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Cellular determinants of subthalamic nucleus function

Applicant Lüscher Christian
Number 186266
Funding scheme Sinergia
Research institution Dépt des Neurosciences Fondamentales Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Interdisciplinary
Start/End 01.06.2019 - 31.05.2023
Approved amount 2'137'488.00
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All Disciplines (4)

Discipline
Interdisciplinary
Genetics
Neurophysiology and Brain Research
Pathophysiology

Keywords (4)

RNA; Human; Single cell; Parkinson

Lay Summary (French)

Lead
Nous proposons de développer un modèle de la maladie de Parkinson en examinant la diversité cellulaire des cellules constituant le noyau sous-thalamique.
Lay summary
Dans la maladie de Parkinson, les circuits cérébraux du contrôle moteur sont dysfonctionnels. L'un de ces circuits implique le noyau sous-thalamique (STN), qui a la taille d'une cacahuète chez l'homme. Dans notre projet, nous étudierons les cellules qui composent le STN en examinant les gènes qu'elles expriment et l'activité électrique qu'elles présentent. Pour obtenir ces informations, nous allons enregistrer des cellules humaines au cours d'une stimulation cérébrale profonde et analyser les quelques cellules collées aux instruments chirurgicaux. Nous effectuerons des recherches analogues chez des souris afin de mieux comprendre les mécanismes. Les résultats de notre projet permettront d’affiner le modèle de circuit de la maladie de Parkinson et d’élaborer de nouvelles stratégies de traitement.
Direct link to Lay Summary Last update: 29.05.2019

Lay Summary (English)

Lead
We propose the development of a refined model of Pakinson's disease by examining the cellular diversity of the cells that make up the subthalamic nucleus.
Lay summary
Dans la maladie de Parkinson, les circuits cérébraux du contrôle moteur sont dysfonctionnels. L'un de ces circuits implique le noyau sous-thalamique (STN), qui a la taille d'une cacahuète chez l'homme. Dans notre projet, nous étudierons les cellules qui composent le STN en examinant les gènes qu'elles expriment et l'activité électrique qu'elles présentent. Pour obtenir ces informations, nous allons enregistrer des cellules humaines au cours d'une chirurgie cérébrale profonde et analyser les quelques cellules collées aux instruments chirurgicaux. Nous effectuerons des recherches analogues chez des souris afin de mieux comprendre les mécanismes. Les résultats de notre projet permettront d’affiner le modèle de circuit de la maladie de Parkinson et d’élaborer de nouvelles stratégies de traitement.
Direct link to Lay Summary Last update: 29.05.2019

Responsible applicant and co-applicants

Employees

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Associated projects

Number Title Start Funding scheme
166575 Genome protection by germline small RNAs 01.06.2016 Project funding (Div. I-III)
189188 Emergence of compulsion in a mouse model of addiction 01.10.2019 Project funding (Div. I-III)
182880 NCCR RNA & disease: The role of RNA biology in disease mechanisms (phase II) 01.05.2018 National Centres of Competence in Research (NCCRs)
170266 Bonus of Excellence - The emergence of a circuit model for addiction 01.10.2016 Project funding (Div. I-III)
166923 GermMethylation (ERC-2014-CoG) 01.06.2016 Temporary Backup Schemes

Abstract

BACKGROUND: A comprehensive description of cellular diversity is an essential prerequisite towards understanding circuit function in health and disease. While the gap between genes, cell-types and circuits is starting to be filled in animal models, little is known in humans, and a cellular comprehension of most brain diseases virtually inexistent. Here, we focus on the cellular diversity of the subthalamic nucleus (STN), located between the thalamus and the midbrain, because of its established role in motor actions, associative integration and emotions as well as a node for therapeutic intervention in Parkinson’s disease. We will take advantage of deep brain stimulation (DBS) targeting the STN to collect genetic and functional information, normally not accessible in humans. Clinical observations and experimental evidence suggest that the functional diversity is indeed based on the diversity of cells within the STN and their afferents. There is evidence for specialized (i) topographical subdivisions; (ii) afferent and efferent connectivity, and (iii) neuronal subclasses. For example, anterograde tracer studies in non-human primates and functional MRI in humans argue for a topographical organization: a “motor territory” located dorsolaterally, and associative as well as limbic territories ventromedially (Accolla et al., 2014; Haynes and Haber, 2013; Krack et al., 2010). Moreover, single unit recordings in humans reveal the existence of neurons that exquisitely code for specific movements (e.g. flexion of the elbow, Tankus et al., 2017). Pathophysiological evidence from local field potentials recordings in humans further support the functional subdivision of the STN: in Parkinson’s disease, excessive, pathological oscillations in the beta range (13-32 Hz) (Beck et al., 2016), that correlate with the severity of symptoms (Kühn et al., 2009), are predominantly observed in the dorsolateral region of the STN. On the other hand, immunohistochemical staining shows a rather homogeneous population of parvalbumim (PV)-positive glutamate neurons (Parent and Hazrati, 1995), yet the existence of subdivisions remains elusive (Keuken et al., 2012). HYPOTHESIS: We posit that distinct neuronal classes sub-serve the functional specialization of the STN, in health & Parkinson’s disease.AIMS & WORKPACKAGES: Aim 1. We will carry out single cell RNA sequencing (scRNA-seq) & single unit recordings (Spike-seq) l in mice (WP1) and humans (WP2). Aim 2. We will identify the coding and non-coding RNA determinants of neural activity and behavior (Patch-seq, Motion-seq) in mice.INTERDISCIPLINARY APPROACH: We propose a collaborative effort between neurosurgery, basic neurosciences (electrophysiology) and RNA biology (single cell transcriptomics). We will take advantage of the unique opportunity to record the activity of single units during DBS surgery in awake humans with PD and in freely moving mice (with and without 6OH-DA-induced parkinsonism) and cluster them according to their firing pattern (Spike-seq). We will harvest neurons in humans from the cannula used to guide the DBS electrodes, and perform scRNA-seq. This data will be compared to RNA expression profiles in mice. Novel tools to analyze human cells by comparing them with rodent neurons (cluster intermapping) reflect the translational nature of the project. Finally, exploring links of causality, we will examine the contribution of cell type-defining genes and non-coding RNAs to electrophysiological parameters and mouse behavior. We will perform scRNA-seq after current clamp recordings (patch-seq). To map the contribution of identified cell types to behavior, we will optogenetically control their activity while monitoring locomotion with a 3D camera at high temporal resolution (Motion-seq).IMPACT & OUTLOOK: Our interdisciplinary & translational project will provide proof-of-principle for a cell-based understanding of the STN function and may transform how we see this nucleus. Our results may constitute foundations in future studies for a cellular understanding of symptoms in PD, and guide research on the mechanism of DBS. Last but not least, our methods development may lead the way for research on cellular diversity in other parts of the brain for other diseases.
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