In Parkinsons disease (PD) patients off medication, atypical oscillatory activity has been found in the beta frequency range. It has been hypothesized that this excessively synchronized activity in the basal ganglia is responsible for the motor impairments seen in these patients and that deep brain stimulation (DBS) of basal ganglia targets is beneficial by disrupting this activity. However, it is also possible that this activity could contribute to non-motor symptoms, such as depression, anxiety and an increased sensitivity to pain which have also been reported in PD. It is hoped that a better understanding of this hypersynchronized state can provide insight into the neuronal circuits undergoing plastic changes after dopamine cell lesion and the relevance of these changes to the symptoms observed in PD. In previous years we have performed simultaneous recordings from the motor cortex and the substantia nigra pars reticulata (SNpr), a basal ganglia output nucleus, in a rat model of PD to explore the potential for this model to provide insight into how this activity emerges in the basal ganglia and whether it is functionally related to the motor symptoms of akinesia and dyskinesia associated with Parkinsons disease. After unilateral dopamine cell lesion, rats show notable motor deficits during treadmill walking in a circular treadmill. Our recording studies have shown that significant increases in local field potential (LFP) spectral power and in SNpr-mCx coherence in the high beta/low gamma 25-40 Hz frequency range emerge in the dopamine-lesioned hemisphere of these rats by day 7 after dopamine lesion which parallel in many ways the increases in oscillatory activity noted in PD patients, indicating that this is a good model for investigating the functional significance of these changes in brain activity. This year we have continued to use this model to better understand the changes in synchronized activity emerging in basal ganglia output after loss of dopamine. In a recently published study, we have used hemiparkinsonian rats performing a treadmill walking task to compare synchronized oscillatory activities in the STN with the motor cortex (MCx) and the medial prefrontal cortex (mPFC), areas involved in motor and cognitive processes, respectively. Data show increases in STN and MCx 29-36 Hz LFP spectral power and coherence after dopamine depletion. These increases are reduced by apomorphine and levodopa treatments. In contrast, recordings from mPFC three weeks after dopamine depletion failed to show peaks in 29-36 Hz LFP power. However, mPFC and STN showed similar and significant peaks in the 45-55 Hz frequency range in LFP power and coherence during the walking task before and 21 days after dopamine depletion. Interestingly, power in this low gamma range was transitory reduced in both mPFC and STN after dopamine depletion but recovered by day 21. In contrast to activity in the 45-55 Hz range, the amplitude of the exaggerated 29-36 Hz rhythm in the STN is modulated by paw movement. Furthermore, as in PD patients, after dopamine treatment, a third band (80-120 Hz) emerged in the dopamine cell lesioned hemisphere. The results suggest that STN integrates activity from both motor and cognitive networks, in a manner that varies with frequency, behavioral state and the integrity of the dopamine system. STN LFP activity can become synchronized with, and presumably modulated by, activity in both limbic and motor cortex networks in a manner that varies with frequency range, behavioral state and the integrity of the dopamine system. We are now following up on 2 relevant observations. First, the low gamma activity observed in the mPFC in normal rats during treadmill walking is dramatically reduced within a day after loss of dopamine. We hypothesize this reflects some direct modulation of local mPFC circuts by dopamine. Interestingly this activity returns to normal levels about 3 weeks after the lesion, showing that the mechanisms governing the cognitively related low gamma activity are relatively plastic. Second, we have also been recording in the anterior cingulate cortex (ACC) together with the STN in the hemiparkinsonian rats. The ACC is another prefrontal area that is well described in the rat and could be relevant to non-motor symptoms in Parkinsons disease. In contrast to the lack of evidence for the high beta activity in the mPFC after dopamine cell lesion, preliminary results show a dramatic increase in high beta activity in the ACC during treadmill walking. The ACC, we have further found is thought to receive input from the ventral medial thalamus, an area receiving from the basal ganglia output, and thus seems part of a larger basal ganglia thalamocortical loop. In a second set of studies, we have completed collecting data for our investigation into changes in spiking and LFP in two areas in the striatum in conjunction with recordings in motor cortex and SNpr in the hemilesioned Parkinsonian rat. Although exaggerated oscillatory activity has been observed in the majority of basal ganglia nuclei in PD, it is still unclear how it emerges and whether it engages the major basal ganglia input nucleus most directly affected by dopamine loss, the striatum. Our results show increases in striatal oscillatory LFP activity after dopamine depletion during treadmill walking in the high beta/low gamma frequency range, and during L-dopa-induced dyskinesia in the high gamma range. However, the oscillatory activity in the striatum was patchy, and striatal projection neurons showed very little phase coupling to the increased oscillatory activity in the 28-36 Hz range in motor cortex and striatum, suggesting a minimum role of the striatum in transmitting this hyper-synchronized activity downstream to the basal ganglia output, the SNpr. On the other hand, we also find evidence that information transfer from the striatum to the globus pallidus pars externa (GPe) may be disrupted. We are in the process of using a stochastic entropy model to study how dopamine depletion alters coding capacity and information flow in the basal ganglia of hemiparkinsonian rats. Analysis of changes in entropy in the spiking of the striatal output is suggestive of changes which may reflect efforts to compensate for loss of dopamine. We are working on a manuscript reporting this data. The absence of oscillatory activity in striatal output calls attention to the role of the STN and GPe circuitry in generating or propagating the excessive activity in the high beta range in the hemiparkinsonian rats. Together with increased phase coupling of cortical, STN and SNpr neurons to the motor cortex LFP activity in the beta frequency range observed after loss of dopamine , these data suggests that this activity propagates via the hyper-direct pathway, that is, from motor cortex to STN, and then to SNpr . A third set of studies have been initiated to explore the role of the STN-GPe circuitry in the initiation and/or propagation of the exaggerated oscillatory acticity emerging in the basal ganglia after loss of dopamine. In these studies we explore the idea that there may be two subsets of neurons in the GPe which become engaged in an antiphase relationship promoting oscillatory activity in conjunction with the STN nucleus. We have begun to use virally-transmitted DREADS to manipulate the activity of these two subsets of neurons to explore the role of these cells in the generation of the high beta rhythms.
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