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.

  • Article
  • Published:

Topographic mapping of VMH → arcuate nucleus microcircuits and their reorganization by fasting

Nature Neuroscience volume 8, pages 1356–1363 (2005)Cite this article

Abstract

In the hypothalamic arcuate nucleus (ARC), pro-opiomelanocortin (POMC) neurons inhibit feeding and neuropeptide-Y (NPY) neurons stimulate feeding. We tested whether neurons in the ventromedial hypothalamic nucleus (VMH), a known satiety center, activate anorexigenic neuronal pathways in the ARC by projecting either excitatory synaptic inputs to POMC neurons and/or inhibitory inputs to NPY neurons. Using laser scanning photostimulation in brain slices from transgenic mice, we found that POMC and NPY neurons, which are interspersed in the ARC, are nevertheless regulated by anatomically distinct synaptic inputs. POMC neurons received strong excitatory input from the medial VMH (mVMH), whereas NPY neurons did not and, instead, received weak inhibitory input only from within the ARC. The strength of the excitatory input from the mVMH to POMC neurons was diminished by fasting. These data identify a new molecularly defined circuit that is dynamically regulated by nutritional state in a manner consistent with the known role of the VMH as a satiety center.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Laser scanning photostimulation for mapping hypothalamic neural circuits.
Figure 2: Excitation profiles and resolution of stimulation by glutamate uncaging.
Figure 3: Synaptic input maps for individual unlabeled ARC, POMC and NPY neurons.
Figure 4: Mean synaptic input maps for unlabeled ARC, POMC and NPY neurons show the strengths and distinct spatial distributions of synaptic inputs onto these neuronal populations.
Figure 5: Analysis of circuit plasticity after fasting and with leptin treatment during fasting.

Similar content being viewed by others

References

  1. Kennedy, G.C. The hypothalamic control of food intake in rats. Proc. R. Soc. Lond. B 137, 535–549 (1950).

    Article  CAS  PubMed  Google Scholar 

  2. Hetherington, A.W. & Ranson, S.W. Hypothalamic lesions and adiposity in the rat. Anat. Rec. 78, 149–161 (1940).

    Article  Google Scholar 

  3. Anand, B.K. & Brobeck, J.R. Hypothalamic control of food intake in rats and cats. Yale J. Biol. Med. 24, 123–140 (1951).

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Majdic, G. et al. Knockout mice lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity. Endocrinology 143, 607–614 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Elmquist, J.K., Elias, C.F. & Saper, C.B. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22, 221–232 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Clark, J.T., Kalra, P.S., Crowley, W.R. & Kalra, S.P. Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115, 427–429 (1984).

    Article  CAS  PubMed  Google Scholar 

  7. Zarjevski, N., Cusin, I., Vettor, R., Rohner-Jeanrenaud, F. & Jeanrenaud, B. Chronic intracerebroventricular neuropeptide-Y administration to normal rats mimics hormonal and metabolic changes of obesity. Endocrinology 133, 1753–1758 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. 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. Nature 385, 165–168 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Pinto, S. et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110–115 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. DeFalco, J. et al. Virus-assisted mapping of neural inputs to a feeding center in the hypothalamus. Science 291, 2608–2613 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Canteras, N.S., Simerly, R.B. & Swanson, L.W. Organization of projections from the ventromedial nucleus of the hypothalamus: a Phaseolus vulgaris-leucoagglutinin study in the rat. J. Comp. Neurol. 348, 41–79 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. van den Pol, A.N. & Cassidy, J.R. The hypothalamic arcuate nucleus of rat–a quantitative Golgi analysis. J. Comp. Neurol. 204, 65–98 (1982).

