DOPAMINERGIC SIGNALING IN THE NUCLEUS ACCUMBENS
Dalton James Surmeier, Professor And Chairman
Northwestern University 750 N. Lake Shore Drive, 7th Chicago, Il 60611
Grant 5R01DA012958-05 from National Institute On Drug Abuse, IRG: ZRG1
Keywords: biological signal transduction, dopamine, dopamine receptor, drug abuse, neurophysiology, neurotransmitter transport, nucleus accumbens, receptor expression, calcium channel, electrophysiology, neuroanatomy, potassium channel, polymerase chain reaction, voltage /patch clamp
Project start date: 2000-02-01
Project end date: 2006-01-31
5R01DA012958-05 (2004): $272248
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DOPAMINERGIC SIGNALING IN THE NUCLEUS ACCUMBENS
Dalton James Surmeier, Professor And Chairman
Northwestern University 750 N. Lake Shore Drive, 7th Chicago, Il 60611
Grant 5R01DA012958-04 from National Institute On Drug Abuse, IRG: ZRG1
Keywords: biological signal transduction, dopamine, dopamine receptor, drug abuse, neurophysiology, neurotransmitter transport, nucleus accumbens, receptor expression, calcium channel, electrophysiology, neuroanatomy, potassium channel, polymerase chain reaction, voltage /patch clamp
Project start date: 2000-02-01
Project end date: 2005-01-31
5R01DA012958-04 (2003): $264318
5R01DA012958-02 (2001): $254146
Grants awarded to Dalton James Surmeier
General Motor Control Mechanisms And Disease Training Program
Dalton James Surmeier, Professor And Chairman
Physiologynorthwestern University
Grant 5T32NS041234-08 from National Institute Of Neurological Disorders And Stroke, IRG: NST
Abstract: This competitive renewal proposal is a request for continued funding of a broadly based pre- and postdoctoral training program in General Motor Control Mechanisms and Disease from the Northwestern University Institute for Neuroscience (NUIN). This training program has grown out of a multidisciplinary group of motor control investigators who have collaborated since the inception of the NUIN in 1989. The program is directed by D. James Surmeier, Ph.D. with the assistance of Enrico Mugnaini, M.D. (Associate Director) and a Steering Committee. Trainees will conduct their research under the guidance of 29 preceptors working in motor control research from 11 departments of 3 schools on the Chicago and Evanston campuses of Northwestern University. The proposal requests support for 5 post-doctoral and 3 pre-doctoral trainees. Post-doctoral trainees will be selected on the basis of previous training and research plan. Pre-doctoral trainees will be selected from NUIN and Medical Scientist Training Program Ph.D. programs on the basis of course performance, rotations and the relevance of dissertation research to the goals of the training program. A concerted effort will be made to continue recruiting women and minorities to the program. The program offers a broad range of interdisciplinary research and training opportunities in the neuroscience of somatic and autonomic motor control. The research of participating preceptors spans molecular, cellular, systems, clinical, behavioral and computational neuroscience. The preceptor faculty will assist and monitor trainee progress through formal advising and evaluations, through the classroom and through informal discussions (in journal clubs, laboratory meetings and research clubs). An important feature of the training program is that it brings together researchers in fundamental and clinical neuroscience, providing a highly productive, interdisciplinary research environment for trainees in motor control and related motor system diseases at Northwestern University. In addition to providing research training, the program will help trainees develop skills in written and oral communication, grant writing/grantsmanship, networking and career development. Instilling a clear awareness of ethical issues facing neuroscientists and responsible conduct in science will be another training goal. The program outlined attempts to exemplify the multidisciplinary and interactive type of neuroscience research training encouraged by NINDS
Project start date: 2001-07-15
Project end date: 2011-06-30
5T32NS041234-07 (2007): $512907
2T32NS041234-06 (2006): $62579
MUSCARINIC AND DOPAMINERGIC CONTROL OF STRIATAL NEURONS
Dalton James Surmeier, Professor And Chairman
University Of Tennessee Health Sci Ctr 62 S. Dunlap Memphis, Tn 38163
Grant 5R29NS028889-03 from National Institute Of Neurological Disorders And Stroke, IRG: NLS
Abstract: Parkinson s disease afflicts 1 in every 1000 adults, rising exponentially in incidence after the age of fifty. The symptoms of this debilitating psycho-motor illness are thought to result from a functional imbalance between cholinergic and dopaminergic systems of the neostriatum. The treatment of this disease has been hampered by the absence of a clear picture of the neuromodulatory actions of these systems in the neostriatum. Electrophysiological studies in other excitable cells have demonstrated that acetylcholine (ACh) and dopamine (DA) exert their effects on electrical excitability primarily by altering the properties of voltage-dependent ionic conductances. These alterations are reflected in the integration of synaptic input, action potential shape and spike patterning. Previous studies of neostriatal neurons have not been able to provide a similar level of understanding because of their reliance upon techniques that cannot definitively characterize ionic conductances or the molecular mechanisms mediating their modulation. In this project, recently developed whole-cell and patch voltage-clamp techniques that overcome these shortcomings will be used to characterize the effects of ACh and DA on the ionic conductances of identified neostriatal neurons dissociated from adult and juvenile rats. It is the central thesis of this proposal that ACh and DA exert their principal effects on neostriatal function by modulating ionic conductances and that the interaction between these transmitters occurs at the level of the molecular events mediating this modulation in individual neostriatal neurons. The proposed experiments test this hypothesis in mature neostriatal neurons with techniques capable of measuring single or multi-channel ionic currents while controlling the biologically relevant variables transmembrane voltage and the biochemical composition of the intra- and extra-cellular environment. Specifically, the proposal has three aims pertinent to a test of this hypothesis (1) to characterize the effects of ACh and DA on the biophysical properties of potassium and calcium conductances in morphologically and immunocytochemically identified postnatal rat neostriatal neurons. Phenotypic identification of studied neurons will focus upon axonal projections using retrograde tracing and transmitter immunocytochemistry; (2) to characterize the role of different receptor subtypes, GTP-binding proteins and second messenger systems in mediating the modulatory effects of ACh and DA; and (3) to characterize the nature of the interaction between cholinergic and dopaminergic signalling pathways in the modulation of ionic conductances. An understanding of the actions of ACh and DA on the electrical excitability of neostriatal neurons should be of significance to the development of effective therapies for Parkinson s disease. The actions of these modulators are also of relevance to the clinical management of Huntington s disease and the psycho-motor side-effects of neuroleptic treatment of schizophrenia.
