Work on this project in the Neurophysiological Pharmacology Section continues to call attention to the important role of the ventral medial (VM) thalamus in mediating changes in cortical activity which reflect alterations in basal ganglia output. In FY 2016 we published a study showing dramatic involvement of the ventral medial thalamus (VM) in the emergence of synchronized high beta (30 35 Hz) local field potential (LFP) activity in the basal ganglia thalamocortical loop in a rodent model of Parkinsons disease (PD). Our study explored the hypothesis that basal ganglia output from the substantia nigra pars reticulata (SNpr) entrains activity in the VM thalamus in this high beta frequency range, which in turn contributes to the entrainment of the motor cortex and basal ganglia. Previous studies have shown that exaggerated synchronization of activity in this frequency range is evident in the subthalamic nucleus, SNpr and motor cortex in rats with unilateral dopamine cell lesions (hemiparkinsonian rats) during periods of motor activity. In our studies, rats with unilateral dopamine cell lesions were trained to walk on a circular treadmill. They could walk relatively effectively if they were oriented in the direction ipsiversive to the unilateral dopamine cell lesion, with their affected paws on the outside of the circular track. This study showed that the high beta range oscillatory activity was observed in the VM thalamus in the lesioned hemisphere of the hemiparkinsonian rats during treadmill walking. Moreover, this activity was coherent with similar range LFP activity in the motor cortex and SNpr. Data also showed that the thalamic component of the basal ganglia- thalamocortical loop is critical to the emergence of these LFP oscillations after loss of dopamine. 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, induced 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. Thus, synchronized neuronal activity in the VM thalamus contributes to the emergence of high beta oscillations throughout the basal ganglia thalamocortical network in the behaving parkinsonian rat. Another interesting aspect of our studies of VM effects on cortical activity in the hemiparkinsonian rat is the evidence in the literature that, unlike other thalamocortical projections, input from the VM thalamus to the motor cortex targets the dendrites of the interneurons extending into the outer layers of the cortex. This arrangement, with thalamic inputs terminating in the outer cortical layers (as opposed to the more common site in layers 5/6) was eloquently described by our neighbor in the 1C pod in Bldg 35, Dr. Miles Herkinham, in 1979, and is relatively unique for thalamocortical projections. It has been suggested that this thalamic to layer 1 cortex input may have an alerting role. The idea that VM thalamus input to the cortex might serve an alerting function is relevant to a second set of studies on VM thalamocortical activity in the hemiparkinson rat initiated in our Section this year. While the motor cortex is a major site of VM thalamus projection, a substantial projection is also sent to the anterior cingulate cortex (ACC). The ACC is involved in the processing of pain, and it is notable that a) pain thresholds are significantly lower in Parkinsonian patients and b) nociceptive information is thought to be conveyed via the VM thalamus from the brainstem to the ACC. These pieces of information have led us to the hypothesize that the increase in high beta oscillatory activity in the projection from the VM to the ACC might be contributing to the disruption of the pain processing in PD patients. Thus we have initiated a study to record behavior together with LFP and spiking activity from the VM and ACC in hemiparkinsonian rats while applying mild pain involving injection of dilute formalin into a paw. This is a standard model for studying pain thresholds in rats. A third set of studies have explored changes in oscillatory activity in the parafascicular nucleus, another thalamic nucleus which is part of the motor circuit as it receives input from basal ganglia output, and projects to striatum and to subthalamic nucleus. AS this thalamic region is, like the VM thalamus, also anatomically positioned to become entrained in the high beta range in the hemiparkinsonian rat during treadmill walking, recordings were performed to assess this hypothesis. Interestingly, we did not find evidence of the entrainment of LFP activity in the parafascicular nucleus in the high beta activity range. However, preliminary results suggest muscimol-induced inhibition of this area may facilitate treadmill walking in the contraversive direction. Thus, further studies are envisioned to assess the role of this nucleus in expression of bradykinesia induced by loss of dopamine. We also published a study in this fiscal year reporting changes in cortical activity associated with the emergence of L-dopa-induced dyskinesia in the hemiparkinsonian rat. 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 dyskinesia (LID). Our study 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 DBS 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 . The dramatic increase in high gamma oscillatory activity in the motor cortex during L-dopa-induced dyskinesia has led to hypotheses that this activity in causally involved in the disruption of motor cortex activity and the emergence of dyskinesia. As a result of our studies with high beta activity in the motor cortex, we were concerned that high gamma activity in the motor cortex might also be induced by changes in basal ganglia output, in this case a reduction of inhibitory SNpr input to the VM thalamus inducing activation of the VM, and influencing activity in the motor cortex. Indeed, ongoing studies are providing very dramatic evidence that this hypothesis is true. Moreover, we have shown that expression of the high gamma activity observed in the motor cortex in the dyskinetic rat can be blocked by disruption of activity in the VM thalamus, BUT, the expression of dyskinetic behavior by the rats remains virtually unchanged. Injection of the GABA agonist muscimol into the VM thalamus eliminated the high gamma activity but not the dyskinesia. This has strong implications for the emerging interest in using LFP as a biomarker for dyskinesia, and leaves questions about neurophysiological correlates of dyskinesia unresolved. While robust high gamma oscillatory activity in both motor thalamus and motor cortex is evident during L-dopa-induced dyskinesia, this aberrant thalamocortical synchronization does not appear to be requisite for the expression of dyskinesia. Thus, an important and clinically difficult state remains wide open for investigation. It remains unclear what the neurophysiological correlates of L-dopa induced dyskinesia are, and how they may be manifested in projections from cortex and/or basal ganglia downstream to motor control centers.
