus, escape it, or fail to respond to it. Subjects treated with LPS at many, but not all, of the time points sampled showed impaired learning, by exhibiting significantly fewer avoidance responses than controls. Furthermore, an LPS-induced increase in non-cued inter-trial interval crossings was observed during the later days of testing, suggesting that a greater percentage of their avoidance responses was not conditioned and their behavior was less efficient. Taken together, the results suggest that LPS-treated animals showed a diminished association between conditioned stimulus (CS) and unconditioned stimulus (US). These results support the theory that peripheral immune stimuli may induce deleterious effects on learning, and extend the work to a negatively reinforced operant procedure.
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ABSTRACT: The administration of bacterial endotoxin (i.e., lipopolysaccharide, LPS) constitutes a well-established experimental approach to study the effects of an acute and transient immune activation on physiological, behavioral, and emotional aspects of sickness behavior in animals and healthy humans. However, little is known about possible effects of experimental endotoxemia on pain in humans. This knowledge gap is particularly striking in the context of visceral pain in functional as well as chronic-inflammatory gastrointestinal disorders. Although inflammatory processes have been implicated in the pathophysiology of visceral pain, it remains incompletely understood how inflammatory mediators interact with bottom-up (i.e., increased afferent input) and top-down (i.e., altered central pain processing) mechanisms of visceral hyperalgesia. Considering the recent findings of visceral hyperalgesia after LPS application in humans, in this review, we propose that experimental endotoxemia with its complex peripheral and central effects constitutes an experimental model to study neuroimmune communication in human pain research. We summarize and attempt to integrate relevant animal and human studies concerning neuroimmune communication in visceral and somatic pain, discuss putative mechanisms, and conclude with future research directions.Annals of the New York Academy of Sciences 07/2012; 1262:108-17. · 4.38 Impact Factor
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ABSTRACT: The relationship between learning/memory performance and long-term potentiation (LTP) induction is ambiguous. Although a large body of data supports a strong correspondence between learning/memory performance and LTP, many studies have also provided evidence to the contrary. In this study, we found that 2-month-old senescence-accelerated mice/prone 8 (SAMP8 mice) displayed both impaired performance in a Morris water maze and enhanced LTP compared to senescence-accelerated mice/resistance 1 (SAMR1). BALB/c mice challenged with Complete Freund's adjuvant (CFA) performed better in the shuttle-box test but displayed impaired LTP compared to intact animals. It is interesting that BALB/c mice challenged with incomplete Freund's adjuvant (IFA) performed better than intact animals, with no LTP impairment. Cytokine analysis showed no significant differences between the IL-6, IL-10 or TNF-α content in the intact hippocampal tissues of either the SAMR1 and SAMP8 mice or the immune challenged BALB/c and intact animals. Further analysis demonstrated that the increase in cytokine content was higher in the hippocampal tissues used for LTP recording in the SAMR1 and CFA-challenged animals compared to the SAMP8 and intact BALB/c mice. A correlation analysis demonstrated that pro-inflammatory cytokines (IL-6 and TNF-α) displayed a negative correlation with LTP, while an anti-inflammatory cytokine (IL-10) displayed a positive correlation with LTP. These results suggest that pro-inflammatory cytokines induced by LTP manipulation in experiments (e.g., via tissue injury caused by electrode insertion) may be one of the factors contributing to the observed lack of correspondence between memory/learning ability and LTP.Neuroscience 11/2012; · 3.12 Impact Factor
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ABSTRACT: Glutaric aciduria type I (GA-I) is characterized by accumulation of glutaric acid (GA) and neurological symptoms, such as cognitive impairment. Although this disease is related to oxidative stress and inflammation, it is not known whether these processes facilitate the memory impairment. Our objective was to investigate the performance of rat pups chronically injected with GA and lipopolysaccharide (LPS) in spatial memory test, antioxidant defenses, cytokines levels, Na+, K+-ATPase activity, and hippocampal volume. We also evaluated the effect of N-acetylcysteine (NAC) on theses markers. Rat pups were injected with GA (5umol g of body weight-1, subcutaneously; twice per day; from 5th to 28th day of life), and were supplemented with NAC (150mg/kg/day; intragastric gavage; for the same period). LPS (2mg/kg; E.coli 055 B5) or vehicle (saline 0.9%) was injected intraperitoneally, once per day, from 25th to 28th day of life. Oxidative stress and inflammatory biomarkers as well as hippocampal volume were assessed. GA caused spatial learning deficit in the Barnes maze and LPS potentiated this effect. GA and LPS increased TNF-α and IL-1β levels. The co-administration of these compounds potentiated the increase of IL-1β levels but not TNF-α levels in the hippocampus. GA and LPS increased TBARS (thiobarbituric acid-reactive substance) content, reduced antioxidant defenses and inhibited Na+, K+-ATPase activity. GA and LPS co-administration did not have additive effect on oxidative stress markers and Na+, K+ pump. The hippocampal volume did not change after GA or LPS administration. NAC protected against impairment of spatial learning and increase of cytokines levels. NAC Also protected against inhibition of Na+,K+-ATPase activity and oxidative markers. These results suggest that inflammatory and oxidative markers may underlie at least in part of the neuropathology of GA-I in this model. Thus, NAC could represent a possible adjuvant therapy in treatment of children with GA-I.PLoS ONE 01/2013; 8(10):e78332. · 3.73 Impact Factor