Research conducted on changes in basal ganglia function in Parkinsons disease (PD) over the past year in the Neurophysiological Pharmacology Section has continued to focus on the nature and functional significance of synchronized and oscillatory activity emerging in motor circuits after loss of dopamine. We are hopeful that further characterization of this phenomena in a rodent model of PD will lead to improved treatments for the PD patient, provide insight into the role of dopamine in motor system function and facilitate our understanding of the significance of synchronized activity in brain circuits. As previously reported, our first goal in investigating the changes in basal ganglia function after dopamine cell lesion was to develop a strategy allowing recording of ongoing activity in motor circuits while the rat performs a task that is relevant to parkinsonian motor deficits. We accomplished this through the use of a circular treadmill with a paddle lowered over the track to encourage the rat to keep walking. A rat with a unilateral dopamine cell lesion - mimicking unilateral PD - is able to walk effectively on this treadmill as long as he is oriented in the direction ipsilateral to the dopamine cell lesion, with the paws opposite the lesioned hemisphere on the outside of the circular track. His ability to walk in the opposite contralateral direction is more variable. The treadmill setup allows us to monitor basal ganglia circuit spiking and local field potential (LFP) activity continuously from the intact and lesioned hemispheres as the animal walks and rests. Importantly, marked increases in synchronized activity in the high beta (30 35Hz) range are observed in these recordings in the lesioned hemisphere of the hemiparkinsonian rats during treadmill walking. These observations have provided multiple avenues for further research. With respect to the treadmill model, in the past year Section investigators have made advances in quantifying the nature of the stepping deficits evident when the rats are engaged in walking in the contralateral direction. While some rats will not walk in this direction at all, and try to reverse direction or simply freeze, other rats, which appear to have less complete dopamine cell lesions, show changes in stepping patterns when walking contralaterally. Our newly refined measures of gait dysfunction allow more meaningful exploration of neurophysiological mechanisms underlying the stepping deficits. A new goal is to modify the circular treadmill to allow recording of the rats stepping patterns from below, to better quantify changes in gait induced by loss of dopamine. A second goal relevant to ongoing studies has been to characterize, over a range of behavioral states, the motor circuit components most clearly entrained to the exaggerated oscillatory activity in the hemiparkinsonian rats. The robust nature of this activity allows us to track it across different nodes within the motor circuits and gather insight into how peak frequency, oscillatory power and coherence within different components of these circuits vary with behavioral state. Our accumulating data sets should provide insight into the source of the abnormal oscillations as well perspectives on imaging studies in rodents and man. Over the first weeks after dopamine lesion, significant increases in LFP spectral power in the subthalamic nucleus (STN), substantia nigra (SNpr) and motor cortex emerge in the high beta 30-35 Hz frequency range in the dopamine-lesioned hemisphere when the hemiparkinsonian rats are active, as in walking or grooming. LFP coherence in the 30 35 Hz range between these nuclei is also high during treadmill walking. Peak frequencies vary with behavioral state, being in 12-25 Hz range during inattentive rest, closer to 28 Hz during alert stationary states and ranging from 30 to 35 Hz, going up about 1 Hz per week post-lesion, during treadmill walking. Most recently we have added simultaneous recordings from the medial prefrontal cortex and anterior cingulate cortex, as well as areas in the motor thalamus. Of interest is the emerging observation that exaggerated 30 35 Hz oscillatory LFP activity during treadmill walking is clearly evident and coherent within and between some areas of the basal ganglia thalamo-cortical motor network and not others. Moreover, spiking activity is significantly phase locked to the LFP oscillations in some but not all of the areas where LFP power is increased. Increased 30 35 Hz oscillatory activity is only patchy in the striatum of the dopamine lesioned hemisphere during treadmill walking, and not evident in the medial prefrontal cortex, and neither area shows significant spike-LFP phase-locking, while robust phase locking is observed in the STN, SNpr and modest phase-locking is observed in layer 5/6 of the motor cortex. These observations are relevant to existing hypotheses regarding the source of the oscillatory activity. Our ongoing studies are indicating a lack of notable phase-locking of spiking activity in the striatum and globus pallidus to cortical beta range activity arguing against synchronized output from these areas driving the oscillatory activity. We are intrigued by the possibility that the high beta rhythms emerge from the dynamic state which evolves within the motor network, after loss of dopamine, with a resonance frequency in the rat in the high beta range. Another on-going effort has been to identify the changes in neurophysiological function which correlate with the earliest signs of motor deficit post lesion. Is there evidence for a causal relationship between motor deficits and increased synchronization in the basal ganglia circuits? Motor deficits are evident within a day after the 6-hydroxydoamine-mediated dopamine cell lesion, but increases in synchronized LFP power are not typically significant at that time point. However, there is an intriguing shift in peak frequency in the motor cortex early after dopamine cell lesion from a peak around 40 Hz to slightly lower, as the peak frequency moves over the early days post lesion toward the 30 Hz peak and coherence increases in the 30 hz range between motor cortex and SNpr. We are currently writing a manuscript describing this phenomenon. Finally, we have begun studies involving infusion of the inhibitory DREADD (Designer Receptors Exclusively Activated by Designer Drugs) virus, AAV2/8-hSyn-Hm4d(Gi)-mCjerry, into the SNpr to evaluate the utility of this approach in manipulating activity in different components of the motor circuit. Effects of injection of the designer drug, CNO (clozapine-N-oxide) can be seen with respect to the duration of cortical high gamma oscillations during l-dopa induced dyskinesia, and the reduction of LFP beta power in the motor cortex during dopamine-lesion-induced bradykinesia. In preparation for obtaining genetically modified rats with potential for targeting subsets of SNpr and globus pallidus neurons with DREADD viruses, we are additionally focused on obtaining a more fine-tuned analysis of how both rate and pattern of the spiking activity, as well as peak frequency of synchronized and oscillatory LFP activity varies with behavioral state within different subsets of neurons within these nuclei. In particular, data is emerging from studies in the globus pallidus and the SNpr suggesting the existence of multiple subtypes which may be differentiated by differences in protein expression and anatomical connections. Ultimately, the goal is to make use of genetic (i.e. DREADD and CRE) based technologies to identify and target specific genetically defined subcomponents of the basal ganglia thalamocortical circuitry to compensate for problems triggered by degeneration of dopamine neurons in PD and and other neurological disorders.
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