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AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors

Nature Neuroscience volume 15, pages 1108–1110 (2012)Cite this article

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Abstract

It is not known whether behaviors unrelated to feeding are affected by hypothalamic regulators of hunger. We found that impairment of Agouti-related protein (AgRP) circuitry by either Sirt1 knockdown in AgRP-expressing neurons or early postnatal ablation of these neurons increased exploratory behavior and enhanced responses to cocaine. In AgRP circuit–impaired mice, ventral tegmental dopamine neurons exhibited enhanced spike timing–dependent long-term potentiation, altered amplitude of miniature postsynaptic currents and elevated dopamine in basal forebrain. Thus, AgRP neurons determine the set point of the reward circuitry and associated behaviors.

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Figure 1: AgRP neurons determine the behavioral response to novelty and cocaine.
Figure 2: AgRP neuronal excitability determines connectivity of VTA dopamine neurons.
Figure 3: AgRP neurons influence the development of VTA dopamine neurons and behavioral responses.

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Acknowledgements

We thank L. Kus from the GENSTAT Project, which provided important information on the AgRP-EGFP mouse (MT25), A. Xu for providing breeding pairs of AgRP-Cre mice (University of California San Francisco), R. Palmiter for providing breeding pairs of the AgRP-DTR mice (University of Washington), and the personnel of the Horvath laboratory for support. This work was supported by a US National Institutes of Health Director's Pioneer Award to T.L.H. I.A. was supported by National Institute on Deafness and Other Communication Disorders (US National Institutes of Health) grants. D.O.S. was supported by grants from Financiadora de Estudos e Projetos/Ministério de Ciência e Tecnologia (FINEP/MCT, Brazil) and Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (Brazil). M.O.D. was partially supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil).

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Authors and Affiliations

  1. Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Marcelo O Dietrich, Jeremy Bober, Xiao-Bing Gao, Zhong-Wu Liu & Tamas L Horvath

  2. Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Marcelo O Dietrich & Diogo O Souza

  3. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

    Jozélia G Ferreira, Luis A Tellez, Yann S Mineur, Marina R Picciotto & Ivan Araújo

  4. The John B. Pierce Laboratory, New Haven, Connecticut, USA

    Jozélia G Ferreira, Luis A Tellez & Ivan Araújo

  5. Departments of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA

    Tamas L Horvath

  6. Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Tamas L Horvath

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  1. Marcelo O Dietrich
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Contributions

M.O.D. designed, executed, collected and analyzed all of the data (except for the electrophysiology experiments). Z.-W.L. designed, executed and analyzed the electrophysiology experiments. J.B. help to design and execute the experiments that involved dopamine measurements and immunohistochemistry, and aided with animal maintenance and genotyping. Y.M. helped with the CPP experiment. M.P. helped to design and discussed the experiments and results of the cocaine experiments. J.G.F. and L.A.T. helped with the microdialysis experiment. I.A. designed, discussed and helped analyze the dopamine measurement experiment. D.O.S. helped to design and discussed the behavioral experiments. X.-B.G. helped to design and analyze the electrophysiology experiments. T.L.H. designed and analyzed all of the experiments. M.O.D. and T.L.H. wrote the manuscript.

Corresponding author

Correspondence to Tamas L Horvath.

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The authors declare no competing financial interests.

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Supplementary Figures 1–8 and Supplementary Tables 1 and 2 (PDF 1839 kb)

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Dietrich, M., Bober, J., Ferreira, J. et al. AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors. Nat Neurosci 15, 1108–1110 (2012). https://doi.org/10.1038/nn.3147

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