Martyn Goulding - US grants

In vertebrates, the nervous system develops from a simple psuedostratified epithelium, the neuroectoderm. Regionalisation of the early neuroectoderm results in the position-specific generation of different classes of neurons within the nervous system. The genetic events that regulate the postional regulation of cell fate are not understood. Differential transcriptional activity within the early nervous system is to believed to be an important factor. A family of paired box (Pax) genes that encode transcription factors are expressed in discrete regions of the early nervous system. We have recently isolated a paired box gene, Pax-3 that is expressed in the early spinal cord in dorso-ventrally restricted populations of neural progenitor cells. We have also isolated the chicken Pax-6 and Pax-7 genes which are also dorso-ventrally restricted in the spinal cord neuroepithelium. It is known that dorso-ventral polarity plays an decisive role in determining neuronal cell fate in the spinal cord, leading us to believe that the expression of Pax-3, Pax-6 and Pax-7 in neural precursors is an important regulatory step in spinal cord patterning. The experiments outlined in this grant are aimed at elucidating the regulatory interactions that establish the dorso-ventral expression of Pax-3 in the spinal cord, by identifying cis-acting sequences and tissues that control expression. The effect that loss of Pax-3 function has on the development of neural precursors cells, in particular those that give rise to the neural crest will also be examined in splotch mice, with the aim of defining those steps in neural crest development that are regulated by Pax-3. The involvement, of Pax-3 in the human hereditary disease Waardenburg Syndrome and the observation that a number of neural tube defects are present in the mouse model of Waardenburg Syndrome, splotch, are an indication of the important insights into these hereditary defects that will be gained from these studies. The long term goal of this project is to define the role of Pax-3 in neural development and begin to identify the signals that regulate its expression pattern in the vertebrate nervous system.

embryo /fetus tissue /cell culture; laboratory mouse

DESCRIPTION: Transcriptional regulation is an important mechanism used to control morphogenesis during embryonic development. Pax-3 is a paired domain transcription factor that plays an essential role in the development of a number of embryonic cell types including neural crest cells and limb muscles. Mutations in Pax-3 are responsible for the Splotch phenotype in mice and Waardenburg Syndrome in humans. Many of the defects found in Waardenburg Syndrome patients and Splotch mice arise from changes in the migration of limb muscle precursors and neural crest cells. Waardenburg Syndrome is the most common cause of hereditary deafness in humans and is associated with the impaired migration of melanocytes into the inner ear during embryonic development. The limb defects in Waardenburg Syndrome patients may also be caused by a cell migration defect. The experiments in this proposal are aimed at analyzing the role Pax-3 plays in cell migration. It is proposed that Pax-3 exerts its effects on limb cell precursor migration by regulating expression of the c-met receptor tyrosine kinase. Loss of Pax-3 function in these cells leads to the down-regulation of the c-met. It will be determined if Pax-3 is required autonomously for c-met expression in limb muscle precursors and whether expression of c-met in these precursor cells is able to rescue the limb muscle phenotype in Splotch mice. The promoter for the c-met gene will be isolated to determine if Pax-3 directly binds to regulatory sequences within it. The relationship will be analyzed between Pax-3 and another homeodomain protein, Lbx-1 that is also expressed in migrating limb muscle precursors. Finally a zinc-finger transcription factor, PIP1, has been identified that interacts specifically with Pax-3. Further studies will be undertaken to analyze the interaction between Pax-3 and PIP1.

DESCRIPTION: The functioning of the nervous system depends on the correct specification and "wiring up" of many different neurons in the nervous system. Goulding is interested in elucidating the molecular mechanisms that control the generation of specific neuronal cell types in the developing spinal cord. A large body of evidence suggests that gene regulation by transcription factors plays an important role in patterning the spinal cord. However, very little is known about the mechanisms that control the generation of specific cell types within the spinal cord. The homeodomain transcription factors, En1 and Ev1, are expressed in two populations of differentiating interneurons in the spinal cord. The expression patterns of both genes during development strongly suggest both proteins may function as determinants of neuronal cell type. As a first step toward analyzing the function of these transcription factors, Goulding and colleagues generated taulacZ knock-in mice in order to mark and morphologically characterize the cells that express En1 and Evx1. Goulding and colleagues will use these mice to investigate the fate of these two neuronal populations in mice that lack En1 and Evx1 function. Furthermore, the generation of these knock-in mice will provide valuable tools for further investigating the mechanisms that control cell fate specification and axonal guidance by neurons in the spinal cord. Goulding also plans to examine the regulation of En1 and Evx1 expression by genes that are expressed in the precursors of these cells. The longterm aim of these studies is to molecularly define how these two populations of interneurons are generated during embryonic development.

