Movatterモバイル変換

[0]ホーム
URL:

Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Advertisement

Nature Neuroscience
  • Article
  • Published:

AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training

Nature Neurosciencevolume 14, pages351–355 (2011)Cite this article

Subjects

This article has beenupdated

Abstract

Two intermingled hypothalamic neuron populations specified by expression of agouti-related peptide (AGRP) or pro-opiomelanocortin (POMC) positively and negatively influence feeding behavior, respectively, possibly by reciprocally regulating downstream melanocortin receptors. However, the sufficiency of these neurons to control behavior and the relationship of their activity to the magnitude and dynamics of feeding are unknown. To measure this, we used channelrhodopsin-2 for cell type–specific photostimulation. Activation of only 800 AGRP neurons in mice evoked voracious feeding within minutes. The behavioral response increased with photoexcitable neuron number, photostimulation frequency and stimulus duration. Conversely, POMC neuron stimulation reduced food intake and body weight, which required melanocortin receptor signaling. However, AGRP neuron–mediated feeding was not dependent on suppressing this melanocortin pathway, indicating that AGRP neurons directly engage feeding circuits. Furthermore, feeding was evoked selectively over drinking without training or prior photostimulus exposure, which suggests that AGRP neurons serve a dedicated role coordinating this complex behavior.

This is a preview of subscription content,access via your institution

Access options

Access through your institution

Subscription info for Japanese customers

We have a dedicated website for our Japanese customers. Please go tonatureasia.com to subscribe to this journal.

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: AGRP neurons are sufficient to evoke voracious food consumption in well-fed mice.
Figure 2: AGRP neuron–evoked feeding is dependent on the stimulation frequency.
Figure 3: AGRP neuron–evoked feeding is rapidly initiated by stimulus onset and terminated after its offset.
Figure 4: POMC neurons inhibit food intake and body weight through melanocortin receptors.
Figure 5: Evoked feeding does not require melanocortin suppression.

Similar content being viewed by others

Change history

  • 25 February 2011

    In the HTML version of this article initially published online, the date published was given as 5 January 2010. The correct date is 5 January 2011. The error has been corrected for all versions of this article

References

  1. Morton, G.J., Cummings, D.E., Baskin, D.G., Barsh, G.S. & Schwartz, M.W. Central nervous system control of food intake and body weight.Nature443, 289–295 (2006).

    Article CAS  Google Scholar 

  2. Ollmann, M.M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.Science278, 135–138 (1997).

    Article CAS  Google Scholar 

  3. Clark, J.T., Kalra, P.S., Crowley, W.R. & Kalra, S.P. Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats.Endocrinology115, 427–429 (1984).

    Article CAS  Google Scholar 

  4. Levine, A.S. & Morley, J.E. Neuropeptide Y: a potent inducer of consummatory behavior in rats.Peptides5, 1025–1029 (1984).

    Article CAS  Google Scholar 

  5. Stanley, B.G. & Leibowitz, S.F. Neuropeptide Y: stimulation of feeding and drinking by injection into the paraventricular nucleus.Life Sci.35, 2635–2642 (1984).

    Article CAS  Google Scholar 

  6. Takahashi, K.A. & Cone, R.D. Fasting induces a large, leptin-dependent increase in the intrinsic action potential frequency of orexigenic arcuate nucleus neuropeptide Y/Agouti-related protein neurons.Endocrinology146, 1043–1047 (2005).

    Article CAS  Google Scholar 

  7. Tsujii, S. & Bray, G.A. Acetylation alters the feeding response to MSH and beta-endorphin.Brain Res. Bull.23, 165–169 (1989).

    Article CAS  Google Scholar 

  8. Yaswen, L., Diehl, N., Brennan, M.B. & Hochgeschwender, U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin.Nat. Med.5, 1066–1070 (1999).

