Thomas Wichmann - US grants

The basal ganglia may be viewed in a larger context as components of segregated cortico-subcortical reentrant circuits that also involve the thalamus. One of these circuits, the ~motor~ circuit, is critically involved in the development of Parkinsonian motor signs. Degeneration of nigrostriatal dopaminergic neurons leads to increased activity in the basal ganglia output nuclei. The neuronal activity in the motor portion of one of these output nuclei, the internal segment of the globus pallidus (GP), has been characterized in detail in intact and Parkinsonian animals. This together with other studies, eventually lead to the reintroduction of GPi lesions as treatment for Parkinson~s disease in humans, with very promising results. The neuronal activity in the motor circuit portion in the second major basal ganglia output nucleus, the substantial nigra pars reticulata (SNr), has received far less attention. In the proposed experiments, we will test the hypotheses that: (1) there is a distinct segregated motor area in the SNr of primates, (2) that abnormal neuronal discharge in this area contributes to motor signs in Parkinsonism, (3) that inactivation of the SNr motor area can alleviate some Parkinsonian motor signs, and (4) that combined lesions of SNr and GPi are more effective that lesions of GPi alone. Responses of SNr neurons to somatosensory examination will be studied with electrophysiologic extracellular recordings, using closely spaced microelectrode penetrations in primates (Specific Aim [S.A.] 1). Anatomic and physiologic studies suggest that neurons with responses to somatosensory examination will be found in centro-lateral regions of SNr. The degree of convergence between motor and non-motor circuits will be explored by assessing the responses of SNr neurons to electrical stimulation at striatal motor and non-motor sites (S.A. 1). Similar recordings will be done after rendering the animals Parkinsonian by injections of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP;S.A.2). It is expected that phasic and tonic activity in SNR is increased after MPTP. The behavioral effects of transient or permanent inactivation of the SNr motor area will be studied with local injections of the GABA-receptor agonist muscimol or the neurotoxin ibotenic acid, respectively (S.A. 3), and effects of combined GPi/SNr lesions will be compared with those of GPi lesions along (S.A. 4). With the hypothesis that abnormal discharge in SNr contributes to Parkinsonian motor signs, it is expected that inactivation of SNr will ameliorate the motor disturbances, and that effects of GPi and SNr lesions will be additive.

DESCRIPTION: (Verbatim from the Applicant's Abstract) The basal ganglia are part of larger circuit that involves thalamus and cortex. Cortical inputs reach striatum and subthalamic nucleus (STN), and are transmitted via internal pallidal segment (GPi) and substantia nigra pars reticulata (SNr) to influence the activity of thalamocortical neurons. The function of this circuitry is disturbed in Parkinson's disease because of loss of dopamine in the basal ganglia. Besides changes in discharge rates, basal ganglia neurons also develop significant abnormalities in their discharge patterns in parkinsonism. One of the most salient abnormalities is the appearance of synchronized oscillatory discharge in STN, the external pallidum (GPe), GPi/SNr, and frontal cortex (detected by EEG). Available data suggest that this may result from altered activity along the cortex-STN-GPi/SNrthalamocortical route. With a combination of extracellular basal ganglia recordings and EEG, the proposed primate experiments explore the relationship between oscillatory activity in cortex and basal ganglia and will test the hypothesis that oscillatory discharge in the cortex-basal ganglia circuitry contributes to parkinsonism. The correlation studies under specific aim (S.A.) 1 assess the link between neuronal discharge in the basal ganglia (GPe, STN GPi, SNr) and EEG with simultaneous recordings in both brain regions. The importance of striatal or extrastriatal dopamine loss for the development of oscillatory discharge in parkinsonism will be tested under S.A. 2 by studying changes in oscillatory activity in basal ganglia and cortex induced by microinjections of the dopamine receptor agonist apomorphine at striatal and extrastriatal basal ganglia sites in parkinsonian animals. The experiments under S.A. 3 will test whether blockade of glutamate receptors in STN (blocking corticosubthalamic inputs) reduces oscillatory activity in basal ganglia and cortex. Finally (S.A. 4), the hypothesis will be tested that synchronized oscillatory discharge in the basal ganglia, induced by electrical stimulation of STN with bursts of stimulation pulses at burst rates between 2 and 30 Hz, disrupts motor performance and induces parkinsonian motor abnormalities in normal monkeys. These studies will help to understand the significance of oscillatory discharge in the basal ganglia and cortex in parkinsonism. This may provide guidance in the development of drug treatments directed at normalizing abnormal discharge patterns, and may help to understand the mechanism of action of existing treatments for Parkinson's disease, including dopamine receptor agonists, glutamate receptor antagonists, and deep brain stimulators.

DESCRIPTION:(from applicant's abstract) Degeneration of the dopaminergic nigrostriatal tract results in Parkinson's disease. Over the last years, rodent studies have provided evidence that the activity of the source neurons of the nigrostriatal tract in the substantia nigra pars compacta (SNc) is modulated by afferents from the subthalamic nucleus (STN). Increased STN output, a central feature of most models of parkinsonian pathophysiology, could impact SNc function in early parkinsonism, helping to compensate for the loss of striatal dopamine by increased driving of nigrostriatal neurons. In rodents, STN and SNc are linked via excitatory glutamatergic projections, or via inhibitory pathways involving GABAergic neurons in the substantia nigra pars reticulata (SNr). Activation of the excitatory projections results in increased bursting in SNc, whereas activation of the inhibitory projections lowers the average discharge rates in SNc. Our preliminary data in primates have also demonstrated excitatory and inhibitory effects of STN stimulation on SNc activity, and have indicated that striatal DA levels may be increased with STN stimulation and reduced with STN inactivation. Effects on striatal dopamine may be explained by the direct synaptic STN-SNc interaction, by actions mediated via long loop circuits through thalamus and cortex, as well as by presynaptic mechanisms. The proposed experiments will explore the STN-SNc relationship in primates, with the general hypothesis that STN activation will result in increased burst discharges in SNc and increased dopamine levels in the striatum, while STN inactivation will result in the opposite. A combination of electrophysiologic, microdialysis and anatomic methods will be used to assess effects of transient manipulations of STN activity, induced by intra-STN injections of the GABA receptor agonist muscimol or the GABA receptor antagonist bicuculline, on the neuronal activity in SNc and SNr and on striatal dopainine levels (S.A. V 1/2). Similarly, effects of "deep brain" stimulation and lesions of STN will be studied to assess the impact of these commonly used neurosurgical interventions on SNc and SNr activity, and on striatal DA. In the case of STN lesions, the density of glutamate and GABA receptors in SNc will also be determined (immunoautoradiography) as an inverse measure of the strength of glutamatergic and GABAergic inputs to SNc. These studies will provide insight into the role of the STN-SNc interaction under normal and parkinsonian conditions and will help to understand the mechanisms of action of neurosurgical treatments aimed at SIN in parkinsonian patients.

