INMED - INSERM U901

Mediterranean Neurobiology Institute

Director : Rosa Cossart

Campus Luminy - BP 13
163, route de Luminy
13273 Marseille CEDEX 9
France

The Institute of Mediterranean Neurobiology (INMED) is a leading Neuroscience Centre affiliated to INSERM and Aix-Marseille University. INMED investigates the development and plasticity of neuronal synapses and circuits in health and disease. Recently, the center became a pioneering leader in the field of Developmental Systems Neuroscience.

Over the years, the INMED scientific strategy has been to gather groups sharing a common scientific goal, but with complementary experimental approaches that enable describing and manipulating structure and function of neuronal synapses and circuits with unprecedented precision in intact preparations. INMED has been internationally recognized for its contributions in the fields of developmental neurophysiology and epilepsy by bringing together electrophysiologists and neuroanatomists. These approaches have been further reinforced during the past years by the recruitment of new leading scientists, examining neuronal circuits from two different directions, genes and behavior, which allowed for a broadening of INMED scientific expertise to other developmental disorders and to psychiatric diseases, as well as to the understanding of information coding in brain circuits of behaving rodents, thus covering the full spectrum of brain description from molecules to behavior.

Developmental neuroscience and circuit neurophysiology are traditionally studied separately for technical and historical reasons. INMED has now become a unique place in the world where the temporal gap between early developmental programs and information coding in adult brain circuits of behaving animals can be bridged.

Currently INMED comprises 9 independent labs, including three ERC projects and two International Affiliated INSERM Units (LIA). Altogether INMED gathers 150 members. INMED hosts shared facilities and services organized in administrative or technological platforms: an imaging platform “Inmagic” that includes two-photon and light-sheet microscopes, a molecular and cellular biology platform “PBMC”, two animal facilities and a service that allows for the development of novel models for brain pathologies based on in utero electroporation, a histology service as well as one of the largest collection of electrophysiology setups (in vivo and in vitro).

Pictures from the INMED laboratory

Research teams

All of the 9 INMED teams are affiliated to the neuroscience master’s program and can thus train neuroscience master’s students and offer them projects to apply for a Neuroscience Ph.D. scholarship:

  • A developmental scaffold for the organization of cortical networks
  • Neuronal coding and plasticity in epilepsy
  • Neuronal coding of space and memory
  • Early activity in the developing brain
  • Adolescence and developmental vulnerability to neuropsychiatric diseases
  • The neural bases of sensorimotor learning
  • Molecular basis and pathophysiology of cortical development disorders
  • Early life imprinting and neurodevelopmental disorders
  • NICE2: Neonatal, Infantile and Childhood Epilepsies and Encephalopathies

A developmental scaffold for the organization of adult cortical networks (Rosa Cossart)

Most adult cortical dynamics are dominated by a minority of highly active neurons distributed within a silent neuronal mass. If cortical spikes are sparse, spiking of single distinct neurons, such as hub neurons (Bonifazi et al. 2009), can impact on network dynamics and drive an animal’s behavior. It is thus essential to understand whether this active and powerful minority is predetermined and if true to uncover the rules by which it is set during development. Current work in the lab aims at testing the possibility that birthdate is a critical determinant of neuronal network function into adulthood, in health and disease. More specifically, we reason that neurons that are born the earliest are primed to participate into adult network dynamics. This hypothesis is considerably fed by our past work aiming at understanding how cortical networks function and assemble during development. To test this hypothesis, and more generally to describe structure-function relationships in cortical networks, we have developed a multidisciplinary approach that combines in vitro and in vivo calcium imaging and electrophysiology, neuroanatomy, notably from clarified intact structures, mathematical analysis and mouse genetics.

Members

Rosa Cossart, Agnès Baude, Yannick Bollmann, Richard Boyce, Marco Bocchio, Loris Cagnacci, Davide Cavalieri, Claire Gouny, Laura Modol-Vidal, Catherine Pauchet, Thomas Tressard, Pierre-Pascal Lenck-Santini , Michel Picardo. Total : 2 HDRs.

