NICN - UMR 7259

Neurobiology of Cellular Interactions and Neurophysiopathology

Director : Michel KHRESTCHATISKY

Faculté Médecine Nord
CS80011
51 Bd Pierre Dramard
13916 Marseille CEDEX 20
France

With complementary skills in animal models and in vitro models, the 4 research teams of the laboratory study the cellular and molecular mechanisms underlying the neural basis of brain function and malfunction. In particular, they are interested in neuronal plasticity and memory, as well as neurodegenerative and neuroinflammatory processes involved for example in Alzheimer’s disease, multiple sclerosis or spinal cord injuries. This research is directly applied in i) cell therapy approaches in the central nervous system (with neural cells and stem cells from nasal olfactory mucosa); ii) molecular therapy using agents that control the action of matrix metalloproteinases, neuroinflammation, leukocyte recruitment, axonal regeneration; iii) innovative vectorization strategies for addressing drugs and imaging agents to the central nervous system (CNS) through the blood-brain barrier (BBB).

Pictures from the NICN laboratory

Research teams

All NICN 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 Ph.D. scholarship.

Blood-brain barrier and neuroinflammation (Michel Khrestchatisky)

Unlike the vessels of the rest of the body, the BBB is characterized by tight junctions that very effectively regulate the molecular and cellular exchanges between blood and nervous parenchyma. Leukocyte recruitment is an essential step of neuroinflammatory processes associated with many diseases and injuries of the CNS; this recruitment depends on various mediators that modulate locally and possibly transiently the BBB properties to increase or conversely reduce its permeability.
The molecular and cellular mechanisms that regulate the fragility and permeability of the BBB in a neuro-inflammatory context remain poorly understood and are the center of our projects.

We are also interested in family of receptors involved in transport processes across the BBB and we develop vector molecules that bind specifically to these receptors to promote the transport of therapeutic and imaging agents across the BBB. These projects are developed in partnership with the company Vect-Horus (www.vect-horus.com), a spin off from our laboratory.

Members

Michel Khrestchatisky, Philippe Benech, Anne Bernard, Daniel Bertin, Amandine Bonnet, Romy Cohen, Max de Reggi, Sophie Desplat-Jego, Nicolas Gaudin, Bouchra Gharib, Stéphane Girard, Grigorios Kyriatzis, Delphine Stephan, Manuel Van Gijsel Bonnello, Karine Varini. Total : 3 HDRs.

Research axes

  • Effects of the proinflammatory cytokine TWEAK on the properties of the BBB
  • Inhibition of transendothelial migration of inflammatory cells and stimulation of energy metabolism: two facets of a neuroprotective molecule, pantethine
  • Neuromodulation of the BBB permeability; vectorization of molecules across the BBB.

Techniques

  • Molecular biology
  • Biochemistry
  • Cell culture
  • Immunostaining, histology, or flow cytometry
  • Microscopy
  • Animal surgery, stereotaxy
  • Pharmacology
  • Animal behavior

Keywords

Blood-brain barrier, neuro-immune interactions, therapeutic agents, vectorization, neuroinflammation, multiple sclerosis, Alzheimer, transcriptional analysis

Animal cognition and behavior - Disorders of the nervous system - Novel methods and technology development

Neural degeneration and plasticity (Santiago Rivera)

We study the basic mechanisms of neurodegeneration, plasticity and inflammation in the central nervous system, with a projection towards new strategies in neuroprotection and neurorepair. The central topic of the group is the study of the role of matrix metalloproteinases (MMPs) in these processes, in particular in the context of Alzheimer’s disease. We discovered new pro-amyloidogenic and pro-inflammatory roles of some MMPs (i.e. MT-MMPs), suggesting that these proteinases could be new therapeutic targets. We validate these targets and study their mechanisms of action in in vivo and in vitro models of the disease, using molecular and cell biology techniques, biochemistry, functional anatomy, imaging, pharmacology, behaviour and IPS cells from Alzheimer’s patients in collaboration with clinicians and other teams of the laboratory. We also study the impact of neuroinflammation on integrity and dynamics of synapses, and the role played in the regulation of these processes by proteins associated with the cytoskeleton

Members

Santiago Rivera, Kévin Baranger, Amandine Bonnet, Eliane Charrat, Lotfi Ferhat, José Morales Poole Jean-Michel Paumier. Total : 2 HDRs.

