Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY ABSTRACT During an infection, animals exhibit adaptive changes in behavior and physiology aimed at increasing survival. Although many causes of acute infection exist, a similar set of stereotyped symptoms occur, which includes increased body temperature or fever, decreased appetite and increased lethargy. Both warm- and cold-blooded animals generate a fever in response infection suggesting that fever circuits are hard-wired and highly conserved, yet exactly how the nervous system alters body temperature and associated behavior in response to infection remains unknown. We have identified a population of neurons in the preoptic area of the hypothalamus that are highly activated following administration of inflammatory lipopolysaccharides (LPS). Due to the close proximity between the organum vasculosum of the laminae terminalis (OVLT), where inflammatory cytokines enter the brain to affect nearby cells, and neurons of the preotpic area regulating normal body temperature, and our preliminary data, we propose that these newly identified LPS-sensitive neurons control fever initiation during an immune response. We will use chemogenetic activation and cell ablation approaches to demonstrate that this population plays a role in increasing body temperature and in affecting other fever-associated behaviors upon LPS injection. Further, we have recently developed new approaches for molecular characterization of genetically defined cell populations in situ using single-cell RNA sequencing (scRNA-seq) and multiplex, error-robust, fluorescent in situ hybridization (MERFISH) to generate a spatially-resolved and functionally-aware atlas of the preoptic area. We will apply a similar strategy to characterize fever-inducing neurons as well as surrounding non- neuronal cell types that are likely to play a role in fever generation through paracrine mechanisms. Finally, we propose to use viral-mediated tracing and functional tools to determine the direct and indirect circuit mechanisms by which LPS-sensitive neurons and their targets exert control over body temperature and fever-related behaviors. Our data will lead to a molecular and functional characterization of LPS-sensitive neurons in the preoptic area and to a better understanding of how inflammatory sickness symptoms, such as fever and related behavioral changes, are regulated in the brain. These efforts have direct implications for understanding the mechanisms underlying human sickness, and may inform new therapeutic strategies for the treatment of fever and associated symptoms.
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