UBC Theses and Dissertations
Hippocampal neurogenesis and the entorhinal-dentate gyrus circuit under healthy and pathological conditions Ash, Alyssa
Adult hippocampal neurogenesis involves the addition of new neurons in the dentate gyrus (DG) region beyond the developmental period, creating adult-born neurons that exhibit different intrinsic properties and plasticity than the older developmental population. Afferent connectivity differs between adult-born and developmentally-born neurons (ABNs/DBNs), with maturing ABNs mainly receiving lateral entorhinal cortex (LEC) input, while DBNs receive inputs from both LEC and MEC. The LEC is implicated in early stages of Alzheimer’s disease (AD), with hallmark tau protein pathology developing here before progressing downstream to the DG and other regions. We sought to examine how adult-born neurons interact with other neurons in the DG during learning under healthy conditions and explore how tau pathology in the LEC affects memory performance and downstream DG neurons of different ages. In chapter 2, we examine the impact of silencing a fraction of the ABN population on DG activity using an inhibitory chemogenetic approach during spatial learning in the Morris Water Maze. We found that silencing ABNs led to an increase in activity in the DBNs via labelling with a DNA marker bromodeoxyuridine (BrdU) and immediate early gene Fos. Silencing ABNs did not alter activity in other ABNs nor in inhibitory interneurons. These data indicate that ABNs can exert inhibition during learning on the developmental population, likely through direct monosynaptic connections from ABNs to DBNs. In chapter 3, we explore the impact of tau pathology in the LEC-DG circuit on memory performance and ABNs and DBNs respective structure and function. By injecting a virus that overexpresses human tau into a transgenic mouse with inducible florescent labelling of DBNs and ABNs, we found that tau pathology led to disrupted object recognition memory and altered morphology of ABNs and DBNs similarly. Overall, our data show that manipulating the ABN population can impact overall DG activity, and under a disease model, both ABNs and DBNs are similarly vulnerable to pathological insult. These findings provide insight into the impact of neurogenesis on hippocampal activity and provide evidence for synaptic changes at a circuit-level model of disease that could ultimately be targeted for early intervention before further disease progression.
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