Understanding mechanisms of brain function

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Department of Cell Biology & Infection

Sandrine Etienne-Manneville - Astrocytic responses to inflammatory situations

Astrocytes form the majority of glial cells of the central nervous system. They play a key role in brain homeostasis, they serve as physical and nutritional support for neurons and they directly participate in synaptic transmission. In inflammatory situations, such as those induced by infections, traumas, autoimmune and neurodegenerative diseases and cancer, astrocytes undergo a reaction called astrogliosis, which is often detrimental to neuroregeneration. Astrogliosis is associated with changes in cell shape and polarity, proliferation and migration together with changes in protein expression.

The Cell Polarity, Migration and Cancer group aim to identify the keys factors controlling to astrogliosis to eventually limit this reaction. We have shown that GFAP a glial intermediate filament protein overexpressed during astrogliosis plays a crucial role in astrocyte polarization and migration. Modulating GFAP-mediated cell responses paves the way to new therapeutic strategy to modulate astrogliosis and its consequences in inflammatory situations.

In addition, we develop a project on Alexander disease, a leukodystrophy characterized by abnormal protein deposits known as Rosenthal fibers. This genetic disorder is caused by GFAP mutations which leads to the disorganization of the intermediate filament network. We investigate the consequence of these mutations on astrocyte behaviour during the disease. 

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Marc Lecuit - Pathophysiology of central nervous system infections, a bedside-to-bench approach

Microbes can reach the central nervous system (CNS) and/or its envelopes, leading to encephalitis and meningitis. CNS infections are associated with high morbidity, mortality and long-term sequelae. Yet the etiology of up to half of CNS infections remains unknown, and the mechanisms by which microbes reach, disseminate in and induce long-term damages to the CNS are far from fully understood. We study the model bacterium Listeria monocytogenes, which in Western countries is a leading cause of encephalitis, as well as neurotropic emerging viruses, including SARS-CoV-2. Our research integrates clinical data (large cohorts of adults and children with CNS infection, MONALISA and SEAe cohorts) and experimental approaches that combine microbiology, cell biology and immunology. We are in particular interested in identifying the microbial and host factors that account for microbial invasion of and dissemination within the CNS, and for host susceptibility to central nervous system infections.

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Thomas Wollert - Preventing neurodegeneration by cellular recycling 

The hallmark of many neurodegenerative disorders including Parkinson’s and Alzheimer’s disease is the accumulation of toxic protein aggregates in neurons. We study cellular recycling systems that efficiently degrade such aggregates. Autophagy is one of the most versatile recycling systems in human cells but its activity decline with age. Furthermore, impaired autophagy is associated with the onset of neurodegeneration and represents a major risk factor. We investigate the interdependence of neurodegeneration and autophagy at a molecular level using innovative biophysical approaches in vitro and in vivo. We are reconstituting critical steps in autophagy in vitro from purified components to study fundamental molecular mechanisms of the pathway. The derived knowledge complements our biophysical studies of autophagy in neurons. Through this powerful combination of in vitro and in vivo approaches, we recently identified an autophagy pathway that counteracts protein aggregation in neural cells. By improving the activity of this pathway, we were able to prevent the accumulation of protein aggregates in neurons and, most importantly, to reverse protein aggregation. This study exemplifies the importance of basic research for the development of novel therapeutic approaches to treat and cure neurodegeneration.

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Chiara Zurzolo - Mechanisms of intercellular communication in the brain and role in the progression of neurodegenerative diseases

Neurodegenerative diseases (NDs) are protein conformational disorders linked to the propagation of protein misfolding in the brain in a prion-like manner. We discovered that, like prions, misfolded amyloid aggregates of a-synuclein and tau (accumulating, respectively, in Parkinson and Alzheimer disease) spread between neurons in Tunneling Nanotubes (TNTs), a new mechanism of intercellular communication. We propose that TNTs are a major avenue for pathology spreading and thus represent a novel therapeutic target in NDs. By using a multidisciplinary approach and different models (primary neurons, human IPCs, mouse brain slices and zebrafish), we are currently studying the mechanisms of amyloid dissemination and the roles of the lysosomal and autophagic pathways in the progression of these diseases (specifically in cellular models of Parkinson’s and Alzheimer’s).

