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Rewiring of inhibitory circuitries in Parkinson's disease

English title Rewiring of inhibitory circuitries in Parkinson's disease
Applicant Tan Kelly
Number 150683
Funding scheme SNSF Professorships
Research institution Biozentrum der Universität Basel Systembiologie
Institution of higher education University of Basel - BS
Main discipline Molecular Biology
Start/End 01.10.2014 - 30.09.2018
Approved amount 1'597'725.00
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Keywords (9)

optogenetic; Substantia nigra pars reticulata; inhibitory systems; neuronal specificity; Parkinson's disease; pharmacology; basal ganglia; neuromodulation; synaptic transmission

Lay Summary (Italian)

Lead
Motor behavior stands at the core of every mammalian organism’s survival and evolvement within its environment. It mediates a broad spectrum of important tasks from simple motion to highly complex abilities such as speech in humans. Any disability affecting motor behavior has the potential to severely compromise life of an organism. Understanding how different motor tasks are distributed and modulated through specific neuronal circuits is crucial for the prevention and correction of pathological conditions. Our research aims at the identification and dissection of specific sub-circuits responsible for both simple and complex tasks.
Lay summary

We mainly focus our research on the output nucleus of the basal ganglia, the substantia nigra pars reticulata. This brain region controls our motor actions among other functions. We use transgenic mice and apply an array of methods including, confocal imaging, in vitro and in vivo electrophysiology and behavior. These techniques are complemented by mapping, pharmacological and optogenetic tools. 
Our aim is to understand how specific subcircuits of the basal ganglia drive precise aspects of simple and more complex motor tasks in physiological conditions. In neurodegenerative diseases such as Parkinson’s disease, these circuits are altered. Identifying the cellular, synaptic and circuit modifications will provide key knowledge on the pathological motor symptoms and therefore allow us to propose specific therapeutic strategies


Direct link to Lay Summary Last update: 07.07.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment
Kojima Ryosuke, Bojar Daniel, Rizzi Giorgio, Hamri Ghislaine Charpin-El, El-Baba Marie Daoud, Saxena Pratik, Ausländer Simon, Tan Kelly R., Fussenegger Martin (2018), Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment, in Nature Communications, 9(1), 1305-1305.
Design and ocnstruction of a low-cost nose poke system for rodents
Giorgio Rizzi, Meredith Lodge, Tan Kelly (2016), Design and ocnstruction of a low-cost nose poke system for rodents, in Methods X, 3, 326-332.
Dopamine and Acetylcholine, a circuit point of view in Parkinson's disease
Giorgio Rizzi, kelly R. Tan, Dopamine and Acetylcholine, a circuit point of view in Parkinson's disease, in Frontiers in Neural circuits.

Collaboration

Group / person Country
Types of collaboration
Martin Fusseneger Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Bettler Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Christoph Handschin Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Neurons, Brains and Behavior Seminar Series (NBBS) Talk given at a conference Neural circuit basis for the physiopathology of motor behaviors 09.11.2018 Washington DC, United States of America Tan Kelly;
SFN 2018 Poster Rubral encoding of complex motor actions 06.11.2018 San diego, United States of America Tan Kelly; Rizzi Giorgio;
FENS Berlin 2018 Poster Distinct nigral subcircuits collaborate to shape locomotion 07.07.2018 Berlin, Germany Tan Kelly; Rizzi Giorgio;
SSN Zurich 2018 Talk given at a conference Distinct nigral subcircuits collaborate to shape locomotion 09.02.2018 Zurich, Switzerland Tan Kelly; Rizzi Giorgio;
SFN 2017 Washington Poster Genetic and functional characterization of rubral pathways 10.11.2017 Wahsington, United States of America Rizzi Giorgio; Tan Kelly;
SFN 2017 Poster Differential impact of specific midbrain to striatal cholinergic interneurons pathways in conditioned behavior 10.11.2017 Washington, United States of America Rizzi Giorgio; Tan Kelly;
Ascona circuit meeting Poster Differential impact of specific midbrain to striatal cholinergic interneurons pathways in conditioned behavior 01.10.2017 ascona, Switzerland Tan Kelly;


Associated projects

Number Title Start Funding scheme
155830 Remodeling of cognitive circuits in Parkinson’s disease 01.02.2015 Temporary Backup Schemes
179088 Deciphering Basal Ganglia Sub-circuits involved in Motor and Cognitive Functions 01.10.2018 SNSF Professorships

