TY - JOUR

T1 - The Absence of Serotonin in the Brain Alters Acute Stress Responsiveness by Interfering With the Genomic Function of the Glucocorticoid Receptors

AU - Sbrini, Giulia

AU - Brivio, Paola

AU - Peeva, Polina Mineva

AU - Todiras, Mihail

AU - Bader, Michael

AU - Alenina, Natalia

AU - Calabrese, Francesca

N1 - Funding Information: This work was supported by grants from MIUR ProgettoEccellenza to FC; by PRIN2017 to FC, by piano sostegno Alla ricerca UNIMI, linea 2 azione A to FC, by the DAAD-MIUR Joint Mobility Program to NA and FC; by German Federal Ministry of Education and Research under the framework of the EU-ERA-NET NEURON project RESPOND to MB and NA; by the project 51143531 of the St. Petersburg State University and the Volkswagen Foundation to NA. GS was supported by cycle XXXIV of the doctorate in Experimental and Clinical Pharmacological Sciences, Department of Pharmacological and Biomolecular Sciences, Università’ Degli Studi di Milano. Publisher Copyright: © Copyright © 2020 Sbrini, Brivio, Peeva, Todiras, Bader, Alenina and Calabrese. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/6/1

Y1 - 2020/6/1

N2 - Alterations in serotonergic transmission have been related to a major predisposition to develop psychiatric pathologies, such as depression. We took advantage of tryptophan hydroxylase (TPH) 2 deficient rats, characterized by a complete absence of serotonin in the brain, to evaluate whether a vulnerable genotype may influence the reaction to an acute stressor. In this context, we investigated if the glucocorticoid receptor (GR) genomic pathway activation was altered by the lack of serotonin in the central nervous system. Moreover, we analyzed the transcription pattern of the clock genes that can be affected by acute stressors. Adult wild type (TPH2+/+) and TPH2-deficient (TPH2−/−) male rats were sacrificed after exposure to one single session of acute restraint stress. Protein and gene expression analyses were conducted in the prefrontal cortex (PFC). The acute stress enhanced the translocation of GRs in the nucleus of TPH2+/+ animals. This effect was blunted in TPH2−/− rats, suggesting an impairment of the GR genomic mechanism. This alteration was mirrored in the expression of GR-responsive genes: acute stress led to the up-regulation of GR-target gene expression in TPH2+/+, but not in TPH2−/− animals. Finally, clock genes were differently modulated in the two genotypes after the acute restraint stress. Overall our findings suggest that the absence of serotonin within the brain interferes with the ability of the HPA axis to correctly modulate the response to acute stress, by altering the nuclear mechanisms of the GR and modulation of clock genes expression.

AB - Alterations in serotonergic transmission have been related to a major predisposition to develop psychiatric pathologies, such as depression. We took advantage of tryptophan hydroxylase (TPH) 2 deficient rats, characterized by a complete absence of serotonin in the brain, to evaluate whether a vulnerable genotype may influence the reaction to an acute stressor. In this context, we investigated if the glucocorticoid receptor (GR) genomic pathway activation was altered by the lack of serotonin in the central nervous system. Moreover, we analyzed the transcription pattern of the clock genes that can be affected by acute stressors. Adult wild type (TPH2+/+) and TPH2-deficient (TPH2−/−) male rats were sacrificed after exposure to one single session of acute restraint stress. Protein and gene expression analyses were conducted in the prefrontal cortex (PFC). The acute stress enhanced the translocation of GRs in the nucleus of TPH2+/+ animals. This effect was blunted in TPH2−/− rats, suggesting an impairment of the GR genomic mechanism. This alteration was mirrored in the expression of GR-responsive genes: acute stress led to the up-regulation of GR-target gene expression in TPH2+/+, but not in TPH2−/− animals. Finally, clock genes were differently modulated in the two genotypes after the acute restraint stress. Overall our findings suggest that the absence of serotonin within the brain interferes with the ability of the HPA axis to correctly modulate the response to acute stress, by altering the nuclear mechanisms of the GR and modulation of clock genes expression.

KW - clock genes

KW - glucocorticoid

KW - HPA axis

KW - prefrontal cortex

KW - rats

KW - serotonin

KW - tryptophan hydroxylase

KW - DEPRESSION

KW - ACTIVATION

KW - RAT

KW - PHOSPHORYLATION

KW - KINASE

KW - MECHANISMS

KW - RELEASE

KW - MODEL

KW - INTEGRATION

KW - EXPRESSION

UR - http://www.scopus.com/inward/record.url?scp=85087848545&partnerID=8YFLogxK

U2 - 10.3389/fncel.2020.00128

DO - 10.3389/fncel.2020.00128

M3 - Article

AN - SCOPUS:85087848545

VL - 14

JO - Frontiers in Cellular Neuroscience

JF - Frontiers in Cellular Neuroscience

SN - 1662-5102

M1 - 128

ER -