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

Giuseppe D'Agostino (Corresponding Author), David J. Lyons, Claudia Cristiano, Luke K. Burke, Joseph C. Madara, John N. Campbell, Ana Paula Garcia, Benjamin B. Land, Bradford B. Lowell, Ralph J. Dileone, Lora K. Heisler (Corresponding Author)

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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.
Original languageEnglish
Article number12225
Pages (from-to)1-15
Number of pages15
JournaleLife
Volume5
DOIs
Publication statusPublished - 14 Mar 2016

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Solitary Nucleus
Cholecystokinin
Appetite
Hypothalamus
Neurons
Paraventricular Hypothalamic Nucleus
Chemical activation
Optogenetics
Receptor, Melanocortin, Type 4
Presynaptic Terminals
Meals
Brain
Body Weight
Networks (circuits)
Fibers

Cite this

D'Agostino, G., Lyons, D. J., Cristiano, C., Burke, L. K., Madara, J. C., Campbell, J. N., ... Heisler, L. K. (2016). Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit. eLife, 5, 1-15. [12225]. https://doi.org/10.7554/eLife.12225

Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit. / D'Agostino, Giuseppe (Corresponding Author); Lyons, David J.; Cristiano, Claudia; Burke, Luke K.; Madara, Joseph C.; Campbell, John N.; Garcia, Ana Paula; Land, Benjamin B.; Lowell, Bradford B.; Dileone, Ralph J.; Heisler, Lora K. (Corresponding Author).

In: eLife, Vol. 5, 12225, 14.03.2016, p. 1-15.

Research output: Contribution to journalArticle

D'Agostino, G, Lyons, DJ, Cristiano, C, Burke, LK, Madara, JC, Campbell, JN, Garcia, AP, Land, BB, Lowell, BB, Dileone, RJ & Heisler, LK 2016, 'Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit', eLife, vol. 5, 12225, pp. 1-15. https://doi.org/10.7554/eLife.12225
D'Agostino G, Lyons DJ, Cristiano C, Burke LK, Madara JC, Campbell JN et al. Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit. eLife. 2016 Mar 14;5:1-15. 12225. https://doi.org/10.7554/eLife.12225
D'Agostino, Giuseppe ; Lyons, David J. ; Cristiano, Claudia ; Burke, Luke K. ; Madara, Joseph C. ; Campbell, John N. ; Garcia, Ana Paula ; Land, Benjamin B. ; Lowell, Bradford B. ; Dileone, Ralph J. ; Heisler, Lora K. / Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit. In: eLife. 2016 ; Vol. 5. pp. 1-15.
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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.",
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note = "ACKNOWLEDGMENTS Authors wish to thank members of staff of the Medical Research Facility (University of Aberdeen) for assisting with mouse care and husbandry and Raffaella Chianese for assisting with mouse genotyping. This work was supported by the Wellcome Trust (LKH; WT098012), Biotechnology and Biological Sciences Research Council (LKH and GD’A; BB/K001418/1), Wellcome Trust and the University of Aberdeen (GD’A; 105625/Z/14/Z), NIDDK (BBLo; R01 DK075632, P30 DK046200, P30 DK 057521) and American Heart Association (JNC; 14POST20100011). Single-cell qPCR experiment was supported in part by the Molecular Medicine Core facility at Beth Israel Deaconess Medical Center.",
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N1 - ACKNOWLEDGMENTS Authors wish to thank members of staff of the Medical Research Facility (University of Aberdeen) for assisting with mouse care and husbandry and Raffaella Chianese for assisting with mouse genotyping. This work was supported by the Wellcome Trust (LKH; WT098012), Biotechnology and Biological Sciences Research Council (LKH and GD’A; BB/K001418/1), Wellcome Trust and the University of Aberdeen (GD’A; 105625/Z/14/Z), NIDDK (BBLo; R01 DK075632, P30 DK046200, P30 DK 057521) and American Heart Association (JNC; 14POST20100011). Single-cell qPCR experiment was supported in part by the Molecular Medicine Core facility at Beth Israel Deaconess Medical Center.

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N2 - 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.

AB - 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.

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