Abstract

The basal ganglia are a complex network of several central nervous system nuclei, which orchestrate voluntary movements. Among these nuclei, the substantia nigra pars reticulata (SNr) is a GABAergic nucleus of particular interest, as it is the output nucleus of this network. The SNr integrates information received from striatal GABAergic neurons and from excitatory neurons of sub-thalamic nucleus. The SNr then projects to motor subdivisions of the thalamus, the superior colliculus and the pedonculopontine nucleus. Pioneering anatomical studies in rodents and non-human primates have suggested that the SNr is composed of cells with heterogeneous morphology. Small cells exhibit thin and small dendrites with nondirectional dendritic fields; they were proposed to be interneurons. Large and medium cell bodies are also found; a subset is oriented rostro-caudally and roughly perpendicular to the course of substantia nigra pars compacta (SNc). Some SNr cells have axon collaterals while others exhibit unbranched axons. Heterogeneity of GABAergic neurons has been characterized in the cortex and in the hippocampus. Similar characterization of GABAergic diversity in the SNr will certainly improve our understanding of the basal ganglia function. The striatum, the input nucleus of the basal ganglia, expresses mainly two types of cells the medium spiny neurons containing dopamine (DA) receptor type 1 (D1R-MSNs) and the DA receptor type 2 (D2R-MSNs). A fine balance between activation of the two MSN pathways allows motor coordination and this balance relies on DA that is released from SNc DA neurons. In Parkinson’s disease (PD), a lack of DA in the basal ganglia modifies this equilibrium and strongly impairs motor control. This disequilibrium produces the typical motor symptoms of the disease, specifically difficulty in initiating movements, resting tremor, stiffness, slowing of movement and postural instability. The cause of PD remains elusive, but numerous studies have focused on different aspects of the disease such as the genetic factors, the neurodegeneration of SNc DA neurons itself, or the appearance of protein aggregates called Lewy bodies. However, the effect of DA depletion on synaptic connectivity in the basal ganglia, and the implications of this altered connectivity on basal ganglia function have not been investigated. Such network rewiring in PD has only been studied in the striatum and was shown to lead to disequilibrium between the D1R-MSN and D2R-MSN pathways. It is therefore likely that DA depletion causes rewiring also in the SNr, which would have important implications for basal ganglia function.The goal of this research project is to dissect the microcircuitry of the basal ganglia circuitry focusing onto the SNr. Preliminary experiments presented in this project proposal show that the SNr is a heterogeneous GABAergic nucleus and identify the majority of cell types (Figure 3). This inevitably raises the issue that our understanding of the function of the SNr and the basal ganglia is over-simplified. Based on this new evidence, I hypothesize that each subpopulation of SNr neurons is differentially involved in a specific circuit to produce a given motor behavior and that the modifications of the specific SNr neuronal circuits leads to the pathological motor symptoms characterizing PD. These questions will be answered following four consecutive aims: (1)Dissect the SNr circuitry.a- Investigate the heterogeneity of SNr neuronsb- Reveal local SNr circuitry c- Characterize the input/output connectivity of SNr subtype neuronsd- Examine the synaptic plasticity rules of the SNr circuitry(2)Investigate the dopamine neuromodulation of each SNr subcircuit.(3)Assess the role of SNr subtype neurons/subcircuits in driving specific motor behaviors.(4)Characterize SNr circuitry rewiring in mouse models mimicking PD’s motor symptoms. The main strategy will rely on the use of cell-specific transgenic mouse lines combined to viral-mediated gene delivery. This will allow the identification and optogenetic manipulation of one SNr subpopulation neuron at a time. In vitro and in vivo electrophysiology will be performed to assess the functional connectivity between SNr neurons and also with their inputs and outputs. Dopamine pharmacological agents will be applied in vitro and in vivo to study DA neuromodulation of the SNr neurons and circuits. Confocal imaging and electron microscopy will represent valuable tools to further confirm neuronal identity and connectivity in baseline conditions and following DA depletion. Finally, motor-based behavioral tests will be combined with optogenetic stimulation of specific SNr neuronal subpopulations to assess their specific role in a precise motor task. I have acquired technical expertise in performing in vitro and in vivo electrophysiology experiments as well as confocal imaging and some behavioral task. I will collaborate with experts in electron microscopy, and behavior to successfully complete this project. This study of the SNr circuitry will offer insights into the still poorly understood physiological mechanisms linking cell-type specificity and synaptic function to basal ganglia network activity and behavior. In addition, the study of modifications or rewiring within this system in a model of PD will provide detailed knowledge of the cellular basis of motor disorders, which may lead to novel therapeutic strategies.
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