DESCRIPTION (appended verbatim from investigator's abstract): Migration of cells plays a critical role in the genesis of many tissues during embryonic development and in tumor metastases. The migration of muscle precursors provides an ideal model system to study the mechanisms that control cell migration in vertebrates. Most muscles in the vertebrate body are derived from migratory precursors that undergo long range cell migration from the somites. Hypaxial muscle precursors leave the ventral dermomyotome and migrate along a lateral route into the limbs to give rise to limb muscles and along ventral routes into the branchial arches and septum transversum to form the tongue and diaphragm muscles, respectively. We have a long term interest in understanding how the migration of these muscle precursors is regulated, since the mechanisms that operate in these cells are likely to apply to other migratory cell populations. Our studies have been directed toward functionally analyzing the role of two transcription factors, Pax3 and Lbxl, in the development of muscles. With this grant, we will dissect early specification and late migration roles of Pax3 in the genesis of hypaxial muscles. Second, we will examine the Lbxl dependent response to a lateral migration cue by a series of explant and misexpression experiments. Third, we will examine which components of FGF signaling are involved in the lateral migration of appendicular muscle precursors. Finally, we will initiate a search for genes that are selectively expressed in migrating muscle precursor cells to identify signaling pathways and proteins that control cell migration .

The spinal cord is an ideal system for elucidating the molecular mechanisms that underlie the patterning of different neuronal cell types during embryonic development. Cell-specific transcription plays a central role in restricting neural precursors cells to specific cell fates during development. Recent studies have identified a number of transcription factors that are expressed in restricted populations of neural precursors in the developing spinal cord. These include the paired domain protein Pax6, and the homeodomain proteins Dbx1 and Dbx2, which are expressed in the precursors of two interneuron populations, V0 and V1 interneurons. We will examine the roles Pax6, Dbx2 and Dbx1 play in the specification of V1 and V0 interneuron identify, by analyzing loss of function phenotypes for Pax6 and Dbx2 in the mouse and by misexpressing Dbx1 and Dbx2 in the embryonic chick spinal cord. We will also examine the function of the Hfh2 winged helix transcription factor in the development of V1 interneurons by specifically inactivating Hfh2 in these cells using the Cre/loxP recombination system. These studies will greatly extend our knowledge of how interneuron cell fate is determined in the embryonic spinal cord and will provide insights into the early events that regulate the development of spinal locomotor circuits.

DESCRIPTION:(provided by applicant) Interneurons are integral components of the neural circuits in the spinal cord that control posture and movement. Among the diverse array of spinal interneurons are cell-types that make direct connections with motor neurons and modify their excitability. In the course of our studies of interneuron patterning and specification in the developing spinal cord, we have identified two classes of early embryonic interneurons (INs), V1 and VO INs, which are likely to synapse directly with motor neurons. V1 and VO INs are marked by the expression of En1 and Evx1, respectively. In this proposal, we will determine the cardinal features of V1 and VO INs in order to define their exact relationship to physiologically identified cell types in the adult spinal cord. We will use transsynaptic tracers and paired cell recordings to directly test whether VO INs constitute a subset of crossed reflex interneurons that synapse with contralateral motor neurons. We will test our hypothesis that V1 INs differentiate into Renshaw cells and Ia inhibitory interneurons, by physiologically characterizing the descendants of En1-expressing neurons in spinal cord slice preparations. In addition, we will undertake functional studies to determine the role that V1 INs play in locomotor reflexes by selectively ablating them. We will also silence Renshaw cells in vivo,thereby defining for the first time the role of recurrent inhibition in locomotor behavior. Finally, we will examine whether V1 INs form topologically ordered connections with pools of motor neurons, and determine when and how these connections become organized. These studies will provide valuable insights into the development and organization of circuits in the spinal cord that control locomotor behavior, and will lay the groundwork for strategies to treat spinal cord injury and degeneration.