Research axes

  • Neurodegenerative diseases, proteinases and neuroinflammation: mechanisms of action and therapeutic validation
  • Inflammation and synapses: role of the cytoskeleton

Techniques

  • Molecular biology
  • Biochemistry
  • Cell culture
  • Immunostaining, histology, flow cytometry
  • Microscopy
  • Pharmacology
  • Animal behavior
  • Brain imaging – Animal

Keywords

Alzheimer, proteinases, amyloid, neuroinflammation, neuronal death cytokines, cytoskeleton, repair, glia, synapse, learning

 

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

Olfactory plasticity and brain repair (François Féron)

Our team co-discovered and characterised the adult human and rodent nasal olfactory stem cells. We use these unique cells to investigate the molecular mechanisms underlying the symptoms of Autism Spectrum Disorders. An abnormal expression of an enzyme (MOCOS) was unveiled in patients’ stem cells. We now assess the role of this enzyme during brain development and try to identify drugs that restore a physiological expression of MOCOS.

The team also uses human olfactory stem cells for repairing the pathological brain. We performed studies based on the transplantation of olfactory stem cells in models of amnesia and Alzheimer’s disease. We are currently devising new protocols for differentiating stem cells into dopaminergic neurons. The team is engaged in translating our basic research into clinical applications. Trials dedicated to nerve and bone repair are in preparation.

In parallel, in order to improve functional recovery, the team assesses the immuno-modulatory and neurotrophic roles of vitamin D. Preclinical studies on animal models of nerve section, paraplegia and Alzheimer’s disease are encouraging.

Members 

François Féron, Lucile Fievet, Madeleine Garcia, Bruno Gepner, Stéphane Girard, Emmanuelle Lacassagne, Véréna Landel, Maria Morello, Emmanuel Nivet, Pauline Rontani, Gaëlle Guiraudie, Fanny Gaudel. Total : 2 HDRs.

Research axes

  • Olfactory stem cells, a diagnosis tool
  • Olfactory stem cells for cell therapy
  • Vitamin D, a neurosteroid hormone

Techniques

  • Molecular biology
  • Biochemistry
  • Cell culture
  • Immunostaining, histology, flow cytometry
  • Microscopy
  • Animal surgery, stereotaxy
  • Animal behavior
  • Brain imaging – Animal
  • Medical data analysis
  • Bioinformatics

Keywords

Stem cells, olfactory system, plasticity, neurogenesis, cell therapy, vitamin D, autism, Parkinson disease, Alzheimer’s disease, spinal cord trauma

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

Neurobiology of mnesic processes (François Roman)

The team is working on changes in the neurobiological substrate during learning and memory processes, including in pathological conditions. The underlying hypothesis is that durable memory traces proceed from the marking of specific neural networks. These synaptic plasticity mechanisms result from molecular and structural changes that largely remain to be identified and integrated at the behavioral level.

In mice, we developed a new olfactory test, “the tubular olfactory maze” where we test the effect of molecules or genetic manipulations on different memory subcategories. We observed specific structural changes in the dorsal and apical dendrite density of CA1 pyramidal cells of the hippocampus, specifically amplified by a 5-HT4 receptor agonist known for his promnesic effect. We are currently using this test in a model of Alzheimer’s disease (5XFAD transgenic mice).

With the same aim of creating animal models to study memory, we developed a deferred task paradigm in mice that highlights specific deficits as observed in patients with frontal lobe syndrome, including a perseveration behavior.

Finally, with a view to overcome the memory deficits in our amnesic syndrome models in mice, we performed intra-hippocampal transplantation of adult stem cells from the human olfactory mucosa. Following these grafts, we observed a recovery of memory capacity and the ability of these cells to acquire a neural or glial phenotype. We are currently conducting autologous grafts in rat models of amnesia and spinal cord injuries.

Members

François Roman, Guy Escoffier, Evelyne Marchetti-Gauthier, Martine Migliorati, Kévin Sadelli, Elodie Salebert, Gilles Sicard, Jean-Claude Stamegna, Antoine Veron. Total : 3 HDRs.

Research axes

  • Effect of an agonist of 5-HT4 receptors on the dendrite structure of hippocampal neurons
  • Memory performance in a model of Alzheimer’s disease (5XFAD transgenic mice) in a tubular olfactory labyrinth
  • Deferred task tests in a mouse model of frontal syndrome
  • Autologous transplants of adult stem cells in rats with amnesia or spinal cord injuries.

Techniques

  • Molecular biology
  • Biochemistry
  • Cell culture
  • Immunostaining, histology, flow cytometry
  • Microscopy
  • Electrophysiology (in vivo)
  • Animal surgery, stereotaxy
  • Pharmacology
  • Animal behavior
  • Psychophysical tests
  • Brain imaging – Animal

Keywords

Synaptic plasticity, learning, memory, 5HT4 receptors, mnemonic disorders, transplantation, olfactory stem cells, Alzheimer’s disease, frontal disorders, spinal cord injuries

Animal cognition and behavior - Disorders of the nervous system - Excitability, synaptic transmission, network functions - Human cognition and behavior - Sensory systems
Share the article on :