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

Giulia Sbrini; Paola Brivio; Polina Mineva Peeva; Mihail Todiras; Michael Bader; Natalia Alenina; Francesca Calabrese

doi:10.3389/fncel.2020.00128

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

Front Cell Neurosci. 2020 Jun 1:14:128. doi: 10.3389/fncel.2020.00128. eCollection 2020.

Authors

Giulia Sbrini¹, Paola Brivio¹, Polina Mineva Peeva², Mihail Todiras², Michael Bader^{2

3}, Natalia Alenina^{2

4}, Francesca Calabrese¹

Affiliations

¹ Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy.
² Cardiovascular and Metabolic Diseases, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
³ Charite-University Medicine, Berlin, Germany.
⁴ Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia.

Abstract

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.

Keywords: HPA axis; clock genes; glucocorticoid; prefrontal cortex; rats; serotonin; tryptophan hydroxylase.