Direct access to content
-, -, -, -
from April 21, 2015 to May 15, 2015
PhD thesis grant available, INSERM U930, team 4 "Affective disorders" Title: Inflammation, P2X7 & Affective Disorders: I.PAD project
PhD thesis grant available, INSERM U930, team 4 "Affective disorders"
Title: Inflammation, P2X7 & Affective Disorders: I.PAD project
Depression is a common and among the most severe and disabling psychiatric condition. Depression is clinically characterized by severe and lasting symptoms of the emotional (depressed mood, sadness, worthlessness, disability, loss of interest and pleasure ...) instinctual (loss of sleep and appetite ... ) and behavioral (motor retardatioin, suicidal thoughts ...) spectrum. It is the most important risk factor for suiide that cause over 10.000 deaths per year in France. Depression is a treatable condition by the said drugs "antidepressants" that act on key brain neurotransmitter systems, particularly those involving serotonin and norepinephrine, and to a lesser extent dopamine and melatonin. But nearly 30 to 40% of patients do not respond or respond only partially to these drug classes. It is therefore necessary to test new pharmacological strategies that reflect the latest advances in knowledge on the neurobiological correlates of depression. Recently it has been demonstrated that a polymorphism in the gene encoding for the P2X7 receptor which is one of the major signaling pathways of the inflammation process, could be associated with an increased risk of depression (Halmai et al., 2013 ; Pereira et al, 2013). In addition, our team has developed an animal model of depression, the Unpredictible Chronic Mild Stress UCMS that induces, in mice, behavioral changes similar to those found in human clinical states of depression and which are reversed by conventional antidepressant treatments. The use of this model has allowed us to better understand the mechanism of action of antidepressants. In particular our group has established that i) the effectiveness of antidepressants, especially those affecting the ways of aminergic neurotransmission (serotonin, norepinephrine) requires the integrity of neuronal regeneration capacity (neurogenesis) in the hippocampus (and Surget al., 2008); ii) depression is associated with brain inflammation, and that neuroinflammation differentially affects specific brain regions with a high level of microglial activation in the hippocampus (Farooq et al., 2012); iii) UCMS impacts Nitric Oxide dependent vasomotor relaxation and consequently induces endothelial dysfunction (Isingrini et al., 2012); and finally that iiii) a non-selective inhibitor of the P2X7 (BBG) is able to reduce brain neuroinflammation and reverse some behavioral changes induced by UCMS (unpublished data from our group). In that contxt, the objective of this project will be to characterize the mechanisms by which the antagonism of P2X7 receptors may reverse the behavioral changes induced by UCMS in mice. The experimental device will take the opportunity to submit P2X7 knockout mouse to UCMS protocol, to assess the effect of specific P2X7 antagonists and test whose role in neurogenesis, microglial activation and endothelial changes induced by UCMS mice, will also be evaluated.
Farooq RK, Isingrini E, Tanti A, Le Guisquet AM, Arlicot N, Minier F, Leman S, Chalon S, Belzung C, Camus V. 2012. Is unpredictable chronic mild stress (UCMS) a reliable model to study depression-induced neuroinflammation?.. Behav.Brain Res.231(1872-7549 (Electronic)): ; 130–137.
Halmai Z, Dome P, Vereczkei A, Abdul-Rahman O, Szekely A, Gonda X, Faludi G, Sasvari-Szekely M, Nemoda Z. 2013. Associations between depression severity and purinergic receptor P2RX7 gene polymorphisms.. Journal of affective disorders150(1): ; 104–109.DOI: 10.1016/j.jad.2013.02.033.
Isingrini E, Belzung C, Freslon JL, Machet MC, Camus V. 2012. Fluoxetine effect on aortic nitric oxide-dependent vasorelaxation in the unpredictable chronic mild stress model of depression in mice.. Psychosom.Med.74(1534-7796 (Electronic)): ; 63–72.
Pereira VS, Casarotto PC, Hiroaki-Sato VA, Sartim AG, Guimarães FS, Joca SRL. 2013. Antidepressant- and anticompulsive-like effects of purinergic receptor blockade: Involvement of nitric oxide.. European Neuropsychopharmacology23(12): ; 1769–1778.DOI: 10.1016/j.euroneuro.2013.01.008.
Surget A, Saxe M, Leman S, Ibarguen-Vargas Y, Chalon S, Griebel G, Hen R, Belzung C. 2008. Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal.. Biol.Psychiatry64(1873-2402 (Electronic)): ; 293–301.
Funding: INSERM-Région Centre
Lab environnement: The laboratory has a platform for mice behavioural studies, particularly Umredictable Chronic Mild Stress (UCMS) including a videotracking system (Ethovision). It also allows histochemical and biochemical analysis of brain tissue as well as epifluorescence microscope analysis. Within the INSERM U930, the group works with a team dedicated to functional brain imaging (PET) for small animals.
Application: Applicants should send CV and letter of motivation not later than may 15th, 2015 at firstname.lastname@example.org address. The research team will audition applicants. Those who will be short-listed will be invited to present a more consistent project to both the University staff and the INSERM research unit on june 24th 2015 for final decision.
Pr Vincent CAMUS
INSERM U930 & Université François Rabelais
+33 247 47 91 30