In the past year, we have continued to make progress in assessing changes in thalamocortical relationships in the rodent model of Parkinsons disease (PD). Both bradykinetic and dyskinetic states have been shown to be associated with dramatic increases in oscillatory and synchronized activity in the motor cortex. Current results support the idea that these changes in motor cortex LFP activity are driven by alterations in the activity of thalamic input to cortex. However, the role of the high beta 30-35Hz oscillatory activity observed in the VM thalamocortical projection and in the motor cortex during periods of bradykinesia in the parkinsonian animals is still under debate. The time frame of the emergence of the bradykinetic behaviors is not well correlated with the emergence of the high beta activity in the motor cortex. Furthermore, our data does not support the view that the increases in narrow range FTG LFP oscillations in the motor cortex are causally involved in the expression of L-dopa induced dyskinesia, as some have suggested. The emergence of dyskinesia in the rodent model of Parkinsons disease can be disassociated from increases in high gamma range LFP activity in the motor thalamus and motor cortex. We have just submitted a manuscript reporting data from recordings of spike/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. While we are unsure of the actual consequences of the high beta/low LFP oscillations in the motor cortex, the thalamic component of the basal ganglia- thalamocortical loop does seem critical to the emergence of these LFP oscillations after loss of dopamine. 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 either the GABAa agonist muscimol or the GABAa antagonist picrotoxin into the ventral medial nucleus to inhibit activity in this nucleus, or block GABAergic input, respectively, induces a reduction of power in both motor cortex and SNpr LFP and reduces coherence between these two sites in the high beta/low gamma range during treadmill walking. This data supports a role for the ventral medial thalamus in induction of high beta/low gamma synchronization of LFP activity in the motor cortex. The data also shows that neuronal activity in the ventral medial thalamus promotes increased coherence within the larger basal ganglia thalamocortical network after loss of dopamine. In a follow up series of studies, we are utilizing electrodes attached to cannula to record locally as we infuse test drugs into the VM nucleus and hope to apply optogenetic techniques to modify spiking activity to more selectively probe the different nodes of this circuit, and the manner in which thalamocortical activity ultimately impacts downstream systems regulating limb movement. We also have a manuscript under review examining the changes in thalamic and thalamocortical activity associated with chronic treatment of L-dopa. The therapeutic effect of treatment of Parkinsons disease 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 high gamma oscillations in the motor cortex of hemiparkinsonian rats and LID expression. This is especially interesting because high gamma has been observed in human PD patients in recordings through deep brain stimulation electrodes, and the role of this activity in generating dyskinesia is unclear. This activity has been referred to in the clinical literature as finely tuned gamma or FTG . While these results supported relationship between the high gamma oscillatory activity and dyskinesia, other results did not. Unexpectedly, as cortical high gamma power increased, phase locking of cortical pyramidal spiking to high gamma oscillations decreased in the motor cortex. This observation suggests that power in this high gamma range can change dramatically in the motor cortex LFP without an associated changes in spike-LFP phase locking. This raises questions regarding the functional correlation between high gamma and dyskinesia. Indeed, follow up studies are providing further evidence that expression of narrow band finely tuned gamma (FTG) and the dyskinetic behavior can be disassociated. In these studies we first established a role for the motor thalamus in generating the FTG band in the motor cortex, and then explored the consequences of reducing the cortical expression FTG by manipulations of VM thalamic activity. This was further correlated with assessment of the expression of dyskinesia. Evidence that the motor thalamus is driving the FTG in the cortex emerged from these studies of rate and spike-LFP phase-locking in the motor thalamus during LID. Interestingly, changes in firing rate and phase-locking are highly correlated with the changes in power in the high gamma range in the ventromedial thalamus, as opposed to the observations, discussed above, with respect to phase locking in the motor cortex. Firing rate changes in the cortex are not obvious either, in our analysis to date. Gamma activity is generally considered an important modulator of cortical function. However, while systemic administration of a 0.3 mg/kg dose of MK-801, the NMDA GluR antagonist, eliminated both FTG and dyskinesia in the L-dopa-primed dyskinetic rats, a lower 0.15 mg/kg dose of the MK-801 administered i.p. abolished the FTG oscillations in the cortex without affecting dyskinesia. Further studies infusing muscimol into the VM show that suppression of ventromedial thalamic activity by local injection of this GABA receptor agonist 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 both motor thalamus and motor cortex is evident during LID, this aberrant thalamocortical synchronization does not appear to be requisite for the expression of dyskinesia. Most recently, we are also exploring the role of the cerebellum in contributing to the dramatic changes in thalamocortical activity observed in this model of L-dopa induced dyskinesia. Further studies are underway to investigate the role of the parafascicular thalamus in expressing and propagating the high beta and gamma activity evident in some parts of the basal ganglia thalamocortical circuit after loss of dopamine and treatment with L-dopa. Studies are underway to explore the role of ketamine in generation of high gamma activity in the medial dorsal thalamic nucleus and the prefrontal cortex in collaboration with Dr. Andreas Buonoanno and his graduate student, Katrina Furth in NICHD. Finally, we are initiating some studies in collaboration with some of our colleagues in Bldg 35 to explore the role of the VM thalamus in the changes in pain threshold reported in Parkinsons disease patients. There are several reports in the literature of nociceptive input to the VM thalamus, and other studies showing projections from the VM thalamus to the anterior cingulate cortex. As we have recently observed an increase in high beta activity in the anterior cingulate cortex after loss of dopamine, we are designing studies to determine the effect of mild pain on neuronal on neuronal activity in the VM thalamus and anterior cingulate cortex in the hemiparkinsonian rat.