    Article CAS  Google Scholar 

  9. Cowley, M.A. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus.Nature411, 480–484 (2001).

    CAS  Google Scholar 

  10. Roseberry, A.G., Liu, H., Jackson, A.C., Cai, X. & Friedman, J.M. Neuropeptide Y-mediated inhibition of proopiomelanocortin neurons in the arcuate nucleus shows enhanced desensitization in ob/ob mice.Neuron41, 711–722 (2004).

    Article CAS  Google Scholar 

  11. Cowley, M.A. et al. Electrophysiological actions of peripheral hormones on melanocortin neurons.Ann. NY Acad. Sci.994, 175–186 (2003).

    Article CAS  Google Scholar 

  12. Luquet, S., Perez, F.A., Hnasko, T.S. & Palmiter, R.D. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates.Science310, 683–685 (2005).

    Article CAS  Google Scholar 

  13. Wu, Q., Howell, M.P., Cowley, M.A. & Palmiter, R.D. Starvation after AgRP neuron ablation is independent of melanocortin signaling.Proc. Natl. Acad. Sci. USA105, 2687–2692 (2008).

    Article CAS  Google Scholar 

  14. Wu, Q., Boyle, M.P. & Palmiter, R.D. Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation.Cell137, 1225–1234 (2009).

    Article  Google Scholar 

  15. Boyden, E.S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity.Nat. Neurosci.8, 1263–1268 (2005).

    Article CAS  Google Scholar 

  16. Li, X. et al. Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin.Proc. Natl. Acad. Sci. USA102, 17816–17821 (2005).

    Article CAS  Google Scholar 

  17. Atasoy, D., Aponte, Y., Su, H.H. & Sternson, S.M.A. FLEX switch targets Channelrhodopsin-2 to multiple cell types for imaging and long-range circuit mapping.J. Neurosci.28, 7025–7030 (2008).

    Article CAS  Google Scholar 

  18. Kaelin, C.B., Xu, A.W., Lu, X.Y. & Barsh, G.S. Transcriptional regulation of agouti-related protein (Agrp) in transgenic mice.Endocrinology145, 5798–5806 (2004).

    Article CAS  Google Scholar 

  19. Balthasar, N. et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis.Neuron42, 983–991 (2004).

    Article CAS  Google Scholar 

  20. van den Top, M., Lee, K., Whyment, A.D., Blanks, A.M. & Spanswick, D. Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus.Nat. Neurosci.7, 493–494 (2004).

    Article CAS  Google Scholar 

  21. Tolkamp, B.J., Allcroft, D.J., Austin, E.J., Nielsen, B.L. & Kyriazakis, I.I. Satiety splits feeding behaviour into bouts.J. Theor. Biol.194, 235–250 (1998).

    Article CAS  Google Scholar 

  22. Tolkamp, B.J. & Kyriazakis, I.I. To split behaviour into bouts, log-transform the intervals.Anim. Behav.57, 807–817 (1999).

    Article CAS  Google Scholar 

  23. Miller, M.W. et al. Cloning of the mouse agouti gene predicts a secreted protein ubiquitously expressed in mice carrying the lethal yellow mutation.Genes Dev.7, 454–467 (1993).

    Article CAS  Google Scholar 

  24. Kristensen, P. et al. Hypothalamic CART is a new anorectic peptide regulated by leptin.Nature393, 72–76 (1998).

    Article CAS  Google Scholar 

  25. Elias, C.F. et al. Leptin activates hypothalamic CART neurons projecting to the spinal cord.Neuron21, 1375–1385 (1998).

    CAS PubMed  Google Scholar 

  26. Rossi, M. et al. A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo.Endocrinology139, 4428–4431 (1998).

    Article CAS  Google Scholar 

  27. Fan, W., Boston, B.A., Kesterson, R.A., Hruby, V.J. & Cone, R.D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome.Nature385, 165–168 (1997).