Keywords: acetylcholine, cholinergic receptor, corpus striatum, dopamine, dopamine receptor, electrophysiology, ion transport, neuron, neurotransmitter metabolism, axon, calcium channel, electrical conductance, electrical potential, guanine nucleotide binding protein, potassium channel, second messenger, fluorescence, immunocytochemistry, juvenile animal, laboratory rat, mature animal, patch clamp, rhodium, tissue /cell culture
Project start date: 1990-08-01
Project end date: 1995-07-31
5R29NS028889-03 (1992): $69031
DOPAMINERGIC AND MUSCARINIC SIGNALING IN THE STRIATUM
Dalton James Surmeier, Professor And Chairman
Northwestern University 750 N. Lake Shore Drive, 7th Chicago, Il 60611
Grant 5R37NS034696-13 from National Institute Of Neurological Disorders And Stroke, IRG: ZRG1
Abstract: Parkinson s disease (PD) is a disabling neurodegenerative disorder that is expected to affect as many as 1,000,000 Americans this year. Human and animals studies have shown that parkinsonism results from the degeneration of nigrostriatal dopaminergic neurons. Currently, treatment strategies for PD patients are limited. Gaining a better understanding of how striatal function is altered by the disease should broaden the range and efficacy of treatments. In the last funding period we focused on how dopamine and acetylcholine modulate the properties of voltage dependent ion channels in identified normosensitive striatal neurons. These studies have provided fundamental new insights into how these neuromodulators control the excitability of striatal neurons. Now, we are in a position to take the next step toward understanding the pathophysiology of PD - namely, how does the depletion of intrastriatal dopamine alter striatal function? Simply stated, our central goals are 1) to determine how DA depletion alters the regulation of voltage-dependent ion channels in striatal medium spiny neurons and 2) to determine how this adaptation alters their integrative, state-dependent behavior. To this end, we will determine how DA depletion alters Na+ and Ca2+ currents and their modulation by D2 (Specific Aim 1) and D1 receptor activation (Specific Aim 2) in identified striatal neurons. These experiments will rely upon voltage-clamp and single cell reverse transcription-polymerase chain reaction (scRT-PCR) approaches in acutely isolated striatal neurons - techniques with which we have an established track record. The proposed studies will employ newly developed mouse transgenic models in which striatal dopamine levels are profoundly reduced, mimicking the state found in advanced PD. Adaptations in the signal transduction pathways linking receptors to channels will be characterized using a combination of pharmacological, molecular and transgenic strategies. Inferences drawn from this work about adaptations in the mechanisms governing state transitions and repetitive spike activity will be explicitly tested using current- and voltage-clamp techniques in a novel corticostriatal slice preparation where medium spiny neurons exhibit state-dependent behavior resembling that seen in vivo (Specific Aim 3).
Keywords: Parkinson s disease, biological signal transduction, cellular pathology, corpus striatum, dopamine, muscarinic receptor, calcium channel, calcium flux, disease /disorder model, dopamine receptor, electrophysiology, molecular biology, neural conduction, neuron, neuronal transport, neuropharmacology, sodium channel, voltage gated channel, gene targeting, genetically modified animal, laboratory mouse, polymerase chain reaction, single cell analysis, tissue /cell culture, voltage /patch clamp
Project start date: 1996-02-01
Project end date: 2008-04-30
5R37NS034696-13 (2007): $325611
4R37NS034696-11 (2005): $343406
5R37NS034696-12 (2006): $335337
5R37NS034696-10 (2004): $367500
3R37NS034696-08S1 (2003): $74500
5R37NS034696-09 (2003): $367500
CELLULAR ADAPTATIONS IN NEOSTRIATAL NEURONS TO DOPAMINE DEPLETION
Dalton James Surmeier, Professor And Chairman
University Of Tennessee Health Sci Ctr 62 S. Dunlap Memphis, Tn 38163
Grant 5U19NS026473-100006 from National Institute Of Neurological Disorders And Stroke, IRG:
Abstract: Parkinson s disease (PD) afflicts roughly 1 in every 1000 adults, rising exponentially in incidence after the age of fifty. Human and animal studies have made it clear that PD results from the degeneration of nigrostriatal dopaminergic neurons. This loss leads to molecular, cellular and systems level adaptations in the principal target of these neurons - the neostriatum. Our long-term goal is to characterize the molecular and cellular consequences of this denervation in the neostriatum. In this proposal, we will focus on adaptations in the cellular mechanisms mediating the actions of dopamine and acetylcholine on neostriatal neurons following the near total loss of their dopaminergic innervation. We propose to achieve our immediate aims by combining two experimental approaches in a rat model of advanced PD created by 6-OHDA lesioning or dopamine depletion. First, functionally significant adaptations in the ability of post-synaptic dopaminergic and cholinergic signaling pathways to modulate neuronal excitability will be studied using a patch-clamp analysis of acutely-isolated and cultured neostriatal neurons identified by retrograde labeling from the substantia nigra and globus pallidus. Second, in biophysically characterized neostriatal neurons, alterations in gene expression will determined using single cell mRNA amplification. Cellular profiles or fingerprints will be constructed by screening for specific mRNAs, including those coding for dopamine and acetylcholine receptors, signaling enzymes, and transmitters. These tools will be used to answer three basic questions. First, do near total 6-OHDA lesions of substantia nigra pars compacta or dopamine depletion induce alterations in the intrinsic excitability of neostriatal neurons? Second, do these lesions alter the neuromodulatory effects of dopamine and, if so, how are specific receptor signaling pathways altered? Lastly, do these lesions alter the neuromodulatory effects of acetylcholine and its interactions with dopamine in shaping excitability in neostriatal neurons? By combining anatomical, physiological and molecular analyses at the single cell level, we should be able to provide an unprecedented breadth of information about the molecular and cellular adaptations that take place in functionally relevant subsets of neostriatal neurons following dopaminergic denervation. The insights gained from this work should provide a cellular framework in which changes in the behavior of large collections of neurons and the neostriatum itself can be understood. In doing so, this work will be of value in the design of rational pharmacological and genetic therapies for Parkinson s disease and other disorders of dopaminergic signaling, such as schizophrenia.
