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Molecular mechanisms of stress-induced autophagic death in adult hippocampal neural stem cells

Title
Molecular mechanisms of stress-induced autophagic death in adult hippocampal neural stem cells
Translated Title
스트레스에 의한 성체해마신경줄기세포의 자가포식사멸 규명 및 관련 분자기전 연구
Authors
Seonghee Jung
DGIST Authors
Jung, Seonghee; Lim, Hyun-Ho; Yu, Seong-Woon
Advisor(s)
유성운
Co-Advisor(s)
Hyun-Ho Lim
Issue Date
2020
Available Date
2020-06-23
Degree Date
2020-02
Type
Thesis
Description
adult hippocampal neural stem cells, chronic stress, autophagic cell death, p53
Table Of Contents
Ⅰ. General Introduction 1 1.1 Adult Neural Stem Cells 1 1.2 Programmed Cell Death 4 1.2.1 Apoptosis 4 1.2.2 Necroptosis 4 1.2.1 Autophagic Cell Death 5 1.3 Autophagy 5 1.3.1 Autophagy dependent cell death 6 1.3.2 Autophagic cell death in hippocampal neural stem cells 7 1.4 Stress 8 1.4.1 Stress and Neurogenesis 9 ⅠI. General Materials and Methods 12 2.1 Animals and CRS procedures 12 2.2 CORT injection 12 2.3 BrdU injection 12 2.4 CORT measurement 13 2.5 Constructs and virus production 13 2.6 Neurosphere assay 13 2.7 Generation of KO or stable knockdown HCN cells 14 2.8 Electron microscopy 14 2.9 Sucrose preference test 15 2.10 Stereotaxic injection 15 2.11 Cell culture 15 2.12 Cell Death Assay 16 2.13 Western Blotting Analysis 16 2.14 Immunofluorescence staining 16 2.15 Stereological cell counting 17 2.16 Elevated Plus Maze Test 17 2.17 Open Field Test 17 2.18 Y-Maze Test 17 2.19 Morris Water Maze Test 18 2.20 Hippocampus tissue lysis 18 2.21 Plasmids and transfection 18 2.22 In situ hybridization 19 2.23 LABORAS test (automated 24-h movement analysis) 19 2.24 Nest building test 19 2.25 Quantitative Real-Time PCR (qRT-PCR) 20 2.26 Co-immunoprecipitation 20 2.27 Statistical analysis 20 ⅠII. Autophagic death of neural stem cells mediates chronic stress-induced decline of adult hippocampal neurogenesis and cognitive deficits 21 3.1 Introduction 21 3.2 Results 22 3.2.1 Adult hippocampal NSCs are protected from chronic restraint stress (CRS) in Atg7-NSC cKO mice 22 3.2.2 CRS-induced autophagy is blocked in Atg7-NSC cKO mice 25 3.2.3 Suppression of neurogenesis and cognitive deficits induced by CRS are prevented in Atg7-NSC cKO mice 29 3.2.4 Loss of NSCs activity after CRS is blocked by autophagy deficiency 32 3.2.5 Chronic CORT injection-induced autophagy is blocked in Atg7-NSC cKO mice 34 3.2.6 CORT induces ACD, but not apoptosis or necroptosis 38 3.2.7 SGK3 is a critical mediator of CORT-induced ACD in HCN cells 44 3.2.8 Deletion of SGK3, but not SGK1, blocks CRS-induced HCN cell death in vivo 48 ⅠV. Cytosolic p53 protects hippocampal neural stem cells and cognitive functions from chronic stress by blocking autophagic cell death. 50 4.1 Introduction 50 4.2 Results 51 4.2.1 High Expression Level of Endogenous p53 in hippocampal NSCs. 51 4.2.2 p53 KO mice is sensitive to stress and induces anxiety like behavior and cognitive deficits. 53 4.2.3 Degradation of p53 by Autophagy 55 4.2.4 Cytosolic p53 protects HCN cells from CORT-induced ACD 57 4.2.5 Specific p53 activator, RITA prevents CORT-induced cell death and stress in-duced cognitive and mood deficits 59 V. Pro-survival roles of cytosolic p53 in adult hippocampal neural stem cells 62 5.1 Introduction 62 5.2 Results 62 5.2.1 Degradation of p53 by Autophagy Following Insulin Withdrawal 62 5.2.2 Endogenous p53 is Transcriptionally Inactive and is Located in the Cytosol of HCN Cells 65 5.2.3 Different Localization of p53 Depending on Cell Type and Change in p53 Locali-zation during Differentiation of HCN Cells 68 5.2.4 Cytosolic p53 Protects HCN Cells from Insulin Withdrawal and Apoptotic Stress. 70 5.2.5 Interaction of p53 with GSK-3β 72 VI. General Discussion 76 Reference Summary (국문요약)
URI
http://dgist.dcollection.net/common/orgView/200000282134
http://hdl.handle.net/20.500.11750/11952
DOI
10.22677/Theses.200000282134
Degree
Doctor
Department
Brain and Cognitive Sciences
University
DGIST
Related Researcher
  • Author Yu, Seong-Woon Laboratory of Neuronal Cell Death
  • Research Interests Molecular mechanisms of neuronal cell death and neurodegeneration
Files:
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Collection:
Department of Brain and Cognitive SciencesThesesPh.D.


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