Furthermore, based on the high frequency of TNTs in non-differentiated cellular states, we hypothesize that TNTs could represent an early feature of cell to-cell communication. Specifically, we propose that in the brain TNTs could serve as a non-synaptic mechanism of communication and be instrumental in early brain development for promoting the emergence of functional mature neuronal networks. We therefore investigate the presence and communicative function of TNTs in the developing brain, by applying a multidisciplinary approach spanning from molecular biology to cellular physiology and a battery of tools relying on cutting edge brain‐mapping methods, computational biology and advanced cellular imaging techniques.

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Department of Computational Biology

Jean-Baptiste Masson - Model organism insights into neural circuit deficits 

The Decision and Bayesian Computation Unit aims at developing a new model for brain connectivity and neurodegenerative disorders, namely the drosophila larva. By combining the advanced genetic toolkits allowing single neuron addressing, optogenetic activation and inactivation of these neurons, the mapping of larva behavior onto the nervous systems, the nearly complete neural connectome (with synaptic resolution) and large scale screens of larva behavioral recordings (up to 20 000 per day), they have a unique opportunity to understand to address diseases at the scale of millions of individual. Furthermore, using electron microscopy and a virtual reality software developed in the lab, they can detect modification of small neural circuit connectivity within the larva nervous system and thus study the evolution of the disease at the synaptic scale.

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Department of Developmental & Stem Cell Biology

Laure Bally-Cuif - Mechanisms of neural stem cell homeostasis 

Adult neural stem cells (NSCs) are key to brain plasticity, and NSC alterations correlate with mood disorders, ageing and cancer. Using the zebrafish model, this team aims to decipher basic genetic principles of adult NSC maintenance and recruitment in the vertebrate brain, with focus on the large-scale spatio-temporal coordination of NSC states and fate choices within their niche in vivo. These studies are directly relevant to the fields of glioblastoma SCs and the in vitro reconstitution of NSC ensembles.

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Department of Neurosciences

Thomas Bourgeron – Basic research on animal communication

Our group explore the factors that influence the social brain in humans and in other species. In parallel to our work on autism spectrum disorders (ASD), we investigate the evolution conservation of the genetic and neuronal circuits associated with our abilities to communicate. We developed new tools and methods to track live mice during a long period in order to analyze their spontaneous interactions and ultrasonic vocalization. We also showed that mice mutated in genes with ASD displayed atypical social behavior suggesting that the genes associated with such abilities are conserved during evolution.

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David Digregorio - Synaptic basis of brain function and dysfunction 

Symptoms of brain diseases often arise from alterations in the functional connectivity of neural networks. This laboratory specializes in understanding the molecular and cellular basis of synaptic function and diversity, and how they play a role in driving neural network activity underlying behavior. The researchers are collaborating with Thomas Bourgeron to examine how gene alterations found in autism patients alter synaptic, neuronal and circuit function, ultimately leading to disease symptoms. They hope that such mechanistic studies will not only provide insight neural basis of behavior, but as well provide the foundation for understanding the pathophysiology brain diseases and identify new therapeutic approaches.

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Florent Haiss - Neocortical circuits for touch perception in health and disease

How sensory information is processed and how it is modulated in different brain areas is a key question in systems neuroscience. The long-term goal of our research is to understand how neuronal networks in different parts of the brain interact during perception and how this interplay forms the basis of learning and decision-making. By unraveling these circuits, this team expects to gain insights into principles of mammalian brain function, and to provide a framework to understand how circuit dysfunction causes mental and behavioral aspects of neuropsychiatric disorders. 

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Pierre-Marie Lledo - How experience and time shape brain circuits.

