During acute infection, animals display a set of highly stereotyped symptoms which are critical for survival. These symptoms include changes in physiology, such as fever, as well as behavioral changes such as lethargy and loss of appetite. How do sickness symptoms arise? The generation of fever in response to infection has been reported in warm-blooded animals as well as cold-blooded reptiles and even invertebrates, suggesting that evolutionarily conserved, hard-wired mechanisms exist to bring about fever during an immune response. Changes to thermoregulatory and other homeostatic circuits in the brain are likely required to generate sickness symptoms, but the mechanisms by which immune signals are translated into the brain and into neuronal activity to alter these circuits are currently unknown. I have identified a population of neurons in the preoptic area of the hypothalamus that is highly sensitive to the administration of pro-inflammatory lipopolysaccharides (LPS). In my preliminary experiments, I have found that these neurons are critical for the initiation of fever and they may also contribute to other sickness symptoms such as warmth-seeking behavior and loss of appetite. In work proposed here I will rigorously test the function of this LPS-sensitive neuronal population using the latest tools for behavior- specific cell type manipulation. I will uncover how these neurons regulate fever as well as other sickness symptoms. In addition, I will use viral-mediated tracing tools to uncover the circuit mechanism by which these LPS-sensitive neurons modulate thermoregulatory and feeding circuits. The successful completion of these aims will reveal the first discovered neural circuits that mediate sickness. Many studies have found increased activation of glial cell types in response to LPS or infection, which may be essential for the activation of fever-initiating circuits. In my final aim, I will use the latest technology for molecular cell type identification to uncover the identity of the neurons as well as the subtypes of non-neuronal populations in the preoptic hypothalamus that contribute to the fever response. During my R00 phase, I will identify the non- neuronal populations that are essential for fever initiation and reveal new molecular mechanisms by which these cell types communicate with neurons and thereby generate a fever. The successful completion of this project will provide a platform for future experiments aimed at understanding the cellular and molecular mechanisms underlying the generation of sickness symptoms. The training phase of the award will be conducted in the laboratory of Dr. Catherine Dulac at Harvard University. In addition, I will be mentored by the outstanding team of scientists on my advisory committee that will assist with specific training goals as well as career guidance. In my application I have outlined a comprehensive plan for the acquisition of conceptual, technical and professional skills that will enable my transition to an independent research position.
The changes in brain circuit activity required to generate sickness symptoms are critical for survival during acute infection. Moreover, a greater understanding of sickness-related changes in brain activity will likely inform upon chronic disease states that are characterized by miscommunication or overactivation of immune signals in the brain such as depression, Alzheimer?s disease, Parkinson?s disease and epilepsy. Thus, uncovering the cell types and brain circuits activated during sickness is critical to understanding brain function in normal and pathological contexts.
