Pharmacology And Physiology Of The Substantia Nigra And

Neurological Disorders And Stroke

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Abstract

Current focus in the Neurophysiological Pharmacology Section is on mechanisms underlying the ability of dopamine-containing neurons to affect information processing in the basal ganglia and associated areas. Dysfunction of the dopaminergic 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 dopamine?s impact on the basal ganglia has evolved from a focus on rate based models to a focus on how dopamine receptor stimulation modulates firing patterns and neuronal synchronization in basal ganglia networks. The Section?s neurophysiological studies in two different rat preparations - locally anaesthetized, immobilized and artificially respired rats, and systemically anesthetized rats - have provided evidence that normal levels of dopamine receptor stimulation act to prevent emergence of inappropriately synchronized and oscillatory neuronal firing activity in basal ganglia networks, while significant increases and decreases in dopamine receptor stimulation enhance the expression of these dysfunctional patterns. These studies have lead to the hypothesis that alterations in the tonic level of dopamine receptor stimulation enhance passage of oscillatory activity in slow frequency ranges (1 ? 10Hz) through basal ganglia networks by differentially modulating transmission of patterned activity through components of the so-called ?direct? and ?indirect ?pathways, allowing antiphase relationships to emerge in convergent excitatory and inhibitory pathways, entraining oscillatory firing patterns in downstream nuclei. In the past year, we have been investigating this hypothesis and exploring the consequences of dysfunctional alterations in basal ganglia output on activity in thalamocortical loops. [unreadable] 1) Section Researchers, in FY2006, have used a rodent model of Parkinson?s disease, the urethane-anesthetized rat with unilateral lesion of midbrain dopamine neurons, to investigate why cortical activity patterns typical of the anesthetized state become much more robustly expressed throughout the basal ganglia after loss of dopamine. In this preparation, there is increased synchronization of 1 Hz oscillatory activity in all basal ganglia nuclei after dopamine cell lesion. Examination of phase relationships has demonstrated that loss of striatal dopamine brings about an increase in the transmission of cortical firing patterns to downstream sites via the striatal-pallidal pathway in collaboration with the cortical-subthalamic projection and in conjunction with reduced transmission of activity through the ?direct? striatonigral pathway. These changes facilitate transmission of cortical oscillatory activity to downstream sites and contribute to the emergence of dysfunctional oscillatory activity in the basal ganglia output nuclei. [unreadable] 2) Section researchers have also made use of the unilaterally lesioned rodent model of Parkinson?s disease to determine how the increased incidence of slow oscillations present in basal ganglia output after dopamine cell lesion affects neuronal activity in thalamo-cortical loops. The goal of these studies is to obtain insight into how tremor frequency activity (6 ? 8 Hz) present in basal ganglia output in unanesthetized models of Parkinson?s disease may affect thalamocortical function. The data from the anesthetized rat model indicates that there is a selective loss of slow oscillations in the ventrolateral (VL) thalamus in the frequency range that dominates basal ganglia output in anesthetized rats. There is also a decrease in activity in the motor cortex in the hemisphere with the dopamine cell lesion. The reduction in slow oscillations in the VL thalamus after DA loss may be related to coincident decreases in activity in the motor cortex. The data suggest that increased synchronization of activity in basal ganglia output interferes with neuronal activity in the same frequency range in thalamocortical loops. [unreadable] 3) Mechanisms contributing to altered firing patterns in the subthalamic (STN) nucleus after loss of dopamine have also been probed. Identifying factors that induce alterations in firing pattern and rate changes in the STN after dopamine cell loss has been an important goal in PD research as the therapeutic efficacy of deep brain stimulation of the STN and GPi supports the significance of firing pattern changes in these nuclei with respect to PD motor symptoms. The Section?s results support the hypothesis that one process contributing to increased burstiness and oscillations in the STN is the modified interplay between cortical and pallidal input that results from dopamine lesion-induced alterations in striatopallidal activity. However, other inputs, such as those from cortex, pedunculopontine nucleus and parafascicular nuclei could also be affected by loss of dopamine and play a role in modulating STN firing patterns after dopamine cell lesion. In this regard, however, Section researchers have shown in anesthetized rats with unilateral 6-OHDA induced dopamine cell lesions no increases in firing rates or increased oscillatory activity in either the anterior cingulate or motor cortex in the lesioned hemisphere. These results argue that while cortical input to the STN from these areas may be a critical partner in helping establish the patterned activity that emerges in the STN after dopamine cell lesion, increases in cortical input, per se, are not contributing to the emergence of patterned activity in the STN. This indicates that the major changes in STN firing patterns which emerge after dopamine cell lesion are due to altered input to the STN from the globus pallidus or to changes within the STN itself after loss of dopamine. [unreadable] 3) To follow up on these observations, Section researchers are currently engaged in recording neuronal activity in basal ganglia output and VL thalamus from awake behaving rats with unilateral dopamine cell lesions. Rats are trained to work on a circular treadmill before unilateral dopamine cell lesion to provide a control for the rotational behavior these animals exhibit after treatment with dopamine agonists following dopamine cell lesion. To date, data shows changes in firing rate in basal ganglia output when rats are engaged in dyskinesias after chronic dopamine administration. These recordings are being analyzed to determine how firing pattern and local field potential in these output nuclei correlates with emergence of dyskinesia. Data is being compared with firing patterns recorded when rats are engaged in simple walking in a circular treadmill, or are rotating in an open field after dopamine agonist administration. [unreadable] 4) An additional series of studies are also being conducted to explore the effects of increased dopamine receptor stimulation on firing patterns in the basal ganglia in intact rats. Using doses of drugs which have been shown to increase impulsivity in a 5 choice task and induce modest hyperactivity, preliminary studies are indicating an increase in coherence in the 6 ? 8 Hz frequency range in activity in prefrontal cortex and the basal ganglia output nuclei ? the substantia nigra pars reticulata. These effects are being further analyzed in animals restrained to walk in a circular treadmill to differentiate between drug effects on movement and network synchronization. Examination of selective dopamine agonists in this paradigm will further enhance understanding of how alterations in dopamine receptor stimulation modulates synchronization and firing patterns in basal ganglia networks.