DESCRIPTION (provided by applicant): Experiments in rodents and cats have indicated that dopamine is released from dendrites of cells in the substantia nigra pars compacta (SNc), and that it may enhance GABA release in the substantia nigra (SN) via an action on D1-like receptors (D1LRs) on terminals of the GABAergic striato-nigral projection, and inhibit its own release via an action on dopamine D2-like autoreceptors (D2LRs). One of the functionally important effects of nigral dopamine release is that it may modulate the activity of neurons in the substantia nigra pars reticulata (SNr). D1LR activation appears to reduce SNr activity via enhanced GABAergic inhibition. Activation of nigral D2LRs may enhance SNr activity via reduction of dopamine release and secondary reduced activation of D1LRs. Local dopaminergic modulation of SNr activity may have significant behavioral effects. Thus, nigral dopamine loss appears to contribute to rodent parkinsonism by increasing SNr activity. The proposed experiments will explore whether this scheme of dopamine actions applies to primates. Anatomic experiments (aim 1) will characterize the subcellular and subsynaptic localization of dopamine receptors in the primate SN with high-resolution immunogold electron microscopy. They will be complemented by functional experiments (aim 2) in which the activity of SNr neurons will be recorded before, during and after local microinfusions of agonists and antagonists for D1LRs or D2LRs in the vicinity of the recorded cells, and in which drug-induced changes in nigral GABA and dopamine levels will be measured with microdialysis. The experiments under aims 3 and 4 will characterize the consequences of dopamine depletion in this system with experiments similar to those under aims 1 and 2 in animals that have been rendered hemiparkinsonian by intracarotid injections of the dopaminergic neurotoxin MPTP. In addition, we will test the hypothesis that nigral infusions of D1LR agonist exert antiparkinsonian behavioral effects. These studies will provide insights into the anatomic basis and functional effects of nigral dopamine release in monkeys in the normal state and in parkinsonism. They will help us to determine whether nigral dopamine loss is involved in parkinsonism, whether antiparkinsonian dopaminergic drugs act in part in SN, and whether restorative therapies aimed at the SN (e.g., transplantation of ventral mesencephalic tissue) may act through local release of dopamine.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cortical inputs reach basal ganglia structures, which project back to thalamus and cortex. Due to the lack of the neurotransmitter dopamine synchronized oscillatory and non-oscillatory activity appears in the basal ganglia which can be measured with local field potential (LFP) recordings. In our primate experiments, we study recordings of LFP changes that are associated with the induction of parkinsonism by treatment with the neurotoxin MPTP. We also studied the local effects of dopaminergic drugs on neuronal synchrony in the basal ganglia nuclei, using a microdialysis/LFP recording probe which allows us to assess the effects of drugs, applied locally via reverse microdialysis, on LFPs in the vicinity of the probe. In this funding period we focused on studies of LFP abnormalities in parkinsonian animals. The studies are carried out in an animal that is undergoing a very slow course of MPTP treatment, combined with careful monitoring of the parkinsonian phenotype. Another animal (the third in this series) is currently being prepared for MPTP treatment. In the last funcitn period we also completed our series of studies of LFP changes produced through blockade of receptors for the inhibitory neurotransmitter GABA in the striatum, and their modulation through the local application of dopamine receptor blockers. GABA receptor blockade induced recurrent large LFP events which were not directly synchronized to neuronal activity in the immediate vicinity of the LFP probe, therefore likely reflecting synchronous synaptic inputs instead. In addition, the study resulted in the creation of a new video analysis method to track wakefulness through observations of eye lid opening.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for patients with Parkinson's disease, but the effects of this treatment on brain activity remain unknown. We therefore study the electrophysiologic and biochemical effects of DBS in normal and parkinsonian monkeys. Parkinsonism is induced by treatment with the dopaminergic neurotoxin MPTP. In the past funding period, we continued to study effects of STN stimulation in two normal animals. We found that STN stimulation produced effects on the activity of basal ganglia neurons that were more varied than previously appreciated. Although the effects of STN stimulation would be expected to be excitatory, firing rate changes in neurons that receive STN input varied substantially, ranging from inhibition to strong excitation. In many neurons the effects of short- and long-term stimulation differed, indicating the presence of adaptive changes. We also undertook a detailed analysis of firing pattern changes associated with STN stimulation. The stimulation-associated firing patterns differed between short- and long-term stimulation. We are currently completing microdialysis studies of the effects of STN stimulation on local levels of the inhibitory neurotransmitter GABA. We also repeated the same studies in two additional animals which were MPTP-treated. These experiments have been completed, but the results have not been analyzed. This part of the studies is crucial for a better understanding of the effects of electrical stimulation on basal ganglia activity in parkinsonian individuals. Insights into the mechanism of action of DBS in parkinsonism are needed to devise better stimulation protocols, may help to optimize placement of the stimulation probes in parkinsonian patients, and may help us to formulate rational pharmacologic approaches to maximize the beneficial effects of DBS and minimize its side effects.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Dystonia is a disabling condition with unsatisfactory treatment choices. Motivated by the observation that dystonia (and not parkinsonism) frequently accompanies states of disturbed dopamine metabolism in young patients, these studies assess the effects of dopamine depletion in infant monkeys. During the reporting period, we completed observations in three infant monkeys which were treated with weekly injections of MPTP. Despite the fact that the cumulative MPTP doses surpassed those used in older animals for the induction of parkinsonism threefold, the animals did not develop significant parkinsonism or dystonia. We also studied two additional younger animals which were treated with higher doses of MPTP over the course of one month. Both developed intermittent neck, trunk and extremity dystonia. One of them also developed mild parkinsonism. As is typical for dystonia, behavioral activation exacerbated abnormal posturing. In the animal that developed parkinsonism, this was weakly correlated with the severity of dystonia. We are still analyzing the histological results. A study of markers of dopamine depletion (stains for tyrosine hydroxylase and the dopamine transporter) showed that symptomatic monkeys showed more pronounced striatal dopaminergic loss than asymptomatic monkeys and that the loss of striatal dopaminergic innervation in the infant monkeys with dystonia was at least as severe as that in parkinsonian adult animals. These results provide evidence that dopamine depletion can lead to dystonia when the depleting intervention occurs at a very young age. We are currently in the process of studying the distribution of cholinergic and serotonergic markers in these animals.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. These studies examine the functional interactions and the anatomy of the connections between the intralaminar nuclei of the thalamus (i.e., the centromedian and parafascicular nuclei (CM/PF)) and the striatum in normal and parkinsonian monkeys. CM and PF send a topographically organized projection to the striatum. Movement-related projections from the CM terminate in the putamen which may act to shape striatal output under normal and pathologic conditions. The CM/PF complex is empirically targeted for neurosurgical interventions, such as deep brain stimulation (DBS), in the treatment of patients with Tourette's syndrome and Parkinson's disease. We have found that electrical CM stimulation with short trains of stimuli results in complex sequences of activation and inhibition in striatal cells, which are most easily explained as the result of intrastriatal spread of activity and processing within the striatal circuitry, for instance through local inhibitory axon collaterals and cholinergic interneurons. The ongoing studies (started earlier this year) contrast striatal responses to CM/PF stimulation in normal and parkinsonian monkeys with a combination of electrophysiologic recordings, microinjections, and anatomic studies. In this funding period, we have started to reconstruct the anatomical inputs from CM to specific dendritic domains of cholinergic striatal interneurons (one of the major striatal recipients of CM inputs). In addition, we are studying CM inputs to chemically defined subtypes of striatal output neurons. Finally, we have started electrophysiological recordings in one animal to study the effects of electrical stimulation of the CM on the activity of cholinergic neurons in the striatum. The proposed studies will provide us with information regarding the anatomy and physiology of the thalamostriatal system, and its involvement in parkinsonism, will clarify the effects of electrical stimulation of CM, and will provide data to help clinicians optimize parameters for CM-DBS therapy in parkinsonian patients.

