Rôle de l’axe intestin-cerveau dans la vulnérabilité émotionnelle induite par le stress précoce.
Thèse soutenue le 15 décembre 2017.
Sous la direction de Muriel Darnaudéry / NUTRINEURO/ Team «Psychoneuroimmunology and Nutrition (Lucile Capuron)
Early-life adversity is a main risk factor for psychiatric disorders at adulthood; however the mechanisms underlying the programming effect of stress during development are still unknown. In rodents, chronic maternal separation has long lasting effects in adult offspring, including hyper-anxiety and hyper-responsiveness to a novel stress, along with gastrointestinal dysfunctions. Moreover, recent studies report gut barrier hyper-permeability in rat pups submitted to maternal separation, an effect that could potentially lead to dysbiosis and altered brain-gut communication.
Therefore, the aim of my PhD was to unravel the role of the brain-gut axis in the neurobehavioral effects of early-life stress. We recently reported that some neural, behavioral and endocrine alterations associated with maternal separation in rats could be prevented by maternal exposure to a high-fat diet. We first addressed the effects of maternal high-fat diet on brain and gut during development in the maternal separation model. We show that maternal high-fat diet prevents the stress-induced spines density decrease and altered dendrites morphology in the medial prefrontal cortex. Moreover maternal high-fat also attenuates the exacerbated intestinal permeability associated with maternal separation. To explore a potential causal role of gut on brain functions, we then examined the impact of manipulations of intestinal permeability on brain and behavior.
We report 1) that restoration of gut barrier function attenuates some of the behavioral alterations associated with maternal separation and 2) that transgenic mice over-expressing intestinal CA-MLCK leading to chronic gut leakiness exhibited the same phenotype than animals exposed to maternal separation. Finally, we examined the effects of multifactorial early-life adversity on behavior, gut function and microbiota composition in males and females using a combination of prenatal inflammation and maternal separation in mice. At adulthood, offspring exposed to early adversity displayed sex-specific behavioral (social behavior deficits in males and hyper-anxiety in females) and intestinal phenotypes.
In conclusion, our work demonstrates an impact of gut dysfunctions, in particular gut leakiness, on the emergence of emotional alterations. Further studies are needed to unravel the role of the gut dysbiosis in the expression of the behavioral phenotypes associated with early-life adversity.
Keywords : animal models of psychiatric disorders; behavior; early-life adversity; gut permeability; gut microbiota; HPA axis, stress, sex differences
Rincel M, Lépinay AL, Janthakhin Y, Soudain G, Yvon S, Da Silva S, Joffre C, Aubert A, Séré A, Layé S, Theodorou V, Ferreira G, Darnaudéry M. Maternal high-fat diet and early-life stress differentially modulate spine density and dendritic morphology in the medial prefrontal cortex of juvenile and adult rats. Brain Struct Funct 2017 Oct 11.
Janthakhin Y*, Rincel M*, Costa AM, Darnaudéry M* and Ferreira G*. Maternal high-fat diet leads to hippocampal and amygdala dendritic remodeling in adult male offspring. Psychoneuroendocrinology 2017 83, 49–57. *contributed equally
Romaní-Pérez M*, Lépinay AL*, Alonso L, Rincel M, Xia L, Fanet H, Caillé S, Cador M, Layé S, Vancassel S and Darnaudéry M. Impact of perinatal exposure to high-fat diet and stress on response to nutritional challenge, food-motivated behaviour and mesolimbic dopamine function. Int J Obes 2017 41,502-509. *contributed equally
Rincel M*, Lépinay AL*, Delage P, Fioramonti J, Théodorou VS, Layé S and Darnaudéry M. Maternal high-fat diet prevents developmental programming by early-life stress. Transl Psychiatry 2016; 6: e966. *contributed equally
Rincel M, Lépinay AL, Gabory A, Théodorou V, Koehl M, Daugé V, Maccari S and Darnaudéry M. [Early life stressful experiences and neuropsychiatric vulnerability: evidences from human and animal models]. Med Sci (Paris) 2016; 32: 93–99.
Articles in preparation:
Rincel M*, Olier M*, Minni A, Monchaux de Oliveira C, Matime Y, Gaultier E, Grit I, Helbling JC, Costa AM, Lépinay AL, Heil SDS, Yvon S, Moisan MP, Layé S, Ferrier L, Parnet P, Theodorou V* and Darnaudéry M* Early restoration of gut barrier function abrogates the long-term neurobehavioral effects of early-life stress in rats.
Rincel M*, Xia L*, Thomas J, Lainé J, Monchaux de Oliveira C, Gros L, Beyris A, Helbling JC, Bacquié V, Capuron L, Moisan MP, Theodorou V, Turner J, Ferrier L* and Darnaudéry M*. Gut-specific overexpression of the myosin light chain kinase impairs emotional behavior, neuroendocrine response to stress and brain expression of stress-related genes in a sex-dependent manner
Rincel M, Aubert P, Chevalier J, Grohard PA, Basso L, Monchaux de Oliveira C, Lévy E, Chevalier G, Leboyer M, Eberl G, Layé S, Capuron L, Vergnolle N, Neunlist M, Boudin H, Lepage P and Darnaudéry M. Sex-specific behavioral alterations are associated with gut dysbiosis in mice exposed to multifactorial early-life adversity.
CAPURON Lucile, DR, Bordeaux Présidente
CRYAN John, Prof. Cork Rapporteur
MACCARI Stéfania, Prof., Lille Rapporteure
EBERL Gérard, Prof. Paris Examinateur
THEODOROU Vassilia, Prof., Toulouse Examinatrice
DARNAUDERY Muriel, Prof. Bordeaux Directrice de thèse