1985 — 1987 |
O'donovan, Michael J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Development of Sensory-Motor Synapses
The developmental mechanisms responsible for formation of neuronal connections in the vertebrate nervous system remain largely unknown. The goal of my research is to elucidate these mechanisms. In these experiments I will analyze the development of connections between sensory afferents and motoneurons in the spinal cord of the chick embryo. The great experimental convenience of this system makes it possible to test several alternative mechanisms that could account for the formation of specific connections between sensory and motor neurons. I will analyze two aspects of the connectivity between afferents and motoneurons: the specific connections between particular muscles and individual motoneuron pools; and the strength of connections between particular muscles and different spinal segments. Connections will be measured by monosynaptic reflex testing and the recording of synaptic potentials in the ventral roots and individual muscle nerves. First, I will test the hypothesis that cell death eliminates erroneous connections between afferents and motoneurons. This will be achieved by preventing sensory and motoneuronal cell death and establishing if this results in abnormal sensory-motor connections. Secondly, I will establish the importance of positional factors in controlling the sensory connections between muscles and the different spinal segments, by comparing the connectivity between afferents and either normally or ectopically located motoneurons. Finally, I will use reversals of the neural crest to test the hypothesis that sensory cells are specified early in development to innervate particular peripheral and central targets.
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0.904 |
1987 — 1988 |
O'donovan, Michael J |
K04Activity Code Description: Undocumented code - click on the grant title for more information. R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cellular Analysis of Motor Development
The experiments in this proposal have been designed to identify the cellular mechanisms underlying motor activity in the chick embryo. The experiments will be performed using an isolated spinal cord preparation that generates spontaneous motor activity. Intracellular recordings will be obtained from motoneurons to identify the nature of their synaptic drive during motor activity and the mechanism of alternation between flexor and extensor motoneurons. We will then determine how these cellular mechanisms become assembled during development. In younger embryos electrotonic recording and current passage through ventral roots will be used instead of intracellular methods. These techniques will allow us to determined when embryonic motoneurons acquire the ability to discharge and whether developmental changes in motoneuron firing are due to changes in synaptic drive, intrinsic motoneuron properties of some combination of both. Finally, we establish if the presence of the hindlimb is casually necessary for the development of motor activity by recording the pattern of ventral root discharge in embryos rendered limbless by surgery or by the limbless mutation. The experiments described in this proposal constitute the first cellular analysis of motor development in the chick embryo. They will not only provide new information about the development of vertebrate motor activity but also may provide insights into the neural mechanisms responsible for coordinated motor behavior in the adult nervous system.
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0.904 |
2007 — 2013 |
O'donovan, Michael J |
Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Cellular and Synaptic Organization of the Spinal Cord @ Neurological Disorders and Stroke
The primary focus of this research is to investigate the synaptic organization of the developing and adult spinal cord in normal and in diseased animals. We have been focusing on the sensory nerves that supply stretch receptors in muscle because they make very simple direct synaptic connections with motoneurons. In collaboration with Dr. Francisco Alvarez (Wright State University, Ohio) we have shown that these sensory nerves also make direct connections onto a class of inhibitory interneurons within the lumbar spinal cord called Renshaw cells. This finding was unexpected because physiological studies in adult cats suggested that such connections did not exist. Using anatomical methods we showed that adult cat Renshaw cells in the adult cat do in fact receive connections from sensory afferents but presumably are functionally inactive. We have also been examining the role of muscle spindle derived factors in determining the strength and specificity of the connections between sensory neurons and motoneurons. We have found that genetically engineered mice in which muscle spindles are greatly reduced in number exhibit normal patterns of connectivity although the strength of the connections is reduced. A similar reduction in the strength of the connections is seen in mice in which muscle spindles no longer express Neurotrophin-3 (NT-3). These finding suggest that NT-3 regulates the functional strength of the connections but not their specificity. [unreadable] In collaboration with Dr. Murat Oz (NIDA) we have been investigating the function of neuropeptides in the spinal cord. Following on an earlier study in which the effects of angiotensin II on spinal neurons were examined, we have found that activation Cholecystokinin B type receptors depolarizes spinal neurons through a G-protein coupled mechanism. We are particularly interested in establishing if endogenous neuropeptide release is involved in the activation of locomotor networks by stimulation of the dorsal or ventral roots and are currently examining the role of Calcitonin Gene Related Peptide - known to be present in the terminals of sensory and motor axons -in this process. [unreadable] In collaboration with Dr. Rita Balice-Gordons group (University of Pennsylvania) we have been examining the role of gap junction proteins in synchronizing motoneuron activity in the neonatal period. We have found that mice lacking one of the junctional proteins (Connexin-40), exhibit reduced electrical coupling between motoneurons and desynchronized muscle electrical activity. We are currently developing mice that lack two connexins (40 and 36) and investigating whether or not this disrupts the spontaneously occurring high frequency oscillatory activity that is synchronized across several segments of the spinal cord. If so, we will then determine the effects on the development locomotor networks.[unreadable] We are also investigating whether motoneurons project to spinal interneurons other than Renshaw cells. Such projections may provide an explanation for the observation that stimulation of the ventral roots (containing motoneuron axons) can trigger locomotor activity.
