TY - JOUR
T1 - The supramammillary nucleus controls anxiety-like behavior; key role of GLP-1R
AU - López-Ferreras, L.
AU - Eerola, K.
AU - Shevchouk, O. T.
AU - Richard, J. E.
AU - Nilsson, F. H.
AU - Jansson, L. E.
AU - Hayes, M. R.
AU - Skibicka, K. P.
N1 - Funding Information:
MRH is a partial owner of Cantius Therapeutics, LLC, and receives research funding from Zealand Pharma,Eli Lilly and Company, Boehringer Igelheim and Novo Nordiskthat was not used to support these studies. All the other authors declare no conflict of interest.This research was funded by the Wallenberg Foundation (WCMTM), Swedish Research Council (2014-2945 and 2018-00660 to KPS; and 2013–7107 to PR), Novo Nordisk Foundation Excellence project grant (to KPS), Ragnar Söderberg Foundation (KPS), Harald Jeanssons Stiftelse and Greta Jeanssons Stiftelse (KPS), and Magnus Bergvalls Stiftelse (KPS), and National Institute of HealthNIH-DK115762 (MRH). We would also like to thank Graziella DiGiacomo for her technical assistance with cryo-sectioning.
Funding Information:
This research was funded by the Wallenberg Foundation (WCMTM) , Swedish Research Council ( 2014-2945 and 2018-00660 to KPS; and 2013–7107 to PR), Novo Nordisk Foundation Excellence project grant (to KPS), Ragnar Söderberg Foundation (KPS) , Harald Jeanssons Stiftelse and Greta Jeanssons Stiftelse (KPS) , and Magnus Bergvalls Stiftelse (KPS) , and National Institute of Health NIH-DK115762 (MRH). We would also like to thank Graziella DiGiacomo for her technical assistance with cryo-sectioning.
Publisher Copyright:
© 2020 The Authors
PY - 2020/9
Y1 - 2020/9
N2 - Anxiety disorders are among the most prevalent categories of mental illnesses. The gut-brain axis, along with gastrointestinally-derived neuropeptides, like glucagon-like peptide-1 (GLP-1), are emerging as potential key regulators of emotionality, including anxiety behavior. However, the neuroanatomical substrates from which GLP-1 exerts its anxiogenic effect remain poorly characterized. Here we focus on a relatively new candidate nucleus, the supramammillary nucleus (SuM), located just caudal to the lateral hypothalamus and ventral to the ventral tegmental area. Our focus on the SuM is supported by previous data showing expression of GLP-1R mRNA throughout the SuM and activation of the SuM during anxiety-inducing behaviors in rodents. Data show that chemogenetic activation of neurons in the SuM results in an anxiolytic response in male and female rats. In contrast, selective activation of SuM GLP-1R, by microinjection of a GLP-1R agonist exendin-4 into the SuM resulted in potent anxiety-like behavior, measured in both open field and elevated plus maze tests in male and female rats. This anxiogenic effect of GLP-1R activation persisted after high-fat diet exposure. Importantly, reduction of GLP-1R expression in the SuM, by AAV-shRNA GLP-1R knockdown, resulted in a clear anxiolytic response; an effect only observed in female rats. Our data identify a new neural substrate for GLP-1 control of anxiety-like behavior and indicate that the SuM GLP-1R are sufficient for anxiogenesis in both sexes, but necessary only in females.
AB - Anxiety disorders are among the most prevalent categories of mental illnesses. The gut-brain axis, along with gastrointestinally-derived neuropeptides, like glucagon-like peptide-1 (GLP-1), are emerging as potential key regulators of emotionality, including anxiety behavior. However, the neuroanatomical substrates from which GLP-1 exerts its anxiogenic effect remain poorly characterized. Here we focus on a relatively new candidate nucleus, the supramammillary nucleus (SuM), located just caudal to the lateral hypothalamus and ventral to the ventral tegmental area. Our focus on the SuM is supported by previous data showing expression of GLP-1R mRNA throughout the SuM and activation of the SuM during anxiety-inducing behaviors in rodents. Data show that chemogenetic activation of neurons in the SuM results in an anxiolytic response in male and female rats. In contrast, selective activation of SuM GLP-1R, by microinjection of a GLP-1R agonist exendin-4 into the SuM resulted in potent anxiety-like behavior, measured in both open field and elevated plus maze tests in male and female rats. This anxiogenic effect of GLP-1R activation persisted after high-fat diet exposure. Importantly, reduction of GLP-1R expression in the SuM, by AAV-shRNA GLP-1R knockdown, resulted in a clear anxiolytic response; an effect only observed in female rats. Our data identify a new neural substrate for GLP-1 control of anxiety-like behavior and indicate that the SuM GLP-1R are sufficient for anxiogenesis in both sexes, but necessary only in females.
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U2 - 10.1016/j.psyneuen.2020.104720
DO - 10.1016/j.psyneuen.2020.104720
M3 - Article
C2 - 32563174
AN - SCOPUS:85086602259
VL - 119
JO - Psychoneuroendocrinology
JF - Psychoneuroendocrinology
SN - 0306-4530
M1 - 104720
ER -