Loss of GABAergic Signaling by AgRP Neurons to the Parabrachial Nucleus Leads to Starvation

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2009 Jul 1

PMID 19563755

Citations 261

Authors

Qi Wu

Maureen P Boyle

Richard D Palmiter

Affiliations

Soon will be listed here.

Abstract

Neurons in the arcuate nucleus that produce AgRP, NPY, and GABA (AgRP neurons) promote feeding. Ablation of AgRP neurons in adult mice results in Fos activation in postsynaptic neurons and starvation. Loss of GABA is implicated in starvation because chronic subcutaneous delivery of bretazenil (a GABA(A) receptor partial agonist) suppresses Fos activation and maintains feeding during ablation of AgRP neurons. Moreover, under these conditions, direct delivery of bretazenil into the parabrachial nucleus (PBN), a direct target of AgRP neurons that also relays gustatory and visceral sensory information, is sufficient to maintain feeding. Conversely, inactivation of GABA biosynthesis in the ARC or blockade of GABA(A) receptors in the PBN of mice promote anorexia. We suggest that activation of the PBN by AgRP neuron ablation or gastrointestinal malaise inhibits feeding. Chronic delivery of bretazenil during loss of AgRP neurons provides time to establish compensatory mechanisms that eventually allow mice to eat.

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References

Hentges S, Nishiyama M, Overstreet L, Stenzel-Poore M, Williams J, Low M . GABA release from proopiomelanocortin neurons. J Neurosci. 2004; 24(7):1578-83. PMC: 6730447. DOI: 10.1523/JNEUROSCI.3952-03.2004. View

Reilly S, Trifunovic R . Lateral parabrachial nucleus lesions in the rat: aversive and appetitive gustatory conditioning. Brain Res Bull. 2000; 52(4):269-78. DOI: 10.1016/s0361-9230(00)00263-x. View

Haskell-Luevano C, Chen P, Li C, Chang K, Smith M, Cameron J . Characterization of the neuroanatomical distribution of agouti-related protein immunoreactivity in the rhesus monkey and the rat. Endocrinology. 1999; 140(3):1408-15. DOI: 10.1210/endo.140.3.6544. View

Wilson J, Nicklous D, Aloyo V, Simansky K . An orexigenic role for mu-opioid receptors in the lateral parabrachial nucleus. Am J Physiol Regul Integr Comp Physiol. 2003; 285(5):R1055-65. DOI: 10.1152/ajpregu.00108.2003. View

DiPatrizio N, Simansky K . Activating parabrachial cannabinoid CB1 receptors selectively stimulates feeding of palatable foods in rats. J Neurosci. 2008; 28(39):9702-9. PMC: 2725524. DOI: 10.1523/JNEUROSCI.1171-08.2008. View

Rinaman L, Dzmura V . Experimental dissociation of neural circuits underlying conditioned avoidance and hypophagic responses to lithium chloride. Am J Physiol Regul Integr Comp Physiol. 2007; 293(4):R1495-503. DOI: 10.1152/ajpregu.00393.2007. View

Wu Q, Howell M, Palmiter R . Ablation of neurons expressing agouti-related protein activates fos and gliosis in postsynaptic target regions. J Neurosci. 2008; 28(37):9218-26. PMC: 2597113. DOI: 10.1523/JNEUROSCI.2449-08.2008. View

Morton G, Cummings D, Baskin D, Barsh G, Schwartz M . Central nervous system control of food intake and body weight. Nature. 2006; 443(7109):289-95. DOI: 10.1038/nature05026. View

Andre V, Dube C, Francois J, Leroy C, Rigoulot M, Roch C . Pathogenesis and pharmacology of epilepsy in the lithium-pilocarpine model. Epilepsia. 2007; 48 Suppl 5:41-7. DOI: 10.1111/j.1528-1167.2007.01288.x. View

10.

Pecknold J . Discontinuation reactions to alprazolam in panic disorder. J Psychiatr Res. 1993; 27 Suppl 1:155-70. DOI: 10.1016/0022-3956(93)90025-w. View

11.

Jacobowitz D, ODonohue T . alpha-Melanocyte stimulating hormone: immunohistochemical identification and mapping in neurons of rat brain. Proc Natl Acad Sci U S A. 1978; 75(12):6300-4. PMC: 393169. DOI: 10.1073/pnas.75.12.6300. View

12.

Lein E, Hawrylycz M, Ao N, Ayres M, Bensinger A, Bernard A . Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2006; 445(7124):168-76. DOI: 10.1038/nature05453. View

13.

Broberger C, Hokfelt T . Hypothalamic and vagal neuropeptide circuitries regulating food intake. Physiol Behav. 2002; 74(4-5):669-82. DOI: 10.1016/s0031-9384(01)00611-4. View

14.

Chattopadhyaya B, Di Cristo G, Wu C, Knott G, Kuhlman S, Fu Y . GAD67-mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex. Neuron. 2007; 54(6):889-903. PMC: 2077924. DOI: 10.1016/j.neuron.2007.05.015. View

15.

Kash S, Johnson R, Tecott L, Noebels J, Mayfield R, Hanahan D . Epilepsy in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci U S A. 1998; 94(25):14060-5. PMC: 28432. DOI: 10.1073/pnas.94.25.14060. View

16.

Tong Q, Ye C, Jones J, Elmquist J, Lowell B . Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci. 2009; 11(9):998-1000. PMC: 2662585. DOI: 10.1038/nn.2167. View

17.

Luquet S, Perez F, Hnasko T, Palmiter R . NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science. 2005; 310(5748):683-5. DOI: 10.1126/science.1115524. View

18.

Erickson J, Clegg K, Palmiter R . Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature. 1996; 381(6581):415-21. DOI: 10.1038/381415a0. View

19.

Flier J . AgRP in energy balance: Will the real AgRP please stand up?. Cell Metab. 2006; 3(2):83-5. DOI: 10.1016/j.cmet.2006.01.003. View

20.

Cone R . Anatomy and regulation of the central melanocortin system. Nat Neurosci. 2005; 8(5):571-8. DOI: 10.1038/nn1455. View