Neurodevelopmental and psychiatric diseases

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Department of Cell Biology & Infection

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 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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Jean-Pierre Levraud – Viral infection / Neuro-inflammation and central nervous system development

Our team studies the impact of viral infection and neuroinflammation on the developing central nervous system (CNS), using the zebrafish larva as a transparent model system.  

We study the impacts of neuroinflammation on the developing CNS, either by microinjection of immunostimulants or by developing optogenetic systems for space- and time-controlled induction of cytokine expression. We analyze how inflammatory cytokines modulate spontaneous electrical activity of nascent neurons during embryonic life, impacting the differentiation of monoaminergic neurons and causing schizophrenia-related phenotypes.

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Department of Neurosciences

Thomas Bourgeron - Neurodevelopmental disorders: from mechanisms to treatments

This group gathers psychiatrists, neuroscientists and geneticists to understand the causes of autism and neurodevelopmental disorders (NDD). They previously identified one synaptic pathway associated with autism – the NLGN-NRXN-SHANK pathway. This pathway is known for playing a role in synapse formation and in the balance of excitation and inhibition within the brain. Their results highlight the genetic heterogeneity of ASD, but also point at common pathways that could constitute relevant targets for new treatments. They are currently performing a thorough genomic and clinical profiling of a large number of individuals using high-throughput sequencing and brain imaging. In parallel, they are focusing on a set of mutations that they identified in genes related to the synapse (NLGN, SHANK, CNTN) by studying in depth their functional impact at the clinical and neuronal levels by using human induced pluripotent stem cells (iPSC) and animal models. This group is developing new methods for analyzing whole genome and brain imaging data as well as new paradigms for characterizing mouse social and vocal behaviors.

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Pierre-Jean Corringer - Allosteric functioning of synaptic receptors and its regulation by pharmaceutical compounds :

The scientists are working on the molecular architecture and conformational dynamics of ligand-gated ion channels that play a central role in chemical synapses. They combine to this aim structural techniques such as X-ray crystallography and cryo-EM, with electrophysiological and fluorescence approaches. The gain knowledge is used to develop original drug-design programs, notably against nicotinic acetylcholine receptors that are involved in addictive and neurodegenerative pathologies.

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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). 

In the "psychiatric disease" context a second pathology addressed is schizophrenia, and its relationship with heavy smoking. There also, large-scale GWAS identified the same human polymorphisms, a haplotype on chromosome 15q. Using advanced two-photon imaging in the wake behaving mouse, we were able to identify a network of cortical interneurons expressing nAChRs, and a key role for the alpha5 SNP in reduced cortical activity reminiscent of “hypofrontality” in human patients. This altered activity is restored by the application of chronic nicotine, lending support to the “self-medication” hypothesis, i.e. psychiatric patients smoke to alleviate symptoms of the disease. The role of the human SNPs in nicotinic receptors is further pursued with our clinical partners at the Fernand Widal university hospital, in the context of a "hospital-university federation" (FHU). 

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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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