The main goal of this research is to elucidate the synaptic organization of circuits in the ventral part of the mouse spinal cord. We now have preliminary evidence that spinal neurons projecting to the cerebellum (hereafter called ventral spinocerebellar - vSCT- neurons) receive monosynaptic input from motoneurons. If these cells are excitatory, they could mediate the activation of locomotor networks by ventral root stimulation. Therefore, we propose to determine their connections, transmitter phenotype and behavior during locomotor-like activity. We made the surprising observation that stimulation of the ventral roots can excite locomotor like activity and entrain disinhibited bursting in the neonatal mouse cord. This was surprising because no known circuitry existed to mediate these excitatory effects. These excitatory effects of motoneurons on spinal networks require both ionotropic and metabotropic glutamate transmission but not cholinergic transmission. This is consistent with our work showing that motoneurons release an excitatory amino acid at their central terminals in addition to acetylcholine. It is not clear if this amino acid is glutamate or aspartate and we propose experiments to resolve this question. In addition, we will examine the hypothesis that ATP is released from motoneuron terminals onto Renshaw cells. Finally, we will establish if stimulation of motor axons activates glial cells within the motor nucleus and if such activation is involved in the excitation of spinal networks by ventral root stimulation. Finally, in collaboration with Drs. Kurt Fischbeck (NINDS) and Charlotte Sumner (Johns Hopkins) we have begun a new project to identify the cellular and synaptic abnormalities in the spinal cord of a mouse model of the hereditary disease spinal muscular atrophy. Our initial results have revealed that motoneurons exhibit a massive loss of functional synaptic input from sensory afferents and from descending pathways. We now propose to examine circuit function in these animals and to characterize the voltage dependent conductances in diseased motoneurons.

Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2010
Total Cost
$996,373
Indirect Cost
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State
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Thirumalai, Vatsala; Behrend, Rachel M; Birineni, Swetha et al. (2013) Preservation of VGLUT1 synapses on ventral calbindin-immunoreactive interneurons and normal locomotor function in a mouse model of spinal muscular atrophy. J Neurophysiol 109:702-10
Aliaga, Leonardo; Lai, Chen; Yu, Jia et al. (2013) Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons. Hum Mol Genet 22:4293-305
Blivis, Dvir; O'Donovan, Michael J (2012) Retrograde loading of nerves, tracts, and spinal roots with fluorescent dyes. J Vis Exp :
Mentis, George Z; Blivis, Dvir; Liu, Wenfang et al. (2011) Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy. Neuron 69:453-67
Haspel, Gal; O'Donovan, Michael J (2011) A perimotor framework reveals functional segmentation in the motoneuronal network controlling locomotion in Caenorhabditis elegans. J Neurosci 31:14611-23
Mentis, George Z; Alvarez, Francisco J; Shneider, Neil A et al. (2010) Mechanisms regulating the specificity and strength of muscle afferent inputs in the spinal cord. Ann N Y Acad Sci 1198:220-30
Jovanovic, Ksenija; Pastor, Angel M; O'Donovan, Michael J (2010) The use of PRV-Bartha to define premotor inputs to lumbar motoneurons in the neonatal spinal cord of the mouse. PLoS One 5:e11743
Mitchell, Kendall; Bates, Brian D; Keller, Jason M et al. (2010) Ablation of rat TRPV1-expressing Adelta/C-fibers with resiniferatoxin: analysis of withdrawal behaviors, recovery of function and molecular correlates. Mol Pain 6:94
Shneider, Neil A; Mentis, George Z; Schustak, Joshua et al. (2009) Functionally reduced sensorimotor connections form with normal specificity despite abnormal muscle spindle development: the role of spindle-derived neurotrophin 3. J Neurosci 29:4719-35
Bonnot, Agnes; Chub, Nikolai; Pujala, Avinash et al. (2009) Excitatory actions of ventral root stimulation during network activity generated by the disinhibited neonatal mouse spinal cord. J Neurophysiol 101:2995-3011

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