Upon infection, bacterial compounds, and the pro-inflammatory cytokines they elicit, induce a complex response coordinated by the brain and known as “sickness behavior”. This response induces stereotyped behavioral changes (reduced locomotion and food intake, social avoidance), metabolic adjustments (fever, glycemia), and autonomic/neuroendocrine responses in ways that increase resistance to infection but also regulate immune responses to prevent runaway responses. Such ability of the brain to regulate immune response provides an interesting framework to understand how dedicated neuronal circuits makes senses of internal immune stimuli and turns this perception into a concerted action. In this talk, I will present our recent progress to better understand the nature of the peripheral immune signals perceived by the brain and highlight a new brainstem-to-hypothalamus circuit capable of regulating systemic immune responses. Aside this homeostatic neuro-immune regulation, I will also show how pathological deregulated inflammation can have a long-lasting impact on specific brain circuits and can lead to the development of persistent anxious-depressive symptoms.