Title Page
Contents
ABSTRACT 13
I. INRODUCTION 15
1. Stress and brain plasticity 15
A. Historical overview of stress concept 16
B. Stress responses in the brain 19
2. Neurobiology of depression 20
A. Diagnosis and current antidepressant treatments 20
B. The relationship between stress and depression 22
C. Animal models of depression 23
D. Hypothetical brain mechanisms of depression 25
3. Posttraumatic stress disorder(PTSD) 27
A. Neural substrates underlying pathological fear responses 28
B. Animal models of PTSD 29
C. Comorbidity of depression and PTSD 29
4. Stress resilience 30
A. Hypothalamus-pituitary-adrenal(HPA) axis 30
B. Neuropeptide Y(NPY) 31
C. Noradrenergic and dopaminergic systems 31
D. Brain-derived neurotrophic factor(BDNF) 32
E. △FosB 32
5. mGluR5 and major depressive disorder 33
6. Aims of this study 35
II. MATERIALS AND METHODS 36
1. Animals 36
2. Drugs 36
3. Behavioral procedures 37
A. Stress based animal model of depression 1: Learned helplessness paradigm 37
B. Stress based animal model of depression 2: Social defeat stress paradigm 39
C. Stress based animal model of depression 3: Restraint stress and anhedonia 41
D. Stress based animal model of PTSD: Single intense footshock paradigm 42
E. Behavioral despair tests : Forced swim test and tail suspension test 44
4. Lentivirus generation for mGluR5 rescue 45
5. Stereotaxic injection and cannula implantation 47
6. Intracranial microinjection 48
7. Immunohistochemistry 48
8. Preparation of whole brain lysates and crude synaptosomal fractions 50
9. Brain dissection and immunoblotting 50
10. Statistical analysis 52
III. RESULTS 53
1. Analysis of synaptosomal protein expression and general behaviors 53
2. Pro-depressive behavioral phenotypes of mGluR5-/- mice after stress 55
3. Increased vulnerability to stress of mGluR5-/- mice in PTSD model 63
4. Activation of mGluR5 signaling decreased the helplessness behavior 65
5. MTEP treatment induced social avoidance in social defeat paradigm 67
6. mGluR5 in the nucleus accumbens was down-regulated by chronic stress 69
7. mGluR5 rescue in the nucleus accumbens shell promoted stress resilience 73
8. △FosB levels in nucleus accumbens were regulated by mGluR5 activity 77
IV. DISCUSSION 85
1. mGluR5 deletion, resilience, and stress-based model system 85
2. Nucleus accumbens mGluR5 and its effects on depressive-like behavior 90
3. Functional relationship between mGluR5 and △FosB 92
V. CONCLUSION 94
REFERENCES 95
ABSTRACT (IN KOREAN) 102
Table 1. Diagnostic criteria for depression (DSM-V) 22
Table 2. Criteria for the validity of animal models of depression 24
Table 3. Animal models or tests of depression 24
Figure 1. Social defeat stress paradigm 40
Figure 2. Restraint stress and anhedonia 42
Figure 3. Time schedule of single intense footshock stress model 43
Figure 4. Validation of mGluR5 expressing lentivirus and verification of injection sites 46
Figure 5. Basic characteristics of mGluR5-/- mice 54
Figure 6. Increased helplessness behavior after footshock stress mGluR5-/- mice 58
Figure 7. Defeat stress-induced social avoidance in mGluR5-/- mice 60
Figure 8. Reduction in sucrose preference after restraint stress in mGluR5-/- mice 62
Figure 9. Increased vulnerability to traumatic stress of mGluR5-/- mice in animal model of PTSD 64
Figure 10. mGluR5 positive allosteric modulator, CDPPB significantly reduced the helplessness behavior 66
Figure 11. mGluR5 antagonist, MTEP induced social avoidance 68
Figure 12. mGluR5 was highly expressed in the nucleus accumbens 70
Figure 13. 3-day defeat stress did not change mGluR5 expression levels in the nucleus accumbens 71
Figure 14. 12-day defeat stress reduced mGluR5 expression levels in the nucleus accumbens 72
Figure 15. Nucleus accumbens shell-specific expression of mGluR5 prevented social avoidance upon defeat stress in mGluR5-/- mice 75
Figure 16. NAc shell-specific expression of mGluR5 reversed the restraint stress-induced anhedonia in mGluR5-/- mice 76
Figure 17. Impaired induction of △FosB upon defeat stress in the nucleus accumbens of mGluR5-/- mice 80
Figure 18. Pharmacological modulation of mGluR5 activity affected △FosB induction levels 81
Figure 19. Normal expression levels of serum response factor(SRF), but increased c-fos levels upon defeat stress in mGluR5-/- mice 84
Figure 20. Increased immobility time of mGluR5-/- mice in the second day of forced swim test and tail suspension test 88