Neural and humoral pathways of communication from the immune system to thebrain: parallel or convergent?

The first studies carried out on the mechanisms by which peripheral immune stimuli signal the brain to induce fever, activation of the hypothalamic-pi tuitary-adrenal axis and sickness behavior emphasized the importance of fen estrated parts of the blood-brain barrier known as circumventricular organs for allowing blood-borne proinflammatory cytokines to act on brain functio ns. The discovery in the mid-1990s that subdiaphragmatic section of the vag us nerves attenuates the brain effects of systemic cytokines, together with the demonstration of an inducible brain cytokine compartment shifted the a ttention from circumventricular organs to neural pathways in the transmissi on of the immune message to the brain. Since then, neuroanatomical studies have confirmed the existence of a fast route of communication from the immu ne system to the brain via the vagus nerves. This neural pathway is complem ented by a humoral pathway that involves cytokines produced at the level of the circumventricular organs and the choroid plexus and at the origin of a second wave of cytokines produced in the brain parenchyma. Depending on th eir source, these locally produced cytokines can either activate neurons th at project to specific brain areas or diffuse by volume transmission into t he brain parenchyma to reach their targets. Activation of neurons by cytoki nes can be direct or indirect, via prostaglandins. The way the neural pathw ay of transmission interacts with the humoral pathway remains to be elucida ted. (C) 2000 Elsevier Science B.V. All rights reserved.