Rôle de la signalisation des enképhalines par les récepteurs opioïdergiques delta dans la résilience au stress chronique
|Advisor:||Drolet, Guy; Tremblay, Marie-Ève|
|Abstract:||The survival of an individual is essentially based on his ability to adapt to ever-changing living conditions. There is a great variability among individuals regarding their response to chronic stress, defining the concept of resilience. Resilience is an active coping mechanism corresponding to an individual's ability to avoid the negative social, psychological and biological consequences of extreme stress that would compromise their psychological or physical well-being. The phenomenon is complex and recruits many brain structures and several neurotransmitters. Among the neuropeptidergic systems, endogenous opioids, such as enkephalins (ENKs), could be potential targets involved in the occurrence of these natural variations and could thus be a crucial determinant of an individual’s capacity to adapt to chronic stress. In a previous study by Dr Guy Drolet's team, ENK mRNA expression levels were shown to be decreased in the nucleus of basolateral amygdala (BLA) in vulnerable rats after chronic social defeat stress (CSDS). In addition, the inhibition of ENKs in the BLA reproduced this vulnerability phenotype in rats, thus demonstrating the preponderant role of the ENK circuitry in the development of resilience. The main objective of this thesis was to investigate the contribution of the ENKs circuit via the Delta opioid receptors (DOPr) in the chronic stress resilience, both at the neuroanatomical and functional levels. We first examined, by in situ hybridization, the expression levels of ENKs in BLA in mice after CSDS: as in rats, susceptible mice showed a decrease in ENK mRNA in BLA compared to resilient and controls animals. This result confirmed the implication of the ENKs in resilience in rodents. Subsequently, we evaluated the expression levels of DOPr in the target structures of the BLA. We specifically targeted the hippocampus, which maintains a privileged dialogue with the amygdala in the response to stress and in which DOPr is strongly expressed. DOPr mRNA expression was reduced in the ventral hippocampal CA1 region (CA1-vHPC) in vulnerable mice while the level was preserved in both resilient and control animals. In order to dissect the importance of DOPr signaling in the development of resilience, pharmacological activation was performed: the administration of a DOPr agonist, SNC80, into the systemic circulation, increased the proportion of resilient mice after the CSDS. In a second step, we hypothesized that the maintenance of DOPr mRNA expression in CA1-vHPC allowed the preservation of a controlled oxidative status in neurons, leading to the phenotype of resilience. Indeed, the neuroprotective role of DOPr activation against cellular oxidative damages (i.e. oxidative stress, OS) was demonstrated in different contexts, particularly in ischemic rats. Thus, we observed markers of OS - such as dark neurons and endoplasmic reticulum dilation - by transmission electron microscopy (TEM) after CSDS, with or without SNC80 treatment. We specifically targeted excitatory and inhibitory neurons of CA1-vHPC. We were able to demonstrate that the SNC80 decreased the proportion of some OS markers in both resilient and vulnerable animals, while for other markers, it restored CSDS-induced oxidative damages only in vulnerable mice. Finally, an ultrastructural study of mitochondria by TEM, confirmed these results where the SNC80 restored the deleterious effects of stress only in vulnerable mice. These results demonstrated that activation of DOPr signaling is responsible for resilience by the preservation of a controlled oxidative status in excitatory and inhibitory neurons of CA1- vHPC. Finally, a molecular study was performed by western blot, in the total hippocampus, to determine the molecular target of DOPr involved in OS, allowing stress resilience. Complexes of the mitochondrial respiratory chain and antioxidant enzymes were measured. The activation of DOPr showed a decrease in the expression of certain complexes without revealing the exact molecular target of DOPr allowing resilience to chronic stress. Overall, these studies propose a novel mechanism by which ENK-DOPr signaling promotes resilience to chronic stress by enhancing a controlled oxidative status in hippocampal neurons.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||5 August 2019|
|Collection:||Thèses et mémoires|
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