Recherche fondamentale

Les équipes de recherche fondamentale

CNRS - CRBM

Manager : Anne DEBANT

 

Role of Rho GTPase signaling in neuronal development 

Our long-term interest is to understand how Rho GTPase signalling controls neuronal development. This is an important process, as Rho GTPases control the morphogenesis of synapses by regulating actin cytoskeleton dynamics and alterations in synaptic function are involved in autism spectrum disorders (ASD) and intellectual disability (ID).

We have a strong expertise in RhoGTPase signalling in different neuronal systems. Our main project concerns the function and the regulation of the Rho GTPase activator Trio,  which is a major regulator of axon guidance and synaptogenesis, and and an essential gene for development.

The goal of our project is to investigate how perturbations of TRIO by mutations alter its function and contribute to the development of ASD and IDs.

 

Site de l'équipe

UMR5203, CNRS, U1191 INSERM

Manager : Fabrice ANGO

 

SOMATOSENSORI-CEREBELLAR CIRCUIT DEVELOPMENT and PLASTICITY

The cerebellum is best known for its role in motor control, but recent evidence showed that cerebellar cortex also regulates cognitive and emotional processing [2, 3]. The role of cerebellum in higher cognitive functions originates early in development. Indeed, cerebellar pediatric insult causes cognitive and affective deficits. Notably, specific neonatal cerebellar injury correlates significantly with increased risk of autism spectrum disorders (ASDs). A major core feature of ASDs is characterized by defective cerebellar associative sensory learning in mouse and human models [3-5]. Sensory information enters the cerebellar cortex via two principal inputs. The mossy fibers which originate from the spinal cord and from a wide range of nuclei in the brain stem, namely the pontine, vestibular, trigeminal and dorsal column nuclei. The other main afferent to the cerebellar cortex are the climbing fibers which arise exclusively from the inferior olive, a well-defined nucleus in the ventral part of the brainstem. Both inputs convey information to the cerebellum from peripheral sensors located on body and head (see for review [6]). Remarkably, the deletion of susceptible ASD gene, Mecp2 or SHANK3, exclusively in peripheral sensory neurons is sufficient to induce altered sensory sensitivity (pain and touch) and behavioral deficits that recapitulate some of the core phenotypes of ASD [7, 8]. Interestingly, this behavioral deficit is caused only by developmental deletion of these genes but not by their deletion at adult stage. Thus, we hypothesize that an essential cell-autonomous role of somatosensory neurons in synaptic transmission might regulate developing cerebellum connections and functions [9, 10]. However, the role of developmentally identified somatosensory projections in cerebellar circuit assembly remains unresolved. Therefore, our aim is to reveal how information from the peripheral somatosensory system is integrated into cerebellar cortex and how the transmitted information will impact cerebellar circuit development and function in normal and in dysfunctional or altered somatosensory model animals.

 

Site de l'équipe

UMR5203, CNRA, U1191 INSERM

Managers : Etienne AUDINA - Nicola MARCHI

 

Role of neurovascular damage and neuro-inflammation in determining neuronal hyper-excitability in vivo

Our research tests the general hypothesis that cerebrovascular permeability and glia-inflammation are hallmarks of brain diseases, contribuiting to pathophysiology and promoting neurological negative outcome. Our research is translational and it focuses on epilepsy, stroke, and psychiatric disorders. Relevant to this consortium we here offer a set of tools and knowledge of:

1) In vivo video-electrographic recordings (telemetry or wired) to monitor and quantify cortical and hippocampal neuronal activity and waves.

2) Combined electrophysiology & optogenetics approches to decipher functional changes of neuro-glio-vascular networks.

3) In depth analysis of the neurovascular unit and brain inflammation.

4) Biomarkers of neurovascular damage and inflammation.

The hypothesis that neurovascular dysfuntion and inflammation contributes to Autism is novel and it has been, so far, only partially adressed.

 

Site de l'équipe

 

 

 

CNRS UMR5203 - INSERM U1191

Manager : Emmanuel BOURINET

 

Dynamique des canaux calciques et nociception

L'équipe explore la fonction du canal de type T codé Cav3.2 dans les voies de la somatosensation. Nous essayons de comprendre i) quel est l'impact de la Cav3.2 sur tous les types de mécanorécepteurs du système nerveux périphérique, ii) d’appréhender la fonction de Cav3.2 dans les réseaux spinaux, et enfin iii) de déchiffrer les circuits supra spinaux activés par des neurones sensoriels C-LTMR.  

