Pavlovian conditioning of endotoxin-tolerance in rats

Electrical activity in rat cortico-limbic structures after single or repeated administration of lipopolysaccharide or staphylococcal enterotoxin B

“…Additionally, these antigens induce corticosterone release [34,57 -59], considered to be part of the adaptive suppressive neuroendocrine response necessary to control immune reactivity [30]. Furthermore, both antigens have been also employed as unconditioned stimuli in associative learning protocols, inducing a conditioned taste avoidance as well as other conditioned responses; fever, sympathetic activity, glucocorticoids and cytokines among other parameters [34,48,60,61]. We further focused on the IC and Am as two structures known to be involved in immune-to-brain communication in general [42,44,62 -64], and in the behaviourally conditioned immune response in particular [45 -47].…”

“…We found no lateralization of the baseline neural activity, and a short latency for the two antigens tested (65-140 min for LPS, 50 -65 min for SEB). This time frame parallels pro-inflammatory cytokine production and release into circulation for SEB [59,65] and for LPS [48]. Because neither of the antigens employed cross the blood -brain barrier in appreciable concentrations [66], and deep-brain recordings took place long enough to recover the blood -brain barrier integrity, an alternative afferent route would be of relevance with likely intermediate messengers such as cytokines or prostaglandins [17,39,67 -70].…”

“…In this regard, Am activity also showed increased electrical activity after repeated LPS injections when circulating cytokines were blunted, additionally demonstrating significantly higher activity than under naive condition. Potential explanations for this phenomenon are: (i) the used LPS regimen implies increasing doses, starting with 0.1 mg kg 21 on day 1 reaching 0.5 mg kg 21 on day 5, which may lead to a potentially confounding dose factor, (ii) other messengers than cytokines may be involved in the afferent communication on day 5, for instance, prostaglandins released by endothelial and/or perivascular cells as a response to circulating LPS [20,39], and (iii) plasticity phenomena leading to neuroimmune sensitization [83] or associative learning [48]. Finally, whether and to what extent the observed changes are 'immune specific' can only be provided in another set of experiments, in which the activity of immunocompetent cells and/or peripheral cytokines will be abolished with concurrent neural recordings.…”

“…Three independent experiments under identical conditions were performed for acquiring data on (A) neural recordings, (B) cytokines, and (C) body temperature. Immune desensitization was induced as previously described for LPS [48] and SEB [29]. Briefly, rats received i. whereas controls were injected with vehicle (1 ml sterile saline).…”

“…Time point was selected based on previous experience with both antigens [34,48]. Plasma was collected after centrifugation (5 min, 10 000 rpm, 48C) and stored at 2808C until cytokine determination.…”