Adult neurogenesis occurs in the subgranular zone (SGZ) of the hippocampal dentate gyrus generating new dentate granule neurons and can be induced with brain injury. Resident microglial cells and infiltrating macrophages produce inflammatory molecules in response to brain injury. While inflammation has been reported to be detrimental to hippocampal neurogenesis, other studies have suggested that the localized inflammatory response and stimulation of microglial cells can promote neurogenesis. The working hypothesis of this work was that activated resident microglia serve a supportive role during injury-induced neurogenesis in the hippocampus. To examine this hypothesis the hippocampal toxicant, trimethyltin was used (TMT; 2.3mg/kg, ip), to selectively target dentate granule cell death in adolescent and 1 year-old CD-1 male mice. mRNA of pro-inflammatory M1 markers and anti-inflammatory M2 genes were measured during the temporal injury response were measured in the subdissected DG. Within 2 d post-TMT, neuronal death was accompanied by resident microglia activation in the absence of infiltrating peripheral macrophages, and elevations in mRNA expression of M1 markers interleukin (IL)-1&agr;, IL-1β, IL-6 and tumor necrosis factor alpha (TNF&agr;). 5-bromo-2'-deoxyuridine (BrdU) incorporation identified the peak time of neurogenesis as coinciding with this upregulation of M1 markers. At 14 d post-TMT new cells migrated to the GCL expressed the mature neuronal marker (NeuN). At this time of differentiation increased expression of the M2 markers IL-1 receptor antagonist (IL-1Ra), arginase 1 (AG-I), chitinase 3-like-3 (YM-1), brain derived neurotrophic factor (BDNF), glial cell line derived growth factor (GDNF), and nerve growth factor (NGF). The proliferative response was sufficient to fully repopulate neurons in the GCL and provide functional recovery. The neurogenic response to injury differs with age. In this model, fewer BrdU+ NPC were observed in naive and injured adult hippocampus as compared to the corresponding number seen in adolescent mice. At 2 d post-TMT, a similar level of neuronal death was observed across ages, yet activated amoeboid microglia were observed in the adolescent and hypertrophic process-bearing microglia in the adult. IL-1α mRNA levels were elevated in the adolescent hippocampus; IL-6 mRNA levels were elevated in the adult. In subgranular zone (SGZ) isolated by laser-capture microdissection, IL-1β was detected but not elevated by TMT, IL-1&agr; was elevated at both ages, while IL-6 was elevated only in the adult. Naïve NPCs isolated from the hippocampus expressed transcripts for IL-1R1, IL-6R&agr;, and gp-130 with significantly higher levels of IL-6R&agr; mRNA in the adult. In vitro, IL-1&agr; (150pg/ml) stimulated proliferation of adolescent NPCs; IL-6 (10ng/ml) inhibited proliferation of adolescent and adult NPCs. Microarray analysis of SGZ post-TMT indicated a prominence of IL-1&agr;/IL-1R1 signaling in the adolescent and IL-6/gp130 signaling in the adult.
|Advisor:||Harry, Gaylia J.|
|Commitee:||Bouldin, Thomas W., Crews, Fulton T., Kleeberger, Steven R., Matsushima, Glenn K.|
|School:||The University of North Carolina at Chapel Hill|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 73/09(E), Dissertation Abstracts International|
|Subjects:||Neurosciences, Toxicology, Surgery|
|Keywords:||Adult neurogenesis, Aging, Brain injury, Hippocampus, Inflammation, Microglia|
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