Brain connectivity and neurodegenerative diseases

The Institut Pasteur has installed a research program to leverage the wide-ranging basic research expertise in the fields of neuroscience, genetics, cell and developmental biology, immunology, microbiology and infection biology to improve the understanding of the complexity of brain function and its associated disorders.

|

Mental and neurological disorders represent a significant health burden in high-income countries (25% of DALYs). Neurodevelopmental disorders can first be observed in late pregnancy or early childhood, and can last throughout the individual’s lifetime. In France, the economic burden of autism is 1.4 billion Euros each year. Higher life expectancy has also increased the prevalence of age-related disorders. For example, 100 million people worldwide will suffer from Alzheimer’s disease by 2050. The increasing prevalence of Alzheimer’s, Parkinson’s and other neurodegenerative disorders requires the search for novel mechanisms (molecular, cellular, physiological and pathogen-associated).

 

Nearly all brain disorders manifest themselves in the dysfunction of communication between brain cells (neurons) as well as communication with other organs (gut, immune system, etc), which we define as Brain Connectivity Disorders. This super-family of neurological disorders includes: neurodegenerative, neurodevelopmental, psychiatric, sensory-motor, immune and infection-related brain diseases. At the Institut Pasteur, we seek to leverage the diverse fundamental research strengths in neuroscience, genetics, cell and developmental biology, molecular and structural biology, immunology, microbiology and infection biology to tackle complexity of brain function and connectivity diseases. Research projects are currently focused on sensory deficits (deafness, blindness), neurodevelopmental (autism) and psychiatric disorders (mood disorders and addiction), neurodegenerative (Alzheimer’s and Parkinson’s diseases), and other neurological diseases (sepsis, neurovascular disorders). While further supporting these research programs, we will also intensify research programs in neuro-inflammation and microbial alterations of brain function, as well as stem cell and regenerative approaches to neural injury and degeneration.

AIMS

  1. We will boost cooperation between the various teams on campus working on these topics to optimize and improve the visibility of our multidisciplinary approach.
  2. We will encourage the investigation of novel mechanisms of brain function, pathology and neurodegeneration, including the links between the brain function and the microbiota and the links between neuroinvasive microbes and brain dysfunction.
  3. We will also reinforce the translation of novel mechanisms into diagnostic and therapeutic strategies for human subjects and patients.

SCIENTIFIC STRATEGY

To reach these goals, we will establish and reinforce cross-discipline technical approaches: genomic and cellular analyses, structure-based drug discovery for brain connectivity disorders, innovative microscopy, intact neuronal and artificial network approaches, integrative data analysis, stem cell and regenerative medicine with human and animal models live organism physiology and behavior, and the development of novel diagnostic and therapeutic approaches and tools (including computational).

Joint projects and initiatives will address fundamental (mechanistic) or translational (diagnostic/therapeutic) research related to:

  • Neurodevelopmental and psychiatric disorders
  • Sensory and motor system diseases
  • Neurodegenerative and age-related cognitive disorders
  • Brain connectivity disorders caused by infectious and commensurate microbes
  • Neuro-immune related disorders
  • Regenerative approaches to neural injury and degeneration
  • Novel computational approaches to understanding brain function or diagnosis and treatment of neurological disorders

MEASURES

  1. Recruit two five-year research groups (G5s)/research units. 
  2. Propose research funding that encourages novel synergistic approaches involving neuroscience and other disciplines, with a view to developing diagnostic and therapeutic strategies.
  3. Support the creation of the Hearing Institute (Institut de l’Audition).          
  4. Foster a partnership with the Brain and Spinal Cord Institute (Institut du Cerveau et de la Moëlle Epinière).
  5. Step up support for the infrastructure of the European Autism Innovative Medicine Studies-2-Trials (AIMS-2-TRIALS) consortium, in connection with the Innovative Medicines Initiative (IMI).
  6. Strengthen and enhance imaging, behavioral research and prototyping facilities.

PRINCIPAL COORDINATORS:

David DiGregorio, Head of Dynamic Neuronal Imaging Unit

Chiara Zurzolo, Head of Membrane Traffic And Pathogenesis Unit

DEDICATED TEAMS

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.

See the website

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.

See the website

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.

See the website

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.

See the website

Gerard Eberl - Chronic inflammation and neurodegeneration

This unit has demonstrated that the symbiotic microbiota sets the reactivity of the immune system early in life. If this ontogenic regulation fails, individuals develop increased susceptibility to inflammatory pathologies later in life, such as allergy, autoimmunity and cancer. The scientists are now assessing whether this microbe-immune system cross-regulation also affects cognition and susceptibility to brain disorders, and how such susceptibility can be prevented or reversed.

