Pharmacology And Physiology Of The Substantia Nigra And Basal Ganglia

黑质和基底神经节的药理学和生理学

• 批准号: 7969508
• 负责人: JUDITH RICHMOND WALTERS
• 金额: $ 154.61万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7969508
• 关键词: Acute; Address; Affect; Animal Model; Animals; Area; Attention; Attention deficit hyperactivity disorder; Basal Ganglia; Behavior; Cell Death; Cell Nucleus; Cells; Chronic; Clinical; Collaborations; Corpus striatum structure; Correlative Study; Data; Deafferentation procedure; Deep Brain Stimulation; Denervation; Disease; Dopa; Dopamine; Dopamine Receptor; Dyskinetic syndrome; Electrodes; Environment; Exhibits; Freezing; Frequencies; Functional Magnetic Resonance Imaging; Gait; Gilles de la Tourette syndrome; Goals; Image; Interneurons; Investigation; Label; Lesion; Limb structure; Maintenance; Medial; Midbrain structure; Modeling; Motor; Motor Cortex; Movement; Mus; Muscle; Neurons; Neurotransmitters; Output; Parafascicular Nucleus; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Pattern; Peripheral nerve injury; Pharmacology; Physiology; Pontine structure; Posture; Preparation; Procedures; Rattus; Recovery; Research Personnel; Rest; Rodent Model; Role; Sensory; Shoulder; Side; Signal Transduction; Site; Somatosensory Cortex; Stroke; Structure of subthalamic nucleus; Substantia nigra structure; Thalamic Nuclei; Thalamic structure; Therapeutic Agents; Time; Training; United States National Institutes of Health; Urethane; Vibrissae; Walking; Work; awake; axon growth; dopaminergic neuron; in vivo; information processing; insight; interest; neurophysiology; novel; prevent; receptor; response; stroke recovery; transmission process

Current focus in the NPS is on mechanisms underlying the ability of dopamine-containing neurons to affect information processing in the basal ganglia and associated areas. 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 exploring the specifics of dysfunctional alterations in basal ganglia output in animal models of Parkinsons disease and the effects of these alterations on sites receiving basal ganglia input, such as the thalamus and peduncular pontine nucleus (PPN). We have also initiated studies to explore the consequences of deep brain stimulation (DBS) of the peduncular pontine nucleus(PPN) and subthalamic nucleus (STN) on motor cortex activity. In addition, through collaborations with researchers working in the Mouse Imaging Facility (MIF) at NIH, we have investigated the neurophysiological correlates of functional magnetic resonance imaging (fMRI) changes in cortex in animal models of stroke and sensory denervation. 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. Our studies have strongly supported the hypothesis that loss of striatal dopamine enhances transmission of cortical firing patterns to downstream sites via the striatal-pallidal pathway, contributing to the emergence of dysfunctional oscillatory activity in the basal ganglia output nuclei as well as in downstream sites such as the PPN. Further studies in the anesthetized rat model in FY 2009 have been directed at determining whether synchronized and oscillatory activity in basal ganglia output affects activity in thalamocortical loops. a) In contrast to the changes observed in the PPN firing patterns after dopamine cell lesion, Section researchers showed in FY 2009 that spike trains in the ventroanterior-ventrolateral (VAVL) nucleus and the parafascicular nucleus (PFN) of the thalamus are not affected as hypothesized by loss of dopamine. It has been predicted that changes in basal ganglia output after dopamine cell lesion should influence VAVL and PFN activity and impact cortical function. Results do not support the view that robust increases in oscillatory activity in basal ganglia output following dopamine loss drive changes in oscillatory activity in either VAVL or PFN thalamic nuclei. Studies are underway to further investigate the effects of basal ganglia output on activity in the ventral medial (VM) nucleus of the thalamus in normal and dopamine lesioned animals. 2) The efficacy of DBS in the STN and GPi in Parkinsons disease has focused attention on the role of dysfunctional firing patterns in the basal ganglia in this disorder. Oscillatory activity in the beta frequency range (8-35 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. However, these clinical observations raise many questions difficult to address in patients, including the extent to which beta activity is differentially expressed in the intact vs. dopamine-depleted state, what drives the increase in beta, whether STN beta activity affects spike timing in basal ganglia output, how beta activity correlates with difficulties in gait, and what the functionally significant consequences of increased basal ganglia beta output are at downstream sites, such as the PPN and motor thalamus. Insight into these questions has been sought in studies in an awake behaving rat model of Parkinsons disease in FY09. a) Rats were trained to walk in a novel rotary treadmill while EMG activity in shoulder muscle and neuronal activity in basal ganglia output were recorded. After unilateral loss of dopamine, rats made progress walking counterclockwise on the rotary treadmill, but tended to freeze during clockwise walking as this required the affected side to make more demanding adjustments of gait and posture. Neurophysiological recordings support the hypothesis that loss of dopamine is associated with increased LFP activity and neuronal spiking in the low beta (12 25 Hz) frequency range in the basal ganglia output during periods when the rats are at rest and inattentive to their environment. Data further suggest that dysfunctional expression of high beta (25 40 Hz) activity in basal ganglia output is associated with alert states and is evident at a slightly higher peak frequency during impaired walking. b) The same rat model was used to study how basal ganglia output is differentially expressed in the dopamine -depleted state before and after chronic l-dopa treatment. Acute treatment with l-dopa restores walking to control levels in the circular treadmill and reduces high beta frequency to levels comparable to those in the intact hemisphere. After chronic treatment with l-dopa, rats exhibited pronounced rotational behavior associated with marked decreases in SNpr firing rate in the dopamine-depleted hemisphere and subsequently, limb dyskinesias associated with more variable changes in SNpr rate and pattern with significant coherence with limb dyskinesia activity. c) Changes in motor cortex network function in conjunction with deep brain stimulation are underway in the urethane-anesthetized rodent model of Parkinsons disease in FY 08. Section researchers are comparing the effects of STN and PPN DBS on motor cortex activity in the rodent model of Parkinsons disease to help understand the immediate and persistent effects of these therapies in the anesthetized model, with plans to extend these studies in the awake behaving rat model of Parkinsons disease. 3) Collaborative studies are on-going in FY09 to explore the neurophysiological mechanisms underlying observations of functional magnetic resonance imaging (fMRI) activation of primary somatosensory cortex associated with reorganization following sensory deafferentation and response to stroke. To date, in vivo electrophysiological recordings and juxtacellular neuronal labeling in somatosensory cortex in urethane anesthetized rats with peripheral nerve injury have shown that deafferentation is specifically accompanied by elevated responsiveness of inhibitory interneurons, a change that is reflected in the fMRI signal but not the evoked local field potential responses. In addition, preparations have begun in FY 2009 to extend correlative studies with the MIF facility to include investigation of neurophysiological changes in cortex associated with unilateral deafferentation of the whiskers, comparing results with changes observed above with peripheral nerve injury. In addition, the section is investigating changes in cortical activity associated with recovery from stroke, focusing on oscillatory activity in the ultraslow frequency range which may facilitate axon growth and rewiring associated with recovery.