    Article CAS  Google Scholar 

  28. Huber, D. et al. Sparse optical microstimulation in barrel cortex drives learned behaviour in freely moving mice.Nature451, 61–64 (2008).

    Article CAS  Google Scholar 

  29. Houweling, A.R. & Brecht, M. Behavioural report of single neuron stimulation in somatosensory cortex.Nature451, 65–68 (2008).

    Article CAS  Google Scholar 

  30. Tsai, H.C. et al. Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning.Science324, 1080–1084 (2009).

    Article CAS  Google Scholar 

  31. Adamantidis, A.R., Zhang, F., Aravanis, A.M., Deisseroth, K. & de Lecea, L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons.Nature450, 420–424 (2007).

    Article CAS  Google Scholar 

  32. Abbott, S.B. et al. Photostimulation of retrotrapezoid nucleus phox2b-expressing neuronsin vivo produces long-lasting activation of breathing in rats.J. Neurosci.29, 5806–5819 (2009).

    Article CAS  Google Scholar 

  33. Belgardt, B.F., Okamura, T. & Bruning, J.C. Hormone and glucose signaling in POMC and AgRP neurons.J. Physiol. (Lond.)587, 5305–5314 (2009).

    Article CAS  Google Scholar 

  34. Broberger, C., Johansen, J., Johansson, C., Schalling, M. & Hokfelt, T. The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice.Proc. Natl. Acad. Sci. USA95, 15043–15048 (1998).

    Article CAS  Google Scholar 

  35. Aravanis, A.M. et al. An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology.J. Neural Eng.4, S143–S156 (2007).

    Article  Google Scholar 

  36. Peng, H., Ruan, Z., Long, F., Simpson, J.H. & Myers, E.W. V3D enables real-time 3D visualization and quantitative analysis of large-scale biological image data sets.Nat. Biotechnol.28, 348–353 (2010).

    Article CAS  Google Scholar 

  37. Abercrombie, M. Estimation of nuclear population from microtome sections.Anat. Rec.94, 239–247 (1946).

    Article CAS  Google Scholar 

  38. Holm, S.A. A simple sequentially rejective multiple test procedure.Scand. J. Stat.6, 65–70 (1979).

    Google Scholar 

Download references

Acknowledgements

We thank G. Shtengel for assistance with photostimulation equipment and software, R. Shusterman for assistance with data analysis, H. Peng for image analysis tools, J. Osborne and T. Tabachnik for equipment design and fabrication, A. Arnold for imaging support, B. Shields and A. Hu for histology support, and J. Cox for mouse breeding and genotyping support. K. Svoboda, G. Murphy, J. Dudman, A. Lee, and S.E.R. Egnor commented on the manuscript. This research was funded by the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia, USA

    Yexica Aponte, Deniz Atasoy & Scott M Sternson

Authors
  1. Yexica Aponte

    You can also search for this author inPubMed Google Scholar

  2. Deniz Atasoy

    You can also search for this author inPubMed Google Scholar

  3. Scott M Sternson

    You can also search for this author inPubMed Google Scholar

Contributions

Y.A. performed the behavioral experiments and D.A. performed and analyzed electrophysiological experiments. Y.A. and S.M.S. designed the study, analyzed the data and wrote the paper.

Corresponding author

Correspondence toScott M Sternson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 9261 kb)

Rights and permissions

About this article

Cite this article

Aponte, Y., Atasoy, D. & Sternson, S. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training.Nat Neurosci14, 351–355 (2011). https://doi.org/10.1038/nn.2739

Download citation

Access through your institution
Buy or subscribe

Associated content

Lighting up the hypothalamus: coordinated control of feeding behavior

  • Kevin W Williams
  • Joel K Elmquist
Nature NeuroscienceNews & Views

Advertisement

Search

Advanced search

Quick links

Nature Briefing

Sign up for theNature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox.Sign up for Nature Briefing
[8]ページ先頭
©2009-2025 Movatter.jp