Anhedonia and Resilience Mechanisms in Chronic Stress-Induced Depression
- Title
- Anhedonia and Resilience Mechanisms in Chronic Stress-Induced Depression
- Alternative Title
- 만성 스트레스 유발 우울증에서 무쾌감증과 탄력성 기전
- Author(s)
- Jeongseop Kim
- DGIST Authors
- Jeongseop Kim ; Yong-Seok Oh ; Ja Wook Koo
- Advisor
- 오용석
- Co-Advisor(s)
- Ja Wook Koo
- Issued Date
- 2023
- Awarded Date
- 2023-08-01
- Type
- Thesis
- Description
- Major depression disorders; chronic stress; Synaptotagmin-4; Metabotropic glutamate receptor 5
- Abstract
-
우울증은 다양한 증상을 나타내는 복잡하고 치료가 어려운 정신 건강 장애로 알려져 있습니다. 현재 사용되는 우울증 치료는 효과적이지만 효과를 보기까지 시간이 소요되고 모든 환자에게 효과가 있는 것은 아닙니다. 또한, 일부 치료는 원치 않는 부작용을 유발할 수 있어 더 효과적인 치료 방법의 필요성이 강조되고 있습니다. 이에 따라, 현재 연구는 우울증의 생물학적 및 환경적 요인을 식별하고, 기존 치료에 반응하지 않는 환자들을 위한 새로운 치료 방법을 탐구하고자 합니다. 만성 스트레스에 의한 우울증 유사 증상은 인간과 동물 모델에서 연구되어 왔습니다. 그러나 스트레스에 취약한 그룹과 그렇지 않은 그룹을 단순히 분류하는 것만으로는 우울증의 다양한 행동 형질을 설명하기에는 충분하지 않습니다. 따라서, 이러한 행동들을 구별하고 그들의 근본적인 신경 연관성을 연구하여 특이한 치료 개입을 찾는 것이 중요합니다. 또한, 이전 연구에서는 사회적 회피와 쾌감 상실과 같은 우울증 유사 행동이 여러 뇌 지역에서 활동이 변경된다는 것이 밝혀졌습니다. 그러나 스트레스에 취약한 그룹은 인지 기능 상의 장애를 나타내는 반면, 스트레스에 강한 그룹은 그렇지 않은 것으로 여전히 논란이 되고 있습니다. 이는 인지 기능 결함이 있는 우울증의 병리 생리학을 더 잘 이해하기 위해 다른 동물 모델을 탐구할 필요성을 시사합니다. 이 연구에서는 만성 사회적 패배 스트레스와 만성 불규칙 스트레스라는 두 가지 동물 모델을 활용하여 우울증의 스트레스-예민군과 저항성 군을 구분하고, 이들이 감정 및 인지적 행동에서 차이가 있는지 조사하였습니다. 또한, 만성 스트레스 유발 우울증에서 무기력 반응의 분자 메커니즘을 조사하여, 만성 스트레스 유발 무기력 반응과 관련된 시냅토태그민-4(SYT4)이 뇌유도 신경영양인자(BDNF)-트로포미오신 수용체 키나아제 B(TrkB) 신호의 감소와 연관되는 것을 발견하였습니다. 더 나아가, 만성 사회적 패배 스트레스 저항성에 중요한 매트로포트릭 글루타메이트 수용체 5(mGluR5)가 회로 별 하향 신호전달을 촉진하여 저항성을 촉진한다는 것을 확인하였습니다. 이러한 연구 결과는 만성 스트레스로 인한 무쾌감 반응의 잠재적 규제 기전을 밝히고, 우울감 유사한 사회적 장애에 대한 회로 별 하향 신호전달을 강조합니다.|Major depression disorder (MDD) is a complex and debilitating mental health disorder that manifests through a wide range of symptoms, including a persistent and intense low mood, suicidal thoughts, slowed or agitated movements, decreased motivation, hopelessness, and a loss of pleasure in previously enjoyed activities. While current medical therapies for depression can be effective, they often require a significant amount of time to take full effect and may not work for everyone. Additionally, some treatments can produce unwanted side effects, emphasizing the need for a more comprehensive understanding of depression’s underlying causes and more effective treatments. As such, ongoing research is focused on identifying the biological and environmental factors that contribute to depression, as well as exploring new and innovative therapies that can offer hope to patients who have not responded to traditional treatments.
Depressive-like symptoms caused by chronic stress in humans have been extensively studied, and animal models have been developed to assess experimentally induced depressive-like behaviors. However simply categorizing animals into stressed and non-stressed groups is insufficient to explain the various behavioral phenotypes of depression. Differentiating between these behaviors is crucial in studying their underlying neural correlates and finding symptoms-specific therapeutic interventions. Additionally, previous studies have shown that depressive behaviors, such as social avoidance and anhedonia, are associated with altered activity in several brain regions, such as the prefrontal cortex (PFC) and hippocampus (HPC). However, it is still debated whether the stress-susceptible group exhibits cognitive impairment, while the resilient group does not, despite cognitive deficits being core symptoms in MDD patients. Therefore, it may be necessary to explore other animal models to better understand the pathophysiology of depression with cognitive impairment.