DESCRIPTION (provided by applicant): There is accumulating evidence that dopamine loss at locations outside of the striatum such as the substantia nigra or the globus pallidus may play a significant role in the development of parkinsonism. Recent studies in animals, primarily rodents) have suggested that dopamine may also act at the level of the subthalamic nucleus (STN). In these animals, a direct dopaminergic projection from the substantia nigra pars compacta to the STN has been demonstrated. Furthermore, it appears that the activity of STN neurons is modulated through actions of dopamine at pre- and post-synaptic dopamine receptors in the STN, and that dopamine depletion in the STN leads to altered firing rates and more intense bursting in this nucleus. The extent and anatomy of the dopaminergic innervation of the STN, the function(s) of dopamine within the STN, and the effects of dopamine loss in the STN in the parkinsonian state have not been explored in primates. With the proposed studies, we will examine the anatomy and function of the dopamine supply to the STN in vivo in primates. With the experiments under aim 1, we will analyze the extent of the dopaminergic innervation and characterize the subcellular localization of dopamine receptors in the STN of normal and MPTP- treated (parkinsonian) monkeys, using a combination of light-microscopic and high resolution electron microscopic immunocytochemical methods. The experiments under aim 2 will study the functional effects of dopaminergic compounds, locally administered in the STN, on the activity of STN neurons in normal and parkinsonian monkeys. We will examine the effects of dopamine receptor agonists and antagonists, injected locally into the STN with a microinjection/recording device. In addition, microdialysis experiments will be carried out to measure the presynaptic effects of dopamine on GABA release in the STN, as well as electrophysiological recordings in the primary targets of STN projections, i.e., the external and internal pallidal segments. Finally, under aim 3, we will study the behavioral effects of dopamine receptor blockade in the STN in normal animals, and activation of dopamine receptors in the STN in parkinsonism, with the expectation that disruption of dopaminergic transmission contributes to parkinsonism, and replacement of dopaminergic function in the parkinsonian state may ameliorate parkinsonian symptoms. Taken together, these studies will provide us with a thorough examination of dopaminergic functions in the primate STN, will help us to understand further the effects of dopamine loss at this extrastriatal site, and may identify the STN as a target for focal dopamine replacement strategies in parkinsonism, such as gene delivery methods or grafting. PUBLIC HEALTH RELEVANCE: The neuronal activity in the subthalamic nucleus is strongly affected by the dopamine depletion in the basal ganglia that occurs in Parkinson's disease, making this nucleus the primary targets of functional neurosurgery to treat parkinsonism. Activity changes in the subthalamic nucleus are usually seen as secondary events, triggered by striatal dopamine loss. However, there is accumulating evidence that dopamine loss within the subthalamic nucleus also contributes to the neuronal activity changes, and to the generation of parkinsonism. We will explore this hypothesis in parkinsonian primates through anatomical, electrophysiologic, biochemical and behavioral experiments. These studies will expand our knowledge of the pathophysiology of parkinsonism, and may identify the subthalamic nucleus as a location at which current dopaminergic therapies work. If significant dopaminergic effects are seen in the subthalamic nucleus, it may emerge as a new target for highly specific local dopamine replacement therapies for parkinsonian patients.