[unreadable] DESCRIPTION (provided by applicant): Local circuit association neurons in the superficial dorsal horn subserve important functions in the gating and transduction of somatosensory information from the periphery. As such, these neurons are important components of pain pathways in the spinal cord. We have recently shown dorsal association interneurons are derived from an embryonic population of cells that express Lbxl (Gross et al., 2002). However, very little is known about how these spinal neurons differentiate to form the many specialized functional cell types that are found in the adult spinal cord. In this grant, we will examine how Lbx 1 neurons are specified, focusing on the role of the Gshl, Gsh2 and Gbx2 homeobox genes in Lbxl neuron progenitors. We will also determine how late-born Lbx I neurons differentiate as either inhibitory or excitatory neurons, and ask whether Notch signaling regulates the developmental switch that selects between excitatory and inhibitory cell fates. The observation that Pax2 is required for dorsal GABAergic and glycinergic development makes these dorsal horn interneurons an excellent model system for probing the molecular mechanisms that regulate the acquisition of an inhibitory neurotransmitter phenotype. We will examine the role that the Pax2, Lhxl/5 and the Ets2 transcription factors play in the development of dorsal inhibitory cell types. In particular, we will ask whether these factors, or other factors that are downstream of Pax2, regulate the expression of genes that are required for the inhibitory transmission machinery. Finally, we will generate conditional Pax2 knockout mice and use these mice to test whether Pax2 has a 'late' function in dorsal inhibitory neurons. We will also use the Pax2 conditional KO mice to begin assessing the function of GABAergic neurons in the dorsal horn with respect to the transduction of noxious and non-noxious stimuli, as well as the development of pain neuropathies such as hyperalgesia. These studies will provide important insights into the development and organization of neural circuits in the dorsal horn that sense and relay pain. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Interneurons in the spinal cord are integral components of the neural networks that control posture and movement. We have characterized a number of embryonic interneuron (IN) cell types in the spinal cord with the long term goal of defining their functional contribution to the neural circuitry that controls locomotion. These studies have led to the identification of 2 classes of inhibitory spinal neurons, V1 and V2B neurons, both of which project ipsilaterally within the ventral horn. Our preliminary evidence indicates that these IN cell types connect to motor neurons and other CPG neurons. In this proposal, we will use a combination of genetic, anatomical and electrophysiological approaches to characterize these 2 cell types and determine their functions in locomotor behaviors. We will perform whole cell recordings on V1 INs to delineate their cellular properties. We will ask whether subsets of V1 INs exhibit specificity in their synaptic connections with motor neurons. We will test our hypothesis that V1 INs provide early cycle inhibition during locomotion to motor neurons. The function of the V1 INs in awake behaving animals will be examined using a novel system that we have developed for acutely silencing neurons in mice. Our analysis of the V2B IN population will focus on characterizing the morphology, neurotransmitter phenotype and connectivity of these neurons. We will determine whether V2B INs are rhythmically active during locomotion, and are thus likely candidates for providing phasic ipsilateral inhibition to other locomotor neurons. Finally, we will test our hypothesis that V2B INs play an essential role in securing flexor-extensor motor activity in the mammalian locomotor CPG. These studies will provide valuable insights into the development and organization of locomotor circuits in the mammalian spinal cord. More importantly, they will lay the groundwork for strategies to treat spinal cord injury and degeneration disorders that affect normal voluntary movements. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This research will be done in Argentina in collaboration with Dr. Guillermo Lanuza as an extension of the NIH/NINDS grant 5 R37 NS037075-09. Functional Analysis of Inhibitory Spinal Cord Interneurons (8/15/2006-3/31/2010). Recent studies in the developing spinal cord have led to a model in which neurons are initially determined by unique genetic programs controlled by the combinatorial action of transcription factors expressed in dorsoventrally restricted populations of precursors. In spite of the considerable progress made in understanding early events in cell fate specification, the mechanisms that lead to the specification and generation of mature neuronal cell types in the adult remain to be elucidated. In this research proposal we will address the diversification of embryonic V2b interneurons of the spinal cord and brainstem in at least two different subsets: a) inhibitory neurons that extend axons ipsilaterally and b) neurons that contact the cerebrospinal fluid (CSF) in the central canal. We will study the development of CSF- contacting neurons and ask whether they constitute a late-born population of V2b neurons. We will define the genetic program that specifies generic V2b or V2b subtype identity by focusing on the role that the transcription factors Foxn4 and Mash1 play in V2b precursors. In addition we will test our hypothesis that Gata2 and Gata3 control the differentiation of CFS-contacting neurons. Finally, we will determine the function in vivo of central canal neurons. Their role as chemosensors and regulators of homeostasis of the internal fluid will be assessed in experiments using genetic ablation approaches to probe their function. PUBLIC HEALTH RELEVANCE: These studies will yield a better understanding of the mechanisms that underlie neuronal diversification in the spinal cord and the brainstem. More importantly, they will lay the groundwork for strategies to treat spinal cord injury, degenerative disorders and respiratory dysfunctions.

