Activation of early neural progenitors is required for traumatic brain injury-induced hippocampal neurogenes

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Activation of early neural progenitors is required for traumatic brain injury-induced hippocampal neurogenes

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Title: Activation of early neural progenitors is required for traumatic brain injury-induced hippocampal neurogenes
Author: Yu, Tzong-Shiue
Abstract: Traumatic brain injury (TBI) is the most common form of acquired brain injury in both children and adults in the United States. TBI causes neuronal loss and results in a variety of neurological impairments and deficits in hippocampus-dependent functions. However, cognitive recovery commonly occurs though the mechanism is unknown. Exploration of post-natal neurogenesis in the hippocampus raises the possibility that adult-born neurons may contribute to cognitive recovery from TBI. Several studies in animal models that mimic TBI demonstrate there is enhanced generation of adult-born neurons in the dentate gyrus and those adult-born neurons may correlate with cognitive recovery. Due to the limits of current methodology in studying neurogenesis, it remains unclear what relevance injury-induced neurogenesis may have in the recovery process following TBI. In order to explore the relevance of injury-induced neurogenesis, I have characterized a previously generated transgenic mouse line that has rtTA-IRES-eGFP expression under the control of a nestin promoter and also contains a neural progenitor-specific regulatory element. By using this line, I have demonstrated that eGFP-expressing cells represent early neural progenitors in the adult dentate gyrus. Performing unilateral controlled cortical injury (CCI) demonstrates that this injury depletes doublecoritn (Dcx)-expressing late neural progenitors while activating eGFP-expressing early neural progenitors. To address whether the subsequent recovery of Dcx-expressing late progenitors was derived from activation of early neural progenitors, I generated a transgenic line that expresses modified herpes simplex viral thymidine kinase (delta-HSV-TK) under the control of the neural progenitor-specific regulatory element of the nestin gene. This allows for temporally regulated ablation of dividing neural progenitors by exposing the animal to ganciclovir. Using this line, I demonstrate that ablation of dividing GFP-expressing early neural progenitors in neurogenic areas occurs only in the presence of ganciclovir. CCI on these mice, reveals that no newly born Dcx-expressing late neural progenitors are observed seven days after injury when exposed to ganciclovir. However, the repopulation of Dcx-expressing cells is apparent when ganciclovir was removed one day before injury. Four weeks after injury, those newly born Dcx-expressing cells became mature NeuN-expressing neurons. This suggests that injury-induced activation of early neural progenitors is required for the recovery of injured hippocampal neurons.
URI: http://hdl.handle.net/2152.5/324
Date: 2008-09-19

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