PhD position: Traumatic stress and hippocampal neurogenesis

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from February 28, 2017 to April 1, 2017

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Supervisor: Catherine Belzung Duration: 3 years, starting as October 2017 Technical competences: animal behavior, immunohistochemistry, optogenetics Deadline for applications: April 1st, 2017




Involvement of hippocampal neurogenesis in remission after stressful events


Recent terrorist attacks in France have highlighted that traumatic events not only induce physical insults, but also pathological psychological states such as for example Post-Traumatic Stress Disorders (PTSD). This pathology is triggered by traumatic events, and translates in a complex symptomatology (avoidance of stimuli associated to the trauma, hyper-arousal, nightmares, physiological hyper-reactivity in case of exposure to stimuli associated to the traumatic event). Prevalence of PTSD is estimated as high as 8% within the general population but this percentage is higher among victims of traumas (for example 50 % among the victims of rape) (Breslau, 2009).

At the cognitive level, two explanations could account for the symptomatology: a) a failure of the subject to extinct fear conditioning; b) an over-generalization in the interpretation of sensorial stimuli, subjects processing stimuli associated to security signal as threatening. This could relate to a deficit in pattern separation, a cognitive process enabling to disambiguate two resembling stimuli. 

These behavioral and cognitive alterations translate into brain alterations, involving a triad of regions from the cortico-limbic system: the prefrontal cortex, the amygdala and the hippocampus. More specifically, neuroimaging studies have shown alterations of the posterior part of the human hippocampus (which corresponds to the dorsal hippocampus) in these patients (Bonne et al., 2008).

Interestingly, the hippocampus is involved in several processes that could relate to the symptoms of PTSD. For example, the hippocampus, and more specifically the dentate gyrus (a subpart of the hippocampus) is involved in the discrimination between threat and safety signals  (Dunsmoor and Paz, 2015; Kheirbeik et al., 2012). This could relate to the role of the dentate gyrus in pattern separation (Sahay et coll., 2011).

It is now well established that within the dentate gyrus, newborn neurons are generated each day in the adult subject, a phenomenon termed as adult neurogenesis. Our hypothesis is that an increase of the adult newborn neurons from the dentate gyrus could enable to counteract a deficit of pattern separation existing in PTSD subjects and therefore counteract the PTSD-related symptomatology.

On the experimental level, the project relies on the utilization of ibax mice (Sahay et al., 2011), mice that display a reduction of the pro-apoptotic gene Bax in the neural progenitors, decreasing the death of newborn neurons and thus causing an increase of adult neurogenesis. The project will include several phases: 1) establish whether an increase of neurogenesis counteracts the symptomatology of PTSD in an animal model of PTSD that has been validated at the laboratory and whether this involves newborn neurons from a particular age; b) investigate the underlying mechanisms involved, and particularly whether this neurogenesis modifies the functioning of the amygdala and of the prefrontal cortex, two other regions whose function is altered in PTSD subjects and to which the hippocampus is projecting; c) in case the activity of one of these regions is modified by the increase of neurogenesis in the dentate gyrus, we will modulate, using optogenetic inhibition, the projection of the hippocampus to this brain regions and assess whether, in case the PTSD-related symptomatology had been improved after increase of neurogenesis, whether this is counteracted once this projection has been inhibited.


Références : Breslau (2009) Trauma Violence Abuse 10 : 198-210 ; Bonne et al. (2008) J Clin Psychiat 69 : 1087-1091 ; Dunsmoor et Paz (2015) Biological Psychiatry 78 : 336–343. Kheirbeik et al. (2012) Nat Neurosci 15 :1613–1620 ; Sahay et al. (2011) Nature 472 : 466–470.