Giuseppe D’Agostino1,2*, David J Lyons1, Claudia Cristiano1, Luke K Burke2,
Joseph C Madara3, John N Campbell3, Ana Paula Garcia2, Benjamin B Land4,
Bradford B Lowell3, Ralph J Dileone4, Lora K Heisler1,2*
Joseph S Takahashi, Reviewing editor
Joseph S Takahashi, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States;
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 hypothalamus circuit controlling appetite.
Photostimulation of channelrhodopsin2 was achieved by 470 nm blue light delivered via the microscope objective. Light was generated by a pE-4000 LED illumination system (CoolLED, Andover, UK) driven via clampex 10.4 software (Molecular Devices, Sunnyvale, CA). For CCK-8 application on MC4R PVH neurons, brain coronal slices from 6–8 week-old Mc4r-GFP or Mc4r-t2a-Cre::tdTomato mice were prepared. Extracted brains were immediately submerged in ice-cold, carbogen-saturated (95% O2, 5% CO2) high-sucrose solution (238 mM sucrose, 26 mM NaHCO3, 2.5 mM KCl, 1.0 mM NaH2PO4, 5.0 mM MgCl2, 10.0 mM CaCl2, 11 mM glucose)
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