ERANET NEURON 1: Establishing an in vivo rodent model to evaluate the behavioural effects of pedunculopontine stimulation in Parkinson’s disease

Lead Research Organisation: University of St Andrews

Abstract

The pedunculopontine tegmental nucleus (PPN) is involved in Parkinson's disease (PD): there is progressive loss of cholinergic neurons and PPN metabolic activity is changed by altered inputs from pallidum, subthalamic nucleus and substantia nigra zona reticulata. Most importantly, low frequency deep brain stimulation (DBS) in the PPN has therapeutic benefits. Gait and postural instability improve, and there are suggestions that some cognitive impairments also benefit. This strongly suggests that the PPN has a more significant role in PD than previously thought. This project will explore the role of the PPN in PD: we will create an in vivo rodent model to evaluate the behavioural effects of PPN stimulation in Parkinsonian conditions. There is a pressing need to do this: (i) There is controversy about the location of DBS in relation to PPN. Are the electrodes truly in PPN, and if so, what is the most effective intra-PPN site? (ii) What functions will benefit? We will test motor and cognitive abilities: it is thought that PPN has motor functions, but recent data show that it has a role in learning. Because these structures have been highly conserved through evolution, the rodent PPN and basal ganglia are excellent models for other species. To create a relevant rodent PD model we will make partial bilateral lesions using the novel agent, urotensin II–diphtheria toxin (DIPtx-UII) selective for PPN cholinergic neurons. In the same rats, we will make bilateral lesions of substantia nigra pars compacta dopamine (DA) neurons with 6-hydroxydopamine. We will test motor (gait; locomotion; reaction time) and cognitive performance (learning, memory) in
rats that bear lesions, in lesioned rats with PPN electrodes (over which the rats and/or experimenters have control), and appropriate controls. Electrode location in and around PPN will be systematically varied. This will enable us to determine: (i) the effects of PPN DBS on motor and cognitive performance; (ii) whether different electrode locations have differential effects on these, and what neural activity (measured using immediate early gene expression) is changed both by the lesions and by PPN DBS.

Technical Summary

The pedunculopontine tegmental nucleus (PPN) is involved in Parkinson's disease (PD): there is progressive loss of cholinergic neurons and PPN metabolic activity is changed by altered inputs from pallidum, subthalamic nucleus and substantia nigra zona reticulata. Most importantly, low frequency deep brain stimulation (DBS) in the PPN has therapeutic benefits. Gait and postural instability improve, and there are suggestions that some cognitive impairments also benefit. This strongly suggests that the PPN has a more significant role in PD than previously thought. This project will explore the role of the PPN in PD: we will create an in vivo rodent model to evaluate the behavioural effects of PPN stimulation in Parkinsonian conditions. There is a pressing need to do this: (i) There is controversy about the location of DBS in relation to PPN. Are the electrodes truly in PPN, and if so, what is the most effective intra-PPN site? (ii) What functions will benefit? We will test motor and cognitive abilities: it is thought that PPN has motor functions, but recent data show that it has a role in learning. Because these structures have been highly conserved through evolution, the rodent PPN and basal ganglia are excellent models for other species. To create a relevant rodent PD model we will make partial bilateral lesions using the novel agent, urotensin II–diphtheria toxin (DIPtx-UII) selective for PPN cholinergic neurons. In the same rats, we will make bilateral lesions of substantia nigra pars compacta dopamine (DA) neurons with 6-hydroxydopamine. We will test motor (gait; locomotion; reaction time) and cognitive performance (learning, memory) in
rats that bear lesions, in lesioned rats with PPN electrodes (over which the rats and/or experimenters have control), and appropriate controls. Electrode location in and around PPN will be systematically varied. This will enable us to determine: (i) the effects of PPN DBS on motor and cognitive performance; (ii) whether different electrode locations have differential effects on these, and what neural activity (measured using immediate early gene expression) is changed both by the lesions and by PPN DBS.

Publications

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Gut NK (2012) Wireless deep brain stimulation of the pedunculopontine in a novel rodent model of Parkinson's disease in http://www.sfn.org/index.aspx?pagename=abstracts_ampublications

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Gut NK (2011) Refining the methods: an enhanced rodent model for PD and wireless DBS in http://www.sfn.org/index.aspx?pagename=abstracts_ampublications

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Gut NK (2016) The pedunculopontine tegmental nucleus-A functional hypothesis from the comparative literature. in Movement disorders : official journal of the Movement Disorder Society

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Gut NK (2015) Deep brain stimulation of different pedunculopontine targets in a novel rodent model of parkinsonism. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Gut NK (2010) CatWalk assisted gait analysis in rodent models of Parkinson's Disease in http://www.sfn.org/index.aspx?pagename=abstracts_ampublications

 
Title Deep brain stimulation 
Description We have been involved (in collaboration with the lab of Professor Judy Pratt) in developing a deep brain stimulation device for use in rodents; it allows rats to move freely while undertaking behavioural tasks, mimicking the DBS devices used in the treament of Parkinsonism and other disorders in humans. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact The device has just been tested by us; in the coming year we will use it as part of the research programme examining novel brain targets for DBS in an animal model of Parkinsonism 
 
Description Physiological mechanisms of deep brain stimulation in Parkinson's disease 
Organisation University of Wurzburg
Country Germany 
Sector Academic/University 
PI Contribution This MRC grant is part of an ERA-Net NEURON collaborative grant led by Priofessor Jens Volkmann (U Wurzburg, Germany)
Collaborator Contribution The Network grant contains projects from Milan (Alberto Priori), Marseilles (Constance Hammond), Dusseldorf (Alfons Schnitzler) as well as Jens Volkmann and me.
Impact This multidisciplinary project has had annual group meetings; all of the grant outcomes are attributable to the project
Start Year 2009
 
Description Presentation to Parkinsons UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact 120 members of the local branch of Parkinson's UK attended a presentation by scientists and clinicians about recent research using animal models of deep brain stimulation; lab research into mechanisms of neurodegeneration; and clinical talks explaining the difficulty of clinical trails in principle and a current trial for statin use in PD. The talks were followed by an enthusiastic Q&A session.
Year(s) Of Engagement Activity 2017
 
Description Presentation to the Parkinson's Disease Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Presentations about this and other research to Parkinson's patients and their carers, organized at St Andrews University with the Parkinson's Disease Society - followed by questions and a reception.

No specific impacts but excellent feedback from individuals and the PDS
Year(s) Of Engagement Activity 2009