Date Available
6-19-2013
Year of Publication
2013
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Medicine
Department/School/Program
Physiology
First Advisor
Dr. Kathryn E. Saatman
Abstract
Traumatic brain injury (TBI) is a prevalent CNS neurodegenerative condition that results in lasting neurological dysfunction, including potentially debilitating cognitive impairments. Despite the advancements in understanding the complex damage that can culminate in cellular dysfunction and loss, no therapeutic treatment has been effective in clinical trials, highlighting that new approaches are desperately needed. A therapy that limits cell death while simultaneously promoting reparative mechanisms, including post-traumatic neurogenesis, in the injured brain may have maximum effectiveness in improving recovery of function after TBI. Insulin-like growth factor-1 (IGF-1) is a potent growth factor that has previously been shown to promote recovery of function after TBI, but no studies have evaluated the efficacy of IGF-1 to promote cell survival and modulate neurogenesis following brain injury. Systemic infusion of IGF-1 resulted in undetectable levels of IGF-1 in the brain, but did promote increased cortical activation of Akt, a pro-survival downstream mediator of IGF-1 signaling, in mice subjected to controlled cortical impact (CCI), a well-established model of contusion TBI. However, systemic infusion of IGF-1 did not promote recovery of motor function in mice after CCI. A one week central infusion of IGF-1 elevated brain levels of IGF-1, increased Akt activation and improved motor and cognitive function after CCI. Central infusion of IGF-1 also significantly increased immature neuron density at 7 d post-injury for a range of doses and when administered with a clinically relevant delayed onset of 6 hr post-injury. To mitigate potential side effects of central infusion, an alternative conditional astrocyte-specific IGF-1 overexpressing mouse model was utilized to evaluate the efficacy of IGF-1 to promote post-traumatic neurogenesis. Overexpression of IGF-1 did not protect against acute immature neuron loss, but did increase immature neuron density above uninjured levels at 10 d post-injury. The increase in immature neuron density appeared to be driven by enhanced neuronal differentiation. In wildtype mice, immature neurons exhibited injury-induced reductions in dendritic arbor complexity following severe CCI, a previously unknown pathological phenomenon. Overexpression of IGF-1 in brain-injured mice promoted the restoration of dendritic arbor complexity to the dendritic morphology observed in uninjured mice. Together, these findings provide strong evidence that treatment with IGF-1 promotes the recovery of neurobehavioral function and enhances post-traumatic neurogenesis in a mouse model of contusion TBI.
Recommended Citation
Carlson, Shaun W., "EVALUATION OF INSULIN-LIKE GROWTH FACTOR-1 AS A THERAPEUTIC APPROACH FOR THE TREATMENT OF TRAUMATIC BRAIN INJURY" (2013). Theses and Dissertations--Physiology. 9.
https://uknowledge.uky.edu/physiology_etds/9
