Brain signaling is a crucial event for the body to mount an appropriate response to invading microorganisms. Pro-inflammatory cytokines are released from infected tissues and reach key structures in the brain via the circumventricular organs, areas of damaged blood brain barrier or they cross actively the blood brain barrier using specific carriers. Alternately, cytokines may activate brain endothelial cells or microglial to produce prostaglandins which then diffuse into the brain to activate neurons. Finally, cytokines may activate the autonomic nervous system at the periphery. The following crosstalk between astrocytes and microglial precedes neuronal activation particularly within the hippocampus, amygdale and hypothalamus. The resulting release of neuro-hormones in the systemic circulation allows restoration of homeostasis. It is likely that an excess in nitric oxide and complement anaphylatoxin C5a contributes to DNA damage within neurons of the hippocampus and hypothalamus and subsequent brain dysfunction.