The loss of appetite (anorexia) associated with eating too much, food poisoning, and nausea is mediated by a neural circuit that starts with activation of vagal afferents, which activate brain stem nuclei and then neurons that express calcitonin-gene-related protein (CGRP) in the parabrachial nucleus (PBN). Transient activation of these CGRPPBN neurons by chemogenetic or optogenetic means is sufficient to inhibit feeding and to induce conditioned taste aversion, the phenomenon by which animals learn to avoid foods that make them sick. Chronic activation of CGRPPBN neurons by various genetic manipulations can result in starvation. Chronic activation of these neurons, as occurs during illnesses such as cancer, promotes anorexia. The CGRPPBN neurons project their axons to forebrain structures, including the central nucleus of the amygdala (CeA). Photoactivation of CGRPPBN axon terminals expressing channelrhodopsin in the CeA also inhibits feeding. This grant proposes to establish the molecular identity of the neurons in the CeA (and possibly other brain regions) that mediate anorexia and then extend the neural circuit by molecular characterization of the neurons that are downstream of the CeA neurons. Thus, this research will extend the ?anorexia neural circuit? by at least two nodes. The molecular profile will be determined by quantification of all mRNAs being translated by the neurons at each of these nodes. That information will provide valuable clues for extending the neural circuit and devising therapeutic solutions to anorexia caused by chronic illness. The results of these experiments will also provide a blueprint for understanding how memories of food-related illness and nausea are established.

Public Health Relevance

Hungry animals will not eat if they are ill, nauseous, dizzy, in pain, or dehydrated or given an unbalanced diet. Previous experiments have elucidated the beginning of a neural circuit that mediates anorexia under these conditions. That circuit begins with vagal and spinal afferents to the parabrachial nucleus and from there to the central nucleus of the amygdala. This proposal aims to use contemporary genetic and viral techniques to extend that neural circuit beyond the amygdala and determine the molecular profile of neurons in the circuit with the aim of identifying potential therapeutic targets.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Berton, Olivier Roland
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University of Washington
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