Le contexte physiopathologique de ces travaux est tout d’abord la douleur chronique et ses mécanismes chez l’animal adulte. Cependant, l’exploration des fibres sensorielle du toucher nous amène à explorer comment les neurones sensoriels spécifiques de toucher plaisant (C-LTMR) façonnent le cerveau social. Nous etudions en particulier un modèle murinde déficit social induit par la dérivation maternelle, et deux modèles génétiques d’hypofonction des C-LTMRs. Nous visons à valider le traiter les déficits sociaux via la modulation de l'excitabilité des C-LTMRs grâce à des approches permettant leur manipulation par des outils génétiques (opto/chémogénétique). L’objectif est de démontrer rationnellement l'importance de l'effet "bottom-up" du toucher plaisant pour protéger le cerveau contre les dysfonctionnements autistiques. Nous pensons que cette notion a des perspectives cliniques importantes pour la définition de nouvelles cibles dans le traitement de l'autisme.

 

Site de l'équipe

UMR5203, CNRS, U1191 INSERM

Manager : Freddy JEANNNETEAU

 

Role of oxytocin and vasopressin in the social brain network

Oxytocin is a peptide hormone produced by hypothalamic neurons involved in social behaviors, parental, friendship and pair bonding throughout lifespan, which deficits are associated with psychopathological disorders. We focused on the role of oxytocin in social behaviors and its disorders, notably Prader Willi syndrome and Schaaf Yang syndrome featuring symptoms of the autism spectrum. In animal models, we find deficits of oxytocin linked to social behavior that can be alleviated with administration of oxytocin early after birth. We are studying these effects on circuit plasticity, development and epigenetics. 

 

Site de l'équipe

 

 

 

UMR5203, CNRS, U1191 INSERM

Manager : Philippe LORY

 

Etude des conséquences fonctionnelles de mutations des canaux calciques (Cav) et des canaux NALCN responsables de maladies neurologiques et neurodéveloppementales

Les travaux de l’équipe sont dédiés à l’étude des propriétés des canaux calciques activés par la dépolarisation membranaire (Cav) et des canaux NALCN. Ces canaux ioniques sont des acteurs essentiels de l’activité électrophysiologique des cellules excitables, des neurones en particulier. Un dysfonctionnement de ces canaux peut conduire à un ensemble de maladies neurologiques (épilepsie, migraine, ataxie, douleur chronique, autisme…) appelées ‘canalopathies’.

L’objectif de nos travaux est de mieux comprendre l’implication de ces canaux ioniques en physiologie et physiopathologie. Nous étudions différents aspects de la modulation des canaux Cav et NALCN. Parallèlement, nous étudions les mécanismes pathogéniques à la base des canalopathies calciques et NALCN (troubles neuro-développementaux, épilepsie, ataxie, ...). Nous développons des modèles animaux (souris, poisson zèbre) de ces pathologies et explorons de nouvelles stratégies thérapeutiques.

 

Site de l'équipe

UMR5203, CNRS, U1191 INSERM

Manager : Philippe MARIN

 

Le ciblage de la voie mTOR, sous le contrôle du récepteur 5-HT6 de la sérotonine, pour traiter les altérations neurodévelopmentales et comportementales dans les troubles du spectre autistique (TSA) 

Le récepteur 5-HT6 de la sérotonine est impliqué dans les processus neuro-développementaux et la cognition. Grâce à un crible interactomique, nous avons démontré que le récepteur active la voie mTOR dans différentes populations neuronales. Nous avons également démontré que l'activation non-physiologique de mTOR, sous le contrôle du récepteur, dans le cortex préffrontal, était à l'origine des déficits cognitifs observés dans plusieurs modèles neuro-développementaux de schizophrénie. Notre projet vise maintenant à évaluer le rôle de la voie 5-HT6/mTOR dans différents symptômes représentatifs des TSA et la morphogenèse des épines dendritiques dans deux modèles de TSA bien caractérisés : les souris dépourvues de récepteur Mu des opioïdes ou de la protéine Shank3B (Collaboration Julie Le Merrer, Univ. Tours). Afin de confirmer le lien entre le récepteur 5-HT6 et les TSA, cette étude préclinique sera complétée par une étude génétique visant à identifier des variants pathogènes dans les gènes codant pour les protéines du réseau de signalisation associé au récepteur chez les patients atteints de TSA (Collaboration Amélie Piton, IGBMC).

 

Site de l'équipe

UMR5203, CNRS, U1191, INSERM

Manager : Julie PERROY

 

Améliorer le diagnostic des Troubles du Spectre de l’Autisme (TSA) en utilisant comme biomarqueurs les réponses neuronales et comportementales aux stimulations sensorielles. 

