Re-Expression of Thrombospondin-1 in the Thalamocortical Whisker Circuit after Experimental Diffuse Traumatic Brain Injury: Potential Role in Mediating Synaptogenesis?

Persistent Link:
http://hdl.handle.net/10150/613437
Title:
Re-Expression of Thrombospondin-1 in the Thalamocortical Whisker Circuit after Experimental Diffuse Traumatic Brain Injury: Potential Role in Mediating Synaptogenesis?
Author:
Ogle, Sarah
Issue Date:
2016
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Introduction: Annually, an estimated 2.5 million traumatic brain injuries (TBI) occur in the United States, of which, over 50,000 result in deaths. Currently, 5.3 million Americans are living with neurological dysfunction secondary to TBIs leading to a $60 billion dollar cost in medical expenses and productivity losses. To date, there are limited treatments available to cure or ease the morbidity of TBI. Despite preventative efforts, traumatic brain injuries (TBI) occur at a staggering rate and it is estimated that 15-20% of survivors develop persistent post-traumatic neurological impairment. The purposed source of neurological dysfunction is a result of circuit reorganization when the brain rebuilds itself. After diffuse TBI, rodents have been shown to develop a late-onset, gain-of-function sensory sensitivity to whisker stimulation; similar to phonophobia and photophobia experienced by human TBI survivors. This morbidity coincides with evidence of post-TBI circuit reorganization, however the etiology of post-traumatic neurological impairment remains largely unknown. Thrombospondin-1 (TSP-1) and thrombospondin-2 (TSP-2) are heavily expressed during pediatric neuronal synapse development. Expression of TSPs, however declines with age. Mechanistically during development, TSP mediates synaptogenesis via bindingα2δ-1 subunit of the voltage-gated calcium channel receptor (α2δ-1). After neurological insult, re-expression of TSPs has been demonstrated and experimental modulation of the TSP/α2δ-1 interaction has led to changes in morbidity. We therefore hypothesize that experimental diffuse TBI will result in re-expression of TSPs, which will be synchronous with increases in synaptic markers in the thalamocortical whisker circuit. Methods: Adult male Sprague-Dawley rats underwent sham or moderate midline fluid percussion brain injury. At multiple time points over 2-months post-injury, expression of TSPs and synaptic markers were quantified from thalamocortical circuit (ventroposterior medial thalamus (VPM), primary somatosensory barrel fields (S1BF)) biopsies using qPCR and automated capillary westerns, respectively. Results: TSP-1 gene expression and protein levels increase in the VPM during the first week after injury. Gene expression of TSP-1 did not significantly change over time in the S1BF, however, there was a significant increase in protein levels in the first and second weeks after injury. No significant changes were demonstrated in synaptic markers in the VPM over the time course. TSP-1 protein levels demonstrated a similar multimodal response to synaptic markers in the S1BF.Conclusion: Re-expression of TSP-1 and synchronous changes in synaptic marker supports a role for TSP-1 mediated synaptogenesis after experimental diffuse TBI in the S1BF. These data positions us for future investigation of pharmacological inhibition of TSP-mediated synaptogenesis after TBI; which may represent a prophylactic strategy against circuit reorganization and neurological dysfunction after TBI.
Type:
text; Electronic Thesis
Keywords:
synaptogenesis; Thrombospondin; Traumatic brain injury; Clinical Translational Sciences; circuit reorganization
Degree Name:
M.S.
Degree Level:
masters
Degree Program:
Graduate College; Clinical Translational Sciences
Degree Grantor:
University of Arizona
Advisor:
Hammer, Ronald; Lifshitz, Jonathan

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleRe-Expression of Thrombospondin-1 in the Thalamocortical Whisker Circuit after Experimental Diffuse Traumatic Brain Injury: Potential Role in Mediating Synaptogenesis?en_US
dc.creatorOgle, Sarahen
dc.contributor.authorOgle, Sarahen
dc.date.issued2016-
dc.publisherThe University of Arizona.en
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en
dc.description.abstractIntroduction: Annually, an estimated 2.5 million traumatic brain injuries (TBI) occur in the United States, of which, over 50,000 result in deaths. Currently, 5.3 million Americans are living with neurological dysfunction secondary to TBIs leading to a $60 billion dollar cost in medical expenses and productivity losses. To date, there are limited treatments available to cure or ease the morbidity of TBI. Despite preventative efforts, traumatic brain injuries (TBI) occur at a staggering rate and it is estimated that 15-20% of survivors develop persistent post-traumatic neurological impairment. The purposed source of neurological dysfunction is a result of circuit reorganization when the brain rebuilds itself. After diffuse TBI, rodents have been shown to develop a late-onset, gain-of-function sensory sensitivity to whisker stimulation; similar to phonophobia and photophobia experienced by human TBI survivors. This morbidity coincides with evidence of post-TBI circuit reorganization, however the etiology of post-traumatic neurological impairment remains largely unknown. Thrombospondin-1 (TSP-1) and thrombospondin-2 (TSP-2) are heavily expressed during pediatric neuronal synapse development. Expression of TSPs, however declines with age. Mechanistically during development, TSP mediates synaptogenesis via bindingα2δ-1 subunit of the voltage-gated calcium channel receptor (α2δ-1). After neurological insult, re-expression of TSPs has been demonstrated and experimental modulation of the TSP/α2δ-1 interaction has led to changes in morbidity. We therefore hypothesize that experimental diffuse TBI will result in re-expression of TSPs, which will be synchronous with increases in synaptic markers in the thalamocortical whisker circuit. Methods: Adult male Sprague-Dawley rats underwent sham or moderate midline fluid percussion brain injury. At multiple time points over 2-months post-injury, expression of TSPs and synaptic markers were quantified from thalamocortical circuit (ventroposterior medial thalamus (VPM), primary somatosensory barrel fields (S1BF)) biopsies using qPCR and automated capillary westerns, respectively. Results: TSP-1 gene expression and protein levels increase in the VPM during the first week after injury. Gene expression of TSP-1 did not significantly change over time in the S1BF, however, there was a significant increase in protein levels in the first and second weeks after injury. No significant changes were demonstrated in synaptic markers in the VPM over the time course. TSP-1 protein levels demonstrated a similar multimodal response to synaptic markers in the S1BF.Conclusion: Re-expression of TSP-1 and synchronous changes in synaptic marker supports a role for TSP-1 mediated synaptogenesis after experimental diffuse TBI in the S1BF. These data positions us for future investigation of pharmacological inhibition of TSP-mediated synaptogenesis after TBI; which may represent a prophylactic strategy against circuit reorganization and neurological dysfunction after TBI.en
dc.typetexten
dc.typeElectronic Thesisen
dc.subjectsynaptogenesisen
dc.subjectThrombospondinen
dc.subjectTraumatic brain injuryen
dc.subjectClinical Translational Sciencesen
dc.subjectcircuit reorganizationen
thesis.degree.nameM.S.en
thesis.degree.levelmastersen
thesis.degree.disciplineGraduate Collegeen
thesis.degree.disciplineClinical Translational Sciencesen
thesis.degree.grantorUniversity of Arizonaen
dc.contributor.advisorHammer, Ronalden
dc.contributor.advisorLifshitz, Jonathanen
dc.contributor.committeememberThomas, Theresa C.en
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