In the past year, we have continued to explore the specifics of dysfunctional alterations in basal ganglia output in the rodent model of Parkinsons disease (PD). In particular, we have focused on the increase in synchronous spiking and oscillatory neuronal activity in the high beta/low gamma (25 40 Hz) range observed in the basal ganglia, motor cortex and motor thalamus in the rodent model of Parkinsons disease (PD). This activity is quite similar in a number of respects to the exaggerated oscillatory activity observed in firing patterns recorded in the subthalamic nucleus (STN) of PD patients during implantation of deep brain stimulating electrodes and has been hypothesized to contribute to the motor deficits observed in these patients. Our goals are to determine how this oscillatory activity emerges in motor networks, whether it is causative, compensatory or irrelevant to the motor disability, and whether reduction of this activity is critical to the mechanism of action of deep brain stimulation. With respect to how these oscillations emerge, we have completed analysis and published results from studies in the awake behaving rat model of Parkinsons disease which show that two qualitatively different patterns are present in measures of power and coherence in motor cortex and substantia nigra pars reticulata (SNpr) after dopamine cell lesion. During inattentive rest, modest but significant increases local field potential ( LFP) coherence are evident over a broad 8 to 40 Hz range coinciding with significant increases in SNpr LFP power in the 8-25 Hz range but no significant increases in motor cortex LFP power. On the other hand, during epochs when rats are engaged in ongoing motor activity, more dramatic increases in LFP power emerge in the motor cortex as well as the SNpr, focused around peak frequencies in the 30-35 Hz range and accompanied by a notable increase in motor cortex-SNpr coherence. These results are consistent with the hypothesis that loss of dopamine facilitates transmission of cortical input to the basal ganglia. In support of the view that these oscillations engage a motor circuit which includes motor cortex and basal ganglia, we have examined the directionality and timing of transmission of the 30 - 35 Hz LFP oscillations between cortex and SNpr. Anatomical considerations of connections between the motor cortex and basal ganglia have, historically, led to a focus on the flow of information from cortex to the striatum, and from the striatum to the SNpr via the direct and indirect pathways, with the latter involving synapses in the external globus pallidus and the STN on the way to the SNpr. Another route, the hyperdirect pathway, involves projections from the cortex to the STN, and from the STN to the SNpr. These pathways would be predicted to produce a lag time between cortical output and SNpr activation sufficient for transmission across 2 - 4 synapses. Data support a scenario wherein the dominant frequency of this oscillations is determined by the time required to allow passage of a pulse of activity through the motor cortex basal ganglia- thalamocortical loop, although other scenarios should be considered, including generation of the 30 35 Hz rhythm within the cortical network and/or within subsets of basal ganglia-thalamic networks. Additional data show that the exaggerated oscillations emerging in the motor cortex and in basal ganglia output after loss of dopamine are coherent with a similar band of activity evident in the ventral medial thalamus, a thalamus nucleus which receives input from the motor thalamus and projects back to the motor cortex. Together, this data support the view that the whole motor circuit becomes engaged in the rhythmic activity evident in the basal ganglia when the rats are motorically active after loss of dopamine. To investigate whether the excessive synchronization in the beta frequency range activity evident after dopamine cell lesion is causally related to the motor symptoms expressed by the hemiparkinsonian rat, we have examined the relationship between the time course of the emergence of synchronized activity in the basal ganglia and the development of motor deficits. We have found that substantia nigra pars reticulata and motor cortex LFP power and coherence in the 30-35 Hz frequency range emerge gradually over the first week post unilateral 6-OHDA DA cell lesion, stabilizing by day 7, while treadmill walking deficits are evident 24 hours after the lesion. To bring further insight into the evolution of this oscillatory activity in conjunction with progression in motor deficits, we examined two additional models for reduction of DA receptors stimulation: unilateral injection of tetrodotoxin (TTX) into the medial forebrain bundle, and administration of a combination of SCH 23390 and eticlopride (D1 and D2 DA antagonists). ). Treatment with TTX induced a temporary unilateral motor deficit during walking similar to that observed after unilateral 6-OHDA-lesion, but produced no significant increase in SNpr and MCx LFP power and coherence in the 30-35 Hz frequency range. Administration of D1D2 antagonists to intact rats also led to expression of motor symptoms, but failed to induce increases of LFP power or coherent synchronization of oscillatory activity in MCx-SNpr. However, with twice daily administration over 7 days, SNpr and MCx LFP power and coherence progressively emerged over a time course similar to that following 6-OHDA-lesion. Results show that early expression of akinesia after loss of DA receptor stimulation is not well correlated with the degree of beta frequency range synchronization in the basal ganglia and support the possibility that these rhythms may be compensatory in nature. This leaves open the question of how DBS ultimately leads to improvement of motor symptoms in PD. Future studies will further explore the underlying mechanisms and functional consequences of the abnormal rhythms evident in PD and consider their role in other disorders positively affected by DBS. In addition to our studies relevant to akinesia and bradykinesia in PD, we have also begun to investigate a striking change in cortical activity that emerges during L-dopa induced dyskinesias ( LID) and the role of the serotonin neurons in the expression of LIDs. We have confirmed that L-dopa treatment leads to high frequency gamma range oscillatory activity (70-80 Hz) in the motor cortex, which appears tightly correlated with expression of the LID in the rodent model of PD. However, as with the exaggerated oscillations present during times when the animals show akinesia and bradykinesia, the relationship between the high frequency activity in the motor cortex and the motor dyskinesias is also unclear. Are these frequency bands causally responsible for the motor deficits, compensatory or irrelevant? Finally, as the serotonin system has been highly implicated in LID we have also begun to explore the potential for modulating the high frequency activity by administering drugs which modify the activity of serotonin neurons. The dorsal raphe nucleus neurons take up, convert, and release L-dopa-derived dopamine in an unregulated manner. Indeed, serotonin 1A receptor agonists have been shown to reduce LID in both experimental and clinical models and we have found that these drugs reverse the ability of L-DOPA to attenuate the exaggerated oscillatory activity in the hemiparkinsonian rat. Future studies will explore the role of the gamma range activity in LID and investigate whether drugs which modulate the activity of the serotonin system and reduce the behavioral abnormalities associated with LID act by reducing the high frequency activity evident during these behaviors.
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