Une sensibilité altérée aux stimuli sensoriels est une caractéristique rémanente des troubles du spectre de l'autisme (TSA). Notre hypothèse de travail est que cette sensibilité particulière puisse empêcher un comportement adapté à la stimulation sensorielle et être la cause d’autres symptômes des TSA. Il parait donc fondamental de caractériser ces déficits d’intégration des informations sensorielles et d’y remédier.

Ce projet translationnel vise à mettre en évidence les bases moléculaires et la micro circuiterie neuronale à l'origine d'une intégration sensorielle atypique dans l'autisme, et d'en comprendre les conséquences comportementales. Pour cela nous avons besoin d’un modèle animal fidèle, et d’une lecture de la maladie transférable à la recherche en psychiatrie. Justement, mimer une mutation monogénique identifiée chez les patients permet de reproduire chez la souris un phénotype de type TSA (déficits d’interaction sociale, comportements répétitifs). De plus, les circuits responsables de l’intégration sensorielle sont conservés au cours de l’évolution. Enfin, nos premiers résultats montrent que chez la souris modèle d’autisme, comme chez les patients, il existe des déficits d’intégration des informations sensorielles qui génèrent une réponse comportementale mal adaptée.

Un test de type Pavlovien conditionne une souris à s’immobiliser en réponse à une stimulation visuelle (un flash lumineux). Les souris contrôles comme les souris modèles d’autisme sont capables d’apprendre à s’immobiliser en réponse à ce flash lumineux ; mais si le flash lumineux est appliqué de façon concomitante à un son, le son perturbe la réponse comportementale des souris modèle d’autisme à la stimulation visuelle, alors que les souris contrôles continuent à s’immobiliser. Ces tests comportementaux sont couplés à l’enregistrement de l’activité des neurones de l’aire visuelle primaire du cortex. De façon attendue, l’activité de ces neurones est modifiée par l’information sensorielle visuelle (modalité spécifique de cette aire corticale), mais chez les souris modèle d’autisme, ces mêmes neurones répondent aussi à l’information sensorielle non spécifique (le son) annihilant l’activité neuronale en réponse au flash lumineux. Ainsi, chez la souris, comme chez l’homme, des déficits d’intégration sensorielle dans les TSA sont source d’un comportement mal-adapté.

Le protocole expérimental défini par cette recherche fondamentale sera transféré à la recherche clinique (collaboration avec l’équipe du Pr. Amaria Baghdadli) pour améliorer le diagnostic des TSA en enregistrant l’activité cérébrale (EEG) et la réponse comportementale des patients à une stimulation sensorielle multimodale.

 

Site de l'équipe

UMR5203, CNRS, U1191 INSERM

Manager : Jean-Philippe PIN

 

Amygdala synaptic neuromodulatory mechanisms and role of mGlu4 in Autism Spectrum Disorders

At the neurobiological level, Autism spectrum disorders (ASD)  are associated with modifications in the excitation/inhibition balance, mainly controlled by two neurotransmitters: GABA (inhibitory) and glutamate (excitatory). Among glutamate receptors, the glutamate receptors type 4 (mGlu4) represent a promising target to develop novel treatments for central nervous disorders, including autism. Indeed, facilitating the activity of these receptors remarkably relieves autistic-like symptoms, namely social withdrawal, stereotypies and anxiety, in a mouse model of ASD. Interestingly, mGlu4 can also modulate the activity of the amygdala, a critical brain region for emotional responses, social behavior, affective states and pain perception, all affected in ASD. The purpose of the present research project is to further investigate the function and therapeutic potential of mGlu4 in ASD using behavioral and electrophysiological approaches, supported by optogenetics and photopharmacology, an innovative promising approach using light-controled drugs to decipher the mechanisms of regulation of brain circuits.

 

Site de l'équipe

UMR 9002, CNRS

Manager : Giacomo CAVALLI

 

Eigenetics in development and cell differentiation

Our team discovered epigenetic inheritance of new phenotypes can occur independently on changes of the DNA sequence. We also discovered that the three dimensional organisation of chromosome in the cell nucleus is a heritable trait that plays an important gene regulatory role. The Cavalli lab identified 3D structural chromosomal domains dubbed Topologically Associating Domains or TADs. Finally, the Cavalli lab has shown that PcG proteins have tumor suppression activity in flies.

