Yulia Golub1, Eva-Maria Schildbach2, Chadi Touma3, Oliver Kratz4, Gunther H Moll4, Stephan von Hörsten5, Fabio Canneva5. 1. Department of Child and Adolescent Mental Health, University Clinic Erlangen, 91054, Erlangen, Germany; Department of Child and Adolescent Psychiatry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany. Electronic address: yulia.golub@uniklinikum-dresden.de. 2. Department of Child and Adolescent Mental Health, University Clinic Erlangen, 91054, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany. 3. Department of Behavioural Biology, University of Osnabrück, 49076 Osnabrück, Germany. 4. Department of Child and Adolescent Mental Health, University Clinic Erlangen, 91054, Erlangen, Germany. 5. Experimental Therapy, Preclinical Experimental Center, University Clinic of Erlangen, 91054 Erlangen, Germany.
Abstract
BACKGROUND: Dipeptidyl peptidase 4 (DPP4, CD26) is a moonlighting enzyme responsible for the proteolytic inactivation of neuropeptide Y (NPY), a peptide known for its anxiolytic effect in the central nervous system. Our previous work revealed a stress-resilient phenotype and a potentiation of short-term fear extinction in a congenic rat model deficient for DPP4 activity (DPP4mut). Here, we investigated neuroendocrine mechanisms underlying the phenotype of the DPP4mut animals. We studied the function of the hypothalamus-pituitary-adrenal (HPA) axis including the expression levels of its key genes and explored the possibility of structural NPY system changes. METHODS AND RESULTS: We find decreased expression of Nr3c1 (glucocorticoid receptor - GR) and Fkbp5 (FK506 binding protein 5) in the amygdala and the hypothalamus of the DPP4mut rats, as well as the lower stress-induced peripheral corticosterone (CORT) levels. We detect no significant alterations in basal and DEX-induced CORT levels in the DPP4mut animals. The abundance of NPY-ergic neurons in the basolateral amygdala, dentate gyrus and hippocampus did not differ between the DPP4mut and their wild type littermates. CONCLUSION: DPP4mut rats show blunted CORT response in line with their lower behavioral stress-response profile. These results are consistent with the hypothesis that increased central NPY levels elevate the threshold of stress response. We suggest that changes in the expression levels of key HPA axis genes (Nr3c1 and Fkbp5) are a consequence of the altered stress-perception of DPP4mut animals, thus further contributing to the stress-resilient phenotype.
BACKGROUND:Dipeptidyl peptidase 4 (DPP4, CD26) is a moonlighting enzyme responsible for the proteolytic inactivation of neuropeptide Y (NPY), a peptide known for its anxiolytic effect in the central nervous system. Our previous work revealed a stress-resilient phenotype and a potentiation of short-term fear extinction in a congenic rat model deficient for DPP4 activity (DPP4mut). Here, we investigated neuroendocrine mechanisms underlying the phenotype of the DPP4mut animals. We studied the function of the hypothalamus-pituitary-adrenal (HPA) axis including the expression levels of its key genes and explored the possibility of structural NPY system changes. METHODS AND RESULTS: We find decreased expression of Nr3c1 (glucocorticoid receptor - GR) and Fkbp5 (FK506 binding protein 5) in the amygdala and the hypothalamus of the DPP4mut rats, as well as the lower stress-induced peripheral corticosterone (CORT) levels. We detect no significant alterations in basal and DEX-induced CORT levels in the DPP4mut animals. The abundance of NPY-ergic neurons in the basolateral amygdala, dentate gyrus and hippocampus did not differ between the DPP4mut and their wild type littermates. CONCLUSION: DPP4mut rats show blunted CORT response in line with their lower behavioral stress-response profile. These results are consistent with the hypothesis that increased central NPY levels elevate the threshold of stress response. We suggest that changes in the expression levels of key HPA axis genes (Nr3c1 and Fkbp5) are a consequence of the altered stress-perception of DPP4mut animals, thus further contributing to the stress-resilient phenotype.
Authors: Yulia Golub; Valeska Stonawski; Anne C Plank; Anna Eichler; Oliver Kratz; Regina Waltes; Stephan von Hoersten; Veit Roessner; Christine M Freitag Journal: Front Psychiatry Date: 2021-06-29 Impact factor: 4.157