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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA024908-10
Application #
9381648
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Berton, Olivier Roland
Project Start
2007-09-25
Project End
2022-05-31
Budget Start
2017-07-01
Budget End
2018-05-31
Support Year
10
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Palmiter, Richard D (2018) The Parabrachial Nucleus: CGRP Neurons Function as a General Alarm. Trends Neurosci 41:280-293
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Campos, Carlos A; Bowen, Anna J; Roman, Carolyn W et al. (2018) Encoding of danger by parabrachial CGRP neurons. Nature 555:617-622
Ryan, Philip J; Ross, Silvano I; Campos, Carlos A et al. (2017) Oxytocin-receptor-expressing neurons in the parabrachial nucleus regulate fluid intake. Nat Neurosci 20:1722-1733
Padilla, Stephanie L; Qiu, Jian; Nestor, Casey C et al. (2017) AgRP to Kiss1 neuron signaling links nutritional state and fertility. Proc Natl Acad Sci U S A 114:2413-2418
Roman, Carolyn W; Sloat, Stephanie R; Palmiter, Richard D (2017) A tale of two circuits: CCKNTS neuron stimulation controls appetite and induces opposing motivational states by projections to distinct brain regions. Neuroscience 358:316-324
Campos, Carlos A; Bowen, Anna J; Han, Sung et al. (2017) Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus. Nat Neurosci 20:934-942
Meng, Fantao; Han, Yong; Srisai, Dollada et al. (2016) New inducible genetic method reveals critical roles of GABA in the control of feeding and metabolism. Proc Natl Acad Sci U S A 113:3645-50

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