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
Wu, Qi; Zheng, Ruimao; Srisai, Dollada et al. (2013) NR2B subunit of the NMDA glutamate receptor regulates appetite in the parabrachial nucleus. Proc Natl Acad Sci U S A 110:14765-70
Whiddon, Benjamin B; Palmiter, Richard D (2013) Ablation of neurons expressing melanin-concentrating hormone (MCH) in adult mice improves glucose tolerance independent of MCH signaling. J Neurosci 33:2009-16
Carter, Matthew E; Soden, Marta E; Zweifel, Larry S et al. (2013) Genetic identification of a neural circuit that suppresses appetite. Nature 503:111-4
Wu, Qi; Whiddon, Benjamin B; Palmiter, Richard D (2012) Ablation of neurons expressing agouti-related protein, but not melanin concentrating hormone, in leptin-deficient mice restores metabolic functions and fertility. Proc Natl Acad Sci U S A 109:3155-60
Wu, Qi; Clark, Michael S; Palmiter, Richard D (2012) Deciphering a neuronal circuit that mediates appetite. Nature 483:594-7
Wu, Qi; Palmiter, Richard D (2011) GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism. Eur J Pharmacol 660:21-7
Parker, Jones G; Wanat, Matthew J; Soden, Marta E et al. (2011) Attenuating GABA(A) receptor signaling in dopamine neurons selectively enhances reward learning and alters risk preference in mice. J Neurosci 31:17103-12
Wu, Qi; Boyle, Maureen P; Palmiter, Richard D (2009) Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137:1225-34
Wu, Qi; Howell, Maureen P; Palmiter, Richard D (2008) Ablation of neurons expressing agouti-related protein activates fos and gliosis in postsynaptic target regions. J Neurosci 28:9218-26
Wu, Qi; Howell, Maureen P; Cowley, Michael A et al. (2008) Starvation after AgRP neuron ablation is independent of melanocortin signaling. Proc Natl Acad Sci U S A 105:2687-92