Research axes

• Developmental systems neuroscience
• Hippocampal circuit function

Techniques

  • Two-photon calcium imaging (in vitro and in vivo)
  • Electrophysiology (in vitro and in vivo)
  • Optogenetics
  • Animal surgery, stereotaxy
  • Electroencephalography (EEG)
  • Computational Neuroscience
  • Mouse genetics
  • Neuroanatomy
  • Light-Sheet Microscopy

Keywords

Development, Hippocampus, GABA, cortex, circuits, electrophysiology, memory, neuronal coding, epilepsy

Neuronal coding of space and memory (Jérôme Epsztein)

The hippocampus is important for our capacity to locate ourselves and navigate in familiar environments (spatial navigation). Our team is interested in understanding spatial navigation and its link with episodic memory formation. We address this question at the behavioral, network and cellular levels. At the behavioral level we train animals to navigate in real or virtual environments. Compared to real environments, virtual reality environments allow a better control of external sensory cues available to the animal to locate itself within the environment. At the network level we use extracellular electrodes (e.g. silicon probes) to record the spiking activity of hundreds of cells in the hippocampal formation (hippocampus, entorhinal cortex) while animals are navigating. Because extracellular recordings can only record the spiking output of neurons but not the intracellular mechanisms leading to that spiking (synaptic inputs and intrinsic properties) we also recently contributed to the development of a new technique allowing to perform intracellular patch-clamp recordings of hippocampal neurons in navigating animals (Epsztein et al., 2011). Intracellular recordings allow us to study the cellular mechanisms of spatial coding in great detail.

Members

Jérôme Epsztein, Julie Koenig, Geoffrey Marti, Peter Morgan, François-Xavier Michon,  Romain Bourboulou.

Research axes

  • Role of local sensory cues in setting hippocampal spatial coding resolution (extra VR)
  • Role of self-motion cues and external visual cues in grid cells activation (extra VR)
  • Role of intrinsic neuronal excitability in place cells’ activation (patch anesth/VR)
  • Effect of locomotion on membrane potential dynamics of hippocampal principal cells (patch VR)

Techniques

  • Immunostaining, histology, or flow cytometry
  • Microscopy
  • Electrophysiology (on slices or cells)
  • Electrophysiology (in vivo)
  • Animal surgery, stereotaxy
  • Animal behavior
  • Optogenetics
  • Virtual reality

Keywords

Network, hippocampus, behavior, virtual reality environment, spatial navigation, memory, episodic memory.

Animal cognition and behavior - Excitability, synaptic transmission, network functions - network functions

Early activity in the developing brain (Rustem Khazipov)

Our team is interested in the neuronal network activity expressed in the brain at the early developmental stages. In particular, we study the generation of the patterns of activity in the sensory (somatosensory and visual) cortices, with the aim to understand the neuronal network mechanisms of the earliest patterns, early gamma oscillations and spindle-burst, and their roles in the activity-dependent formation of the cortical maps. Consequently, we extrapolate our hypothesis made in the animal models to the human premature neonates, with the aim to understand how the brain operates during fetal stages. We are also studying the developmental changes in GABAergic neurotransmission, and its roles in the generation of physiological and pathological activities in the developing and mature brain after trauma (hypoxia, epilepsy and tramatic brain injury).

Members 

Rustem Khazipov, Rivera Claudio, Minlebaev Marat, Molinari Florence, Pellegrino Christophe, Carabalona Aurélie, Tessier Marine, Di Scala Coralie. Total : 2 HDRs

Research axes

  • Physiological patterns of activity in the developing brain
  • Developmental changes in GABA signaling
  • Epileptic activity in the developing brain
  • Neuroprotection of newborn during delivery
  • Secondary neurogenesis in link with post traumatic depression

Techniques

  • Molecular biology (PCR…)
  • Biochemistry (Western blot…)
  • Cell culture
  • Immunostaining, histology, flow cytometry
  • Microscopy (fluorescence, confocal, electronic…)
  • Calcium imaging
  • Electrophysiology (on slices or cells)
  • Animal surgery, stereotaxy
  • Pharmacology
  • Animal behavior
  • Movement or posture analysis, electromyography (EMG)
  • Optogenetics
  • Electroencephalography (EEG)
  • Bioinformatics

Keywords

Development, neonate, electroencephalogram, cortex, barrel system, visual system, GABA, epilepsy, hypoxia, depression, secondary neurogenesis, oxytocin, fetal alcohol syndrome, chloride transporters.