DESCRIPTION (provided by applicant): The Morris K. Udall Parkinson's Disease Center of Excellence at Emory University will be a highly collaborative research program in which electrophysiologists, pharmacologists, and anatomists work together to study the effects of existing and new treatments for parkinsonism from a circuit perspective. The Center draws upon the proven ability of the basal ganglia research community at Emory to conduct translational research. Other Center assets will be its close ties to the clinical movement disorders group at Emory, the fact that a portion of the research will be carried out in primates at the Yerkes National Primate Research Center, and the Center's connection to an active population of patients with Parkinson's disease in the Atlanta area. Emory University is strongly committed to Parkinson's Disease research, and will support the Center by funding pilot grants and an invited speaker seminar series. The center will consist of four projects and two cores. Project 1 (Dr. Jaeger) will examine changes imposed by altered basal ganglia input onto thalamic neurons in the parkinsonian state. Project 2 (Dr. Wichmann) is a series of experiments in parkinsonian primates to compare the thalamic effects of pallidal and subthalamic nucleus inactivation and stimulation, as are commonly used to treat advanced parkinsonism in patients, with the goal of identifying changes in thalamic activity that are associated with the antiparkinsonian effects of these procedures. Project 3 (Dr. Miller) is a series of translational experiments that examine the use of orally active TrkB receptor agonists as symptomatic or neurorestorative treatment for Parkinson's disease in different rodent and primate models. Project 4 (Dr. Conn, Vanderbilt), investigates the effects of a series of novel subtype-selective muscarinic acetylcholine receptor antagonists and activators on basal ganglia activity, and on parkinsonism in rodent models. The projects will be supported by an administrative core (Core A, Dr. Wichmann, PI;Dr. DeLong, Co-1, Dr. Pearson, administrator), and by an anatomy and behavior core (Core B, Dr. Smith) which will provide immunohistochemistry and electron microscopy services to all of the center projects, and will conduct behavioral testing in MPTP-treated monkeys under project 3. PUBLIC HEALTH RELEVANCE: The Center will foster collaborative Parkinson's disease research, train young investigators, and educate the public about the disease. The Center's research will take a circuit level approach to explore synaptic and circuit interactions in the basal ganglia-thalamo-cortical network. It will increase our understanding of how existing therapies work, and develop and explore the mechanisms of action of new antiparkinsonian treatments. PROJECT 1 Principal Investigator: Dieter Jaeger, PhD Title: The Role of Mouse Motor Thalamus Relaying Basal Ganglia Outflow Description (provided by applicant): We will examine how the motor thalamus in mouse models of Parkinson's disease (PD) Is Involved In transmitting Parkinsonian activity patterns generated In the basal ganglia to the cerebral cortex. We will use simultaneous electrophysiological recordings from basal ganglia, thalamus, and cortex In anesthetized and awake mice to determine the presence of pathological activity patterns, and their relations between structures. One strength of the proposal consists of the use of in vivo intracellular thalamic recordings, which will allow us to examine the hypothesis that strong basal ganglia bursting activity observed In PD will trigger post inhibitory rebound bursting In thalamus. Previous work suggests that such bursting in the basal ganglia Is one of the characteristics of pathological activity patterns in PD, but the transmission of this activity through thalamus to cortex remains unclear. We will carry out a detailed analysis of the specific mechanisms of synaptic integration in motor thalamus of the mouse In the brain slice preparation, where we test the control of action potential initiation by Parkinsonian patterns of Input. Finally, we will determine whether pharmacological compounds known to Interact with thalamic cellular properties (M1 and M4 muscarinic receptor agonists or antagonists or selective Cav3 calcium channel blockers) can be used to reduce the transmission of pathological activity from the basal ganglia through thalamus to cortex. This project is tightly Integrated with the other projects of the overall Emory Udall Center grant application: We share the focus on thalamic processing with project 2, where it will be examined In primates rendered Parkinsonian with MPTP. We share the VMAT2L0 mouse model of PD with project 3, where it will be used to determine possible neuroprotective treatment strategies. Our analysis of pathological electrical activity patterns In the VMAT2L0 mouse developed by Dr. Miller at Emory will aid in the validation of this model. We obtain the pharmacological compounds to be tested for specific effect on thalamic processing through our interactions with project 4. These compounds mentioned above are promising novel specific receptor agonists and antagonists as well as channel blockers that are not otherwise available Public Health Relevance: The public health relevance of this project is the study of novel treatments for Parkinson's disease that target the motor thalamus. In addition, the expected results will help us to better understand how much transgenic mouse models of Parkinson's disease repeat the same pathological activity patterns in the brain as seen in human patients, and to determine which mouse model can be best used for detailed treatment studies.

Neurosurgical interventions, such as deep brain stimulation (DBS) of the internal pallidal segment (GPi) or the subthalamic nucleus (STN), or GPi lesions (pallidotomy), are commonly used to help patients with advanced Parkinson's disease. DBS and lesioning procedures produce contrasting effects on their immediate brain targets: Lesions reduce the output of the lesioned nucleus, while electrical stimulation of STN or GPi is thought to lead to complex activity changes in the stimulated tissue, including local neuron inhibition, and stimulation of efferent or afferent fibers. Despite these differences, lesions and stimulation have remarkably similar clinical and behavioral effects. We hypothesize that one of the reasons for this paradox is that, although the surgical interventions produce different local effects, they lead to similar effects in nuclei further downstream, particularly in the anterior ventrolateral thalamus (VLa), the recipient of a dense GABAergic projection from the motor portion of the basal ganglia output nuclei. Previous studies have suggested that VLa neurons show an increased tendency to fire in bursts and to generate oscillatory patterns of activity in parkinsonism, which may act to disrupt thalamocortical interactions, and may be involved in the generation of parkinsonian signs. We hypothesize that lesions and DBS aimed at GPi or STN have different effects on VLa firing rates, but that both regularize the firing patterns of VLa neurons, thus allowing cortico-thalamo-cortical interactions to proceed more normally. To test these hypotheses, we will examine the effects of GPi inactivation on neuronal activities, GABA levels, and morphological aspects of the synaptic pallldothalamic interactions in MPTP-treated (parkinsonian) monkeys (aim 1). Results from these studies will then be compared with the effects of electrical stimulation of STN or GPi on thalamic neuronal activity in MPTP-treated monkeys (aim 2). A better understanding of the common downstream effects of lesions and stimulation may help us to define more specific neurosurgical or pharmacological therapies, or therapies that combine pharmacologic treatments with the neurosurgical interventions, in order to eliminate parkinsonisian motor signs.

