Pharmacology And Physiology Of The Substantia Nigra And Basal Ganglia

Neurological Disorders And Stroke

Investigators

Linked publications & trials

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 Parkinsons disease, tardive dyskinesia, Huntingtons chorea and attention deficit hyperactivity disorder. The Sections neurophysiological studies in several different rat preparations - locally anaesthetized, immobilized and artificially respired rats, freely moving 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. 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] [unreadable] 1) Section Researchers in previous years have used a rodent model of Parkinsons disease, the urethane-anesthetized rat with unilateral lesion of midbrain dopamine neurons, to investigate how dopamine cell death brings about alterations in neuronal firing patterns in basal ganglia output. Neurophysiological evidence has strongly supported the hypothesis that loss of striatal dopamine enhances transmission of cortical firing patterns to downstream sites via the striatal-pallidal 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. Further studies in this model in FY 2007 have been directed at determining how synchronized and oscillatory activity in basal ganglia output may affect activity in thalamocortical loops as well as in downstream sites such as the pedunculopontine nucleus (PPN).[unreadable] a) The PPN has robust connections with the basal ganglia, thalamus and motor cortex, and is a new target for deep brain stimulation (DBS) for the alleviation of medically intractable akinesia in Parkinsons disease. In FY 07 we have investigated the effect of dopamine loss on spike timing in the PPN using motor cortex local field potential (LFP) activity as a reference. Observations show that timing of PPN activity with respect to motor cortex is dramatically affected by DA cell lesion, consistent with a dominant effect of increased inhibitory oscillatory input to the PPN from basal ganglia output nuclei. These findings highlight processes that may be involved in motor dysfunction and PPN DBS efficacy in PD patients.[unreadable] b) Section researchers are also exploring the impact of oscillatory and synchronized basal ganglia output on firing patterns in the cingulate and sensorimotor cortex and in the parafascicular nucleus and motor nuclei of the thalamus in the urethane-anesthetized 6-OHDA lesioned rat to determine how dopamine loss modifies thalamocortical loop function. Single unit and local field potential activities are being recorded from the dopamine-lesioned, non-lesioned and control hemispheres in these areas, and the impact of deep brain stimulation (DBS) of the STN on cingulate and parafascicular activity is being examined. In contrast to observations in basal ganglia nuclei, the results to date show that unilateral depletion of dopamine does not robustly alter firing patterns in the anterior cingulate or sensorimotor cortices in lesioned and non-lesioned hemispheres in the anesthetized rat. However, changes in parafascicular activity supports the hypothesis that spike timing in the thalamus is affected by synchronized hyperpolarizing input from the basal ganglia and strongly modulated by deep brain stimulation of the STN. [unreadable] [unreadable] 2) The efficacy of DBS in the STN in Parkinsons disease has focused attention on the role of dysfunctional firing patterns in the STN. Oscillatory activity in the beta frequency range (8-18 Hz) is of special interest as LFP recordings in bradykinetic parkinsonian patients during DBS electrode placement show prominent activity in this frequency range, which is reduced by dopamine receptor stimulants. Insight into mechanisms promoting emergence of beta range activity in the STN and potential significance of STN output in this range has been sought in FY07. [unreadable] a) Results in an awake behaving rat model of Parkinsons disease support a role for increased synchronization between STN and GP in the beta range activity after dopamine loss and suggest a greater impact of GP on STN activity in conditions of decreased dopamine receptor stimulation. These observations are consistent with the hypothesis that alterations in striatal dopamine lead to increased transmission of cortical firing patterns to downstream nuclei in awake animals as well as in anesthetized rats. Results also show a desynchronizing effect of dopamine receptor stimulation on GP-STN relationships in both intact and lesioned rats.[unreadable] b) To further explore the significance of beta range activity in the STN and GP after loss of dopamine, rats were trained to walk in the rotating treadmill and implanted bilaterally electromyogram bundles for recording muscle activity in the forelimb and with microwire bundles for chronic recording of spike and local field potential (LFP) activity in the SNpr, a basal ganglia output nucleus receiving input from the STN and GP. Results indicate that changes in beta power in the SNpr are more consistent than changes in rate in the context of alterations in motor activity and dopamine system function. This behavioral paradigm will be useful for further probing of relationships between spiking activity and beta power in SNpr and the source/significance of beta activity recorded in the SNpr.[unreadable] [unreadable] 3) In contrast to effects of dopamine cell lesion, treatments which lead to increases in dopamine receptor stimulation lead to hyperactivity. Correlations between this behavioral state and basal ganglia output have been also explored in FY07 in awake behaving rats. We have examined cortico-basal ganglia network function in the awake behaving animal, with the aim of understanding the role of dopaminergic modulation of information flow from the cortex to the basal ganglia output nuclei in freely-moving animals in an open field environment. Methylphenidate, an indirect dopamine agonist, significantly increased locomotor activity as well as prefrontal cortex SNpr coherence in a frequency range previously associated with motor activity in studies of firing pattern the hippocampus and prefrontal cortex. Results extend this correlation to the cortico-basal ganglia circuites and indicate that increased catecholamine efflux induced by methylphenidate promotes neural synchrony in these circuits in the 6-12 Hz range.[unreadable] [unreadable] 4) Collaborative studies have been initiated in FY07 to explore the neurophysiological mechanisms underlying observations of functional magnetic resonance imaging (fMRI) activation of primary somatosensory cortex associated with reorganization following sensory deafferentation. The goal of these studies is to further understand processes involved in interhemispheric plasticity which impact the probability of recovery. [unreadable] Rsults suggest that there is an increase in interneuron activity in the deprived cortex following forepaw denervation. Increased cortical inhibition may affect the degree of rehabilitation following stroke and injury.