Keywords: Parkinson s disease, biological signal transduction, corpus striatum, dopamine, dopamine receptor, ion transport, neural plasticity, G protein, acetylcholine, calcium channel, cooperative study, disease model, gene expression, membrane potential, muscarinic receptor, neuropharmacology, potassium channel, receptor coupling, receptor sensitivity, second messenger, sodium channel, antisense nucleic acid, experimental brain lesion, laboratory rat, patch clamp
Project start date: 1997-07-01
Project end date: 1998-06-30
CELLULAR AND MOLECULAR MECHANISMS GOVERNING RHYTHMICITY AND SYNCHRONY IN NEURONS
Dalton James Surmeier, Professor And Chairman
Northwestern University Evanston, Il 602081110
Grant 5P50NS047085-050001 from National Institute Of Neurological Disorders And Stroke, IRG: ZNS1
Abstract: Parkinson s disease (PD) afflicts roughly 1 in 1000 adults, rising exponentially in incidence after the age of fifty. Human and animal studies have shown that parkinsonism results from the degeneration of the mesencephalic dopaminergic neurons. In PD patients and in primate PD models, the electrical activity of neurons in external globus pallidus (GPe) is abnormal. Unlike neurons from normal animals, GPe neurons in these animals exhibit synchronous, rhythmic burst discharges. It is our working hypothesis that this abnormal activity is attributable to adaptations in intrinsic properties of GPe neurons and their synaptic input following dopamine (DA) depletion. In the last grant period, our work focused on intrinsic properties controlling repetitive firing of GPe and STN neurons. In this upcoming award period, we plan to build upon these studies and those of other program participants to provide a more complete understanding of the mechanisms controlling rhythmic activity and synchrony in GPe neurons. Specifically, a combination of cellular and molecular approaches will be used to address two specific aims that are natural extensions of the aims in the previous grant period. Our first specific aim is to characterize the role of intrinsic, voltage-dependent Na+ and HCN channels in controlling rhythmic activity in identified GPe neurons in normal and dopamine-depleted mice. It is our working hypothesis that Na+/HCN channels are primary determinants of rhythmic discharge in GPe neurons. The molecular, biophysical and pharmacological properties of these channels and their susceptibility to modulation will be characterized using a combination of electrophysiological, biochemical and scRT-PCR approaches in neurons derived from wild-type, transgenic/knockout and dopamine-depleted mice.Our second specific aim is to characterize the role of GABAergic signaling in controlling activity patterning and synchrony in identified GPe neurons in normal and dopamine-depleted mice. Modeling work sponsored by this PPG predicts that diminished intrapallidal and increased striatal GABAergic input to GPe neurons may be a major factor in the emergence ofsynchrony and burst firing. To test this hypothesis, a combination of electrophysiological, pharmacological and scRT-PCR approaches will be used in neurons derived from wild-type, transgenic/knockout and dopamine-depleted mice. The successful attainment of these specific aims should provide much needed information about the properties of normal and dopamine-depleted GPe neurons - placing the neuroscience community in a much better position to devise new and more effective pharmacological and genetic treatments for Parkinson s disease.
Keywords: Parkinson s disease, brain electrical activity, dopamine, lenticular nucleus, neural transmission, neurologic manifestation, synapse, basal ganglia, biological signal transduction, biophysics, gamma aminobutyrate, membrane channel, membrane potential, messenger RNA, neural degeneration, neuropharmacology, neuroregulation, psychomotor function, sodium channel, subthalamus, gene targeting, genetically modified animal, laboratory mouse, polymerase chain reaction, voltage /patch clamp
Rhythmicity And Synchrony In The Basal Ganglia
Dalton James Surmeier, Professor And Chairman
Northwestern University 750 N. Lake Shore Drive, 7th Chicago, Il 60611
Grant 5P50NS047085-05 from National Institute Of Neurological Disorders And Stroke, IRG: ZNS1
Abstract: Parkinson s disease (PD) afflicts roughly 1 in 1000 adults, rising exponentially in incidence after the age of fifty. Human and animal studies have shown that parkinsonism results from the degeneration of the mesencephalic dopaminergic neurons ? In PD patients and in primate PD models, the electrical activity of neurons in globus pallidus (GP) and the subthalamic nucleus (STN) is abnormal. Unlike neurons from normal animals, GP and STN neurons in these animals exhibit synchronous, rhythmic burst discharges. It has been hypothesized that this abnormal activity is responsible for the motor symptoms in PD, providing a rationale for surgical intervention either in the form of pallidal electrolytic lesions or deep brain stimulation of the STN. It is the central hypothesis of this program proposal that the abnormal activity responsible for the symptoms of PD is attributable to adaptations in intrinsic properties of GP and STN neurons and their synaptic interaction following dopamine (DA) depletion. To test this hypothesis, the program brings together four groups with well-established expertise in the electrophysiological analysis of basal ganglia function. The first three projects will use a combination of molecular, pharmacological and electrophysiological approaches to study intrinsic ionic and synaptic mechanisms governing the activity patterns of GP and STN neurons and how these mechanisms are modulated by dopamine. Project 1 (Surmeier) first will generate a molecular and biophysical characterization of voltage-dependent and ligand-gated ion channels governing discharge in identified neurons of the rodent GP and then show how these channels are modulated by dopamine. A combination of !single cell RT-PCR, voltage-clamp and current clamp approaches will be used in acutely-isolated neurons and neurons in tissue slices. Project 2 (Bevan) will provide a similar level of analysis of identified rodent STN neurons using a common set of experimental approaches, in addition to anatomical strategies? Project 3 (Kita) will focus on how STN glutamatergic synaptic input regulates GP neuron activity and how alterations in this input might lead to dyskinesias. These studies will utilize pharmacological, anatomical and electrophysiological approaches in rodents and behaving primates. Project 4 (Wilson) brings these experimental results together to forge biologically grounded compuational model of the GP/STN circuit in normal and dopamine-depeleted states? The successful attainment of these program aims should provide critical information about DA-depletion induced adaptations in basal ganglia neurons most directly linked to the motor symptoms ofPD - placing the neuroscience community in a much better position to devise new and more effective pharmacological and genetic treatments for this debilitating disease.
