Thalamo-Cortical Plasticity: Sensory Denervation and Loss of Dopamine

神经生理药理学部分在这个项目上的工作继续引起人们对腹侧内侧丘脑（VM）在调节反映基底神经节输出变化的皮质活动变化中的重要作用的关注。在2016财年，我们发表的一项研究显示，在帕金森病（PD）啮齿动物模型中，丘脑腹侧内侧（VM）参与了基底节区丘脑皮质环同步高β (30 35 Hz)局部场电位（LFP）活动的出现。我们的研究探索了一种假设，即基底神经节输出的黑质网状部（SNpr）在这个高频率范围内携带VM丘脑的活动，这反过来又有助于运动皮层和基底神经节的携带。先前的研究表明，在运动活动期间，患有单侧多巴胺细胞病变的大鼠（半帕金森病大鼠）的丘脑下核、SNpr和运动皮层在该频率范围内的活动同步明显夸大。在我们的研究中，单侧多巴胺细胞损伤的大鼠被训练在圆形跑步机上行走。如果它们的方向与单侧多巴胺细胞损伤的方向相反，它们的受影响的爪子在圆形轨道的外侧，它们可以相对有效地行走。本研究表明，在半帕金森病大鼠的损伤半球VM丘脑在跑步机时观察到高β范围振荡活动。此外，这种活性与运动皮层和SNpr中相似范围的LFP活性一致。数据还显示，基底神经节的丘脑成分-丘脑皮质环对多巴胺缺失后LFP振荡的出现至关重要。将GABAa激动剂muscimol或GABAa拮抗剂picrotoxin分别注入腹侧内侧核以抑制该核的活性，或阻断GABAa能输入，分别诱导运动皮质和SNpr LFP的能量降低，并降低这两个部位在跑步机行走时高β /低γ范围内的一致性。因此，VM丘脑的同步神经元活动有助于在行为帕金森大鼠的基底神经节丘脑皮质网络中出现高β振荡。

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.