The Lledo laboratory has developed a multi-scale approach to understand the function and the plasticity of neuronal circuits involved in sensory perception, memory and mood control. In particular, researches are aimed at the interface between neuroscience and behavioral science to elucidate complex neural systems underlying behaviors. The team gathers neuroscientists, psychiatrists, and computational scientists to combine modern neurophysiological techniques —in vitro and in vivo awake electrophysiology, optogenetics, awake 2-photon imaging, deep-brain fiber photometry— with behavioral analysis (both human and mice) and theoretical modeling in order to monitor and manipulate neuronal circuits during behavior and in pathological contexts. The team has solid expertise in animal models and behavior, having developed a wide range of behavioral tests to evaluate sensory modalities, mood states, cognitive functions and social interactions. The scientists visualize the dynamic re-wiring of connections (triggered by adult neurogenesis) in mouse models to provide further insight for translational research into mood disorders or viral infections.

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Uwe Maskos - Nicotinic receptors and brain disease

This unit is studying nicotinic acetylcholine receptors (nAChRs) and the role of their human polymorphisms in a number of models like Alzheimer's disease, schizophrenia, and nicotine addiction. This team is specifically interested in "humanising" our models by the use of human induced pluripotent stem cells (hiPSC). 

Our "fundamental" research theme is the nicotinic receptor, at the basis of nicotine addiction, which presents a serious social and public health problem. It is the single most important preventable factor of mortality and morbidity worldwide. More than 100 million people are expected to die this century from the consequences of smoking, and also second hand smoke.  

But it is also a major player in a number of other pathologies, including Alzheimer’s disease, Parkinson’s disease, schizophreniamultiple sclerosis and ALS. Hence, the identification of the molecular mechanisms and circuits involved urgently requires the development of novel tools allowing genetic and molecular manipulation in vivo, in experimental animals, and human induced pluripotent stem cells (hiPSC). 
Over the last years, we have based most of our work on robust Genome-wide Association Studies (GWAS) linking human polymorphisms in genes coding for the nicotinic acetylcholine receptor (nAChR) to smoking. We have focused on a coding Single Nucleotide Polymorphism (SNP) in the CHRNA5 gene, coding for the alpha5 nAChR subunit, and dissected its role in reinforcement, consumption levels, and relapse. Analysing the role of a second gene linked through GWAS, CHRNB4, coding for the beta4 nAChR, we were able to identify a new circuit determining nicotine intake, and implicating the medial habenula-interpeduncular pathway. These findings have led to an approach of “precision medicine”. 

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Christine Petit (and the Hearing Institute) - Hearing and associated disorders, from mechanisms to treatment

Exploring the neuronal network functional connectivity of auditory central pathways and cortices, associated plasticity and multimodal sensory integration as well as how they are altered by hearing deficits of genetic and non-genetic origins including those present in schizophrenia and autism... Understanding the link between auditory impairment and dementia (Alzheimer), with prospects of prevention and curing. Noise-Induced Hearing Loss, the major environmental cause of hearing loss and presbycusis (age-related hearing impairment): development of corresponding biomarkers for multiparametric diagnosis (innovative audiometric tests, brain imaging, psychoacoustics, genomics, epigenomics, other biological markers with integration by Artificial Intelligence), rationalization of clinical trials (stratification of populations) for the testing candidate therapeutic agents and search for new therapeutic agents. Gene therapy for curing monogenic severe to profound deafness. The strategy is based on a continuous back and forth movement between patients and animal models. Collaborative works in perspective with the Immunology Department.

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Christoph Schmidt-Hieber - Cellular and circuit basis of memory formation in health and disease

Forming distinct memories of episodes that closely resemble each other is a critically important task for our brain, as it allows us to distinguish between similar places, events, or people. The input gate to the hippocampus, the “dentate gyrus”, has been suggested to serve this purpose. Intriguingly, during adult life, the dentate gyrus is also one of the few brain regions that is constantly supplied with new neurons. How the activity of new adult-born and mature neurons combines to drive the production and storage of distinct memories represents a new frontier in understanding brain function. This team combines electrophysiological, imaging and behavioural techniques in rodents to explore how this challenge is resolved in the hippocampus and associated brain structures, and how these processes are disrupted in pathological states such as Alzheimer’s Disease.

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