Animal cognition and behavior - Computational neuroscience - Development of the nervous system - Disorders of the nervous system - Excitability, synaptic transmission, network functions - Motor systems - Novel methods and technology development - Sensory systems

Adolescence and developmental vulnerability to neuropsychiatric diseases (Olivier Manzoni/ Pascale Chavis)

Our general aim is to understand how meso-corticolimbic (MCL) microcircuits are shaped throughout early life critical periods especially adolescence, to give rise to harmonious emotional behaviors and cognitive functions in adulthood. Specifically, we want to understand how environmental and genetic insults modeling neuropsychiatric diseases transform the architecture and the functionality of synaptic networks and reduce the behavioral working range.

Our previous work fueled the concept that structural and functional damages during early life periods including adolescence are causal in disease-linked behavioral deficits. Our core hypothesis is that adolescence delineates a period of maximal vulnerability and consequently is a critical determinant of how environments and genes shape neuronal network functions into adulthood (Bara et al. 2018; Labouesse et. al. 2017; Manduca et al. 2017; Bouamrane et al. 2017; Iafrati et al. 2016; Iafrati et al. 2014).

Our research project will allow disambiguating complex phenotypes into new developmental endophenotypes and rational design of innovative therapeutic strategies

Members

Olivier Manzoni, Pascale Chavis, Anne-Laure Pelissier, Olivier Lasalle, Milene Borsoi, Antonia Manduca, Andrew Scheyer, Aurore Thomazeau, Axel Bernabeu, Marion Deroche, Pauline Guily, Pierre Castel, Pauline Simon. Total : 3 HDRs.

Research axes

  • Neurophysiology synaptic networks
  • Neuropsychiatric diseases

Techniques

  • Microscopy
  • Calcium imaging
  • Electrophysiology
  • Animal behavior
  • Optogenetics

Key words

Synapse, synaptic plasticity, accumbens, prefrontal cortex, endocannabinoid, mGluR, pharmacotherapy, addiction, autism, Fragile X, nutrition, adolescence, omega 3

Animal cognition and behavior - Development of the nervous system - Disorders of the nervous system - Excitability, synaptic transmission, network functions

The neural bases of sensorimotor learning (David Robbe / Ingrid Bureau)

Associative and procedural forms of learning require the detection and integration of sensory information and the generation, through trial-and-error, of adaptive motor responses. Such processes rely on changes in neuronal activity in the primary sensory cortex and in motor regions such as the basal ganglia. The goal of the team is to understand how animals learn and control their actions and the neural processes implementing learning and behavior control. For this, we design and engineer new behavioral tasks in rodents (mice and rats) that allow to dissect the main constraints of performance (what strategies/algorithms are used by animals). We combined these tasks with  in vivo electrophysiology (tetrodes, silicon probes, optrodes), manipulation of neuronal activity (close-loop optogenetic stimulation, brain lesions, pharmacological inactivation), ex vivo electrophysiology (patch-clamp, functional mapping with laser scanning photostimulation) and behavioral/neural statistical analysis to draw correlations and causal links between features of the animal behavior and changes in the dynamics of neuronal population or single cell activity and in the pattern of circuits. Finally we are also interested in understanding brain diseases during which learning and motor control are altered (such as Parkinson disease, autistic disorders, epilepsy). In this general framework we are particularly interested in 1) the role of the motor cortex and basal ganglia in the control of locomotion, 2)  how tactile information gathered by whiskers are processed in barrel cortex and 3) how sensory information influence the dynamics of locomotion.

Members

David Robbe, Ingrid Bureau, Maria Teresa Jurado-Parras, Mostafa Safai, Jordane Louis, Pauline Perron, Anas Tinakoua. Total : 1 HDR

Research axes

Neuronal bases of sensorimotor learning and motor control.

Techniques

  • Electrophysiology (in vivo, in vitro)
  • Histology/Anatomy
  • Animal surgery, (stereotaxic injection of excitotoxic compounds,  virus, tracers)
  • Animal behavior
  • Movement or posture analysis (EMG)
  • Optogenetics
  • Electroencephalography (EEG)
  • Data Analysis/Modeling
  • Programming

Key words

Learning, basal ganglia, barrel cortex, motor cortex, neuronal coding, circuits, behavior, electrophysiology, optogenetics, multi-electrode.

