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Mol Metab. 2017 Jan 27;6(4):374-381. doi: 10.1016/j.molmet.2017.01.004. eCollection 2017 Apr.

Cannabinoid type 1 receptor-containing axons innervate NPY/AgRP neurons in the mouse arcuate nucleus.

Author information

1
Department of Neuroscience, Yale University School of Medicine, 06520 New Haven, CT, USA; Kavli Institute for Neuroscience, Yale University School of Medicine, 06520 New Haven, CT, USA. Electronic address: yury.morozov@yale.edu.
2
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, 06520 New Haven, CT, USA; Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany.
3
Department of Neuroscience, Yale University School of Medicine, 06520 New Haven, CT, USA; Kavli Institute for Neuroscience, Yale University School of Medicine, 06520 New Haven, CT, USA.
4
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, 06520 New Haven, CT, USA. Electronic address: tamas.horvath@yale.edu.

Abstract

OBJECTIVES:

Phytocannabinoids, such as THC and endocannabinoids, are well known to promote feeding behavior and to control energy metabolism through cannabinoid type 1 receptors (CB1R). However, the underlying mechanisms are not fully understood. Generally, cannabinoid-conducted retrograde dis-inhibition of hunger-promoting neurons has been suggested to promote food intake, but so far it has not been demonstrated due to technical limitations.

METHODS:

We applied immunohistochemical labeling of CB1R for light microscopy and electron microscopy combined with three-dimensional reconstruction from serial sections in CB1R-expressing and CB1R-null mice, which served as a negative control. Hunger-promoting neurons expressing Agouti-related protein and neuropeptide Y (AgRP/NPY) in the hypothalamic arcuate nucleus were identified in NPY-GFP and NPY-hrGFP mice.

RESULTS:

Using three-dimensional reconstruction from serial sections we demonstrated numerous discontinuous segments of anti-CB1R labeling in the synaptic boutons and axonal shafts in the arcuate nucleus. We observed CB1R in the symmetric, presumed GABAergic, synaptic boutons innervating AgRP/NPY neurons. We also detected CB1R-containing axons producing symmetric and asymmetric synapses onto AgRP/NPY-negative neurons. Furthermore, we identified CB1R in close apposition to the endocannabinoid (2-arachidonoylglycerol)-synthesizing enzyme diacylglycerol lipase-alpha at AgRP/NPY neurons.

CONCLUSIONS:

Our immunohistochemical and ultrastructural study demonstrates the morphological substrate for cannabinoid-conducted feeding behavior via retrograde dis-inhibition of hunger-promoting AgRP/NPY neurons.

KEYWORDS:

3D reconstruction; Agouti-related protein; Arcuate nucleus; Electron microscopy; Hypothalamus; Neuropeptide Y

PMID:
28377876
PMCID:
PMC5369208
DOI:
10.1016/j.molmet.2017.01.004
[Indexed for MEDLINE]
Free PMC Article

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