    Article  CAS  PubMed  Google Scholar 

  14. Callaway, E.M. & Katz, L.C. Photostimulation using caged glutamate reveals functional circuitry in living brain slices. Proc. Natl. Acad. Sci. USA 90, 7661–7665 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sawatari, A. & Callaway, E.M. Convergence of magno- and parvocellular pathways in layer 4B of macaque primary visual cortex. Nature 380, 442–446 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Dantzker, J.L. & Callaway, E.M. Laminar sources of synaptic input to cortical inhibitory interneurons and pyramidal neurons. Nat. Neurosci. 3, 701–707 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Shepherd, G.M., Pologruto, T.A. & Svoboda, K. Circuit analysis of experience-dependent plasticity in the developing rat barrel cortex. Neuron 38, 277–289 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Brivanlou, I.H., Dantzker, J.L., Stevens, C.F. & Callaway, E.M. Topographic specificity of functional connections from hippocampal CA3 to CA1. Proc. Natl. Acad. Sci. USA 101, 2560–2565 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yoshimura, Y., Dantzker, J.L. & Callaway, E.M. Excitatory cortical neurons form fine-scale functional networks. Nature 433, 868–873 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Shepherd, G.M., Stepanyants, A., Bureau, I., Chklovskii, D. & Svoboda, K. Geometric and functional organization of cortical circuits. Nat. Neurosci. 8, 782–790 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Callaway, E.M. Cell type specificity of local cortical connections. J. Neurocytol. 31, 231–237 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Cowley, M.A. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Ahima, R.S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Faletti, A.G. et al. beta-Endorphin blocks luteinizing hormone-releasing hormone release by inhibiting the nitricoxidergic pathway controlling its release. Proc. Natl. Acad. Sci. USA 96, 1722–1726 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kreek, M.J. Methadone-related opioid agonist pharmacotherapy for heroin addiction. History, recent molecular and neurochemical research and future in mainstream medicine. Ann. NY Acad. Sci. 909, 186–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Shimizu, N., Oomura, Y., Plata-Salaman, C.R. & Morimoto, M. Hyperphagia and obesity in rats with bilateral ibotenic acid-induced lesions of the ventromedial hypothalamic nucleus. Brain Res. 416, 153–156 (1987).

    Article  CAS  PubMed  Google Scholar 

  27. Stenger, J., Fournier, T. & Bielajew, C. The effects of chronic ventromedial hypothalamic stimulation on weight gain in rats. Physiol. Behav. 50, 1209–1213 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Elmquist, J.K., Bjorbaek, C., Ahima, R.S., Flier, J.S. & Saper, C.B. Distributions of leptin receptor mRNA isoforms in the rat brain. J. Comp. Neurol. 395, 535–547 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Ono, T. et al. Glucoresponsive neurons in rat ventromedial hypothalamic tissue slices in vitro . Brain Res. 232, 494–499 (1982).

    Article  CAS  PubMed  Google Scholar 

  30. Christensen, L.W., Nance, D.M. & Gorski, R.A. Effects of hypothalamic and preoptic lesions on reproductive behavior in male rats. Brain Res. Bull. 2, 137–141 (1977).

    Article  CAS  PubMed  Google Scholar 

  31. Pfaff, D.W. & Sakuma, Y. Deficit in the lordosis reflex of female rats caused by lesions in the ventromedial nucleus of the hypothalamus. J. Physiol. (Lond.) 288, 203–210 (1979).

    CAS  Google Scholar 

  32. Theodosis, D.T. & Poulain, D.A. Activity-dependent neuronal-glial and synaptic plasticity in the adult mammalian hypothalamus. Neuroscience 57, 501–535 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Bouret, S.G., Draper, S.J. & Simerly, R.B. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 108–110 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Slimko, E.M., McKinney, S., Anderson, D.J., Davidson, N. & Lester, H.A. Selective electrical silencing of mammalian neurons in vitro by the use of invertebrate ligand-gated chloride channels. J. Neurosci. 22, 7373–7379 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lechner, H.A., Lein, E.S. & Callaway, E.M. A genetic method for selective and quickly reversible silencing of Mammalian neurons. J. Neurosci. 22, 5287–5290 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to K. Svoboda for his generous assistance in implementing LSPS (funding to K.S. from the Howard Hughes Medical Institute (HHMI)) and to X.-L. Cai for assistance with mouse breeding. Support by Helen Hay Whitney Foundation (S.M.S.), HHMI (G.M.G.S., J.M.F.) and the US National Institutes of Health (J.M.F.).

Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute and Laboratory of Molecular Genetics, The Rockefeller University, 1230 York Ave., New York, 10021, New York, USA

    Scott M Sternson & Jeffrey M Friedman

  2. Howard Hughes Medical Institute and Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 11724

    Gordon M G Shepherd

Authors
  1. Scott M Sternson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gordon M G Shepherd
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeffrey M Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey M Friedman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Wiring diagram of hypothalamic microcircuits. (PDF 90 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sternson, S., Shepherd, G. & Friedman, J. Topographic mapping of VMH → arcuate nucleus microcircuits and their reorganization by fasting. Nat Neurosci 8, 1356–1363 (2005). https://doi.org/10.1038/nn1550

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1550

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature 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