The administrative core will support all aspects of the Center's overall mission. In terms of the Center's research mission, Core A will provide the organizational structure for meetings of Center personnel, advisory boards and other researchers, compile progress and budgetary reports for the NIH, facilitate resource sharing, and serve as a nodal point for PD-related research at Emory University, so that the collaborative interactions within the research community at this institution are enhanced. The Core will also administer a pilot grant program, financed through University matching funds. In addition, the administrative core will oversee and organize the numerous opportunities for students, postdoctoral fellows, and clinical residents and fellows to learn about PD and participate in PD-related research with Center investigators. In conjunction with a Community Outreach Board, the Core will also administer resources for the Center's outreach efforts to the larger community.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Udall Center's administrative core supports Center investigators in carrying out their research, and facilitates communication of Center personnel with other Emory researchers, with the Center's advisory boards, with the general public, and with other Centers within the Udall network. Specifically, the core support the Center's collaborative research and facilitate regulatory oversight through the organization of meetings of the Center's scientific staff and meetings with internal and external advisors. Core A is currently in the process of setting up the Center's website. Core personnel have already participate in one of the annual Udall Center network meetings, and keep track of accounting issues to compile progress and budgetary reports for the NIH. The core has also gone through its first round of pilot grant reviews, and has recently selected three outstanding proposals from Parkinson's disease researchers at Emory who are not otherwise related to the center. In order to also foster Parkinson's disease-related awareness, the Center provides educational opportunities for students, postdoctoral fellows, and Neurology/Neurosurgery residents and fellows, such as lectures and hands-on training. Finally, the core has set up its first public outreach event (a series of round table discussions) which will be held in May of this year.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The recently funded Morris K. Udall Parkinson's Disease Center of Excellence at Emory University is a highly collaborative research program in which electrophysiologists, pharmacologists, and anatomists work together to study the effects of existing and new treatments for parkinsonism from a circuit perspective. The center consists of four projects and two cores. Project 1 (Dr. Jaeger) examines changes imposed by altered basal ganglia input onto thalamic neurons in the parkinsonian state. Project 2 (Dr. Wichmann) is a series of experiments in parkinsonian primates to compare the thalamic effects of pallidal and subthalamic nucleus inactivation and stimulation, as are commonly used to treat advanced parkinsonism in patients, with the goal of identifying changes in thalamic activity that are associated with the antiparkinsonian effects of these procedures. Project 3 (Dr. Miller) is a series of translational experiments that examine the use of orally active TrkB receptor agonists as symptomatic or neurorestorative treatment for Parkinson's disease in different rodent and primate models. Project 4 (Dr. Conn, Vanderbilt) investigates the effects of novel subtype-selective muscarinic acetylcholine receptor antagonists and activators on basal ganglia activity, and on parkinsonism in rodent models. The projects are supported by an administrative core (Core A, Dr. Wichmann, PI;Dr. DeLong, Co-I, Dr. Pearson, administrator), and by an anatomy and behavior core (Core B, Dr. Smith) which provides immunohistochemistry and electron microscopy services to all of the center projects, and conducts behavioral testing in MPTP-treated monkeys under project 3.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Neurosurgical interventions, such as deep brain stimulation (DBS) of the internal pallidal segment (GPi) or the subthalamic nucleus (STN), or GPi lesions, are helpful in patients with Parkinson's disease. DBS and lesioning procedures produce contrasting effects on their immediate brain targets: Lesions reduce the output of the lesioned nucleus, while electrical stimulation may lead to local neuron inhibition, and stimulation of efferent or afferent fibers. Despite these differences, lesions and stimulation have remarkably similar clinical and behavioral effects, perhaps because they lead to similar effects in nuclei further downstream, particularly in the thalamus, the recipient of a dense projection from the basal ganglia. Previous studies have suggested that thalamic neurons show an increased tendency to fire in bursts and to generate oscillatory patterns of activity in parkinsonism, which may act to disrupt thalamocortical interactions, and may be involved in the generation of parkinsonian signs. To test whether lesions and DBS aimed at GPi or STN have the same or different effects on thalamic firing we examine the effects of GPi inactivation, and of electrical stimulation of the STN or GPi on neuronal activities, GABA levels, and morphological aspects of the synaptic pallidothalamic interactions in parkinsonian monkeys. These studies have just started, and we are currently doing the first studies to examine the effects of STN stimulation on thalamic activities. A better understanding of the downstream effects of lesions and stimulation may help us to define more specific neurosurgical or pharmacological therapies, or therapies that combine pharmacologic treatments with neurosurgical interventions.

DESCRIPTION (provided by applicant): The motor dysfunction of Parkinson's disease is usually described as the result of changes in the activity of basal ganglia-thalamocortical circuits. However, recent research has shown that the heterogeneous family of thalamostriatal projections may also be strongly affected by the disease, and that these changes may contribute to the development of parkinsonian signs and symptoms. The most substantial thalamostriatal projection comes from the caudal intralaminar nuclei in the thalamus (the centromedian and parafascicular nuclei [CM/Pf]). The CM/Pf-striatal projection gives rise to clusters of axon terminals that target preferentially dendritic shafts of striatal projection neuros, as well as cholinergic interneurons. This projection may be prominently involved in the processing of reward information and in the regulation of vigilance and attention. Another major source of thalamostriatal fibers are the 'basal ganglia receiving' ventral anterior (VA) and ventrolateral (VL) nuclei. Neurons in these nuclei send long un-branched axons to the striatum, with many en passant-type varicosities. The impact of the VL-striatal projections on striatal function is unknown. Postmortem analysis of brain tissue from parkinsonian patients has demonstrated that the source nuclei of the thalamostriatal projection and the organization of their synapses in the striatum are strongly affected by the neurodegenerative process. Neurons in the CM/Pf are particularly affected, with degeneration of more than 50% of neurons early in the course of the disease. We have demonstrated that these aspects of neuron loss are faithfully replicated in MPTP-treated (parkinsonian) monkeys, along with a corresponding decrease in thalamostriatal terminals. In addition, there are extensive changes in the morphology and density of dendritic spines in the striatum, which are the primary recipients of VL input. The functional impact of these changes on striatal activity is not known, but is likely t be substantial, and, given the anatomical and pathological differences, may differ between the two projection systems. We propose to test this hypothesis with a combination of functional and anatomical studies in monkeys. The functional studies (aim 1) will make use of an optogenetic approach that will allow us to selectively activate terminals of the CM-striatal or VL-striatal projections, and to examine the resulting effects on the activity of striatal projection neurons an cholinergic interneurons in awake primates. These studies will first be done in the normal state, and then again after the animals have been rendered parkinsonian by treatment with MPTP. The functional studies will be complemented with quantitative electron microscopic analyses in the same animals, in which opsin expression will be used as an anatomic marker to identify parkinsonism-related changes in the postsynaptic targets of CM- or VL-striatal terminals (aim 2). The proposed studies will help us to gain a more complete understanding of the circuit pathophysiology of parkinsonism, and set the stage for the development of therapeutic strategies to treat Parkinson's disease through influencing specific thalamostriatal interactions.