DESCRIPTION (provided by applicant): The function of the nervous system is dependent on complex interactions between networks of neurons composed of multiple neuron types. Understanding how these networks function both in health and disease is dependent on understanding the precise connectivity between specific neurons types. It is therefore apparent that, in order to have an adequate understanding of the nervous system, it is necessary to have detailed descriptions of neuronal connectivity with the same level of precision at which these systems operate. The research proposed here is aimed at the development, refinement, and validation of a novel set of tools that will allow researchers to readily and systematically uncover neural circuits with cell type-specific resolution. These tools build on previous work in one of the PIs lab, developing and validating the potential for use of genetically modified rabies viruses, in combination with other genetic and viral technologies, to probe neural circuits. The new tools to be developed and tested include mouse lines and helper viruses which can be used to achieve cell type specific expression of genes that interface with the rabies tracing system. This will allow the modified rabies viruses to selectively infect specific cell types and to label the direct inputs to those cells. These new tools will be tested and protocols developed for their use in a broad range of nervous system structures, whose function is relevant to understanding disease states. New variants of rabies virus will also be generated in order to interface with the newly developed mouse lines. These variants will express genes to drive conditional expression of genes encoded in the genomes of the transgenic mice, such that inputs to specific cell types targeted for infection by the rabies virus can be identified. These new rabies viruses will also be tested and protocols developed for assaying neural circuits in a broad range of relevant structures. Overall, this project will result in the generation and validation of very valuable new tools which will then be available to the neuroscience research community. PUBLIC HEALTH RELEVANCE: Understanding neural circuits with increasingly sophisticated and higher resolution tools is crucial to understanding diseases that are caused by neural circuit disorders, including Parkinson's, neuromuscular disorders, paralysis, schizophrenia, depression, autism and attention disorders, among many others. The development of new tools for revealing circuits will therefore have a large impact on these diseases.

DESCRIPTION (provided by applicant): A fundamentally important question in neuroscience is how sensory feedback and supraspinal commands control the spinal motor programs that control movement. This study will begin to address this issue by examining the connectivity and function of excitatory neurons in the dorsal spinal cord, focusing primarily on cells that express the nuclear orphan receptor RORa. Preliminary findings from the Goulding lab indicate that these sensory interneurons receive convergent inputs from descending motor pathways and from cutaneous sensory afferents. More importantly, loss of the RORa interneurons results in a pronounced motor defect, suggesting these cells form an important excitatory relay that connects sensory and descending pathways to the spinal motor system. In this study, we will use the RORa interneurons to address three important questions that are required to understand how sensory and descending control pathways interface with the spinal motor circuitry. The first involves identifying the source of inputs to the RORa interneurons, using a new genetic transsynaptic tracing system that was developed in the Goulding lab. This will lead to a better understanding of how neurons in the dorsal horn integrate sensory and descending commands (Aim 1). The second is to identify the neurons in the spinal cord that are innervated by RORa interneurons, with a particular focus on neurons that have previously been demonstrated to be key components of the locomotor circuitry (Aim 2). Finally, the role that RORa neurons and other dorsal interneuron cell types play in eliciting and shaping movement will be analyzed by genetic manipulations that use conditional reporter mice to either ablate and silence neurons, or activate them optogenetically (Aim 3). This study, when completed, will be the first to comprehensively analyze the contribution that a population of sensory interneurons makes to motor control. It will provide insights into how the spinal cord integrates tactile sensor stimuli with descending signals from motor centers in the brain to control locomotor movements. The information gained from these studies will aid the generation of new therapeutic approaches for functional recovery following spinal cord injury. It will also provide novel insight into the descending command pathways that control movement and locomotion, whose functioning is compromised in motor disorders such as Parkinson's Disease.

