Recent advances in the study of human Parkinson's disease and experimental animal models of the disease have directed attention to oscillatory electrical activity in the basal ganglia. Low frequency oscillations in the beta range (13-30 Hz) have been shown to be exaggerated in Parkinson's disease, and to occur normally when movements are inhibited. The oscillations are measured as field potentials using gross electrodes, so their cellular origins are not known, but they are in part generated in the striatum. Because field potentials are a population measure, they must reflect synchronous activity in groups of neurons. Studies of experimental parkinsonism in monkeys have shown that neurons firing in rhythm with the low frequency oscillation are all tonically active striatal interneurons. These cells maintain their background firing, even when animals are not moving. In contrast, the principal cells of the striatum, the spiny neurons, and the best-studied interneurons (the fast-spiking interneurons) fire episodically in relation to movement and are mostly silent otherwise. Thus, the striatal generator for the low frequency oscillations associated with bradykinesia is probably tonically firing interneurons. It has previously been thought that all tonically active interneurons in the striatum are cholinergic interneurons. Recently, it has become clear that there are two kinds of tonically active interneurons in the striatum (i.e. active in the absence of excitation from elsewhere). They are the cholinergic interneuron and the LTS (low-threshold spike) bursting interneuron. Together, these two neuron types comprise a spontaneously active network in the striatum that generates continuous oscillatory activity, even in the absence of input. The spontaneously active network receives sparser synaptic input from striatal afferents, and interacts with the phasic striatal cells primarily by way of neuromodulatory control of excitability and synaptic plasticity via acetylcholine, nitric oxide, somatostatin, and neuropeptide Y. The experiments proposed here will determine the connectivity and dynamic properties of the network of spontaneously-active interneurons. They will determine whether the intrinsic resonant properties of the network consisting of tonically active striatal interneurons are appropriate for generation of oscillations in the beta frequency band. We will determine the mechanism of spontaneous oscillations in LTS cells, and whether synaptic connections between them act to promote or oppose synchronous activity. We will also examine the changes in the intrinsic oscillations and synchronization that follow chronic dopamine depletion with 6- hydroxydopamine. The two autonomously active cell types can be readily identified in slices, and targeted for study. These experiments will reveal mechanisms promoting synchronization that may be points of action of dopaminergic depletion and possible targets for future anti-parkinsonian therapies.
Although Parkinson's disease is caused by the loss of dopaminergic neurons in the substantia nigra, the actual symptoms of PD are caused by abnormal firing patterns of the intact neurons in the basal ganglia, and the disease as we see it is a change in the dynamics of neuronal activity. The most prominent change in neuronal dynamics is the exaggeration of beta band synchronous rhythms in the basal ganglia. The goal of these studies is to discover the origin of those rhythms in the striatum, in the hope of understanding the mechanism of action of deep brain stimulation and other current treatments, and identifying a therapeutic target that would allow a next generation treatment.
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