In mammals, the Cavalli lab has provided the most accurate description to date of the process of 3D genome regulation during the differentiation of stem cells to neural progenitors and then into cortical neurons. This work has highlighted fundamental features of this process and paves the way to the study of neural perturbations in disease. The Cavalli lab is involved in the E-RARE project impact, to study the perturbations in neural differentiation of a number of syndromes with neurobiology perturbations

 

Site de l'équipe

 

Manager : Karine Loulier

 

Neural cell diversity and balance in brain development and pathologies

The mammalian cerebral cortex relies on many distinct cell types to exert its high cognitive functions. Recent works using high throughput techniques such as single-cell RNA sequencing performed over thousands of cells in distinct brain areas had shed a new light on brain complexity and unraveled greater cell diversity in the mature cerebral cortex than previously thought. How neural diversity arises from seemingly homogeneous population of cortical progenitors and how the balance between neuronal and glial cell types is achieved and regulated during development remain challenging questions not yet fully addressed in vivo. To shape an operative brain, neuronal and glial cells must be produced in defined proportions and locations following a strict spatiotemporal regulation whose imbalance may lead to dramatic brain disorders, such as neurodevelopmental pathologies. From progenitors located in the embryonic cortical niche and subsequently in the dorsal part of postnatal germinative zone, excitatory neurons, then glia and finally both glia and inhibitory neurons are produced. Focusing on mouse cortical progenitors and their descendants encompassing neurons and glia, our research aims at deciphering the cellular and molecular mechanisms accountable for neural diversity generation and adequate subsequent neuron-glial partnerships in normal resting brain and dramatic pathologies such as autism spectrum disorder. In our team, we focus on in vivo neural diversity achievement and maintenance from embryonic to mature stages using a combination of cutting-edge molecular genetic engineering, advanced surgery and imaging techniques. We characterize i) the cellular and molecular mechanisms accountable for neuronal-glial transition and balance over time, ii) the potentialities and functions of a still enigmatic cell population born also from dorsal progenitors: the cortical satellite cells, and iii) how neural diversity and neuronal-glial interactions are imbalanced in neurodevelopmental pathologies. Our research program provides a better understanding of how neurons and glial cells cooperate to build a functional brain, while unraveling key elements of cortical satellite cell properties in both healthy and diseased brain, and offering new insights on cellular and molecular components involved in the etiology of neurodevelopmental disorders.

 

Site de l'équipe

U1183 INSERM

Manager : Carole CROZET

 

Neural stem cells at the frontiers of neurodevelopmental and neurodegenerative diseases

The group "Neural stem cell, MSC and neurodegenerative diseases", headed by Carole Crozet, belongs to the IRMB (Institue for regenerative medicine and biotherapy) Montpellier.

We mainly focus on the role of neurogenesis (foetal and adult) during the development of two neurodegenerative diseases (Alzheimer's disease (AD) and Creutzfeldt-Jacob's disease. In this context, we have developped several tools in culture such as the culture of foetal and adult neural stem cells, graft of neural stem cells in organotypic culture of mouse brain slices, generation of induced pluripotent stem cells from AD patients'fibroblasts.  We were able to show that NSC derived from AD iPSC exhibit some AD hallmarks not only in mature neurons but also in neural stem cell and during the early step of the neuronal differentation arguing thus for a potential role of the develoment in the establishment of the disease. We recently set up 3D neural networks recapitulating brain environment and contain brain cellular partners (neurons, astrocytes, oligodendrocyte and microglia..). To complete our panel, we are now working on the implementation of these cultrure through the elaboration of cerebral organoids that mimick the early stages of neurogenesis and corticogenesis. Recapitulating the early brain development in culture will help us to decipher mechanisms involved at the frontiers of neurodevelopment and neurodegenaration in several pathological contexts.

 

Site de l'équipe

Manager : A. Kheddar

 

Interactive Robotics and AI

Humanoids have been shown to be useful to teach social skills to young children with ASD, and to improve their capabilities to understand the meaning of communicative facial and body expressions. A major problem in the treatment of ASC children is the high variability and individual specificity of ASC. This makes it necessary to use socialization and treatment approaches that are optimized for each individual participant. Finding ways to raise the interest of children with ASC to engage in communication and play, and keep them focused is difficult and requires a lot of patience, and ideally intense and multimodal stimulation.  We will devise and evaluate a new class of robot-assisted training systems, including touch (human-robot contact). The idea is to provide professionals and parents with a solution to interact with children with ASC through robot beaming using immersive embodied telepresence and gather experience and knowledge using artificial techniques.

 

Site de l'équipe

U 1198 - mixte EPHE et Université de Montpellier

Manager : Tangui Maurice

 

Impact of environmental pollutants on neurodevelopment

Studies have suggested that the origin of neurological diseases is due to brain exposure to contaminants during the fetal stage. Our current project is to study the neuropathophysiological effects of pesticide exposure during gestation in brain development in relation to neurological disorders.

