Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit

  1. Giuseppe D'Agostino
  2. David Joseph Lyons
  3. Claudia Cristiano
  4. Luke Kennedy Burke
  5. Joseph C Madara
  6. John N Campbell
  7. Ana Paula Garcia
  8. Benjamin Bruce Land
  9. Bradford B Lowell
  10. Ralph Joseph Dileone
  11. Lora K Heisler  Is a corresponding author
  1. University of Aberdeen, United Kingdom
  2. University of Cambridge, United Kingdom
  3. Harvard Medical School, United States
  4. Yale University School of Medicine, United States

Abstract

The nucleus of the solitary tract (NTS) is a key gateway for meal-related signals entering the brain from the periphery. However, the chemical mediators crucial to this process have not been fully elucidated. We reveal that a subset of NTS neurons containing cholecystokinin (CCKNTS) is responsive to nutritional state and that their activation reduces appetite and body weight in mice. Cell-specific anterograde tracing revealed that CCKNTS neurons provide a distinctive innervation of the paraventricular nucleus of the hypothalamus (PVH), with fibers and varicosities in close apposition to a subset of melanocortin-4 receptor (MC4RPVH) cells, which are also responsive to CCK. Optogenetic activation of CCKNTS axon terminals within the PVH reveal the satiating function of CCKNTS neurons to be mediated by a CCKNTS→PVH pathway that also encodes positive valence. These data identify the functional significance of CCKNTS neurons and reveal a sufficient and discrete NTS to hypothalamic circuit controlling appetite.

Article and author information

Author details

  1. Giuseppe D'Agostino

    Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. David Joseph Lyons

    Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Claudia Cristiano

    Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Luke Kennedy Burke

    Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Joseph C Madara

    Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. John N Campbell

    Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ana Paula Garcia

    Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Benjamin Bruce Land

    Department of Psychiatry, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Bradford B Lowell

    Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Ralph Joseph Dileone

    Department of Psychiatry, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Lora K Heisler

    Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom
    For correspondence
    lora.heisler@abdn.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All experimental procedures were performed in accordance with the UK Animals (Scientific Procedures) Act 1986 (Project License No. 60/4565).

Copyright

© 2016, D'Agostino et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 8,492
    views
  • 1,538
    downloads
  • 145
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Giuseppe D'Agostino
  2. David Joseph Lyons
  3. Claudia Cristiano
  4. Luke Kennedy Burke
  5. Joseph C Madara
  6. John N Campbell
  7. Ana Paula Garcia
  8. Benjamin Bruce Land
  9. Bradford B Lowell
  10. Ralph Joseph Dileone
  11. Lora K Heisler
(2016)
Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit
eLife 5:e12225.
https://doi.org/10.7554/eLife.12225

Share this article

https://doi.org/10.7554/eLife.12225

Further reading

    1. Neuroscience
    Zachary Fournier, Leandro M Alonso, Eve Marder
    Research Article

    Circuit function results from both intrinsic conductances of network neurons and the synaptic conductances that connect them. In models of neural circuits, different combinations of maximal conductances can give rise to similar activity. We compared the robustness of a neural circuit to changes in their intrinsic versus synaptic conductances. To address this, we performed a sensitivity analysis on a population of conductance-based models of the pyloric network from the crustacean stomatogastric ganglion (STG). The model network consists of three neurons with nine currents: a sodium current (Na), three potassium currents (Kd, KCa, KA), two calcium currents (CaS and CaT), a hyperpolarization-activated current (H), a non-voltage-gated leak current (leak), and a neuromodulatory current (MI). The model cells are connected by seven synapses of two types, glutamatergic and cholinergic. We produced one hundred models of the pyloric network that displayed similar activities with values of maximal conductances distributed over wide ranges. We evaluated the robustness of each model to changes in their maximal conductances. We found that individual models have different sensitivities to changes in their maximal conductances, both in their intrinsic and synaptic conductances. As expected, the models become less robust as the extent of the changes increases. Despite quantitative differences in their robustness, we found that in all cases, the model networks are more sensitive to the perturbation of their intrinsic conductances than their synaptic conductances.

    1. Neuroscience
    Jacob A Miller
    Insight

    When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.