Keywords: Parkinson s disease, basal ganglia, brain electrical activity, lenticular nucleus, membrane channel, membrane potential, neural transmission, neurologic manifestation, subthalamus, synapse
Project start date: 2003-09-30
Project end date: 2008-06-30
5P50NS047085-05 (2007): $1122988
5P50NS047085-04 (2006): $1122795
5P50NS047085-03 (2005): $1089325
5P50NS047085-02 (2004): $1058344
1P50NS047085-01 (2003): $1085019
MUSCARINIC AND DOPAMINERGIC CONTROL OF STRIATAL NEURONS
Dalton James Surmeier, Professor And Chairman
University Of Tennessee Health Sci Ctr
62 S. Dunlap
memphis, Tn 38163
Grant 5R29NS028889-04 from National Institute Of Neurological Disorders And Stroke, IRG: NLS
Abstract: Parkinson´s disease afflicts 1 in every 1000 adults, rising exponentially in incidence after the age of fifty. The symptoms of this debilitating psycho-motor illness are thought to result from a functional imbalance between cholinergic and dopaminergic systems of the neostriatum. The treatment of this disease has been hampered by the absence of a clear picture of the neuromodulatory actions of these systems in the neostriatum. Electrophysiological studies in other excitable cells have demonstrated that acetylcholine (ACh) and dopamine (DA) exert their effects on electrical excitability primarily by altering the properties of voltage-dependent ionic conductances. These alterations are reflected in the integration of synaptic input, action potential shape and spike patterning. Previous studies of neostriatal neurons have not been able to provide a similar level of understanding because of their reliance upon techniques that cannot definitively characterize ionic conductances or the molecular mechanisms mediating their modulation. In this project, recently developed whole-cell and patch voltage-clamp techniques that overcome these shortcomings will be used to characterize the effects of ACh and DA on the ionic conductances of identified neostriatal neurons dissociated from adult and juvenile rats. It is the central thesis of this proposal that ACh and DA exert their principal effects on neostriatal function by modulating ionic conductances and that the interaction between these transmitters occurs at the level of the molecular events mediating this modulation in individual neostriatal neurons. The proposed experiments test this hypothesis in mature neostriatal neurons with techniques capable of measuring single or multi-channel ionic currents while controlling the biologically relevant variables transmembrane voltage and the biochemical composition of the intra- and extra-cellular environment. Specifically, the proposal has three aims pertinent to a test of this hypothesis (1) to characterize the effects of ACh and DA on the biophysical properties of potassium and calcium conductances in morphologically and immunocytochemically identified postnatal rat neostriatal neurons. Phenotypic identification of studied neurons will focus upon axonal projections using retrograde tracing and transmitter immunocytochemistry; (2) to characterize the role of different receptor subtypes, GTP-binding proteins and second messenger systems in mediating the modulatory effects of ACh and DA; and (3) to characterize the nature of the interaction between cholinergic and dopaminergic signalling pathways in the modulation of ionic conductances. An understanding of the actions of ACh and DA on the electrical excitability of neostriatal neurons should be of significance to the development of effective therapies for Parkinson´s disease. The actions of these modulators are also of relevance to the clinical management of Huntington´s disease and the psycho-motor side-effects of neuroleptic treatment of schizophrenia
Keywords: acetylcholine, cholinergic receptor, corpus striatum, dopamine, dopamine receptor, electrophysiology, ion transport, neuron, neurotransmitter metabolism axon, calcium channel, electrical conductance, electrical potential, guanine nucleotide binding protein, potassium channel, second messenger fluorescence, immunocytochemistry, juvenile animal, laboratory rat, mature animal, patch clamp, rhodium, tissue /cell culture
Project start date: 1990-08-01
Project end date: 1995-07-31
5R29NS028889-04 (1993): $71789
Rhythmicity And Synchrony In The Basal Ganglia
Dalton James Surmeier, Professor And Chairman
Physiologynorthwestern University
Grant 2P50NS047085-06 from National Institute Of Neurological Disorders And Stroke, IRG: NSD
Abstract: Parkinson´s disease (PD) is the second most common neurodegenerative disease in the U.S., extracting an enormous human and economic toll. PD has no cure and nothing is known to slow the progression of the disease. Moreover, the therapeutic strategies for treating PD are limited. Building upon mechanistic insights gained in the last grant period, this Udall Center competitive renewal application proposes two major lines of study with strong translational potential. The first line of study focuses on the mechanisms underlying the pathological rhythmic bursting activity patterns in the basal ganglia network formed by the external segment of the globus pallidus (GPe) and the subthalamic nucleus (STN). This activity is thought to be responsible for the motor symptoms of PD. Our group has identified molecular adaptations in the GPe-STN network in PD models that could be responsible for this pathophysiology. The proposed studies will pursue this discovery and attempt to translate it into a gene therapy appropriate for late stage PD patients. The second line of study builds upon recent insights gained into the factors underlying vulnerability of dopaminergic neurons in the substantia nigra pars compacta (SNc) that are lost in PD. These studies suggest that the reliance upon voltage calcium channels to drive autonomous pacemaking renders SNc neurons vulnerable to mitochondria! insults. These studies also suggest this reliance can be reversed with a drug that is approved for human use. The proposed studies examine the cellular and molecular basis for this linkage and pursue questions that should be answered prior to a clinical neuroprotection trial. The Udall Center brings together five principal investigators (Pis) with