Format

Send to

Choose Destination
Brain Struct Funct. 2019 Nov;224(8):2983-2999. doi: 10.1007/s00429-019-01949-y. Epub 2019 Sep 4.

Two distinct GUCY2C circuits with PMV (hypothalamic) and SN/VTA (midbrain) origin.

Author information

1
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, 368 JAH, Philadelphia, PA, 19107, USA.
2
Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.
3
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, 368 JAH, Philadelphia, PA, 19107, USA. scott.waldman@jefferson.edu.

Abstract

Guanylyl cyclase C (GUCY2C) is the afferent central receptor in the gut-brain endocrine axis regulated by the anorexigenic intestinal hormone uroguanylin. GUCY2C mRNA and protein are produced in the hypothalamus, a major center regulating appetite and metabolic homeostasis. Further, GUCY2C mRNA and protein are expressed in the ventral midbrain, a principal structure regulating hedonic reward from behaviors including eating. While GUCY2C is expressed in hypothalamus and midbrain, its precise neuroanatomical organization and relationship with circuits regulating satiety remain unknown. Here, we reveal that hypothalamic GUCY2C mRNA is confined to the ventral premammillary nucleus (PMV), while in midbrain it is produced by neurons in the ventral tegmental area (VTA) and substantia nigra (SN). GUCY2C in the PMV is produced by 46% of neurons expressing anorexigenic leptin receptors, while in the VTA/SN it is produced in most tyrosine hydroxylase-immunoreactive neurons. In contrast to mRNA, GUCY2C protein is widely distributed throughout the brain in canonical sites of PMV and VTA/SN axonal projections. Selective stereotaxic ablation of PMV or VTA/SN neurons eliminated GUCY2C only in their respective canonical projection sites. Conversely, specific anterograde tracer analyses of PMV or VTA/SN neurons confirmed distinct GUCY2C-immunoreactive axons projecting to those canonical locations. Together, these findings reveal two discrete neuronal circuits expressing GUCY2C originating in the PMV in the hypothalamus and in the VTA/SN in midbrain, which separately project to other sites throughout the brain. They suggest a structural basis for a role for the GUCY2C-uroguanylin gut-brain endocrine axis in regulating homeostatic and behavioral components contributing to satiety.

KEYWORDS:

Guanylyl cyclase C; Leptin receptor; Obesity; Substantia nigra; Ventral premammillary nucleus; Ventral tegmental area

PMID:
31485718
PMCID:
PMC6778723
[Available on 2020-11-01]
DOI:
10.1007/s00429-019-01949-y

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center