Characterization of the Neurogenic Microenvironment in the Mouse Hippocampus Following Chemical-Induced Neuronal Injury Public Deposited

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  • March 22, 2019
  • McPherson, Christopher A.
    • Affiliation: School of Medicine, Curriculum in Toxicology
  • Adult neurogenesis occurs in the subgranular zone (SGZ) of the hippocampal dentate dyrus generating new dentate granule neurons and can be induced with brain injury. Resident microglia 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 neurogensis. The working hypothesis of this work was that activated resident mircroglia serve a supportive role during injury-induced neurogenesis in the hippocampus. To examine this hypothesis the hippocampal toxicant, trimethyltin was used (TMT; 2.3 mg/kg, i.p.) to selectively target dentate granule cell death in adolescent and 1 year-old CD-1 male mice. mRNA of proinflammatory M1 markers and anti-inflammatory M2 genes were measured during the temporal injury response were measured in subdissected DG. Within 2 d post- TMT, neuronal death was accompanied by resident microglia activation in the abscence of infiltrating peripheral macrophages, and elevations in mRNA expression of M1 markers interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosiss factor alpha (TNFα). Bromodeoxyuridine (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+ NPCs 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 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 the SGZ isolated by laser capture microdissection, IL-1β was detected but not elevated bby TMT, IL-1α was elevated at both ages, while IL-6 was elevated only in the adult. Naive NPCs isolated from the hippocampus expressed transcripts for IL-1R1, IL-6Rα, and gp-130 with significantly higher levels of IL-6Rα mRNA in the adult. In vitro, IL-1α (150 pg/ml) stimulated proliferation of adolescent and adult NPCs. Microarray analysis of the SGZ post-TMT indicated a prominence of IL- 1α/IL-1R1 signaling in the adolescent and IL-6/gp130 signaling in the adult.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Toxicology
  • Harry, G. Jean

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