complementary expertise from three research institutions. Three theme-based projects are proposed, each with three or more Pis contributing to the plan of attack. Projects 1 and 2 pursue the first line of study, one focusing on the adaptations in GPe neurons, the other focusing on adaptations in STN neurons in rodent and monkey models of PD. Project 3 pursues the second line of study, focusing on mechanisms controlling the vulnerability of SNc dopaminergic neurons in rodent models. In addition to three research projects, the Center has an Administrative Core to coordinate activities of the projects and a Molecular Core to serve the genetic profiling and gene therapy aims of the projects. Lay summary The proposed studies are focused on why dopamine neurons die in PD and what happens to the brain circuitry they control. Our near term goal is to develop therapeutic strategies that will slow the loss of dopamine neurons and to re-engineer the networks these neurons control so that they perform correctly, even in the absence of dopamine
Project start date: 2003-09-30
Project end date: 2013-07-31
DOPAMINERGIC AND MUSCARINIC SIGNALING IN THE STRIATUM
Dalton James Surmeier, Professor And Chairman
Physiologynorthwestern University
750 N. Lake Shore Drive, 7th
chicago, Il 60611
Grant 2R37NS034696-07 from National Institute Of Neurological Disorders And Stroke, IRG: ZRG1
Abstract: Parkinson´s disease (PD) is a disabling neurodegenerative disorder that is expected to affect as many as 1,000,000 Americans this year. Human and animals studies have shown that parkinsonism results from the degeneration of nigrostriatal dopaminergic neurons. Currently, treatment strategies for PD patients are limited. Gaining a better understanding of how striatal function is altered by the disease should broaden the range and efficacy of treatments. In the last funding period we focused on how dopamine and acetylcholine modulate the properties of voltage dependent ion channels in identified normosensitive striatal neurons. These studies have provided fundamental new insights into how these neuromodulators control the excitability of striatal neurons. Now, we are in a position to take the next step toward understanding the pathophysiology of PD - namely, how does the depletion of intrastriatal dopamine alter striatal function? Simply stated, our central goals are 1) to determine how DA depletion alters the regulation of voltage-dependent ion channels in striatal medium spiny neurons and 2) to determine how this adaptation alters their integrative, state-dependent behavior. To this end, we will determine how DA depletion alters Na+ and Ca2+ currents and their modulation by D2 (Specific Aim 1) and D1 receptor activation (Specific Aim 2) in identified striatal neurons. These experiments will rely upon voltage-clamp and single cell reverse transcription-polymerase chain reaction (scRT-PCR) approaches in acutely isolated striatal neurons - techniques with which we have an established track record. The proposed studies will employ newly developed mouse transgenic models in which striatal dopamine levels are profoundly reduced, mimicking the state found in advanced PD. Adaptations in the signal transduction pathways linking receptors to channels will be characterized using a combination of pharmacological, molecular and transgenic strategies. Inferences drawn from this work about adaptations in the mechanisms governing state transitions and repetitive spike activity will be explicitly tested using current- and voltage-clamp techniques in a novel corticostriatal slice preparation where medium spiny neurons exhibit state-dependent behavior resembling that seen in vivo (Specific Aim 3)
Keywords: Parkinson`s disease, biological signal transduction, cellular pathology, corpus striatum, dopamine, muscarinic receptor calcium channel, calcium flux, disease /disorder model, dopamine receptor, electrophysiology, molecular biology, neural conduction, neuron, neuronal transport, neuropharmacology, sodium channel, voltage gated channel gene targeting, laboratory mouse, polymerase chain reaction, single cell analysis, tissue /cell culture, transgenic animal, voltage /patch clamp
Project start date: 1996-02-01
Project end date: 2005-04-30
2R37NS034696-07 (2001): $367500
WINTER CONFERENCE ON BRAIN RESEARCH
Dalton James Surmeier, Professor And Chairman
Northwestern University 750 N. Lake Shore Drive, 7th Chicago, Il 60611
Grant 5R13NS040776-04 from National Institute Of Neurological Disorders And Stroke, IRG: NSD
Abstract: Funds are requested for travel fellowships to attend the Winter Conference on Brain Research (WCBR). WCBR is an interdisciplinary, week-long meeting that offers a unique opportunity for junior investigators to interact and network with senior scientists and NIH/NSF staff. The meeting, which is in its thirty-fourth year, is held in an isolated mountain setting to promote interaction between participants in both scientific and recreational settings. Although the meeting is limited to roughly 450 registrants, participation is open to the entire neuroscience community. The scientific program consists of two-hour morning, afternoon, and evening sessions for six consecutive days. During each session, there are 4-5 informal panel/workshop presentations focused on topics of current interest in basic and clinical neuroscience. In addition, there are presentations by NIH/NSF staff on issues relevant to extramural funding. These presentations are structured to promote an open exchange of ideas and information between presenters and attendees. Lastly, there are two poster sessions during the week that offer an additional venue for scientific discussion. The goal of the fellowship program is to provide junior investigators with the opportunity to present their work and interact with more senior investigators in an informal setting. In addition to scientific guidance, fellowship recipients also will be receive guidance as to the best way to attend the meeting, to present their work, and to make use of new found colleagues. Particular emphasis will be placed on obtaining a diverse group of fellows with respect to parent institution, gender, and minority status.
