NEURAL CIRCUITRY OF CYTOKINE-INDUCED ANOREXIA

Salk Institute For Biological Studies, La Jolla CA

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Abstract

Loss of appetite is a significant obstacle in the treatment of chronic illnesses, including certain cancers and HIV infection. Pro-inflammatory cytokines released from activated immune cells are prime candidates for mediating this anorexia, yet a complete understanding of the neural pathways and mechanisms involved in this response remains elusive. The overall goal of this proposal is to explore the functional organization of neural circuits that underlie IL-1-induced anorexia. Interleukin-1 (IL-1), a cytokine which can potently inhibit feeding, will be used to model an acute infectious/inflammatory event. The arcuate nucleus (ARC) of the hypothalamus can be accessed directly by circulating macromolecules, expresses IL-1- receptors, and houses peptidergic neurons strongly implicated in the control of feeding. Correlated behavioral (feeding) and functional neuroanatomical (induced patterns of immediate-early gene expression) assays will be used to test a role of IL-1-sensitive ARC neurons in IL-1-induced anorexia. First, a discrete lesioning method will be used to test if the ARC plays a prominent and specific role in IL-1 mediated inhibition of food intake. Next, IL-1 sensitive ARC neurons will be characterized with respect to their expression of IL-1 receptors, and/or neuropeptides implicated in the stimulation and inhibition of appetite. Finally, axonal transport and selective fiber transection methods will be used to identify and characterize behaviorally relevant downstream targets of IL-1-sensitive ARC neurons. Collectively, the proposed studies will serve as a initial step in delineating the circuitry underlying the cytokine-induced feeding inhibitory response.