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

Giuseppe D'Agostino; 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

doi:10.7554/eLife.12225

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

Giuseppe D'Agostino, 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

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	1-15
Number of pages	15
Journal	eLife
Volume	5
DOIs	https://doi.org/10.7554/eLife.12225
Publication status	Published - 14 Mar 2016

Keywords

Animals
Appetite
Brain Mapping
Cholecystokinin/metabolism
Mice
Neural Pathways/anatomy & histology
Optogenetics
Paraventricular Hypothalamic Nucleus/physiology
Solitary Nucleus/physiology

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10.7554/eLife.12225

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@article{fbbe332495b34fb09201df4ab4db2929,

title = "Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit",

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.",

keywords = "Animals, Appetite, Brain Mapping, Cholecystokinin/metabolism, Mice, Neural Pathways/anatomy & histology, Optogenetics, Paraventricular Hypothalamic Nucleus/physiology, Solitary Nucleus/physiology",

author = "Giuseppe D'Agostino and Lyons, {David J} and Claudia Cristiano and Burke, {Luke K} and Madara, {Joseph C} and Campbell, {John N} and Garcia, {Ana Paula} and Land, {Benjamin B} and Lowell, {Bradford B} and Dileone, {Ralph J} and Heisler, {Lora K}",

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{\textquoteright}A; BB/K001418/1), Wellcome Trust and the University of Aberdeen (GD{\textquoteright}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. M1 - 12225",

year = "2016",

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day = "14",

doi = "10.7554/eLife.12225",

language = "English",

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T1 - Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit

AU - D'Agostino, Giuseppe

AU - Lyons, David J

AU - Cristiano, Claudia

AU - Burke, Luke K

AU - Madara, Joseph C

AU - Campbell, John N

AU - Garcia, Ana Paula

AU - Land, Benjamin B

AU - Lowell, Bradford B

AU - Dileone, Ralph J

AU - Heisler, Lora K

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. M1 - 12225

PY - 2016/3/14

Y1 - 2016/3/14

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.

KW - Animals

KW - Appetite

KW - Brain Mapping

KW - Cholecystokinin/metabolism

KW - Mice

KW - Neural Pathways/anatomy & histology

KW - Optogenetics

KW - Paraventricular Hypothalamic Nucleus/physiology

KW - Solitary Nucleus/physiology

U2 - 10.7554/eLife.12225

DO - 10.7554/eLife.12225

M3 - Article

C2 - 26974347

SN - 2050-084X

VL - 5

SP - 1

EP - 15

JO - eLife

JF - eLife

ER -

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

Abstract

Keywords

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