See the website

Aziz El Amraoui - Progressive sensory disorders, pathophysiology and therapy

In the absence of a cure, the highly prevalent hearing and vision disorders often lead to social isolation, depression and decreased cognitive abilities. Through cellular and animal modelling of the disease related to specific sense causal genes, the reserchers showed recently that it’s possible to single out risk factors accelerating hearing decline, and also demonstrated that gene therapy can be used to prevent and/or slow-down hearing deterioration. The team projects, focused on late-onset & progressive forms of hearing and vision impairments, are designed to: i) understand how, despite constant use from birth & throughout life, our eye and ear continue to ensure normal vision and hearing, ii) identify the disease causal genes, impact of external cues & the underlying molecular, cellular, & physiological pathogenic pathways; and iii) seek potential treatment solutions, including for vision loss in Usher syndrome, the first cause of deaf-blindness in humans.

See the website

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.    

See the website

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. 

See the website

Pierre-Lafaye: Towards amyloid plaques and tangle imaging with nanobodies

In vivo neuroimaging of the key lesions of Alzheimer Disease (AD) (amyloid plaques, Neuro Fibrillary Tangles) is urgently needed to improve the diagnosis in clinical routine, to evaluate disease progression and to screen the effects of new drugs. The use of antibodies to detect AD lesions in vivo is limited by their weak passage of the blood brain barrier (BBB). We have previously shown that VHHs or nanobodies directed against human GFAP, an intermediate filament protein specific for astrocytes have however the potential to transmigrate across the BBB in vivo. Recently, we designed VHHs against Aß and phosphorylated-tau. These VHHs have been labelled with a fluorophore and we have shown that that they can cross the BBB and reach their target. These VHH have then been labelled with Gadolinium contrastophores in order to be used as imaging probes for plaques and tangles. We were able to perform in vitro MR imaging of amyloid plaques and tangles using these conjugates. This project is developed in close collaboration with Sylvie Bay (Unité de Chimie des Biomolécules-IP) who designed and synthesized the VHH conjugates for imaging and the overall work is also a long-term collaboration with Benoît Delatour and Charles Duyckaerts, (Institut du Cerveau et de la Moëlle Épinière, Paris) and Marc-Dhenain (MIRCen-CEA).

See the website

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. 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.

See the website

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.

See the website

Monique Lafon - Pathology of viruses that target the nervous system

Research in the Viral NeuroImmunology Unit aims to establish the molecular basis for the pathogenicity of viruses that infect the nervous system, such as rabies virus. The team has discovered this virus has the intriguing property to promote the survival of the neurons it infects. Elucidation of the mechanisms of action and identification of the critical domain of the viral protein that controls survival have resulted in the development of a new drug candidate for the treatment of neurodegenerative diseases.

See the website

Uwe Maskos - Nicotinic receptors and brain disease

This unit is studying nicotinic receptors 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).

See the website

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.

See the website

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.

See the website

Christophe Schmidt-Hieber - Cellular 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, routes, events, or people, and it is perturbed in devastating neurodegenerative diseases such as Alzheimer’s dementia. 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. To address these challenges, this team combines molecular, physiological and optical approaches to read out and manipulate the activity of hippocampal neurons in navigating mice.

See the website

Timothy Wai: Dysfunctional mitochondria in inherited neuromuscular diseases

The morphology of mitochondria is inextricably linked to its many essential functions in the cell and we are interested in understanding the relationship between mitochondrial shape changes and metabolism in the context of acquired and inborn human diseases. 

Balanced fusion and fission events shape mitochondria to meet metabolic demands and to ensure removal of damaged organelles. The dynamism of mitochondria is highlighted by the dramatic changes in morphology they undergo in response to metabolic inputs. Mitochondrial fragmentation occurs in response to nutrient excess and cellular dysfunction and has been observed in mitochondrial genetic diseases that are characterized by neuromuscular dysfunction in human patients.  We use genetic screens to identify factors novel regulators and modulators of mitochondrial morphology in cells from patients that suffer from mitochondrial genetic diseases and the lessons we are learning regarding the importance of balanced mitochondrial dynamics.  Through these approaches we seek to identify and understand the role of novel regulators of mitochondrial morphology and design strategies that capable of rebalancing mitochondrial dynamics in cellular and animal models of mitochondrial genetic disease.

See the website

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.

See the website

Chiara Zurzolo - Mechanisms of 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. This unit 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. The scientists 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), they are currently studying the mechanisms of amyloid dissemination (with a specific focus on the role of TNTs); 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).

See the website

Back to top