Neural control of sickness physiology

Abstract: Infections induce a set of conserved, pleiotropic responses in animals, including anorexia, adipsia, lethargy and changes in temperature, collectively termed sickness behaviors. While studies have shown that aspects of these responses are adaptive and aid animals in surviving infection, we have a poor understanding of the underlying neural mechanisms. We aimed to identify neural substrates of this sickness response using lipopolysaccharide (LPS) induced sickness, which caused dose-dependent decreases in food consumption, water intake, and locomotor activity, as well as changes in thermoregulation. Whole-brain activity mapping revealed significant increases in FOS expression in several regions early on, with a rapid, high level of activation in the Nucleus Tractus Solitarii/Area Postrema (NTS/AP). Using the TRAP2 system, we reactivated neurons previously activated by LPS. The TRAP2 system links the expression of tamoxifen-inducible Cre recombinase to fos induction in neurons, enabling the subsequent expression of genes of interest in "TRAPed" neurons. Reactivating NTS/AP neurons replicated the effects of LPS on food and water intake and locomotion, while inhibiting these neurons reduced all three effects of LPS. We then performed single-nucleus RNA sequencing (snRNA-seq) of the NTS/AP at baseline and of neurons that had been "TRAPed" to identify LPS-activated neuronal types in these regions. Several different LPS-activated populations were identified, and subsequent functional tests showed that activation of each population reduced feeding, drinking, and locomotion to varying degrees, with different effects on temperature. However, only inhibition of an NTS/AP neural population expressing Adcyap1 reduced the response to LPS, while inhibiting other populations had no effect. These findings indicate that various behavioral components of the LPS-induced sickness response are mediated by a subpopulation of NTS/APAdcyap1+ neurons. Subsequent studies are now focusing on how additional populations activated in the brain during infection-induced sickness control changes in autonomic and metabolic function during this state.

Bio: Dr. Ilanges is a group leader at HHMI’s Janelia Research Campus. Anoj Ilanges studies the role of the nervous system in coordinating changes in behavior, autonomic function, and metabolism during shifts in physiological states. Our bodies maintain our physiology within a narrow range, but they can also drastically change our physiology in response to both external and internal stimuli. These physiological state changes can be transient (for minutes or hours) or can last for much longer (on the order of days or weeks). Ilanges and his team use a combination of molecular profiling, cellular imaging, functional manipulations, and organism-level phenotyping in mice and zebrafish to interrogate the mechanisms driving dramatic, adaptive states such as the sickness state during our body’s response to infection.

Lab's webpage: https://www.janelia.org/lab/ilanges-lab

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