Project Summary ? Project 2 It is not known how dopamine depletion in the basal ganglia in Parkinson's disease and the resultant abnormal activity in these structures, alter information processing in brain areas that are downstream from them, specifi- cally the basal ganglia receiving motor thalamus (BGMT). Information processing in the BGMT remains enig- matic. Unlike other areas of the thalamus, the BGMT receives no peripheral glutamatergic input and only weak glutamatergic `driver' input from the cerebral cortex. In addition, it is unique among thalamic nuclei because it is subject to massive inhibitory modulation from the basal ganglia. The BGMT projects to the primary motor cor- tex (M1), the supplementary motor area (SMA) and other cortical areas, but it is not known how these projec- tions influence cortical activities. As we and others have shown, information processing in thalamus and cortex are strongly altered by abnormal basal ganglia output in the parkinsonian state. There is also strong new evi- dence for synaptic (functional/morphologic) plasticity in the parkinsonian state that will further affect the activity of thalamic and cortical neurons (project 3). In the planned studies, we will assess how parkinsonism affects the processing of basal ganglia or cortical inputs to BGMT, and BGMT inputs to motor cortices. Under aim 1, we will use a combination of optogenetic and electrical stimulation methods to probe the impact of activating M1, SMA, or basal ganglia inputs on BGMT activity in normal and parkinsonian (MPTP-treated) monkeys. Based on preliminary findings, we expect to find that light activation of opsin-transfected corticothalamic termi- nals will lead to short-latency excitatory and long-latency inhibitory responses in BGMT, while (electrical) acti- vation of pallidothalamic fibers inhibits BGMT. We will also study interactions between these inputs. In aim 2, we will examine responses of cortical neurons to optogenetic activation of BGMT projections in normal and parkinsonian primates. We expect that the prominent and layer-specific parkinsonism-related plasticity at thalamocortical synapses (project 3) alters responses of cortical neurons to their BGMT inputs. We will particu- larly focus on cortical neurons with antidromic responses to electrical internal capsule stimulation, because the activity of these cells is known to be strongly altered in parkinsonian monkeys. Interactions with project 1 will provide important mechanistic information regarding parkinsonism-related changes in the excitability and spike patterning of thalamic and cortical neurons, while collaboration with project 3 will help us to incorporate mor- phological changes into our analysis. Core B will add essential anatomical results to our study, and will help us by generating parkinsonian animals. Taken together, the planned studies will help us to understand how pal- lidal and cortical inputs shape BGMT activity, how these effects influence M1/SMA activities, and how cortico- thalamic and thalamocortical transmission changes in parkinsonism. This knowledge may alter our view of the pathophysiology of parkinsonism, and will be essential for the rational development or optimization of surgical or pharmacological antiparkinsonian neuromodulation strategies that target basal ganglia or thalamus.  

DESCRIPTION (provided by applicant): The long-term objective of this application is to foster the development of clinician- investigators in neuroscience. The goal of the research education program proposed here is to allow selected Emory neuroclinical trainees (in Neurology, Neurosurgery, Neuropathology, Neuroradiology and Emergency Medicine), during residency and fellowship training, to acquire the necessary research skills and background to enable them to be competitive for mentored career development awards and thus catalyze the continuity of the neuroclinician-investigator species. To this end, the specific aim of this application is to provide an outstanding research education experience to one or more residents each year from Neurology, Neurosurgery, Neuropathology, Neuroradiology or Emergency Medicine, to be complemented by a continuation of the participants' research education during subsequent fellowship training. A key component of the research education will be mentored laboratory or clinical research under the supervision of an experienced mentor. The participants in the present program will also have the benefit of a mentor team comprising 1-2 members in addition to the primary mentor, and their development will be closely monitored by the PIs. The participants in the present program will also be able to take advantage of additional educational resources, including courses in research design and analysis, grant-writing and research ethics.

Summary ? Administrative Core (Core A) The administrative Core will support all aspects of the Center's research, training and career enhancement, and outreach missions. In terms of the Center's collaborative research mission (Aim 1), Core A will provide the organizational structure for meetings of Center personnel, advisory boards and other researchers. The Core will also foster collaboration among Center investigators and other researchers in the Parkinson's disease (PD) research community at Emory University and within the Udall Center network. The Core will administer the Center's internally funded pilot grant program for PD research at Emory University. Further, The Core will provide fiscal and regulatory oversight, will prepare and submit progress reports to the NIH and facilitate resource sharing by handling all external requests for Center research resources and materials. In support of the Center's training and career enhancement mission, the administrative Core will oversee the Center's extensive educational and training activities for students, postdoctoral fellows, clinical residents and fellows, and junior faculty members (Aim 2). Besides helping with the organizational aspects of laboratory-based training, the Core will organize a quarterly PD research seminar series as well as other recurring educational sessions. Core A will closely interact with partners at Emory to optimize career enhancement options for trainees. In conjunction with a Community Outreach Board, the Core will also plan and implement the Center's active outreach program (Aim 3). Outreach activities will include lectures at PD support group meetings, and other public teaching sessions, as well as an annual symposium which will be organized in a small-group roundtable format, allowing patients and care givers to learn about ongoing PD research within the Udall Center and across the Emory campus. Many of the these outreach activities will utilize partnerships with local and national PD organizations. Serving all three aims, the Core will maintain the Center's website. The Core's three aims will be strongly supported by internal resources, generously contributed by multiple stakeholders at Emory University in recognition of the importance of the Center's research, training and outreach missions.