Keywords: brain, meeting /conference /symposium, neuroscience, travel
Project start date: 2002-01-01
Project end date: 2005-12-31
5R13NS040776-04 (2005): $21391
5R13NS040776-03 (2004): $20914
5R13NS040776-02 (2003): $20450
DOPAMINERGIC AND MUSCARINIC SIGNALING IN THE STRIATUM
Dalton James Surmeier, Professor And Chairman
Physiologynorthwestern University
750 N. Lake Shore Drive, 7th
chicago, Il 60611
Grant 5R03TW001214-02 from Fogarty International Center, IRG: ICP
Abstract: Disorders in neostriatal dopaminergic and cholinergic signaling underlie a wide variety of psychomotor disorders. One of these disorders- Parkinson´s disease (PD)-afflicts roughly 1 in every 1000 adults, rising exponentially in incidence after the age of fifty. Human and animal studies have made it clear that PD results from the degeneration of nigrostriatal dopaminergic neurons. Accompanying the loss of the dopaminergic innervation is a disruption of normal cholinergic functioning. Treatment strategies for PD commonly attempt to elevate neostriatal dopamine and depress cholinergic signaling to help re- establish a balance between these systems. In spite of the profound importance of neostriatal dopamine (DA) and acetylcholine (ACh) to this disease process, relatively little is known about how these neuromodulators control cellular excitability and function. Our long-term goal is to characterize the molecular and cellular mechanisms of dopaminergic and cholinergic signaling in the neostriatum. The overarching goal of this FIRCA proposal is to further these aims by incorporating patch clamp recording discharge patterning in medium spiny neurons. We will focus on those effects directly attributable to modulation of voltage-dependent Ca2+ channels. Understanding how these channels are modulated by dopamine and acetylcholine has been a major goal of NS 34696. In addition, single cell RT-PCR techniques will be used to phenotype recorded neurons and to provide some insight into the molecular identify of the channels regulating repetitive firing in medium spiny neurons. This FIRCA proposal has two specific aims 1) To determine the role of L-type Ca2+ channels in the interaction of dopaminergic and muscarinic signaling pathways regulating repetitive discharge identified medium spiny neurons and 2) to determine the role of and P/Q-type Ca2+ channels in the interaction of dopaminergic and muscarinic signaling pathways regulating repetitive discharge in identified medium spiny neurons. These aims are natural extensions of those outlined in NS34696. By establishing a formal collaboration with Drs. Bargas and Galarraga, we will be able to bring their expertise in current clamp recording in striatal slices to bear on the originally stated research questions. The collaboration will assist in the development of voltage-clamp and single cell RT-PCR approaches in the lab of Drs. Bargas and Galarraga. Also, this collaboration will serve as a means of means of brining these techniques to other neuroscience research programs at UNAM and Mexico City. In so doing, this collaborative award will achieve both the development goals of the Fogarty program and significantly advance the scientific goals of N.I.H
Keywords: calcium channel, corpus striatum, dopamine receptor, muscarinic receptor, voltage gated channel Parkinson`s disease, biological signal transduction, enkephalin, neuron, neuropharmacology, nicardipine, nifedipine, okadaic acid, reptile poison, substance P Mexico, laboratory rat, microelectrode, polymerase chain reaction, video microscopy, voltage /patch clamp
Project start date: 2000-03-01
Project end date: 2003-02-28
5R03TW001214-02 (2001): $36446
1R03TW001214-01 (2000): $35412
MONOAMINERGIC MODULATION OF PREFRONTAL CORTEX
Dalton James Surmeier, Professor And Chairman
Physiologynorthwestern University
750 N. Lake Shore Drive, 7th
chicago, Il 60611
Grant 5R01MH062070-02 from National Institute Of Mental Health, IRG: ZRG1
Abstract: Disordered dopamine signaling has long been known to be a critical factor in the etiology of schizophrenia. This view is based upon several key observations. Foremost among them is the ability of neuroleptics that antagonize DA receptors to alleviate the positive symptoms of schizophrenia. However, in recent years, the exclusive involvement of DA in schizophrenia has been questioned. In part, the clinical effectiveness of atypical neuroleptics like clozapine has motivated this new line of thought. The ability of atypical neuroleptics to antagonize both DA receptors and serotonin receptors is generally thought to be critical to their efficacy. Although there is evidence for altercations in neuronal function at several levels of the neuroaxis in schizophrenia, most experimental evidence points to the prefrontal cortex. It is the central hypothesis of this proposal that the cognitive deficits observed in schizophrenics and their close relatives are a direct consequence of altered DA and 5-HT signaling within the prefrontal cortex. This disruption may have a common cellular locus-that is, interactions between these two monoamines at the single cell level may be responsible for the pathophysiology in schizophrenia. However, at present there are fundamental gaps in our understanding of how DA and 5-HT regulate neural activity in the PFC. To begin to fill these gaps, we propose to apply a combination of electrophysiological, anatomical, pharmacological and molecular techniques to achieve four specific aims. Our initial aim is to use single cell RT-PCR techniques and retrograde labeling to identify the DA and 5-HT receptors expressed by PFC pyramidal neurons participating in circuits thought to be affected in schizophrenia. Next, the impact of D1/D5 DA receptors on voltage-dependent Na and Ca channels will be determined in retrogradely identified PFC pyramidal neurons using a combination of RT-PCT, voltage-clamp and fluorometry. In parallel, the modulatory effects of 5-HT-2 receptors on these same channel populations will be determined using a similar combination of techniques. Lastly, the nature of the interaction between these two schizophrenia linked signaling pathways in the modulation of Na and Ca channels will be determined. It is our thesis that these two pathways synergistically interact in ways critical to the disease process. Achieving these specific aims will provide the molecular and cellular framework necessary to begin building an accurate, integrative model of PFC function and dysfunction in schizophrenia
