Spontaneous injury-induced hippocampal neurogenesis following kainic acid-mediated neurodegeneration and its effects on cognitive function

Abstract

Adult mammalian neurogenesis occurs throughout life within two discrete brain regions; subventricular zone (SVZ) and subgranular zone (SGZ). Acute brain insults are associated with spontaneous increases in neurogenesis. This has been observed in both the SVZ and SGZ, as well as non-neurogenic regions. In some cases, this neurogenic response has been linked to cognitive recovery, although a direct functional relationship between injury-induced neurogenesis and cognitive recovery remains to be elucidated. The present work aimed to explore the functional relevance of spontaneous injury-induced neurogenesis in relation to recovery of hippocampal-dependent memory functions following acute brain injury. The kainic acid (KA) model of acute excitotoxic injury is a widely used model of acute neurodegeneration. Increases in SGZ neurogenesis have been well documented to occur following KA-induced injury, while evidence of neurogenesis occurring outside the SGZ is sparse. Prior work by our group had established the occurrence of neurogenesis in discrete non-neurogenic hippocampal regions; CA1 and CA3. However, several questions have remained, such as where the newborn cells are initially generated and whether or not they functionally integrate into existing circuits. In our efforts to establish a reproducible model of KA-induced hippocampal neurodegeneration that facilitated subsequent neuronal repopulation, we investigated the impact of several variables that may have been affecting the inconsistencies we observed in our initial attempts to reproduce the model. In parallel, we investigated the origin and functional significance of the KA-induced neurogenic response previously observed by our group. Lastly, we undertook histopathological analyses of the APPswe/PS1ΔE9 mouse model of Alzheimer’s disease (AD), a neurodegenerative disease where neurogenesis appears dysregulated, and established a baseline phenotype for future investigations into dysregulation of neurogenesis in AD.