The Morris K. Udall Parkinson's Disease Center of Excellence for Parkinson's Disease Research at Emory University is a collaborative research program in which electrophysiologists and anatomists study the pathophysiology of parkinsonism, and examine and optimize the effects of existing treatments for Parkinson's disease. The Center draws upon the proven ability of the basal ganglia research community at Emory to conduct translational research. Other Udall Center assets are its close ties to the clinical movement disorders group at Emory, and the availability of primates for research at the Yerkes National Primate Research Center at Emory University. Emory is strongly committed to the Udall Center's research, and supports the Center by funding pilot grants, invited speakers, and portions of its education and outreach programs. The Center consists of three tightly linked projects and two cores. The planned research will shed light on the poorly understood parkinsonism-related activity changes in thalamus and cortex which, in turn, will help us to better understand the pathophysiology of parkinsonism, and to optimize existing neuromodulation strategies and to develop new ones. Project 1 (led by Dr. Jaeger) will utilize brain slice and in vivo recordings in rodents, as well as a neural computational approach to develop mechanistic models of thalamocortical dysfunction in parkinsonism. Project 2 (Dr. Wichmann), will continue the exploration of thalamic and cortical abnormalities in parkinsonian monkeys, using selective activation and inactivation approaches which are designed to study corticothalamic, pallidothalamic and thalamocortical information transfer. Project 3 (Dr. Smith) will examine morphological changes in the thalamic and cortical microcircuitry in parkinsonian primates, a topic that is virtually unexplored at this time and of high relevance to the interpretation of data in the other projects. All projects will be supported by an Administrative Core (Dr. Wichmann, PI; Dr. DeLong, Co-I, Dr. Smith, Co-I, Ms Holbrook, administrator), and by an Anatomy and Behavior Core (Dr. Galvan) which will provide immunohistochemistry and electron microscopy services to all of the center projects, and standardized MPTP treatment and quantification of parkinsonism to the primate experiments in Projects 2 and 3. In addition to pursuing its research mission (Aim 1), the Center will help junior scientists to develop their career in Parkinson's disease research (Aim 2), and will engage in extensive outreach efforts, aimed at communicating the Center's (and Udall Center network) research findings to the public (Aim 3), reaching all age groups and background levels, ranging from K-12 children to retirees in assisted living facilities. As part of the outreach agenda, the center plans to organize annual symposia for patients and their caregivers. The center will be generously supported by the University. These internal support funds will help the Center to fund some of its education and outreach missions, as well as its pilot grant program, designed to expand Parkinson's disease research at Emory University.

SUMMARY According to current models, the involvement of the basal ganglia in motor and non-motor functions is explained in the context of information processing in segregated basal ganglia-thalamocortical loops. These models predict that striatal dopamine loss in Parkinson?s disease (PD) eventually leads to abnormal processing in the ?motor? thalamocortical network, and the antiparkinsonian effects of deep brain stimulation (DBS) of the sensorimotor internal globus pallidus (GPi) is explained as a release of movement-related thalamic neurons from overactive inhibitory GPi inputs. However, recent evidence suggests that descending basal ganglia output, specifically the massive projection of GPi to the pedunculopontine nucleus (PPN), may also be relevant for normal behavior and parkinsonism. Thus, manipulations of the PPN influence limb movements and postural adjustments, PPN activation has antiparkinsonian effects in monkeys, and DBS of the PPN ameliorates gait disturbances in some PD patients. The PPN is a highly heterogeneous brain region that gives rise to widespread ascending and descending projections. Our lack of knowledge of the anatomical targets of GPi projections to the PPN, and the effects of activation of the GPi-PPN pathway on PPN activity limits our understanding of the normal role of the GPi-PPN interaction and its role in the pathophysiology of PD, particularly in primates. The proposed studies aim therefore to examine the functional connectivity between the GPi and the PPN (aims 1 and 2), determine whether the anatomy and physiology of these networks are altered in the parkinsonian state (aims 2 and 3), and how GPi-DBS alters firing rates and patterns of GPi-receiving PPN neurons, as well as local field potential activity in the PPN (aim 3). These studies will be done in normal and MPTP-treated parkinsonian monkeys, using a combination of state-of-the-art optogenetic, anatomical and electron microscopy procedures. The knowledge gained from these studies is needed to develop or refine antiparkinsonian therapies that target the PPN or its projections for treatment of PD or other basal ganglia disorders.

ABSTRACT In current schemes of the pathophysiology of Parkinson?s disease (PD), neuronal activity changes in the sen- sorimotor region of the subthalamic nucleus (STN) play a central role in the development of parkinsonism. Until recently, the changes in STN activity were thought to result solely from reduced inhibition from the external globus pallidus (GPe). However, recent findings from animal models of advanced parkinsonism have suggested that a profound loss of glutamatergic cortico-subthalamic terminals and an increased strength of GABAergic pallidosubthalamic synapses may contribute to activity changes in the STN and to the development of parkin- sonism. Our preliminary data demonstrate that a loss of cortico-subthalamic terminals is also present in the sensorimotor STN territory of people with advanced PD. It remains unclear, however, how these anatomical and physiologic changes relate to the degree of nigrostriatal dopamine loss and to the expression of parkinsonism. Further, it is unknown if these changes also affect non-motor regions of the STN, perhaps contributing to cogni- tive or affective PD symptoms. We will examine these issues with neuropathological and electrophysiological studies in monkeys with different degrees of MPTP-induced dopamine loss (Aim 1), and with longitudinal 7T ultra-high field MRI studies in people with early PD (Aim 2). In Aim 1, we will record responses of STN neurons to optogenetic activation of cortical and pallidal inputs in monkeys that remained either asymptomatic after ex- posure to small dose of the dopamine-depleting neurotoxin MPTP or became parkinsonian after exposure to (larger doses of) MPTP. We will also assess changes in local field potentials (LFPs) and abnormal spiking activity in STN, and in the coherence between STN LFPs and motor cortical electrocorticograms. In postmortem studies of the same animals, we will use high resolution microscopic immunohistochemical studies and 3D-EM reconstructions to assess whether the number, localization, and morphology of glutamatergic and GABAergic synapses in the STN changes as a function of dopamine loss. We will also compare the number of cortico- subthalamic terminals and examine changes in GABAergic markers in STN tissue from patients with PD and age-matched controls. In Aim 2, we will use state-of-the-art diffusion and resting state functional MRI to test whether humans with early stage PD exhibit significant changes in the volume and microstructural organization of the STN and its cortical and pallidal afferents, and determine if these changes are related to the expression and progression of motor and non-motor impairments. The same patients will be studied at enrollment and 30 months later to examine changes in the MRI measures. The results of this project will increase our understanding of the temporal evolution of parkinsonism-associated plastic changes in the STN, and determine their potential relationships to the development and severity of motor and non-motor signs and symptoms of the disease. These studies may lead to novel interventions to control or prevent abnormal firing patterns in STN and may contribute to the development of imaging biomarkers to identify early stages of PD and predictors of disease progression.

