Cycle 1 project 8

Disturbed neural synchrony in an animal model of Parkinson’s Disease

 

PhD student: Borbála Nóra Duray, Hungary
Home Institute: Amsterdam Neuroscience; Principle Investigator: Pieter Voorn
Host Institute: Bordeaux Neurocampus; Principle Investigator: Erwan Bézard

Executive Summary
Parkinson’s disease (PD) is characterized by motor disturbances as well as cognitive deficits that occur in both early and more advanced stages of the disease. A good pathophysiological model is crucial to our understanding of PD and to the development of novel therapeutical approaches. Our current concept of PD leans mostly on the models put forward by Albin and Alexander et al. (1989, 1990). These models have proven very robust and they have contributed strongly to the current application of high frequency deep brain stimulation (DBS). The ameliorating effects of DBS, however, are very difficult to explain in our present model of cortex-basal ganglia circuitry. In fact, the only sign in PD that the model satisfactorily explains is hypokinesia/akinesia. The model does not take into account pathological changes in the functional dynamics of the system, i.e. firing patterns, oscillatory activity and synchronization of firing discharge between and within brain regions. Recent clinical findings by us and others demonstrate that major changes in these dynamics take place over the course of the disease.

EEG and MEG studies show that PD is associated with changes in temporal neural firing patterns leading to increases and decreases in synchronization of neural activity between and within brain regions (Berendse and Stam, 2007). Some of the disturbances in synchronization appear associated with particular motor or cognitive impairments (Berendse and Stam, 2007). Studies focusing on pathological changes in oscillatory activity have shown that DBS of the subthalamic nucleus at particular frequencies aggravates motor symptoms, indicating that such oscillatory activity probably contributes to motor deficits (Timmermann and Fink, 2009). In contrast, such stimulation concomitantly resulted in an improvement of executive tasks. This suggests that the parallel cortex-basal ganglia loops that are involved in motor and executive tasks (Voorn et al., 2004) are modulated at different frequencies which are probably differently involved in the pathological process (Timmermann and Fink, 2009). Indeed, de novo patients present with functional connectivity changes in frequency bands of oscillatory neural activity that are different from those of patients in more advanced stages (Berendse and Stam, 2007; Stoffers et al., 2008). The mechanisms underlying the occurrence of altered local and inter-regional synchrony and the transitions between diverse frequency bands are not clear. Since dopaminomimetic treatment was found to have a different effect on abnormal synchrony patterns in early vs advanced stage patients (Berendse and Stam, 2007), the severity of the dopamine depletion might play an important role. Therefore, we hypothesize in the current project that, in a rat model of dopaminergic neuron-specific degeneration, changes in functional connectivity within and between cortical regions and basal ganglia will depend on the magnitude and progression of the dopamine depletion.

Our main objective is to provide functional dynamic aspects to our current pathophysiological model, by showing dopamine-dependent changes in neural activity patterns of anatomically identified neuronal subsystems of the cortex-basal ganglia circuitry. We propose to investigate the fundamentals of pathological oscillations and functional connectivity in dopamine-depleted behaving animals using neurophysiological methods (EEG, i.e. local field potentials) and postmortem neuroanatomical (histochemical imaging of neuronal activity) tools.

Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12:366-375.
Alexander GE, Crutcher MD (1990) Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 13:266-271.
Timmermann L, Fink GR (2009) Modulating pathological oscillatory activity in Parkinson’s disease: What’s the rhythm? Exp Neurol 215:209-211.

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