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Title: Ghrelin-axis function in the context of adult hippocampal neurogenesis
Author: Hornsby, Amanda K. E.
ISNI:       0000 0004 7967 439X
Awarding Body: Swansea University
Current Institution: Swansea University
Date of Award: 2018
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The dentate gyrus (DG) is a neurogenic niche in the adult mammalian brain where new neurones are formed from neural stem/progenitor cells (NSPCs) throughout life. These adult born neurones play a key role in learning and memory, however, this process is not fully understood. Calorie restriction (CR) has been shown to modulate the DG and improve cognition albeit via unknown mechanisms. The gut hormone ghrelin, which is acylated by Ghrelin-O-acyl transferase (GOAT), is elevated during CR and travels via the blood to the brain where it binds to its receptor, GHSR, in several sites, including the hippocampus. We show that acyl-ghrelin significantly increases adult hippocampal neurogenesis (AHN) in the DG. Immunofluorescent analysis of adult male GHSR-eGFP mice showed no GHSR expression in Sox2+, Nestin+ or Ki67+ NSPCs in the DG, but confirmed high expression on mature DG NeuN+ cells, suggesting a non-cell autonomous mechanism of action. Following this, we show that CR enhances AHN in wild-type but not GHSR-KO mice, demonstrating that CR induces AHN in a GHSR-dependant manner. To determine whether un-acylated ghrelin treatment negatively affects AHN, wild-type and GOAT-KO mice, which have an absence of circulating acyl-ghrelin, were treated with either vehicle or unacylated-ghrelin. Wild-type mice treated with un-acylated ghrelin showed a significant reduction in proliferating (Ki67+) cells and immature (DCX+) neurones in the subgranular zone of the DG. Similarly, neurogenesis was impaired in GOAT-KO mice. Lastly, to determine whether our rodent work was relevant to humans, circulating acyl-ghrelin was quantified in patients diagnosed with Parkinson's disease dementia (PDD). Notably, fasted and post-prandial plasma acyl-ghrelin levels were significantly reduced in PDD patients relative to healthy age-matched controls. In summary, the results from this thesis suggest that acyl-ghrelin may be a biomarker for dementia, shown in PDD, and that elevating circulating acyl-ghrelin or reducing unacylated-ghrelin represents a novel therapeutic approach for preventing the decline in AHN.
Supervisor: Davies, Jeffrey S. ; Thornton, Catherine A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral