Pharmacology And Physiology Of The Substantia Nigra And

Neurological Disorders And Stroke

Investigators

Linked publications & trials

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. Dopamine acts in the brain through at least 5 dopamine receptor subtypes to alter the activity of a variety of voltage and receptor modulated ion channels. The net effect of these changes in ion channel function provides dopaminergic innervation of the striatum and other basal ganglia nuclei with the ability to modulate the impact of synaptic input onto dopamine receptor bearing neurons and to gate neuronal stimulus/response relationships in the basal ganglia. In the FY 2004 we have investigated how alterations in dopamine receptor stimulation affects neuronal activity in the basal ganglia. These studies were designed to address how dopamine modulates basal ganglia activity and how loss of dopamine neurons or decreases in dopamine system function dysfunctionally affects neuronal activity at downstream sites in the basal ganglia. The long term goal of these studies is to design more effective treatment for disorders involving dopamine system function. 1) Section Researchers, in FY2004, 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. We have found that globus pallidus (GP), subthalamic nucleus (STN) and substantia nigra pars reticulta (SNpr) spike trains exhibit dramatically altered firing patterns 1- 2 weeks after unilateral 6-OHDA-mediated dopamine cell lesion in urethane-anesthetized rats. When recordings from the lesioned hemisphere were compared to those from the intact side, intermittent bursts are more notable in STN and SNpr trains, and GP trains appear to have more defined intermittent pauses. Phase relationships are such that the oscillations are focused on the SNpr. Thus, loss of dopamine at D2 receptors in the striatum appears to bring about increased striatal sensitivity to slow cortical oscillatory firing patterns in the anesthetized rats and results in increased synchronization of striatal influence on GP and SNpr. Synchronized pauses in GP activity may also contribute to synchronized bursts in 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. Simultaneous recordings on the intact side of the brain shows lack of this effect 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) Studies are also underway to explore these issues in awake unanesthetized rats, treated either with dopamine receptor blockers, or dopamine agonists in combination with dopamine cell lesion. To date, observations suggest a role for dopamine in modulating the passage of coherent oscillatory activity through basal ganglia-thalamocortical loops. The net effects of alterations in dopamine receptor stimulation appears to reflect a complex interplay of effects of dopamine on processes generating the oscillatory activity associated with a given state and on processes regulating the transmission of those oscillatioons through the basal ganglia. Sortingg out the ways in which alterations in dopamine receptor stimulation facilitates or reduces passage of coherent oscillatory activity through basal ganglia-thalamocortical loops may provide insight into the dysfunctional effects of abnormal levels of dopamine receptor stimulation on affective and motor behavior. 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 GP ipsi and contralateral to the unilateral lesion. We found that SNpr and GP 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 SNpr but not in the GP. This observation suggests LFP measurements can reflect differences in firing pattern and synchronization between paired neuronal populations in this frequency range - but may not necessarily do so. 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. We have previously shown that systemic administration of drugs that increase dopamine receptor stimulation such as apomorphine, amphetamine, cocaine and selective dopamine uptake blockers increase the frequency of these oscillations and pairs of basal ganglia neurons demonstrate a greater number of correlated multisecond oscillatory activity after dopamine agonist stimulation. In FY04, we have explored the potential significance of these oscillations through collaborations with clinicians. In collaboration with Dr. Castellanos of the NYU Child Study Center, we have examined the reaction time variability in children with attention deficit hyperactivity disorder (ADHA). Results suggest that these individuals may have a dopaminergically mediated deficit in the ability to appropriately modulate oscillations in neuronal activity in multisecond time scales. A paper is in press in Biological Psychiatry reviewing this novel approach to developing measures of variability as a putative endophenotype for ADHD. Collaborations with Dr. Braun to study relationships between movement and multisecond oscillations in cortical EEG in humans is also underway.