DESCRIPTION (provided by applicant): The long-range goal of this joint application is to identify the spinal circuits that process cutaneous somatic sensory information with a focus on pain and itch pathways. The overall research strategy employs cutting edge intersectional genetic manipulations to mark and ablate more than 10 classes of excitatory and inhibitory interneurons (INs) in the dorsal spinal cord, coupled with behavioral tests to assess the functional contribution that these cell types make to gating and transducing pain, itch and temperature. The experimental approach will utilize three sets of mice. The first is an intersectional DTR mouse in which the diphtheria toxin receptor (DTR) protein is only expressed after FlpO- and Cre- mediated removal of two stop cassettes. The second is the Lbx1FlpO mouse strain, in which the expression of FlpO recombinase is restricted to neurons in the dorsal horn of the medulla and spinal cord and dorsal hindbrain neurons. The third set includes eleven Cre mouse lines that express Cre recombinase in various subsets of excitatory or inhibitory dorsal horn INs. Crosses of these will enable investigators to ablate specific populations of dorsal interneurons so that their specific contributions to pain and itch pathways can be determined. Three issues will be addressed: 1) The molecular identity of neurons that transduce and gate specific pain and itch modalities, 2) a determination of the cellular basis of allodynia, and 3) the anatomical and functional organization of the circuits in the dorsal horn that gate pain and itch. These analyses, which combine rabies virus-based retrograde tracings, molecular neuroanatomy electrophysiological recordings, genetic manipulations and behavioral testing, will provide the first comprehensive picture of how the spinal circuits that process the noxious somatosensory modalities are organized at a cellular level. They will be used to examine in more detail the population-coding hypothesis and the cellular basis for the gate control theory of pain. Finally, they will provide new insights into the antagonistic interactions that occur among different sensory modalities, which when altered are a major factor in the pathogenesis of pain and itch.

The Salk Institute for Biological Studies requests support for a new Center Core Grant for Neuroscience Research. Since the founding of the Institute in the 1960s, neuroscience has grown to be the major research emphasis of Salk faculty. Over half of the faculty, heading 32 Institute laboratories, are currently engaged primarily in neuroscience research. The major research interests of the faculty are grouped into several broad programmatic areas: Clinical and Translational Neuroscience, Molecular and Cellular Neuroscience, Neural Development, and Systems Neuroscience. Seventeen research projects, supporting twelve faculty as principal investigators, are currently funded by NINDS. These awards include nine independent R01/R37 research projects, an active RC2 (Grand Opportunities) award, a K99, and a P01 program project. Nine Salk investigators are either current or past Jacob Javits awardees. The specific aim of this Center Core Grant application is to provide support for key resources that are needed for current and future NINDS-funded research projects. Three new core resources are proposed: 1) a Genome Manipulation Core, providing services to produce gene-targeted ES cell lines for in vivo and in vitro models for functional analysis of genes and neurologic disease, 2) an Imaging Core, focusing on dedicated support for TEM ultrastructural imaging and fostering integrated structural analysis across multiple advanced imaging platforms, and 3) a Behavior Core, providing both dedicated expertise in small animal behavioral analysis and consistency across different testing modalities. The management of these cores will focus first on providing support for the eight Salk Institute investigators with current NINDS-funded R01/R37 research programs. Any excess core capacity will be made available to other investigators at The Salk Institute who have research projects that are consistent with the mission of NINDS. This infrastructure program will provide core services that will facilitate application of continually evolving advanced technologies to the NINDS-funded research projects at the Salk Institute, and leverage existing funding as a resource multiplier to better advance these projects in addressing important problems relevant to the NINDS mission.

Project Summary: Project 2 ? Connectivity and Circuit Organization Neural circuits in the cervical spinal cord generate a range of rhythmic and dexterous motor behaviors that are essential for life. These circuits, aside from being important in their own right, serve as a window into how other brain areas are functionally organized by providing a critical readout of behavior, namely motor action. The analyses in this project will use cutting-edge genetic tools and anatomical approaches, many of which were developed at the Salk Institute, to create a scalable and interactive connectivity map of the pre- motor interneuron circuits in the cervical spinal cord. This connectivity map will be registered to motor pools innervating specific forelimb muscles in order for the connectivity datasets to be informative for the modeling and interpretation of motor behaviors that are key components of this Team SCC initiative. Intersectional mouse genetics will be used to target specific populations of spinal interneurons and annotate key information about position, and connectivity, in order to generate a physical wiring diagram for forelimb pre- motor circuits. The pre-motor wiring diagram will serve as a template for a subsequent more expansive analysis of spinal connectivity that will include sensory, propriospinal, and descending connections to forelimb pre-motor neurons. These studies, when completed, will provide unparalleled insights into the organization of the spinal motor circuitry and the motor system as a whole. They will also lead to a better understanding of the cellular interactions and neural computations that give rise to rhythmic and skilled forelimb movements.

