系統識別號 U0026-2406201416592900
論文名稱(中文) 探討壓力對於海馬迴神經突觸可塑性以及新生神經細胞之影響
論文名稱(英文) The study of stress on hippocampal synaptic plasticity and adult neurogenesis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 陳建仲
研究生(英文) Chien-Chung Chen
學號 S58971471
學位類別 博士
語文別 英文
論文頁數 97頁
口試委員 指導教授-許桂森
中文關鍵字 壓力,海馬迴  突觸可塑性  神經新生 
英文關鍵字 Stress  hippocampus  Synaptic plasticity  Neurogenesis 
中文摘要 不論是動物實驗或者臨床研究已經有許多的證據顯示充滿壓力的生活因子會對於認知功能以及行為表現產生嚴重的影響,而在海馬迴神經細胞本身神經突觸可塑性所產生的影響,然而對於其中細胞以及分子機制的改變至今仍然不清楚。因此我們研究了對於壓力敏感的海馬迴三突觸循環結構中的調控者,其中苔狀纖維(mossy fiber)是一個具有特殊分子機制以及高可塑性的一部分,當一個無法預測的急性壓力,會造成一個明顯的苔狀纖維長期增益現象(LTP)的抑制,並且發現,主要是因為壓力所促進了環腺苷酸(cAMP)專一的磷酸二酯酶(PDE4)的活性所造成的。
而慢性壓力的暴露則會抑制神經新生作用,但是對於其發育過程的影響卻仍然未知的,因此我們試著透過慢性社會壓力 (CSDS) 模式,並且利用反轉錄病毒標記新生神經細胞來研究各個時期的發育,去探討壓力對於發育過程的型態以及電生理特性的成熟化所造成的影響。我們所使用的C57BL/6小鼠可根據其行為模式的表現以區分為耐受性高以及耐受性低的組別,而兩組老鼠也在尾巴懸吊測試以及糖水偏好測試相對表現了不同程度的憂鬱行為。不過令人意外的是,這兩組小鼠在於新生神經細胞的存活率以及樹突複雜程度的表現卻不若行為一般有差異,同樣受到抑制,不過並沒有影響新生神經細胞在顆粒細胞層的分布。反轉錄病毒所標記的不同時間點的新生神經細胞,其基礎電生理活性並不會受到壓力刺激所影響,不過我們觀察到了一種對於其N-甲基-D-天冬氨酸受體 (NMDAR) 在發育過程中,由含有2B型態轉換為含有2A型態的加速過程,其中對於細胞表現長期增益現象 (LTP) 的表現具有非常大的影響。更進一步我們透過調控神經限制因子 (REST) 去改變這種受體轉換的過程,而了解慢性壓力刺激會改變新生神經細胞成熟的過程,透過這種神經限制因子的表現,而在壓力刺激下生存下來。
英文摘要 More evidence from animal and human study indicates that stressful life event may result in massive influence on cognitive function and behavior change based on the synaptic plasticity of hippocampus. However the underlying cellular and molecular mechanism by which stress exerts it effects on behavior remain unclear. Here we demonstrate several key regulator of hippocampal trisynaptic circuit which is sensitive to stress response. The mossy fiber synapse onto hippocampal CA3 neurons shows unique molecular features and a wide dynamic range of plasticity. An acute unpredictable and inescapable restraint tail-shock stress showed a marked impairment of long-term potentiation (LTP) expression in this region through a interruption of a cAMP-specific PDE4 activity.
Chronic stress has been found to suppress adult neurogenesis, and we examined the influence of chronic social defeat stress (CSDS) on the morphological and electrophysiological properties of retrovirally-labeled adult-born dentate granule cells (DGCs) at different maturation stages. Our results confirm that C57BL/6 inbred mouse strain subjected to CSDS can be separated into susceptible and unsusceptible subpopulations that displayed different levels of depressive-like behaviors but identical reductions in the survival and dendritic complexity of adult-born DGCs. Combining electrophysiology with retrovirus- mediated birthdating and labeling, we find that although CSDS does not alter the intrinsic electrophysiological properties and synaptic transmission of surviving adult-born DGCs, it accelerates the developmental switch of synaptic N-methyl-D- aspartate receptors (NMDARs) from predominance of GluN2B- to GluN2A- containing receptors, which, in turn, transforms the immature synapse of adult-born DGCs from one that exhibits enhanced LTP to one in which has normal levels of LTP. Furthermore, knockdown of the repressor element 1 silencing transcription factor (REST) in adult-born DGCs prevented CSDS-induced accelerated developmental switch of NMDAR subunit composition. Together, these results reveal a novel role for CSDS in regulating adult neurogenesis and suggest that CSDS may accelerate the rate of maturation of surviving adult-born DGCs through the expression of REST to overcome the neurotoxic effect.
論文目次 摘要‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧I
List of figures‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧IX
Chapter I:Introduction‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧1
1.1 Acute stress and chronic stress
1.2 Hypothalamic-pituitary-adrenal axis
1.3 Stress and synaptic plasticity in hippocampus
1.4 Stress and adult neurogenesis
1.5 Adult neurogenesis and neuronal plasticity
1.6 N-Methyl-D-aspartate receptor in neuronal maturation
1.7 Repressor element 1 silencing transcription factor (REST) in adult neurognesis regulation
1.8 Specific aims
Chapter II:Materials and methods‧‧‧‧‧‧‧‧‧‧9
2.1 Animal
2.2 Stress protocol
2.2.1 Acute stress
2.2.2 Chronic social defeat stress
2.3 Adrenalectomy and corticosterone replacement
2.4 Plasma corticosterone assay
2.5 Behavioral test
2.5.1 Tail suspension test
2.5.2 Sucrose preference test
2.5.3 Contextual discrimination fear conditioning between contexts
2.6 cAMP assay
2.7 Phosphodiesterase activity assay
2.8 BrdU labeling newborn neurons
2.9 Retrovirus production, stereotaxic injection and analysis
2.10 Electrophysiological recordings
2.10.1 Extracellular recordings
2.10.2 Whole-cell patch-clamp
2.11.1 Preparation of synaptosomes
2.12 Pharmacological drugs
2.13 Statistical analysis
Chapter III:Results‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧22
3.1 Effects of stress on mossy fiber synaptic transmission and frequency facilitation
3.2 Stress impairs mossy fiber LTP
3.3 Putative mechanisms of the effect of stress on mossy fiber LTP
3.4 Stress increases PDE4 activity to enhance cAMP degradation
3.5 Individual differences in responses to CSDS
3.6 CSDS reduces survival of adult-born DGCs in both susceptible and unsusceptible mice
3.7 Contextual discrimination is impaired in CSDS mice for a highly similar context pair
3.8 CSDS alters dendritic morphogenesis of adult-born DGCs in both susceptible and unsusceptible mice
3.9 CSDS facilitates the developmental switch in synaptic plasticity of adult-born DGCs
3.10 CSDS reduces synaptic GluN2B subunit expression in adult-born DGCs via an REST-dependent mechanism
Chapter IV:Discussion‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧40
4.1 The effect of acute stress on hippocampal CA3 synaptic plasticity through regulate PDE4 activity
4.2 Chronic social defeat stress alters the maturation stage of adult neurogenesis through a REST dependent regulation
Chapter V:Conclusion‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧48
Chapter VI:Figures and ledgends‧‧‧‧‧‧‧‧‧‧52
Chapter VII:References‧‧‧‧‧‧‧‧‧‧‧‧‧‧83
Chapter VIII:Publications‧‧‧‧‧‧‧‧‧‧‧‧‧97
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