Pharmacology And Physiology Of The Substantia Nigra And

Neurological Disorders And Stroke

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Abstract

The dopamine system is critical to appropriate information processing in the basal ganglia. Dysfunction of this neuronal system has been implicated in the etiology of many neurological diseases, including Parkinson?s disease, tardive dyskinesia, Huntington?s chorea and attention deficit hyperactivity disorder. Current thinking about the dopamine?s impact on the basal ganglia has moved from a focus on rate based models to a focus on the effects of dopamine receptor stimulation on synchronous and oscillatory activity in basal ganglia networks. Our interest in the role of dopamine and oscillatory activity in the basal ganglia goes back many years and it is exciting that these issues are coming to the fore in current discussions in the literature regarding the functional role of dopamine and the mechanisms underlying dysfunction associated with dopamine cell death or over activity. Our older studies in locally anaesthetized, immobilized and artificially anesthetized rats indicated that dopamine agonists induced a dramatically enhanced oscillatory activity in ultraslow frequency ranges. Our more recent studies using the slow oscillation in cortical activity induced by some anesthetics as a tool have allowed us to develop a hypothesis regarding how dysfunctional increases and decreases in dopamine receptor stimulation may enhance passage of oscillatory activity through the basal ganglia networks. These extremes in dopamine receptor stimulation, we hypothesize, lead to disruption of the normal filtering effect of moderate levels of stimulation and promote coalescing of phase relationships and increased synchronization of oscillatory activity in basal ganglia output as a result of the imbalance in transmission of oscillatory activity through the indirect and direct pathways. We have been investigating this hypothesis in a variety of ways in the past year. 1) Section Researchers, in FY2005, have used a rodent model of Parkinson?s disease, rats with unilateral lesion of midbrain dopamine neurons, to study changes in neuronal function in the basal ganglia. One approach has taken advantage of the fact that systemic anesthesia induces slow synchronized oscillations in cortical activity. The effect of unilateral lesion of striatal dopaminergic innervation on the passage of these slow oscillations in neuronal activity through the basal ganglia nucleus has been examined in cojunction with the dramatically altered firing patterns observed in basal ganglia nuclei after -6-OHDA lesions. Examination of phase relationships has lead to the hypothesis that loss of dopamine at D2 receptors in the striatum brings about increased striatal sensitivity to slow cortical oscillatory firing patterns in the anesthetized rats and results in increased synchronization of striatal influence on globus pallidus and substantia nigra pars reticulata (SNpr). Synchronized pauses in pallidal activity may also contribute to synchronized bursts in the subthalamic nucleus (STN) and SNpr. These studies show that in a relatively simple system, the anesthetized rat, loss of dopamine brings about a consolidation of oscillatory activity via the striatal-pallidal and cortical-subthalamic pathways which coalesces at downstream sites and contributes to dysfunctional strong oscillatory activity in the basal ganglia output nuclei and highlights the dramatic difference the dopamine cell lesion makes on passage of this slow oscillation though the basal ganglia nuclei and focusing of the oscillatory activity on the output. 2) We have further used this model to determine whether the increased incidence of slow oscillations present in STN and SNpr spike trains after unilateral 6-OHDA-induced DA cell lesion are also present in the entopeduncular nucleus (EPN) spike trains, and whether slow oscillations from the SNpr and EPN influence neuronal activity in the ventrolateral (VL) thalamus and motor cortex. The data indicate that there was selective loss of slow oscillations in the VL thalamus, in the frequency range that dominates in the EPN and SNpr in anesthetized rats. The reduction in slow oscillations in the VL thalamus with DA loss may be related to coincident increased inhibitory oscillatory activity from SNpr and EPN dampening excitatory oscillatory activity from the motor cortex. These results suggest that increased synchronization of activity in basal ganglia output may interfere with activity in the same frequency range in thalamocortical loops. 3) To follow up on the observations above, Section researchers have gone on to take advantage of the changes in firing pattern induced in the basal ganglia by loss of dopamine neurons to investigate how changes in firing pattern and synchronization of activity relate to changes in local field potential (LFP). Clinical investigators have begun to record LFP from patients being treated for neurological disorders with implantation of deep brain stimulation electrodes. It is becoming an important issue how changes in LFP in basal ganglia nuclei reflect population activity. LFP and spike activity data were obtained from paired simultaneous recordings of SNpr neurons ipsi and contralateral to unilateral 6-OHDA lesions in anesthetized rats. Data were also obtained from paired recordings in the STN in intact rats and lesioned rats ipsilateral to the unilateral lesion. We found that STN spike train firing patterns ipsilateral to the dopamine cell lesion are highly correlated with LFPs on both lesioned and intact sides. Spectral power of LFP oscillations in slow and delta frequency ranges is significantly higher ipsilateral to the dopamine cell lesion in the STN but relative change in firing pattern as reflected in burstiness and spike train oscillations are much greater. This observation suggests LFP measurements can reflect differences in firing pattern and synchronization between paired neuronal populations in this frequency range - but do not adequately predict the extent of synchronization in neuronal populations. This agrees with last years?s observation that LFP differences were significant in only one of two sets of paired populations with notably different firing patterns - i.e. in the SNpr-SNpr paired recordings, but not in the GP-GP paired recordings. This study implies caution should be used in using LFP to assess changes in population activity in in vivo recordings from patients with neurological disorders performed for the purpose of placement of deep brain stimulation electrodes. 4)Section researchers have extensively documented the presence of ultraslow oscillation (2 - 60 sec periods) in the basal ganglia of immobilized, awake rats. Drugs which alter dopamine receptor stimulation have the ability to modulate the properties of these ultraslow oscillations in the activity of tonically active neurons throughout the basal ganglia. Questions have always come up, however, regarding the functional significance of these multisecond oscillations in normal preparations. In FY 2005 collaborations began with Dr. Braun to determine the presence of these oscillations in human EEG and with Dr. Wassermann and Dr. Guilbert to investigate whether they were evident in measures of the sensitivity of motor cortex to transcortical magnetic stimulation (TMS). We found multisecond oscillations in both EEG and TMS measures. Further supporting the idea that multisecond oscillations in cortical activity have functional significance, we found that self-paced movements are regularly initiated during the negative phase of ultraslow oscillation in cortical EEG, when the neurons are relatively more depolarized (excited) on this ultraslow time scales, as reflected by movement-triggered averages of the DC EEG. This has implications for the understanding of phenomena such as the Readiness Potential.