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 are studying 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. Further studies in FY 2008 have been directed at determining whether synchronized and oscillatory activity in basal ganglia output affects activity in thalamocortical loops as well as in downstream sites such as the PPN.? a) The PPN has robust connections with the basal ganglia, thalamus and motor cortex, and is a new target for DBS for the alleviation of medically intractable akinesia in Parkinsons disease. In FY 08 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 indicate that dopamine loss alters PPN spike timing by increasing inhibitory oscillatory input to the PPN from basal ganglia output nuclei, a phenomenon that may be relevant to motor dysfunction and PPN DBS efficacy in PD patients.? b) In contrast to the changes observed in the PPN firing patterns after dopamine cell lesion, Section researchers showed in FY 2008 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.? ? 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. However, these observations raise questions difficult to address in patients, including the extent to which beta activity is differentially expressed in the intact vs. dopamine-depleted state, whether STN beta activity affects spike timing in basal ganglia output, how beta activity correlates with difficulties in gait, and how basal ganglia output correlates with motor activity during l-dopa-induced dyskinesias. Insight into these questions has been sought in studies in an awake behaving rat model of Parkinsons disease in FY08. ? 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 frequency range during rest in the basal ganglia output. Data further suggest that dysfunctional expression of high beta/low gamma activity in basal ganglia output may be associated with motor impairment during effort to walk.? 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. After chronic treatment with l-dopa, rats exhibited pronounced rotational behavior and limb dyskinesias. Results show that l-dopa-induced rotational behavior was associated with marked decreases in SNpr firing rate in the dopamine-depleted hemisphere while limb dyskinesias were associated with more variable changes in SNpr rate and pattern with weak but 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. It has recently been suggested that high frequency (>100 Hz) DBS of the STN could reduce parkinsonian motor symptoms via antidromic enhancement of resonant motor cortical activity. In addition, DBS of the PPN at lower frequencies (10-20 Hz) has been shown to ameliorate medically intractable parkinsonian axial symptoms. 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.? ? 3) Collaborative studies were undertaken in FY08 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. Section researchers have set up a rat preparation anesthetized according to the protocol employed for the imaging studies to facilitate these studies on intra and interhemispheric responses to stroke and deafferentation. ? a) In vivo electrophysiological recordings and juxtacellular neuronal labeling in somatosensory cortex in urethane anesthetized rats with peripheral nerve injury showed 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. Results suggest that increased cortical inhibition may affect the degree of rehabilitation following stroke and injury. ? b) Preparations have begun to extend colaberative studies with MIF facility researchers to investigation of neurophysiological changes in cortex associated with recovery from stroke. Studies will focus on oscillatory activity in the ultraslow frequency range which may facilitate axon growth and rewiring associated with recovery.
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