Etho-Psychiatry : animal model to model animal: Identification of a "spontaneous" non-human primate model of depressive symptoms

octobre 2013

Directeur(s) de thèse : Erwan BEZARD

Résumé de thèse

More than 150 million people worldwide suffer from major depressive disorder (MDD). Although investigations of its pathophysiology have dramatically increased in the last decade, no substantial improvement has been made concerning the treatments and the understanding of its underlying mechanisms. A genetic predisposition and stressful experiences have been acknowledged as risk factors involved in MDD. However, no specific genes have been identified so far and little is known about the gene x environment interactions. This is likely due to the lack of bona fideanimal models of depressive-like symptoms. Indeed, there is a huge gap between the knowledge / diagnostic methodology of clinical research and the animal models used in fundamental research, mainly focusing on environmental, pharmacological, lesional or genetic manipulations. Phylogenetically and behaviourally closer to Humans compared to rodents, non-human primates (NHPs) can show spontaneous behavioural and physiological modifications in response to stressful life events. Although promising results had been reported in the 1960’s by the pioneering studies of Harlow and colleagues, the investigation of depressive-like symptoms in macaques are scarce in the current literature.

We hypothesize that, among large captive NHP populations, a few individuals will display atypical behaviours that could mimic depressive symptoms. Combining the skills and knowledge of ethology, psychiatry and neurosciences, my PhD project aimed at proposing an innovative non-invasive detection method of such depressive-like profiles. The impact of birth origin and species was questioned as well. Behaviours, body postures, body orientations, spatial location, gaze direction and/or inter-peer distances were collected among more than 200 rhesus and cynomolgus captive- or wild-born farm-bred macaques. Using multifactorial analyses, clusters of individuals displaying distinct behavioural profiles were identified. In each population, a common depressive-like profile was characterised by its similarities with symptoms described in the Diagnostic and Statistical Manual of Mental Disorder and with other animal models of depression. The prevalence of such profiles was increased in the rhesus populations and by captive early life experience, corroborating the role of stress in the development of MDD. In addition to expressing depressive-like features in their home cage, these animals displayed higher levels of plasmatic cortisol and cerebrospinal noradrenaline which correlated with a passive emotional reactivity in 2 behavioural paradigms. Altogether these promising results conferred good face validity to our NHP model of depressive-like symptoms. Further characterization of this model is required and might bring new insights to the understanding of MDD pathophysiology and etiology.