In this study, we utilized two animal models of depression to distinguish between stress-susceptible and resilient groups based on the sequence of depressive-like behaviors. Chronic social defeat stress, which involves social violence, and chronic unpredictable stress, which involves persistent mental stress, were used for this purpose. Our aim was to investigate whether the stress-susceptible group exhibited differences in emotional and cognitive behavior compared to the resilient group. Also, we investigated the molecular mechanisms of anhedonic responses in chronic stress-induced depression and found that synaptotagmin-4 (SYT4) in the medial prefrontal cortex (mPFC) is implicated in chronic stress-induced anhedonia through reduction of brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling. We also identified metabotropic glutamate receptor 5 (mGluR5) as a critical mediator of stress resilience, promoting resilience to chronic social defeat stress through circuit-specific downstream signaling in the mPFC and ventral hippocampus (vHPC). These findings shed light on potential regulatory mechanisms of anhedonic susceptibility to chronic stress and highlight circuit-specific downstream signaling for depressive-like social impairment.
- Table Of Contents
-
Chapter 1. Background 1
1. Major depressive disorder (MDD) 1
1.1 Caused of depression: Hereditary or Environmental factor 2
1.2 Stress and Depression: unpacking the complex relationship 4
1.2.1 The dual nature of stress: Protective or Harmful 4
1.3 Decoding heterogeneity in stress response: Insight from animal models 6
1.3.1 Individual differences in stress response 6
1.3.2 Animal Models for Depression Research: Transitioning from an Acute Stress Paradigm to a Chronic Stress Model 7
1.3.3 Animal Models for Depression Research: Transitioning from an Acute Stress Paradigm to a Chronic Stress Model 9
1.4 Stress and Depression: Brain’s circuitry 13
1.4.1 Brain imaging studies 13
1.4.2 Default mode network 14
1.4.3 Default mode circuit disruptions in depression and anxiety 14
1.4.4 In vivo imaging of neurotransmission in MDD 16
1.5 Glutamate dysregulation in MDD 18
Chapter 2. The Interplay of Stress, Depression, and Cognitive Dysfunction 21
2.1. INTRODUCTION 21
2.2. MATERIALS AND METHODS 24
2.2.1 Experimental Animal 24
2.2.2 Chronic unpredictable stress and subthreshold unpredictable stress 25
2.2.3 Two bottle Sucrose preference test 27
2.2.4 Forced swim test 27
2.2.5 Elevated Plus-maze 28
2.2.6 Novelty suppressed feeding 28
2.2.7 Three-chamber sociability and novelty test 29
2.2.8 Stereotaxic surgery, cannula implantation, and micro-infusions 30
2.2.9 Optogenetic manipulation 31
2.2.10 Tamoxifen injection 31
2.2.11 RNA extraction and quantitative Real-time PCR 32
2.2.12 Immunofluorescence and c-Fos+ cell counting 33
2.2.13 Western blot analysis 33
2.2.14 Clustering analysis 34
2.2.15 RNA sequencing 34
2.2.16 Weighted gene co-expression network analysis 35
2.2.17 DATA analyses and statistics 38
2.3. RESULTS 39
2.3.1 Chronic unpredictable stress triggers diverse depression-like behaviors 39
2.3.2 Anhedonic behaviors can distinguish susceptible and resilient subtypes in depression 44
2.3.3 mPFC is the most associated with anhedonic behaviors 59
2.3.4 Transcriptional patterns differ based on the severity of anhedonia following CUS 64
2.3.5 Pro-susceptible role of SYT4 in anhedonia responses 71
2.3.6 SYT4 plays a role in the development of depression by contributing to the BDNF-TrkB pathway 79
2.4. DISCUSSION 88
Chapter 3. Glutamate and Stress Susceptibility 92
3.1. INTRODUCTION 92
3.2. MATERIALS AND METHODS 94
3.2.1 Experimental Animals 94
3.2.2 Chronic Social Defeat Stress (CSDS) 94
3.2.3 Subthreshold Social Defeat Stress (SSDS) 95
3.2.4 Social Interaction Test (SIT) 95
3.2.5 Sucrose Preference Test (SPT) 96
3.2.6 Viral injection 96
3.2.7 Optogenetics Manipulation 97
3.2.8 Cannula implantation and Microinfusion 98
3.2.9 Ex vivo Electrophysiology 98
3.2.10 Immunofluorescence and Cell counting 100
3.2.11 RNA extraction and quantitative Real-time PCR 101
3.2.12 Western blot 102
3.2.13 Statistical Analysis 102
3.3. RESULTS 108
3.3.1 CSDS reduce cell activity in BLA projection neurons 108
3.3.2 Stimulation of BLA-projecting neurons rescues CSDS-induced social avoidance 128
3.3.3 Inhibition of BLA-projecting neurons has pro-depressive like effects 136
3.3.4 Functional independence of the BLA projections in depressive-like behaviors 139
3.3.5 Pro-resilient role of mGluR5 in behavioral responses to CSDS 144
3.3.6 Pharmacological modulation of mGluR5 downstream signaling affects depressive-like behaviors 151
3.4. DISCUSSION 158
Chapter 4. Conclusion 162
Reference 165
Summary in Korean 181
- URI
-
http://hdl.handle.net/20.500.11750/46381
http://dgist.dcollection.net/common/orgView/200000685368
- Degree
- Doctor
- Department
- Department of Brain Sciences
- Publisher
- DGIST
- Related Researcher
-
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Oh, Yong-Seok
- Research Interests Monoaminergic regulation of the CNS and mood;anxiety disorder; 모노아민 (세로토닌; 도파민)에 의한 신경조절과 기분;불안 장애 기전 연구
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