Keywords: dopamine receptor, prefrontal lobe /cortex, pyramidal cell, schizophrenia, serotonin receptor calcium channel, dopamine antagonist, neuropharmacology, reserpine, sodium channel Animalia, fluorimetry, polymerase chain reaction, voltage /patch clamp
Project start date: 2000-09-01
Project end date: 2005-08-31
5R01MH062070-02 (2001): $294000
1R01MH062070-01 (2000): $283557
Interdepartmental Two-photon Imaging Center
Dalton James Surmeier, Professor And Chairman
Physiologynorthwestern University
Grant 5P30NS054850-02 from National Institute Of Neurological Disorders And Stroke, IRG: NSD
Abstract: Cellular and molecular imaging technologies are revolutionizing neuroscience. The technology with the biggest potential impact on this field is "non-linear optical microscopy" which enables two-photon (2P) imaging of fluorescent structures deep in living tissue with unprecedented spatial and temporal resolution. Combining 2P imaging with electrophysiology and molecular uncaging creates an extraordinarily powerful tool that is having a profound effect on the conduct of neuroscientific study. The strategic goal of this revised proposal is to put this critical technology in the hands of a two highly productive groups of neuroscientists at Northwestern University (NU) that receive nearly $8M/year (direct costs) in funding from NINDS. One of these groups is focused on the properties of neuronal dendrites in health, aging and disease; the other group is focused on neural stem cell biology and its application to neuroregeneration. To maximize the investment of NU and NINDS in these research programs, both groups need ready access to user-friendly, multifunctional 2P imaging workstations. The following specific aims are designed to achieve this goal 1. to further characterize and optimize the performance of our existing 2P imaging workstations; 2. to extend the capabilities of the existing workstations by adding new hardware and software features integrating electrophysiology and molecular uncaging; 3. to create additional core facilities with 2P imaging workstations and technical support for NIH funded investigators who do not currently have access to these resources; 4. to establish an infrastructure that ensures the safe, efficient and productive operation of all the cores; 5. to create an Internet-based distribution point for dissemination of information about applications, software and hardware design/implementation A corporate partner with expertise in the production of 2P workstations, Prairie Technologies, has been recruited to help achieve these aims. By establishing a dialogue between industry and researchers, we hope to accelerate the development of hardware and software that best meets the needs of the neuroscience community. The attainment of these aims will not only have a transforming impact on the NIH funded research programs at NU but it will significantly accelerate the delivery of these technologies to the broader neuroscience community, quicken the pace of scientific discovery and promote the development of new treatments for neurological disorders
Keywords: electromagnetic radiation
Project start date: 2007-05-01
Project end date: 2012-04-30
1P30NS054850-01A1 (2007): $616616
MONOAMINERGIC MODULATION OF PREFRONTAL CORTEX
Dalton James Surmeier, Professor And Chairman
Northwestern University 750 N. Lake Shore Drive, 7th Chicago, Il 60611
Grant 5R01MH062070-05 from National Institute Of Mental Health, IRG: ZRG1
Abstract: Adapted from the Investigator s ) Disordered dopamine signaling has long been known to be a critical factor in the etiology of schizophrenia. This view is based upon several key observations. Foremost among them is the ability of neuroleptics that antagonize DA receptors to alleviate the positive symptoms of schizophrenia. However, in recent years, the exclusive involvement of DA in schizophrenia has been questioned. In part, the clinical effectiveness of atypical neuroleptics like clozapine has motivated this new line of thought. The ability of atypical neuroleptics to antagonize both DA receptors and serotonin receptors is generally thought to be critical to their efficacy. Although there is evidence for altercations in neuronal function at several levels of the neuroaxis in schizophrenia, most experimental evidence points to the prefrontal cortex. It is the central hypothesis of this proposal that the cognitive deficits observed in schizophrenics and their close relatives are a direct consequence of altered DA and 5-HT signaling within the prefrontal cortex. This disruption may have a common cellular locus-that is, interactions between these two monoamines at the single cell level may be responsible for the pathophysiology in schizophrenia. However, at present there are fundamental gaps in our understanding of how DA and 5-HT regulate neural activity in the PFC. To begin to fill these gaps, we propose to apply a combination of electrophysiological, anatomical, pharmacological and molecular techniques to achieve four specific aims. Our initial aim is to use single cell RT-PCR techniques and retrograde labeling to identify the DA and 5-HT receptors expressed by PFC pyramidal neurons participating in circuits thought to be affected in schizophrenia. Next, the impact of D1/D5 DA receptors on voltage-dependent Na and Ca channels will be determined in retrogradely identified PFC pyramidal neurons using a combination of RT-PCT, voltage-clamp and fluorometry. In parallel, the modulatory effects of 5-HT-2 receptors on these same channel populations will be determined using a similar combination of techniques. Lastly, the nature of the interaction between these two schizophrenia linked signaling pathways in the modulation of Na and Ca channels will be determined. It is our thesis that these two pathways synergistically interact in ways critical to the disease process. Achieving these specific aims will provide the molecular and cellular framework necessary to begin building an accurate, integrative model of PFC function and dysfunction in schizophrenia.
