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The Development and Regeneration of the Serotonergic System

Hawthorne, Alicia Lynn
http://rave.ohiolink.edu/etdc/view?acc_num=case1264027000

Abstract Details

2010, Doctor of Philosophy, Case Western Reserve University, Neurosciences.
Serotonergic fibers project throughout the central nervous system (CNS). Since the expression of 5-hydroxytryptamine (5-HT) beings after the completion of migration from the germinal zone, the early migration of serotonergic neurons has not previously been studied. Two main modes of radial neuronal migration are radial glial-guided locomotion and somal translocation. Radial glial-guided locomotion has dominated as the major mode of migration within the CNS, by which radial glia act as a scaffold for migrating neurons. In somal translocation, the neurons themselves are radial and migrate by moving their cell body through their pial process. We studied the migration of serotonergic neurons by utilizing mice that have serotonergic neurons specifically labeled with enhanced yellow fluorescent protein (EYFP) under control of the Pet-1 enhancer/promoter region (ePet-EYFP), which turns on after a serotonergic neuron has differentiated but before the neuron expresses 5-HT. Both histologically and in living slice cultures, we show that E10.5-E11.5 serotonergic neurons migrate by somal translocation through areas of high chondroitin sulfate proteoglycan (CSPG) and toward regions of laminin. The intracellular motors non-muscle myosin II, kinesin, and dynamin were inhibited pharmacologically, but only dynamin slowed translocation, demonstrating for the first time that neurons use dynamin during migration. In the adult, serotonergic neurons have an enhanced capacity for sprouting after injury, but have never been investigated in an ischemic brain lesion. We used a focal cortical thermocoagulatory lesion to study the response of serotonergic and callosal projection fibers after injury. Callosal fibers became dystrophic and died back and after injury, whereas serotonergic fibers persisted and sprouted in the lesion among high levels of CSPG and laminin. Using P3-4 ePet-EYFP serotonergic neurons or cortical neurons from EYFP-negative littermates, growth cones were compared in vitro on substrates of low laminin with or without high CSPG. Serotonergic growth cones maintained a more active growth state when challenged with CSPG, while cortical growth cones collapsed. Serotonergic neurites were also longer when grown on CSPG alone. Higher levels of GAP-43 and beta1 integrin expression may explain this robust growth. The mechanisms responsible for serotonergic sprouting may lead to therapies for both brain and spinal cord injury.
Evan Deneris, PhD (Committee Chair)
Jerry Silver, PhD (Advisor)
Lynn Landmesser, PhD (Committee Member)
Susann Brady-Kalnay, PhD (Committee Member)
153 p.
Biology; Biomedical Research; Cellular Biology; Neurology; Scientific Imaging; Surgery
serotonin; 5-HT; migration; somal translocation; chondroitin sulfate proteoglycan; ischemia; sprouting; glia; GAP-43; beta1 integrin; laminin; dynamin; non-muscle myosin II; kinesin; slice culture; Pet-1; growth cone

Recommended Citations

Citations

  • Hawthorne, A. L. (2010). The Development and Regeneration of the Serotonergic System [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1264027000

    APA Style (7th edition)

  • Hawthorne, Alicia. The Development and Regeneration of the Serotonergic System. 2010. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1264027000.

    MLA Style (8th edition)

  • Hawthorne, Alicia. "The Development and Regeneration of the Serotonergic System." Doctoral dissertation, Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1264027000

    Chicago Manual of Style (17th edition)

case1264027000
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© 2010, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.