PROJECT SUMMARY Parkinson?s disease (PD) is associated with abnormally increased, synchronized and oscillatory neuronal activity in the basal ganglia output circuitry, i.e., the subthalamic nucleus (STN) and the major target of its efferents, the internal pallidal segment (GPi). These changes are thought to be causally related to the emergence of parkin- sonism. Modulation of STN output with neurosurgical methods such as deep brain stimulation (DBS) have be- come standard treatments for advanced PD. However, these interventions are non-specific and can have signif- icant side effects. This project explores novel regulatable genetic approaches to reduce the parkinsonism-asso- ciated activity changes in STN and GPi and to ameliorate parkinsonism with fewer side effects (and potentially greater effects) than achieved with the currently available surgical methods. Under aim 1, we will examine the electrophysiologic and behavioral effects of doxycycline-controlled tetanus toxin light chain (TeTxLC) based si- lencing of synaptic transmission at efferents of STN neurons in parkinsonian (MPTP-treated) monkeys. The use of this approach is based on the well-documented effectiveness of STN or GPi inactivation in parkinsonian mon- keys, and on preliminary studies in rodents. The experiments under aim 2 will explore in rodents whether par- kinsonism can be treated by altering plasticity at synapses within the STN. The role of maladaptive plasticity in the STN of parkinsonian animals has recently been stressed in both non-human primates and rodent species, and there is preliminary evidence that it also applies to human patients with PD. We will explore two new regu- latable genetic approaches aimed at reducing these changes in the STN of 6-hydroxy dopamine (6-OHDA) treated, parkinsonian rats. In one approach, transmission at a sub-type of glutamatergic NMDA receptors (GluN2D receptors) which is strongly enriched in the STN will be manipulated by using a membrane-tethered GluN2D-specific toxin, and, as an alternative approach, microRNA-mediated Grin2D knockdown. Secondly, based on preliminary data in other fields, we will examine the effects of blocking gliotransmission using TeTxLC targeted to astrocytes in the STN to reduce (maladaptive) synaptic plasticity. The planned collaborative work is highly innovative, using new chemogenetic tools to achieve antiparkinsonian effects in parkinsonian primates and rodents. The results of our studies may provide guidance for larger systematic projects to explore these novel approaches. If successful, the new methods could be rapidly translated to improve the care of PD patients.

Project Summary ? Overall Center The Morris K. Udall Parkinson's Disease Center of Excellence for Parkinson?s Disease Research at Emory University is a collaborative research program that studies the pathophysiology of parkinsonism with the goal of optimizing the treatment for Parkinson?s disease (PD). The Center draws upon the proven ability of the basal ganglia research community at Emory to conduct collaborative translational research. Other Udall Center assets are the availability of primates for research at the Yerkes National Primate Research Center at Emory, and the presence of one of the largest movement disorders clinic in the US. The Center consists of four projects and three cores. The planned research will shed light on the poorly understood parkinsonism-related activity changes of specifically identified groups of projection neurons in the cerebral cortex which, in turn, will help us to better understand the pathophysiology of parkinsonism, and to optimize therapeutic strategies. Project 1 (led by Dr. Jaeger) will utilize rodent experiments for large-scale voltage imaging and brain slice recordings and use neural computational approaches to develop mechanistic models of cortical dysfunction in parkinsonism. Project 2 (Dr. Galvan), will explore the spontaneous and task-related activity of corticostriatal and corticospinal neurons in the primary motor cortex (M1) and the supplementary motor area (SMA) in normal and parkinsonian monkeys, using an opto-tagging approach to identify the projection targets of the recorded neurons. Project 3 (Dr. Smith) will examine morphological changes in the M1 and SMA microcircuitry and parkinsonism-associated changes in the connectome of cortical projection neurons in primates, a topic that is virtually unexplored and of high relevance to the interpretation of data in projects 1 and 2. The clinical ?Catalyst? project 4 is an examination of parkinsonism-related changes in cortical activity in response inhibition tasks, studied in electrocorticography and electroencephalography signals in patients with PD. The functional experiments will also study the effects of levodopa and deep brain stimulation treatments in these paradigms. All projects will be supported by an administrative core (Core A, Dr. Wichmann, PI; Dr. Smith, Associate Director, Ms Holbrook, administrator), and by a service core that provides anatomical services to projects 1 and 2, behavioral assessments to projects 2 and 3, and statistical services to all projects (Core B, Dr. Galvan). A clinical core (Core C) will support project 4 with recruitment and logistic services for the human studies. In addition to pursuing its research mission (aim 1), the Center will help young scientists to develop their career in PD research (aim 2), and will engage in extensive outreach efforts, aimed at communicating the Center?s (and Udall Center network) research findings to the public (aim 3), reaching all age groups and background levels. As part of the outreach agenda, the center plans to organize annual outreach events for patients and their caregivers. Generous internal support funds will help the Center to fund some of its education and outreach missions, as well as its pilot grant program, designed to expand PD research at Emory.