Animals and humans display a vast repertoire of behaviors, many of which are generated by motor networks in the spinal cord. This coordinated spinal motor activity is strongly regulated by descending motor control pathways and sensory afferent feedback. Sensory feedback is essential for both stereotypical protective reflexes, such as limb withdrawal, and for regulating ongoing motor behaviors, such as walking, running, and reaching. Interestingly, many descending motor control pathways converge on interneurons in the dorsal spinal cord that transmit sensory information, indicating a prominent role for these cells in motor control. Currently, very little is known about how sensorimotor networks in the spinal cord are organized at a cellular level. Efforts proposed here will use cutting-edge genetic manipulations and sensitive behavioral assays to deconstruct the cellular composition and synaptic connectivity of these sensorimotor circuits. The goals of this study are to functionally define the neuronal cell types that make up the sensorimotor circuitry and to generate a connectivity map that can then be used to construct a working model of how the sensorimotor circuitry is organized. Intersectional mouse genetics will be used to target specific populations of spinal neurons and ask whether inactivating or activating them with chemogenetic and optogenetic reporters perturbs specific sensorimotor pathways, including those that generate corrective behaviors during ongoing movement and noxious mechanical pathways that induce protective reflexes. Studies of protective and corrective reflexes will be complemented with an analysis of the sensory circuitry for the control of forelimb reaching and grasping behaviors. These studies, when completed, will provide new insights into the organization of the spinal reflex circuitry, and improve our understanding of the cellular computations that underlie sensorimotor transformation in the spinal cord.

Project Summary: Overall Local networks within the spinal cord represent an essential computational layer for the control of limb-driven motor behaviors, integrating descending and sensory inputs to coordinate dexterous motor output. Significant advances have been made in characterizing the developmental programs that specify the core cardinal interneuron types that make up these motor networks. This knowledge has been used to develop a battery of mouse genetic reagents for spinal circuit anatomical and functional dissection. To date, these genetic tools have been primarily used to study locomotion and spinal reflexes in the lumbar spinal cord. Given the wider range of dexterous motor behaviors that are produced by cervical circuits and the increased oversight of these behaviors by descending motor pathways, the mouse cervical spinal cord provides a unique and tractable mammalian model system for understanding how coordinated movements are generated by local motor networks and how these motor behaviors are regulated by the brain. The overall goal of this U19 Team-Research BRAIN Circuit Program proposal is two-fold: 1) the generation of a scalable, high-resolution atlas of forelimb-premotor interneurons in the cervical spinal cord that describes their connectivity, molecular phenotypes, electrophysiological properties, and functional contributions to forelimb behaviors, and 2) the development of testable predictive neural models that describe the network interactions that give rise to limb control. The functional interrogation and modeling of these circuits, based on real behavioral outcomes and detailed information about the cell types that generate these behaviors, will ensure that the overall project is greater than the sum of its parts. Specifically, the research plan will address two overarching questions: 1) How do rhythmic spinal networks control non-rhythmic movements, which represent the majority of forelimb motor behaviors, and 2) How are these spinal circuits modified to control more complex joint movements to achieve forelimb dexterity? To address these questions, the Spinal Cord Circuit Team (TeamSCC) will generate: (a) a pre-motor interneuron connectome that includes information on cell positions and synaptic weightings, (b) a comprehensive index of the physiological properties and molecular identities of genetically distinct neuronal subtypes within each cardinal interneuron class, (c) a functional description of spinal circuit control of natural forelimb motor behaviors, and (d) a working model of the motor network that describes how circuit connectivity and dynamics give rise to key elements of forelimb behavior. Ultimately, these data will be used to generate a searchable web-based portal with 3D visualization tools linked to the molecular, electrophysiological, functional, and network model databases. Together, this work will lead to a deeper understanding of the organization and function of cervical circuitry, which will be of great value to groups that are grappling with the issue of how motor centers in the brain communicate with sensorimotor circuits in the spinal cord to control movement.

Project Summary: Administrative Core The Spinal Cord Circuit Team (TeamSCC) Administrative Core will coordinate all the scientific, regulatory, and external reporting activities of this U19 project. It will provide oversight for all four Research Projects, as well as the Data Science Resource Core to ensure that experiments are coordinated, and that proposed schedules for milestones are met. The Administrative Core will support a Program Manager who will help coordinate all scientific activities and regulatory responsibilities. The Core will also provide for an Administrative Assistant who will support the Project Manager and scientific personnel. The Administrative Core will coordinate meetings between the research teams and the Data Science Resource Core. The Administrative Core will also coordinate scientific leadership meetings between the Principal Investigators, the Project Manager, and personnel from Metacell who are providing software support for the Data Science Resource Core. The Administrative Core will also be responsible for overseeing data sharing between each Research Project to ensure that all generated data are available to all members of TeamSCC.