Pathogenicity of chronic stress during adulthood in a mouse model : long-term impact and role of somatostatin
Defended on December 15, 2015
PhD supervisor: Pr Jean-Louis GUILLOU – INCIA.
Stress has an adaptive function but it can have also deleterious effects on physical, cognitive and mental health when its intensity and/or chronicity increase. A large body of evidence supports the idea that young children, adolescents and aged people are highly sensitive to stress.
The aim of this study was to determinate if a critical period of sensitivity to stress may be evidenced during adulthood. The Unpredictable Chronic Mild Stress protocol developed in the mouse was used. Short and long-term impacts of stress were quantified by assessing somatic, hedonic, anxious, depressive and cognitive troubles which are characteristic of a stress syndrome. Unlike the view that adults are resistant and resilient to stress, the results presented in this thesis show that a stress period during adulthood induces immediate and long-lasting deleterious effects. However, middle-aged adults were more resistant and more resilient than younger or older subjects which both displayed a more severe symptomatology.
The anxiety level initially induced by chronic stress is correlated with the persistence of troubles and with modifications of gene repression marks in the hippocampus, indicating the presence of an epigenetic signature of the chronic stress episode in the long-term. Recent studies have suggested that central somatostatin is involved in emotional regulations, linking the vulnerability of somatostatinergic neurons to chronic stress with the instatement of anxio- depressive disorders.
We showed herein that hippocampal sst2 and sst4 receptor subtypes mediate the inhibition of HPA axis and improve anxio-depressive behaviors. Behavioral patterns induced by either selective agonists or deletions of these receptors suggest that two regulatory pathways respectively interact with the serotoninergic system (sst2) and the noradrenergic system (sst4). In addition, sst2 receptors mainly regulate anxiety whereas sst4 is mainly involved in the regulation of cognitive and depressive disorders.
As a whole, this thesis corroborates the idea that chronic stress has pathogenic effects even in adulthood and highlights the importance of neuroendocrine and cognitivo-emotional regulations by sst2 and sst4 receptor subtypes, a specificity that has to be considered in the use and the development of somatostatin treatments targeting HPA deregulations and stress-related disorders.
- Jacques EPELBAUM (Pr. UMR INSERM 894, Univ. Paris-Descarte) : Président du jury
- Catherine BELZUNG (Pr., INSERM 930, Institut Univ. de France) : Rapporteur
- Jean-Louis MILLOT (Pr. EA 481, Univ. Franche-Comté) : Rapporteur
- Daniel BERACOCHEA (DR, UMR CNRS 5287, Univ. Bordeaux) : Examinateur
- Jean-Philippe GUILLOUX (MCU, UMRS INSERM 1178, Univ. Paris-Sud) : Examinateur
- Cécile VIOLLET (DR, UMR INSERM 894, Univ. Paris-Descarte) : Examinateur
- Jean-Louis GUILLOU (Pr. UMR CNRS 5287, Univ. Bordeaux) : Directeur de thèse