In the past year, progress has been made in assessing changes in thalamo-cortical relationships in the rodent model of Parkinsons disease in conjunction with bradykinesia associated with dopamine cell death and in conjunction with dyskinesia associated with chronic L-dopa treatment. Both bradykinetic and dyskinetic states have been shown to induce dramatic changes in oscillatory and synchronized activity in the motor cortex activity. We have been exploring the extent to which these changes in motor cortex activity may be linked, and potentially driven by, alterations in the activity of thalamic input to cortex. We are also examining the extent to which these changes in motor cortex activity correlate with the emergence of bradykinesia and dyskinesia in this animal model of Parkinsons disease. To examine the role of thalamo-cortical component of the basal ganglia- thalamo-cortical loop in the emergence of bradykinesia associated with loss of dopamine, we have been analyzing data from recordings of spike/local field potential (LFP) relationships between basal ganglia output (substantia nigra pars reticulata (SNpr), motor thalamus and motor cortex in hemiparkinsonian rats trained to walk on a circular treadmill. These recordings of LFP activity from multiple sites within the motor network show correlated increases in coherence between motor cortex and SNpr, between motor cortex and ventral medial thalamus, and between SNpr and ventral medial thalamus in the 30-35 Hz range after dopamine cell lesion during treadmill walking. Infusion of the GABA agonist muscimol into the ventral medial nucleus to inhibit activity in this nucleus causes a reduction of power in both motor cortex and SNpr LFP and reduced coherence between these two sites in the high beta/low gamma range during treadmill walking during muscimol infusion. We have also found that muscimol infusion in both the unilaterally lesioned rat and the normal rat reduce walking in the circular treadmill. This data supports a role for the ventral medial thalamus in maintenance of normal motor function and is consistent with a role for the motor thalamus in induction of high beta/low gamma synchronization of LFP activity in the motor cortex and with the hypothesis that neuronal activity in the ventral medial thalamus promotes increased coherence within the larger network after loss of dopamine. We are currently using new approaches to assess more precisely the relationships between spiking activity in the LFP oscillations in these nuclei in order to further examine the relative roles of these different areas in driving spiking in the different nodes of this circuit. The manuscript is close to completion. A second series of studies has examined the changes in thalamic and thalamic-cortical activity associated with chronic treatment of L-dopa. The therapeutic effect of treatment of Parkinsons disease (PD) patients with the dopamine precursor L-dopa has been well established. However, over time, L-dopa therapy leads to severe motor complications referred as L-dopa-induced dyskinesias (LID). Recently, we have confirmed that there is a strong association between the presence of 80-100 Hz oscillations in the motor cortex of hemiparkinsonian rats and LID expression. This is especially interesting because high gamma activity resembling that observed in this rat model of PD has been observed in human PD patients in recordings throught deep brain stimulation electrodes, and the role of this activity in generating dyskinesia is unclear. As L-dopa administration is believed to lead to a reduction in basal ganglia output and disinhibition of the thalamocortical pathway in Parkinsons disease, we are currently investigating the role of the motor thalamus in contributing to the 80-100 Hz activity evident in the motor cortex during LID in the hemiparkinsonian rat primed for 7 days with L-dopa. We are also examining the time course and correlations between the LID and the changes in cortical activity. LFPs and neuronal activity recorded from electrodes chronically implanted in the motor cortex, ventral medial thalamic nucleus and SNpr show prominent increases in a strickingly focused band of 100 Hz gamma range in both the ventral thalamus and motor cortex LFP activity and in coherence between these two structures. This high gamma 100 Hz activity is strongly associated with the emergence of LID over 7 days of priming. Pre-treatment with amantadine, a weak NMDA glutamate receptor antagonist (GluR ant) used clinically to treat dyskinesia, mildly reduced both 100 Hz LFP power and LID, while a 0.3 mg/kg dose of MK-801, the NMDA GluR ant, eliminated them. These results support the idea of a causative association between LID and 100 Hz activity in the thalamocortical circuit. However, a lower 0.15 mg/kg dose of the MK-801 abolished 100 Hz band oscillations without affecting LID. Moreover, preliminary results show that suppression of Vm activity by local injection of the GABA receptor agonist muscimol completely eliminated aberrant 100 Hz synchronization within the motor cortex, but had nearly no effect on LID. The results suggest that while robust high gamma oscillatory activity in the VM and MCx is evident during LID, this aberrant thalamocortical synchronization does not appear to be requisite for the expression of dyskinesia. We are currently adding to the Ns in this study and exploring the possible role of the cerebellum in contributing to the dramatic changes in thalamocortical activity observed in this model of L-dopa induced dyskinesia.

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Brazhnik, Elena; McCoy, Alex J; Novikov, Nikolay et al. (2016) Ventral Medial Thalamic Nucleus Promotes Synchronization of Increased High Beta Oscillatory Activity in the Basal Ganglia-Thalamocortical Network of the Hemiparkinsonian Rat. J Neurosci 36:4196-208
Dupre, Kristin B; Cruz, Ana V; McCoy, Alex J et al. (2016) Effects of L-dopa priming on cortical high beta and high gamma oscillatory activity in a rodent model of Parkinson's disease. Neurobiol Dis 86:1-15
Delaville, Claire; McCoy, Alex J; Gerber, Colin M et al. (2015) Subthalamic nucleus activity in the awake hemiparkinsonian rat: relationships with motor and cognitive networks. J Neurosci 35:6918-30
Delaville, Claire; Cruz, Ana V; McCoy, Alex J et al. (2014) Oscillatory Activity in Basal Ganglia and Motor Cortex in an Awake Behaving Rodent Model of Parkinson's Disease. Basal Ganglia 3:221-227
Yu, Xin; Chung, Seungsoo; Chen, Der-Yow et al. (2012) Thalamocortical inputs show post-critical-period plasticity. Neuron 74:731-42