This grant builds upon the research from a prior grant: Development of a Model of Postural Disturbance by Lesioning Non-cholinergic Neurons
Promising Outcomes of Original Grant:
The aim of our previous study funded by The Michael J. Fox Foundation for Parkinson’s Research was to unravel the role of non-dopaminergic lesion in gait and postural disorders, which are the most debilitating dopamine-resistant symptoms in advanced parkinsonian patients. We demonstrated that these symptoms can be induced by pedunculopontine nucleus (PPN) lesions in normal pre-clinical models. The lesions preferentially destroyed PPN cholinergic neurons, suggesting a role for these neurons in the control of gait and posture. From these results, we propose to analyze the effect of the combination of both PPN and dopaminergic lesions on gait and posture in models.
Objectives for Supplemental Investigation:
We first propose to analyze gait and postural disorders in the usual MPTP pre-clinical models of PD where no lesion in the PPN has been described. The analysis will be performed in five models using the same paradigm as that developed in our previous study. Gait and postural deficits obtained after MPTP intoxication will be compared with those observed after PPN lesions.
Because PPN lesions may interact with dopaminergic nigral lesions, the second step will consist in analyzing the combination of PPN and dopaminergic lesions in the same models. We expect that postural deficit should be more severe after double lesions, and not totally reversed by dopamine agonist. This model with both dopaminergic and extra-dopaminergic lesions will be the first realistic model of advanced PD.
Importance of This Research for the Development of a New PD Therapy
The major interest of our study is to propose a new model of advanced PD with persistence of axial signs despite dopaminergic treatment. Making such a model available may offer the opportunity to study gait failure and postural instability, and should provide insights into the specific behavioral contribution of each of these neuronal systems on symptoms observed in PD. This will hopefully open new avenues for pre-clinical testing of Symptoms & Side Effects pharmacological or surgical strategies to address levodopa-resistant symptoms.
Progress Report
Several studies suggest that the pedunculopontine nucleus (PPN) is involved in the development of axial symptoms in Parkinson’s disease. In a previous study, we were able to induce gait and postural disorders by a bilateral lesion of neurons of the PPN in pre-clinical models. Furthermore, we observed that these symptoms were not alleviated by dopaminergic agonist treatment. The aim of our project was to determine if a PPN lesion in parkinsonian pre-clinical models might add gait and postural disorders to the classical parkinsonian symptoms.
We first observed that gait and postural disorders obtained in four pre-clinical models rendered parkinsonian by MPTP intoxication were significantly reversed by dopamine agonist treatment and differed from those developed by pre-clinical models with a bilateral PPN lesion. Second, a bilateral PPN lesion performed in two parkinsonian pre-clinical models resulted in a worsening of axial rigidity but an improvement in akinesia. Third, additional MPTP injections in these two models resulted in a severe parkinsonian syndrome with gait and postural disorders resistant to dopamine agonist treatment. If our results are confirmed next year, we will obtain a new model of advanced Parkinson’s disease that could be helpful to test new pharamacological and surgical therapeutic approaches.
Researchers
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Chantal Francois, PhD