Animal cognition and behavior - Disorders of the nervous system - Excitability, synaptic transmission, network functions - Motor systems - Sensory systems

NICE2: Neonatal, Infantile and Childhood Epilepsies and Encephalopathies (Pierre Szepetowski)

Genetic and nongenetic (viruses, drugs…) factors may cause or influence a broad range of neurodevelopmental disorders, including severe epilepsies and encephalopathies, which can be associated with comorbid manifestations (e.g. cognitive or behavioral impairment).

Despite the recent identification of various genes participating in such disorders, the underlying pathogenic mechanisms and rationale for treatment still remain poorly understood. In these conditions, identifying the early events likely altered during brain development and deciphering the underlying pathophysiological processes is mandatory.

The NICE2 team aims at studying and at targeting the early pathophysiological events associated with epilepsies and encephalopathies of genetic or nongenetic origin, using multidisciplinary approaches in vitro and in vivo.

We are particularly interested in the pathological alterations that occur early in the developing brain and that may have profound and long-term consequences on brain development and functioning.

Our main objectives are:

  • to better understand pediatric epilepsies and epileptic encephalopathies of genetic origin, and to design novel rescue strategies in those contexts;
  • to investigate on secondary pathophysiological events, such as neuroimmune alterations (e.g. microglia dysfunctioning), that are likely to impact on the severity, the comorbidity, the outcome and the responses to treatments;
  • to decipher how nongenetic factors (e.g. viral infections) impact on brain development and ultimately lead to neurodevelopmental disorders.

Members

Laurent Aniksztejn, Sylvain Bauer, Hélène Becq, Nadine Bruneau, Nail Burnashev, Alexandre Pons-Bennaceur, Manal Salmi, Pierre Szepetowski. Total : 3 HDRs

Research axes

We study four rodent models of different neurodevelopmental disorders where both specific and non-specific determinants are likely involved, albeit at different levels, in the emergence and in the variable evolution of the phenotypes. Those disorders are:

  • KCNQ2-related early-onset epileptic encephalopathies
  • GRIN2A-related disorders
  • TSC1-related disorders
  • Cytomegalovirus (CMV)-related disorders

Techniques

  • Molecular biology
  • Biochemistry
  • Cell culture
  • Immunostaining, histology, flow cytometry
  • Microscopy (confocal, 2-photon)
  • Electrophysiology (in vitro, in vivo)
  • Animal surgery, stereotaxy
  • In utero electroporation
  • Animal behavior

Key words

Epilepsy / Encephalopathies /Brain development / NMDA Receptors / GRIN2A / Kv7.2 / Tuberous sclerosis complex /Congenital cytomegalovirus / Microglia / Rodent models

 

Animal cognition and behavior - Development of the nervous system - Développement du système nerveux - Disorders of the nervous system

Neuronal coding and plasticity in epilepsy (Valérie Crépel)

Our team is interested in the coding of information in the hippocampus, a structure involved in memory. We focus our works on the dentate gyrus, sitting between the entorhinal cortex and area CA3. This region is both anatomically well positioned and physiologically predisposed to play the role of a gate, blocking or filtering excitatory activity from the entorhinal cortex. We investigate the neuronal computation and plasticity of dentate granule cells in normal and pathological conditions. Our studies are conducted at multiscale levels i.e. from the individual spine to the microcircuit. We also analyze the role of cell adhesion molecules implicated in ion channel positioning which are implicated in autoimmune diseases.

Members

Valérie Crépel (DR), Catherine Faivre-Sarrailh (DR), Edouard Pearlstein (CR), Céline Boileau (IR), Angélique Péret (IR),Guilia Bonnetto (Post-doc), Thomas Marissal (Post-doc), Claire Pléau (PhD Student), Shu Ho (PhD Student), Lucas Goirand-Lopez (Engineer student). Total : 2 HDR.

Research axes

  • The coding of information in the hippocampus
  • The neuronal computation and plasticity of dentate granule cells in normal and pathological conditions
  • The role of cell adhesion molecules

Techniques

  • Electrophysiology
  • Cell culture
  • Calcium imaging
  • Immuno-histochemistry
  • Animal behavior

Key words

hippocampus, rodent, lobe epilepsy, autoimmune diseases, dentate gyrus.

Animal cognition and behavior - Disorders of the nervous system - Excitability, synaptic transmission, network functions

Molecular basis and pathophysiology of cortical development disorders (Carlos Cardoso)

INMED

Early life imprinting and neurodevelopmental disorders (Françoise Muscatelli-Bossy)

INMED

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