NeuroPSI – Paris-Saclay University

Role of the Neural Crest-derived Meninges and Pericytes in Cognitive Impairment at Birth

Summary of my work
The neural crest is an embryonic multipotent cell population deriving from the neural ectoderm during neurulation. These cells migrate throughout the embryo to generate different cell lineages. In the cephalic region, they also play a major morphogenetic role in the development and give rise to the meninges and microvascularization of the telencephalon and diencephalon. Previous work done by the group has shown that the absence of cephalic neural crest (CNC) coincides with brain defects, and led to the emerging picture that the CNC plays a key role in forebrain development, before birth. The aim is to study the role of neural crest-derived meninges and their pericytes in brain homeostasis and the long-term consequences of their dysfunction on the development of social behavior at birth. For this purpose, the chick embryo is used as a model for the analysis of social interactions, called filial imprinting. The objective of this project is, as a first step, to validate the disorders of social behavior due to defects in microvascularization. When embryos are treated with valproate (VPA), an anticonvulsant drug known to cause cognitive disorders, they show severe alterations in social behavior after birth. These impairments coincide with early hypervascularization of the brain, and the acquisition of macrophagic phenotypes of meningeal cells. In a second step, the defects in microvascularization were inhibited with an anti-angiogenic drug called Sunitinib in order to observe a significant rescue of social behavior and hypervascularization. Furthermore, we show that pericytes, in this developmental context, act as professional immune cells and exert immune surveillance of the embryonic brain. In meninges subjected to toxic (VPA) or septic (E. coli particles) stimuli, RNA sequencing reveals a differential enrichment in genes involved in innate immune responses but also neurological disorders, thus preceding cognitive defects at birth, through the deregulation of GABAergic and glutamatergic pathways. Our data show that CNC-derived pericytes express inflammatory molecules whose deregulation generates negative effects on the development of cognitive functions in the embryo. This work opens new avenues to further explore the role of CNC-derived pericytes in embryonic brain physiology by modulating cerebrospinal fluid composition, and their involvement in the etiology of developmental encephalopathies.

Members of the jury

• • Heather ETCHEVERS, rapporteure et examinatrice (Marseille Medical Genetics, Marseille)
  • Farida DJOUAD, rapporteure et examinatrice (Institute for Regenerative Medecine and Biotherapy, Montpellier)
  • Salvador MARTINEZ PEREZ, examinateur (Instituto de Neurosciencias UMH-CSIC, Alicante)
  • Eric BELLEFROID, examinateur (Université Libre de Bruxelles, Bruxelles)
  • Christelle GOLZIO, examinatrice (Institut de Génétique, de Biologie Moléculaire et Cellulaire, Illkirch)
  • Jean-Loup DUBAND, examinateur (Sorbonne Université, Paris)

and

• Dr. Sophie CREUZET (Institut NeuroPSI, Saclay)