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An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger

Nature volume 507, pages 238–242 (2014)Cite this article

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Abstract

Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake1,2,3,4,5. Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding3,6,7. Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity8,9,10. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.

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Figure 1: Mapping and evaluating connectivity of inputs to AgRPARC neurons.
Figure 2: TRHPVH and PACAPPVH neurons provide excitatory input to AgRP neurons.
Figure 3: Fidelity of TRHPVH/PACAPPVH→ARC and AgRPARC→PVH circuitry.
Figure 4: DREADD-mediated manipulation of TRHPVH or PACAPPVH neurons mediates feeding through AgRP neurons.

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Acknowledgements

This research was funded by the following NIH grants to B.B.L.: R01 DK096010, R01 DK089044, R01 DK071051, R01 DK075632, R37 DK053477, BNORC Transgenic Core P30 DK046200 and BADERC Transgenic Core P30 DK57521; to M.J.K.: F32 DK089710; to D.P.O.: K08 DK071561; to L.V.: F32 DK078478; to N.U.: R01 MH095953; and an ADA Mentor-Based Fellowship to B.P.S. and B.B.L. We thank D. Cusher and Y. Li for mouse genotyping, J. Carroll and Y. Guo for perfusions and tissue removal, B. L. Roth and S. C. Rogan for generating the AAV-DIO-hM3Dq-mCherry plasmid, K. Deisseroth for generating the AAV-DIO-ChR2-mCherry plasmid and A. N. Hollenberg for the TRH riboprobe.

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Author notes

  1. Michael J. Krashes, Bhavik P. Shah, David P. Olson & Linh Vong

    Present address: Present addresses: Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA (M.J.K.); National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA (M.J.K.); Cardiovascular and Metabolic Diseases, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, USA (B.P.S.); Division of Pediatric Endocrinology, Departments of Pediatrics, University of Michigan, Ann Arbor, Michigan 48105, USA (D.P.O.); Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, Massachusetts 02139, USA (L.V.).,

  2. Michael J. Krashes and Bhavik P. Shah: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Endocrinology, Department of Medicine, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Michael J. Krashes, Bhavik P. Shah, Joseph C. Madara, David P. Olson, Alastair S. Garfield, Linh Vong & Bradford B. Lowell

  2. Department of Cell Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    David E. Strochlic & Stephen D. Liberles

  3. Program in Neuroscience, Harvard Medical School, Boston, 02115, Massachusetts, USA

    David E. Strochlic, Naoshige Uchida, Stephen D. Liberles & Bradford B. Lowell

  4. Center for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK,

    Alastair S. Garfield

  5. Division of Pediatric Endocrinology, Departments of Pediatrics, University of Michigan, Ann Arbor, 48105, Michigan, USA

    Hongjuan Pei

  6. Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, 16 Divinity Avenue, Cambridge, Massachusetts 02138, USA,

    Mitsuko Watabe-Uchida & Naoshige Uchida

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Contributions

M.J.K., B.P.S. and B.B.L. designed the experiments and analysed data. M.J.K., B.P.S., J.C.M., D.E.S., A.S.G., L.V. and H.P. performed experiments. M.J.K. generated Pdyn-IRES-Cre, Trh-IRES-Cre and Pacap-IRES-Cre mice, D.P.O. generated Oxt-IRES-Cre, Avp-IRES-Cre, Crh-IRES-Cre and R26-loxSTOPlox-L10-GFP mice and L.V. generated Vglut2-IRES-Cre mice. M.W.-U. and N.U. generated, provided and advised on use of AAV-FLEX-TVA-mCherry, AAV-FLEX-RG and SADΔG–EGFP (EnvA) viruses. S.D.L. advised on in situ hybridization experiments. M.J.K and B.B.L. wrote the manuscript with comments from all of the authors.

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Correspondence to Bradford B. Lowell.

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Krashes, M., Shah, B., Madara, J. et al. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507, 238–242 (2014). https://doi.org/10.1038/nature12956

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