This system enables the simultaneous real-time measurement of food intake, water intake and movement in an automated and continuous manner with high resolution. The lethal dose of LPS is about 10 mg kg −1, and we tested the effects of a single intraperitoneal (i.p.) injection of three lower doses of LPS (0.1 mg kg −1, 0.5 mg kg −1 and 2.5 mg kg −1) on each of the components of sickness behaviour using a custom home-cage system that we developed (Extended Data Fig. We thus used LPS to study sickness behaviour and established a dose–response relationship for each of its behavioural effects over time. The use of LPS also enables one to control for variability in individual animal responses to an infection while also dissociating host responses from pathogen-induced effects that damage and alter organ function 16. We studied the sickness responses using LPS, which yields a more consistent response than does bacterial infection. Sickness behaviour can be induced by bacterial infections or endotoxin treatment, and the qualitative response to each is indistinguishable 15. These studies thus identify a critical node linking the immune response to a series of adaptive responses coordinated by the brain. Here we report that multiple different responses to LPS can be mapped to a core population in the sensory dorsal vagal complex of the brainstem expressing the neuropeptide ADCYAP1. However, although bacteria, endotoxins and the cytokines they induce can elicit aspects of the sickness response 9, 10, 11, 12, the neural substrate for the behavioural and autonomic effects of infection has not been elucidated 13, 14, nor is it clear whether one or more neuronal populations are required for different aspects of the response. Moreover, forced feeding of animals 4, 6, 7 or changing the thermal environment 8 after bacterial infection or treatment with LPS increases mortality, showing that these responses are part of a coordinated adaptive response. Thus, animals infected with pathogens, or their components such as LPS, develop anorexia, adipsia and lethargy, and also show altered thermoregulation. The response to infectious agents is not limited to immune cells but also includes a coordinated set of responses collectively known as sickness behaviour 1, 2, 3. Mechanisms that enable animals to survive an infection are thus under intense selective pressure 5. Infections are an omnipresent threat to all species, and effective adaptive responses are essential for survival. Together these studies map the pleiotropic effects of LPS to a neural population that is both necessary and sufficient for canonical elements of the sickness response, thus establishing a critical link between the brain and the response to infection. Furthermore, inhibition of these neurons significantly diminished the anorexia, adipsia and locomotor cessation seen after LPS injection. Single-nucleus RNA sequencing of the NTS–AP was used to identify LPS-activated neural populations, and we found that activation of ADCYAP1 + neurons in the NTS–AP fully recapitulates the responses elicited by LPS. In addition, inhibition of LPS-activated neurons diminished all of the behavioural responses to LPS. Whole-brain activity mapping revealed that subsets of neurons in the nucleus of the solitary tract (NTS) and the area postrema (AP) acutely express FOS after LPS treatment, and we found that subsequent reactivation of these specific neurons in FOS 2A-iCreERT2 (also known as TRAP2) mice replicates the behavioural and thermal component of sickness. Here we use of a set of unbiased methodologies to show that a specific subpopulation of neurons in the brainstem can control the diverse responses to a bacterial endotoxin (lipopolysaccharide (LPS)) that potently induces sickness behaviour. Although these responses have been shown to be adaptive, the underlying neural mechanisms have not been elucidated 2, 3, 4. Infections induce a set of pleiotropic responses in animals, including anorexia, adipsia, lethargy and changes in temperature, collectively termed sickness behaviours 1.
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