No Cover Image

E-Thesis 306 views 213 downloads

Ghrelin-axis function in the context of Adult Hippocampal Neurogenesis / Amanda K. E. Hornsby

DOI (Published version): 10.23889/Suthesis.50587

Abstract

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)...

Full description

Published: 2018
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa50587
Tags: Add Tag
No Tags, Be the first to tag this record!
first_indexed 2019-06-05T11:07:53Z
last_indexed 2019-10-21T16:56:21Z
id cronfa50587
recordtype RisThesis
fullrecord <?xml version="1.0"?><rfc1807><datestamp>2019-06-06T16:43:45.7044512</datestamp><bib-version>v2</bib-version><id>50587</id><entry>2019-05-31</entry><title>Ghrelin-axis function in the context of Adult Hippocampal Neurogenesis</title><swanseaauthors/><date>2019-05-31</date><abstract>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&#x2019;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.</abstract><type>E-Thesis</type><journal/><publisher/><keywords/><publishedDay>31</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2018</publishedYear><publishedDate>2018-12-31</publishedDate><doi>10.23889/Suthesis.50587</doi><url/><notes>A selection of third party content is redacted or is partially redacted from this thesis.</notes><college>COLLEGE NANME</college><CollegeCode>COLLEGE CODE</CollegeCode><institution>Swansea University</institution><degreelevel>Doctoral</degreelevel><degreename>Ph.D</degreename><apcterm/><lastEdited>2019-06-06T16:43:45.7044512</lastEdited><Created>2019-05-31T14:07:02.6761337</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Amanda K. E.</firstname><surname>Hornsby</surname><order>1</order></author></authors><documents><document><filename>0050587-31052019142233.pdf</filename><originalFilename>Hornsby_Amanda_K_E_PhD_Thesis_Final_Redacted.pdf</originalFilename><uploaded>2019-05-31T14:22:33.4470000</uploaded><type>Output</type><contentLength>82900697</contentLength><contentType>application/pdf</contentType><version>Redacted version - open access</version><cronfaStatus>true</cronfaStatus><embargoDate>2019-05-30T00:00:00.0000000</embargoDate><copyrightCorrect>true</copyrightCorrect></document></documents><OutputDurs/></rfc1807>
spelling 2019-06-06T16:43:45.7044512 v2 50587 2019-05-31 Ghrelin-axis function in the context of Adult Hippocampal Neurogenesis 2019-05-31 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. E-Thesis 31 12 2018 2018-12-31 10.23889/Suthesis.50587 A selection of third party content is redacted or is partially redacted from this thesis. COLLEGE NANME COLLEGE CODE Swansea University Doctoral Ph.D 2019-06-06T16:43:45.7044512 2019-05-31T14:07:02.6761337 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Amanda K. E. Hornsby 1 0050587-31052019142233.pdf Hornsby_Amanda_K_E_PhD_Thesis_Final_Redacted.pdf 2019-05-31T14:22:33.4470000 Output 82900697 application/pdf Redacted version - open access true 2019-05-30T00:00:00.0000000 true
title Ghrelin-axis function in the context of Adult Hippocampal Neurogenesis
spellingShingle Ghrelin-axis function in the context of Adult Hippocampal Neurogenesis
,
title_short Ghrelin-axis function in the context of Adult Hippocampal Neurogenesis
title_full Ghrelin-axis function in the context of Adult Hippocampal Neurogenesis
title_fullStr Ghrelin-axis function in the context of Adult Hippocampal Neurogenesis
title_full_unstemmed Ghrelin-axis function in the context of Adult Hippocampal Neurogenesis
title_sort Ghrelin-axis function in the context of Adult Hippocampal Neurogenesis
author ,
author2 Amanda K. E. Hornsby
format E-Thesis
publishDate 2018
institution Swansea University
doi_str_mv 10.23889/Suthesis.50587
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description 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.
published_date 2018-12-31T04:02:05Z
_version_ 1763753198521155584
score 11.013776

Similar Items