Keywords: dopamine receptor, prefrontal lobe /cortex, pyramidal cell, schizophrenia, serotonin receptor, calcium channel, dopamine antagonist, neuropharmacology, reserpine, sodium channel, Animalia, fluorimetry, polymerase chain reaction, voltage /patch clamp
Project start date: 2000-09-01
Project end date: 2006-02-28
5R01MH062070-05 (2004): $257250
5R01MH062070-04 (2003): $257250
DOPAMINERGIC AND CHOLINERGIC SIGNALING IN THE STRIATUM
Dalton James Surmeier, Professor And Chairman
Northwestern University 750 N. Lake Shore Drive, 7th Chicago, Il 60611
Grant 5R01NS034696-06 from National Institute Of Neurological Disorders And Stroke, IRG: NLS
Abstract: adapted from Applicant s ) Disorders in neostriatal dopaminergic and cholinergic signaling underlie a wide variety of psychomotor disorders. One of these disorders - Parkinson s disease (PD) - afflicts roughly one in every 1000 adults, rising exponentially in incidence after the age of fifty. Human and animal studies have made it clear that PD results from the degeneration of nigrostriatal dopaminergic neurons. Accompanying the loss of the dopaminergic innervations is a disruption of normal cholinergic functioning. Treatment for PD commonly attempts to elevate neostriatal dopamine and depress cholinergic signaling to help re-establish a balance between these systems. In spite of the profound importance of neostriatal dopamine (DA) and acetylcholine (ACH) to this disease process, relatively little is known about how these neuromodulators control cellular excitability and function. The long-term goal is to characterize the molecular and cellular mechanisms of dopaminergic and cholinergic signaling in the neostriatum. This proposal will focus on characterizing how these transmitters modulate voltage-dependent Ca2+ currents within functionally and anatomically defined populations of neostriatal neurons. The investigators propose to achieve their immediate aims by combining three powerful experimental approaches. The impact of postsynaptic dopaminergic and cholinergic signaling pathways on the biophysical properties of voltage-dependent Ca2+ currents will be studied using patch-clamp analyses of acutely-isolated and cultured neostriatal neurons identified by retrograde labeling and mRNA profiling. In biophysically characterized neurons, the molecular identity of the signaling elements used by DA and ACH will be determined using pharmacological, fluorometric and single cell mRNA profiling methods. Cellular profiles or fingerprints will be constructed by screening for specific mRNAs, including those coding for DA and ACH receptors, signaling enzymes, transmitters and targeted ion channels. These tools will be used to achieve three specific aims 1) to characterize the postsynaptic mechanisms mediating dopaminergic modulation of voltage-dependent Ca2+ channels within defined neostriatal phenotypes; 2) to characterize the postsynaptic mechanisms mediating cholinergic modulation of voltage-dependent Ca2+ channels within these same cell types; 3) to determine how dopaminergic and cholinergic pathways interact at the cellular level. By combining anatomical, physiological and molecular analyses at the single cell level, the investigators should be able to provide detailed information about the molecular and cellular mechanisms mediating dopaminergic and cholinergic signaling in functionally relevant subsets of neostriatal neurons. The insights gained from this work should provide a cellular framework in which the behavior of large collections of neurons and the neostriatum itself can be understood. In so doing, it should open the door to the development of novel and powerful therapeutic strategies not only for Parkinson s disease but other disorders with neostriatal determinants such as schizophrenia.
Keywords: acetylcholine, calcium channel, corpus striatum, dopamine, neural conduction, voltage gated channel, calcium flux, cholinergic receptor, dopamine receptor, messenger RNA, neuronal transport, neuropharmacology, fluorimetry, laboratory mouse, patch clamp, single cell analysis, tissue /cell culture
Project start date: 1996-02-01
Project end date: 2001-01-31
5R01NS034696-06 (2000): $170452
5R01NS034696-02 (1997): $182537
3R01NS034696-06S1 (2001): $35742
7R01NS034696-04 (1998): $120192
GENERAL MOTOR CONTROL MECHANISMS AND DISEASE TRAINING
Dalton James Surmeier, Professor And Chairman
Northwestern University 750 N. Lake Shore Drive, 7th Chicago, Il 60611
Grant 5T32NS041234-05 from National Institute Of Neurological Disorders And Stroke, IRG: NST
Abstract: Adapted From ?s ) This new proposal is a request for funding of a broadly-based Post-doctoral Training Program in General Motor Control Mechanisms and Disease from the Northwestern University Institute for Neuroscience (NUIN). This training program has grown out of a multidisciplinary group of motor control investigators who have collaborated since the inception of the NUIN in 1989. The program will be directed by Dr. D. James Surmeier with the assistance of Dr. Enrico Mugnaini (Associate Director) and a Steering Committee. Trainees will conduct their research under the guidance of 29 mentors working in motor control research from 11 departments of 3 schools on the Chicago and Evanston campuses of Northwestern University. The proposal requests support for 6 post-doctoral and 2 pre-doctoral trainees. Postdoctoral trainees will be selected on the basis of previous training and research plan. Pre-doctoral trainees will be selected from NUIN and Medical Scientist Training Program Ph.D. programs on the basis of course performance, laboratory rotations and the relevance of dissertation research to the goals of the training program. A concerted effort will be made to recruit women and minorities to the program. The program will offer a broad range of interdisciplinary research and training opportunities in the neuroscience of somatic and autonomic motor control. The research of participating preceptors spans molecular and cellular neuroscience, systems neuroscience, clinical and behavioral neuroscience and computational neuroscience. The mentor faculty will assist and monitor the trainee?s progress through formal advising and evaluations, and through formal classroom and informal discussions (in journal clubs, laboratory meetings and research clubs). An feature of the training program is that it brings together researchers in fundamental and clinical neuroscience, providing a highly productive, interdisciplinary research environment for trainees in motor control and related motor system diseases at Northwestern University. In addition to providing research training, the program will help trainees to develop skills in written and oral communication, grant writing, networking and career development. A clear awareness of ethical issues facing neuroscientists and a responsible conduct in science will be a primary training goal. The program outlines attempts to exemplify the multidisciplinary and interactive type of neuroscience research training encouraged by NIH.
Project start date: 2001-07-15
Project end date: 2006-06-30
5T32NS041234-05 (2005): $395249
5T32NS041234-04 (2004): $160364
5T32NS041234-03 (2003): $429435
1T32NS041234-01 (2001): $336743
FSM Core - Interdepartmental Two-photon Imaging Center
Dalton James Surmeier, Professor And Chairman
Northwestern University 750 N. Lake Shore Drive, 7th Chicago, Il 60611
Grant 1P30NS054850-01A19003 from National Institute Of Neurological Disorders And Stroke, IRG: NSD
Project start date: 2006-12-01
Project end date: 2011-11-30
Dalton James Surmeier, Professor And Chairman
Northwestern University Evanston, Il 602081110
Grant 5P50NS047085-059001 from National Institute Of Neurological Disorders And Stroke, IRG: ZNS1
Keywords: biomedical facility, polymerase chain reaction, Parkinson s disease, neuron, reagent /indicator, tissue /cell preparation