To this aim, we have developed models of  contamination from mother to child using low doses of pesticides alone or in cocktail. Mothers were exposed to low doses of pesticide during gestation and we study their impact on brain development  at various stages : early post-natal (3 and 10 dpp), adolescent (30 dpp) and adult (3, 6 and 9 months). Tissue section and immunoblotting analyses showed that pesticide exposure triggered chronic inflammation and modified the pool of neural stem cells (Wang et al., in preparation). We could search in our model if the expression of proteins involved in autism (as CPEB4) could be modified. Our model could be useful and adapted to autism, and we are ready to collaborate and share our expertise with those who will be interested. 

 

Site de l'équipe

UMR1198, INSERM, UNIVERSITÉ MONTPELLIER

Manager : Tangui MAURICE

 

Neuropharmacologie visant la communication ER-mitochondrie, dans les maladies neurodégénératives et psychiatriques

Nous travaillons sur une protéine chaperonne modulant l'efficacité des échanges, notamment du Ca2+ entre le reticulum endoplasmique et la mitochondrie dans les neurones et cellules gliales, la protéine sigma-1. Cette proteine peut être activée par des molecules synthétiques agassant comme agonistes, modulateurs positifs ou antagonistes. Les  agonistes  ont des effets neuromoulateurs, anti-amnésiants, antidépresseurs et cytoprotecteurs, que nous caractérisons dans les maladies neurodégénératives (Alzheimer, Huntington, SLA...). Une molécule, l'ANAVEX2-73, pour laquelle nous avons montré l'efficacité pré-clinique sur des modèles pharmacologiques et génétiques de la maladie d'Alzheimer est actuellement en phase clinique IIb/III. Elle est également efficace et développée en phase II dans la maldaie de Parkinson et le syndrome de Rett. Nous sommes intéressés à explorer le rôle et l'intérêt thérapeutique de cette protéine sigma-1 dans les modèles précliniques d'autisme. Notre expertise en comportement rongeur peut également permettre de mieux caractériser des modèles utilisés par les collègues du réseau.

 

Site de l'équipe

UMR1198, INSERM

Manager : Véronique PERRIER

 

Impact of environmental pollutants on neurodevelopment 

Studies have suggested that the origin of neurological diseases is due to brain exposure to contaminants during the fetal stage. Our current project is to study the neuropathophysiological effects of pesticide exposure during gestation in brain development in relation to neurological disorders.

To this aim, we have developed models of  contamination from mother to child using low doses of pesticides alone or in cocktail. Mothers were exposed to low doses of pesticide during gestation and we study their impact on brain development  at various stages : early post-natal (3 and 10 dpp), adolescent (30 dpp) and adult (3, 6 and 9 months). Tissue section and immunoblotting analyses showed that pesticide exposure triggered chronic inflammation and modified the pool of neural stem cells (Wang et al., in preparation). We could search in our model if the expression of proteins involved in autism (as CPEB4) could be modified. Our model could be useful and adapted to autism, and we are ready to collaborate and share our expertise with those who will be interested. 

 

Site de l'équipe

INSERM U1047

Manager : Jean-Philippe LAVIGNE

 

Bacterial Virulence and infectious diseases

For many years, our team has been working on chronic infections. We studied three axes:

1- A model of chronic infection: the diabetic foot ulcers. The aim is to understand the bacterial cooperation via the microbiota organisation, to develop diagnostic tools to distinguish infections from colonization, and to develop new innovative treatments,

2- The understanding of the diffusion of multidrug resistant bacteria to antibiotics in the hospital, animal and environments according to the One Health concept,

3- The participation of microbiota in chronic diseases.

It is in this third part that we have designed tools to establish the inflammatory status of patients, intestinal permeability and microbial translocation (bacterial and fungal). Coupled with studies of the digestive microbiota and proteomic analyzes of the host, these tools provide a new perspective on chronic inflammation, clinical symptomatology and therapeutic possibilities..

 

Université Montpellier III

Member : Florence COUSSON-GELIE

 

Psychological factors and processes underlying trajectories in the filed of somatic, psychiatric and neurodegenerative diseases.

 

Site de l'équipe

INSERM U1061

Manager : Claudine BERR

Marion MORTAMAIS

 

Risk factors of depression, post-traumatic stress disorder and aging.

Etiological role of polluants and pesticides on neuropsychiatric diseases.

 

Site de l'équipe

INSERM U1061

 

Amaria BAGHDADLI

Risk factors of neurodevelopmental disorders and rare psychiatric disease.

 

Tasnime AKBARALY

Nutritional psychiatry

 

Site de l'équipe

Université de Montpellier

Ludovic MARIN

 

Social motor coordination in patients suffering from social deficit

 

Site de l'équipe