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From molecules to circuits to behavior: building corticospinal circuits for skilled behavior

Gu, Zirong
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1428070602

Abstract Details

2015, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
Skilled behavior has its basis in neuronal connections that channel central commands from the motor cortex towards motor neurons (MNs) in the ventral spinal cord, translating motor plans into action. Sensory feedback from the periphery also plays a critical role in reporting and modulating movement. Without proper development of connections from the motor cortex and sensory neurons to motor neurons, skilled behavior would not be possible. This dissertation focuses on the genetic and activity dependent programs that direct the formation of motor circuits underlying skilled behavior in mice. I begin my dissertation with an overview of the development of motor circuits and a description of the gaps of current understanding. Fine synaptic specificity of group Ia proprioceptive sensory-motor connections is the anatomical foundation of the sensory feedback to MNs, however, the genetic determinants that specify such fine specific connections are poorly understood. In chapter two, I study the possible role of IgSF recognition molecules in determining this synaptic specificity. I examine the expression of many IgSF in the developing sensory-motor circuits and identify a list of candidates for regulating fine synaptic specificity for sensory-motor reflexes. Corticospinal circuits (CSCs) connect corticospinal neurons in the motor cortex with their target neurons in the spinal cord. CSCs in mice are characterized by the corticospinal tract (CST) traveling in dorsal column of the spinal cord (dCST) and disynaptic connections between corticospinal neurons and MNs through interneurons (INs) in the spinal cord. The genetic program that direct the formation of mouse specific CSCs is unknown. Using a combination of virus tracing and genetic labeling, large scale synapse and axon eliminations are identified during the postnatal development of CSCs in mice. I find the presence of the transient corticomotoneuronal (CM) connections and ipsilateral CST in the lateral and ventromedial funiculi of the spinal cord in the early postnatal mice. Elimination of these transient anatomical features during development leads to the mouse specific CSCs characterized by dCST and disynaptic connections in adult. This pruning has been shown to be mediated by Sema6D-PlexA1 signaling. Perturbation of this process results in the maintenance of vlCST and CM connections to adult, thereby, disrupts the mouse specific CSCs. The synaptic refinements of CSCs occur during a protracted postnatal period in mice. These refinements includes both the addition and elimination of axonal collaterals and their associated synapses. In chapter four, I use a retrograde tracing virus based connectivity assay to define the nature of these refinements at the circuit level. My study reveals a reorganization of corticospinal connectivity that controls antagonistic muscle pairs from segregated in the postnatal mice to convergent in the adult mice. I further identify activity dependent activation of the Bax/Bak-caspase pathway as the molecular mechanism that regulates this refinement. Loss of Bax/Bak in the motor cortex results in the failure of this refinement and severe deficits in the expression of skilled behaviors in adult mice. Collectively, these studies have defined some of the genetic and activity dependent strategies for the assembly of functional motor circuits controlling skilled behaviors.
Yutaka Yoshida, Ph.D. (Committee Chair)
Steve Crone, Ph.D. (Committee Member)
David Ladle, Ph.D. (Committee Member)
Kenneth Campbell, Ph.D. (Committee Member)
Masato Nakafuku, M.D. Ph.D. (Committee Member)
294 p.
Biology
Corticospinal circuits; skilled behavior

Recommended Citations

Citations

  • Gu, Z. (2015). From molecules to circuits to behavior: building corticospinal circuits for skilled behavior [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1428070602

    APA Style (7th edition)

  • Gu, Zirong. From molecules to circuits to behavior: building corticospinal circuits for skilled behavior. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1428070602.

    MLA Style (8th edition)

  • Gu, Zirong. "From molecules to circuits to behavior: building corticospinal circuits for skilled behavior." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1428070602

    Chicago Manual of Style (17th edition)

ucin1428070602
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This open access ETD is published by University of Cincinnati and OhioLINK.