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1 |
2007 — 2012 |
O'donovan, Michael J |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Genetic Dissection of Abnormal Oligodendrocyte and Myelin Function Schizophrenia @ Icahn School of Medicine At Mount Sinai
We intend to examine oligodendrocyte/myelin related (OMR) genes in schizophrenia in order to identify those specific OMR genes that initiate the pathophysiological processes in schizophrenia. By identifying new genes, we will also provide etiologically relevant foci for other CCNMD components whose aims are to elucidate the pathophysiological cascades through cell biology and animal models. We will also enable externally validated exploration of the diagnostic boundaries of psychosis and of endophenotypes, and the construction of etiologically relevant animal models in which to explore pathophysiology, develop novel endophenotypes and markers of disease, and model novel therapeutic interventions. Aim1. Identify causal pathways: Genes that regulate oligodendrocyte development and maturation will be tested by genetic association based on whole genome data plus additional focused genotyping, and by replication in large samples. Aim 2. Determine how OMR genes relate to white matter imaging abnormalities in schizophrenia and to clinically important neuropsychological measures. Genes associated from aim 1 will be examined in subjects who have had diffusion tensor imaging and neuropsychological profiling. Aim 3. Determine how OMR genes relate to the clinical phenotype. We postulate that OMR genes confer risk beyond diagnostic boundaries, and may influence particular domains of psychopathology and/or clinical outcome. We will test this by examining genes associated from aim 1 in large samples of individuals with schizoaffective disorder, bipolar disorder and psychotic unipolar disorder. We will also examine relationships with the clinical variables we have collected with the minimal imposition of nosological models. Aim 4. Identifying Animal Models. Mouse strains carrying spectra of nonsense and missense mutations in the genes identified as mediators of schizophrenia risk will prove of value in identifying the functions, normal and pathogenic of the susceptibility genes, the disease mechanisms, and in the development of treatments. We will identify mouse mutants for key OMR genes by screening DMA from the MRC UK Harwell END series. The work proposed relates to improving mental health on several levels. New understandings of fundamental disease mechanisms will ultimately lead to new therapeutic opportunities. We also expect to contribute to the development of improved diagnostics and classification based upon etiology and pathophysiology. Success here will have wide ranging consequences for all clinical and research that use psychiatric classification, including diagnostics and treatment.
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0.915 |
2007 — 2018 |
O'donovan, Michael |
Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Mechanisms of Rhythmicity in the Spinal Cord @ Neurological Disorders and Stroke
The main goal of this research is to understand how the spinal cord generates locomotion. This involves identifying the essential components of the locomotor network, recording their activity patterns and isolating the critical cellular and synaptic properties responsible for locomotor network function. In collaboration with Dr. A. Lev-Tov (Hebrew University, Israel), we have identified a novel class of sacral commissural interneuron whose axons travel in the ventral funiculus. These neurons appear to mediate, in part, the excitation of lumbosacral locomotor networks by stimulation of afferents in the sacrocaudal cord. We now propose to identify their connections, transmitter phenotype and function during locomotor-like activity. We are also proposing an ambitious set of experiments to image the activity of all (or most) of the neurons and glia during a single cycle of locomotor activity in a hemi-segment of the spinal cord. This information will allow us to establish how neurons are recruited during each cycle of activity and how variable the recruitment patterns are from cycle to cycle and from animal to animal. Moreover, it will enable us to determine if the different methods for inducing locomotor-like activity (drug-induced, brainstem stimulation, dorsal/ventral root stimulation) all activate the same networks. In addition, we will exploit the growing list of mouse cell lines, in which various interneuron classes have been marked with GFP or one of its variants, to identify the activity patterns of identified interneurons. Finally, we are using calcium and voltage sensitive dye imaging to identify the activity patterns of motoneurons during locomotion of the nematode worm C.elegans. C. Elegans is a simple worm in which calcium and voltage sensitive dyes can be expressed in the identified neurons of motor circuits. Because of its rapid generation time compared to mice, this organism can serve as a test bed for introducing genes into specific sets of neurons and evaluating their utility as probes of neural activity. In addition, the neural mechanisms that underlie movement in this animal will provide specific hypotheses that can be tested in the much more complex nervous systems of mice.
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0.915 |