Neural Substrates for Behaviorally Conditioned Immunosuppression in the Rat

Abstract

We have previously demonstrated behaviorally conditioned immunosuppression using cyclosporin A as an unconditioned stimulus and saccharin as a conditioned stimulus. In the current study, we examined the central processing of this phenomenon generating excitotoxic lesions before and after acquisition to discriminate between learning and memory processes. Three different brain areas were analyzed: insular cortex (IC), amygdala (Am), and ventromedial nucleus of the hypothalamus (VMH). The results demonstrate that IC lesions performed before and after acquisition disrupted the behavioral component of the conditioned response (taste aversion). In contrast, Am and VMH lesions did not affect conditioned taste aversion. The behaviorally conditioned suppression of splenocyte proliferation and cytokine production (interleukin-2 and interferon-␥) was differentially affected by the excitotoxic lesions, showing that the IC is essential to acquire and evoke this conditioned response of the immune system. In contrast, the Am seems to mediate the input of visceral information necessary at the acquisition time, whereas the VMH appears to participate within the output pathway to the immune system necessary to evoke the behavioral conditioned immune response. The present data reveal relevant neural mechanisms underlying the learning and memory processes of behaviorally conditioned immunosuppression.

Placebo and the New Physiology of the Doctor-Patient Relationship

“…Conversely, the amygdala has been found to mediate the afferent signals at the time of acquisition. The ventromedial hypothalamic nucleus has been found to participate in the efferent signals to the immune system, which are necessary to elicit the behaviorally conditioned immune response (252,253).…”

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

“…We employed a wireless recording method, allowing unrestricted animal behaviour, minimizing stress artefacts and providing in our hands reliable electrophysiological data [41]. The study focused on the Am and IC since these structures have previously been shown to be involved in immune-visceral inputs, independently of the afferent route involved [36,[42][43][44], and because lesion experiments documented the relevance of these two structures during processing immune signals employed as unconditioned stimuli [45][46][47]. Furthermore, in independent experiments, changes in body temperature and circulating cytokine profiles were monitored to further evaluate the immune reactivity under the various experimental conditions.…”

Placebo mechanisms across different conditions: from the clinical setting to physical performance

“…For instance, both in multiple sclerosis patients [55] and in healthy subjects [56], immunosuppression after placebo could be induced after conditioning with immunosuppressive drugs, possibly by calcineurin inhibition [57]. In an attempt to elucidate the nervous structures involved in central processing of conditioned immunosuppression, Pacheco-López et al [58] carried out selective excitotoxic lesions of rat brain, highlighting a role for the amygdala and the insular cortex in the acquisition phase, and for the insular cortex and the ventromedial nucleus of the hypothalamus in the evocation phase. All these data should be interpreted in the light of psychoneuroimmunological research, where recent findings have identified neural circuits that operate reflexively, with an afferent branch bringing to the central nervous system (CNS) information about injury and infection, and an efferent branch operating through cholinergic and catecholaminergic output in the autonomic nervous system, the most prominent example being perhaps the cholinergic anti-inflammatory pathway.…”