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Abstract
The first studies carried out on the mechanisms by which peripheral immune stimuli
signal the brain to induce fever, activation of the hypothalamic-pituitary-adrenal
axis and sickness behavior emphasized the importance of fenestrated parts of the blood-brain
barrier known as circumventricular organs for allowing blood-borne proinflammatory
cytokines to act on brain functions. The discovery in the mid-1990s that subdiaphragmatic
section of the vagus nerves attenuates the brain effects of systemic cytokines, together
with the demonstration of an inducible brain cytokine compartment shifted the attention
from circumventricular organs to neural pathways in the transmission of the immune
message to the brain. Since then, neuroanatomical studies have confirmed the existence
of a fast route of communication from the immune system to the brain via the vagus
nerves. This neural pathway is complemented 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 their source, these locally produced cytokines can either activate neurons that
project to specific brain areas or diffuse by volume transmission into the brain parenchyma
to reach their targets. Activation of neurons by cytokines can be direct or indirect,
via prostaglandins. The way the neural pathway of transmission interacts with the
humoral pathway remains to be elucidated.