We are pursuing the striking observation that ablation of hypothalamic AgRP neurons in adult, but not neonatal, mice results in severe anorexia. We discovered that the anorexia is due to sudden loss of GABA signaling by AgRP neurons to the parabrachial nucleus (PBN) by showing that the lethal anorexia can be prevented by chronic infusion of a benzodiazepine GABAA receptor agonist into the PBN, but not other nuclei. We hypothesize that balanced input to the PBN maintains normal feeding and that excessive activity of the PBN (e.g. due to loss of GABA) results in anorexia. We propose to identify the source of the excitation to the PBN, as well as the neurotransmitter(s) and receptor(s) involved using pharmacological and genetic tools. We also propose to discover a gene that is specifically expressed in the critical PBN neurons that mediate anorexia, and then target Cre recombinase to that gene, which would greatly facilitate further genetic, tracing and electrophysiological studies. Our experiments indicate that mice can adapt to loss of AgRP neurons and resume normal eating, when chronically treated with a GABAA agonist (bretazenil) a 5HT3 antagonist (ondansetron), LiCl or exposed to a high-fat diet. We will explore the hypothesis that these treatments lead to adaptations in neuronal inputs or outputs of the PBN, or plasticity within the relevant PBN neurons themselves. We anticipate that these experiments will delineate a neural circuit that is important for maintenance of normal feeding behavior. We have established powerful pharmacological and genetic techniques that will allow us to identify the critical neurotransmitters and receptors that are used by neurons within that circuit. Our ultimate goals are to understand how this circuit adapts to changing environmental conditions and identify the molecular and cellular changes involved. This research is relevant to a better understanding normal and addictive feeding behavior, neuronal plasticity, and diseases such as anorexia nervosa.

Public Health Relevance

The major goal of this proposal is to decipher the neural circuitry controlling anorexia. We aim to discover the neurotransmitters and receptors involved in this circuit, identify molecular markers for the relevant neurons, and learn how the circuit adapts to changes in environment, for example, consumption of a high-fat diet. We anticipate that understanding this circuit will provide insight to how the brain integrates taste and palatability of food with visceral signals and energy balance.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA024908-07
Application #
8636000
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Pilotte, Nancy S
Project Start
2007-09-25
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
7
Fiscal Year
2014
Total Cost
$278,100
Indirect Cost
$98,100
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
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
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
Campos, Carlos A; Bowen, Anna J; Schwartz, Michael W et al. (2016) Parabrachial CGRP Neurons Control Meal Termination. Cell Metab 23:811-20
Roman, Carolyn W; Derkach, Victor A; Palmiter, Richard D (2016) Genetically and functionally defined NTS to PBN brain circuits mediating anorexia. Nat Commun 7:11905
Padilla, Stephanie L; Qiu, Jian; Soden, Marta E et al. (2016) Agouti-related peptide neural circuits mediate adaptive behaviors in the starved state. Nat Neurosci 19:734-741
Carter, Matthew E; Han, Sung; Palmiter, Richard D (2015) Parabrachial calcitonin gene-related peptide neurons mediate conditioned taste aversion. J Neurosci 35:4582-6
Han, Sung; Soleiman, Matthew T; Soden, Marta E et al. (2015) Elucidating an Affective Pain Circuit that Creates a Threat Memory. Cell 162:363-374
Sanz, Elisenda; Quintana, Albert; Deem, Jennifer D et al. (2015) Fertility-regulating Kiss1 neurons arise from hypothalamic POMC-expressing progenitors. J Neurosci 35:5549-56

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