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Remodeling of cognitive circuits in Parkinson’s disease

Applicant Tan Kelly
Number 155830
Funding scheme Temporary Backup Schemes
Research institution
Institution of higher education University of Basel - BS
Main discipline Neurophysiology and Brain Research
Start/End 01.02.2015 - 31.05.2021
Approved amount 1'499'976.00
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Keywords (5)

Parkinson's disease; cholinergic modulation; substantia nigra pars reticulata; cognitive actions; inhibitory circuitry

Lay Summary (French)

Lead
La maladie de Parkinson (PD) est une maladie neurodégénérative caractérisée par des symptômes moteurs; cependant, ces patients souffrent également de déclin cognitif et dans certains cas de démence.
Lay summary

La mémoire de travail, la fonction exécutive et le traitement de l'information sont les principaux domaines cognitifs touchés dans PD. Ces changements peuvent être présents dès le diagnostic, et affecter fortement la qualité de vie des patients. Un déséquilibre entre l'acétylcholine (ACh) et la dopamine (DA) dans le striatum médie certains déficits cognitifs. Et en accord avec ces observations, les médicaments anticholinergiques ont prouvé leur efficacité. Une zone d'intérêt dans le cerveau de PD est la substantia nigra pars reticulata (SNR). Notre travail préliminaire fournit des preuves de son hétérogénéité, qui dicte un modèle d'expression de récepteur spécifique cholinergique. En outre, l'acétylcholine est libérée localement et par des afférences du tronc cérébral. Sur la base de cette nouvelle conclusion, nous émettons l'hypothèse que ACh coordonne finement l'activité du circuit SNr par la modulation des sous-populations spécifiques de cellules SNR. De plus, nous proposons que la perte de DA induit un remodelage des circuits tels que cette modulation cholinergique est modifié, conduisant à des symptômes cognitifs pathologiques observées dans la PD.

Direct link to Lay Summary Last update: 08.12.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Design and construction of a low-cost nose poke system for rodents
Giorgio Rizzi, Meredith Lodge, Kelly Tan (2016), Design and construction of a low-cost nose poke system for rodents, in MethodsX, 326-332.

Associated projects

Number Title Start Funding scheme
150683 Rewiring of inhibitory circuitries in Parkinson's disease 01.10.2014 SNSF Professorships
142663 Dopamine modulation of inhibitory microcircuits in the barrel cortex 01.10.2012 Ambizione

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor symptoms; however, these patients also suffer from cognitive decline and in some cases dementia. Attention, working memory, executive function and information processing are the main affected cognitive domains in PD. These changes may be present as early as the time of diagnosis, and strongly affect the patients’ quality of life. An imbalance between acetylcholine (ACh) and dopamine (DA) in the striatum has been shown to mediate some cognitive deficits. And in line with these observations, anticholinergic drugs have proved effective. A brain area of relevance in PD is the substantia nigra pars reticulata (SNr). Our preliminary work provides evidence for its heterogeneity, which dictates a specific ACh receptor expression pattern. In addition, ACh is released locally and by brainstem cholinergic afferences. Based on this new finding, we hypothesize that ACh finely coordinates the activity of the SNr circuitry through the modulation of specific subpopulations of SNr cells. In addition we propose that DA depletion induces a remodeling of SNr circuitry such that ACh modulation is altered, leading to the pathological cognitive symptoms observed in PD. We will use multiple techniques such as confocal imaging to visualize cholinergic receptor expression by SNr cell subtypes, in vitro and in vivo electrophysiology to characterize these cells and their modulation by ACh. Finally a set of behavioral tasks will be performed to measure the impact of such modulation on cognitive processes. Both pharmacological and optogenetic tools will supplement these techniques to selectively manipulate one circuital component at a time.These four aims will be pursued:1- Identify the cholinergic modulation of SNr neuron subtypes.2- Dissect the underlying sub-circuits. 3- Assess the role of ACh in cognitive behaviors.4- Identify the morphological, functional and behavioral alterations of the cognitive loops in a mouse model mimicking PD’s symptoms (DA depletion through DA toxin infusion). The ultimate goal is to develop strategies compensating for circuit dysfunction caused by DA-ACh deficits and would thereby alleviate the PD cognitive symptoms.
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