臺灣博碩士論文加值系統

在哺乳類動物中，適度的表現及控制情緒對生命的延續是很關鍵的。焦慮症是一種失常的情緒表現，與腦神經迴路中的興奮及抑制訊號失衡有關。近期的研究顯示，在腦中降低γ-氨基丁酸在神經迴路中的抑制作用及提升海馬回的活性常會伴隨過度焦慮之情緒反應。具體來說，調節海馬回中齒狀回的興奮性，可以調控個體的焦慮程度。苔狀細胞為位於齒狀回門區中的麩胺酸神經元(興奮性神經元)，會接受來自齒狀回中顆粒細胞的興奮性訊號，並透過回饋興奮及回饋抑制作用來調節顆粒細胞的活性。然而苔狀細胞的活性與個體焦慮程度間的相關性，以及苔狀細胞是透過何種神經機制將焦慮相關訊息傳遞到其他海馬回次核區，仍有待釐清。在此論文中，我從神經網絡到系統性的階層，探討齧齒類動物中的苔狀細胞是如何調控焦慮行為。首先，我利用光纖光度技術偵測自由活動小鼠中苔狀細胞鈣離子活性的變化。結果顯示，腹側海馬回中苔狀細胞的鈣離子活性會在老鼠探索較為焦慮的環境時上升。此外，進一步分析發現苔狀細胞的活性與老鼠內在焦慮程度呈負相關。接著，以光遺傳學活化苔狀細胞的同時結合活體近細胞記錄，我發現苔狀細胞偏好於活化γ-氨基丁酸抑制性神經元，因而抑制齒狀回中顆粒細胞及海馬回CA1次核區錐狀細胞的神經活性。最後，不論是在健康還是高焦慮的小鼠模型中，利用化學遺傳學活化腹側海馬回中的苔狀細胞都能有效地降低實驗老鼠的躲避行為。此項研究結果不僅表明苔狀細胞的抗焦慮角色，也暗示著苔狀細胞在焦慮症治療上可能是有潛力的治療標靶。

Expression and control of emotion is pivotal for survival in mammalians. Malfunctions such as anxiety disorders are associated with excitation/inhibition imbalance in brain network activity. Recently, studies have revealed that reduced γ-aminobutyric acid (GABA)-mediated inhibition and enhanced hippocampal network activity result in hyper-anxiety. Specifically, modulation of hippocampal dentate gyrus (DG) excitability regulates anxiety. In the DG, glutamatergic mossy cells (MCs) receive the excitatory drive from principal granule cells (GCs) and mediate feedback excitation and inhibition of GCs. However, the circuit mechanism by which MCs regulate anxiety-related information routing through hippocampal circuits remains unknown. Moreover, the correlation between MC activity and anxiety states is unclear. In this thesis, I examined the functional roles of rodent MCs in anxiety regulation from network to systemic levels. Using calcium fiber photometry in freely-moving mice, I first demonstrated that the calcium activity of MCs in the mouse ventral hippocampus increased while they explored anxiogenic environments. Further analysis showed the negative correlation between MC activity and innate anxiety level of mice. Next, in vivo juxtacellular recordings revealed that optogenetic activation of MCs preferentially recruited GABAergic neurons, thereby suppressing GCs and ventral CA1 neurons in the hippocampal circuitry. Finally, chemogenetic excitation of MCs in the ventral hippocampus reduced avoidance behaviors in both healthy and anxious mice. These results not only indicate an anxiolytic role of MCs, but also suggest that MCs may be a potential therapeutic target for anxiety disorders.

中文摘要 i
ABSTRACT ii
GRAPHICAL ABSTRACT AND HIGHLIGHTS iii
TABLE OF CONTENTS iv
LIST OF FIGURES vii
LIST OF TABLES viii
ABBREVIATIONS ix
1. INTRODUCTION 1
1.1. The network of hippocampal formation 1
1.1.a. The hippocampus 1
1.1.b. The dentate gyrus subregion 2
1.1.c. The CA1 subregion 4
1.2. The function of hippocampal formation 5
1.2.a. The hippocampal functions 5
1.2.b. The functions of dentate gyrus 7
1.2.c. The CA1 functions 8
1.3. The hilar mossy cell in the hippocampal DG 9
1.3.a. Discovery of mossy cells and their characteristics 9
1.3.b. Physiological properties of MCs 10
1.3.c. Input-output organization of MCs 11
1.3.d. Functions of MCs 12
1.4. Anxiety disorder and measurement of avoidance behaviors in rodents 14
2. AIMS OF THIS THESIS 16
2.1. Aim1. To investigate if MCs encode anxiety-related information. 16
2.2. Aim2. To examine the circuit mechanism underlying MC activation. 16
2.3. Aim3. Functional interrogation of the roles of MCs in avoidance behaviors. 17
3. MATERIALS AND METHODS 18
3.1. Experimental Models and Subject Details 18
3.1.a. Animal model 18
3.1.b. Fibromyalgia model 18
3.2 Method Details 18
3.2.a. Viruses 18
3.2.b. Stereotaxic injection 19
3.2.c. Fiber optic implantation 20
3.2.d. In vivo fiber photometry 20
3.2.e. Behavioral tests 21
3.2.f. In vivo juxtacellular recording 23
3.2.g. Slice preparation and patch-clamp recording 24
3.2.h. Solutions and drugs 25
3.2.i. Immunohistochemistry and histology 26
3.3 Quantification and Statistical Aanalysis 27
4. RESULTS 29
4.1. Majority of viral-expressing MCs are GluR2/3 immunoreactive 29
4.2. MC activity increased during open-arm exploration 29
4.3. MC activation recruited GABAergic INs and suppressed GCs 31
4.4. Optogenetic activation of MCs suppressed CA1 PCs 33
4.5. Elevating ventral MC activity decreased avoidance behaviors 33
4.6. Decreasing ventral MC activity had no impact on avoidance behaviors 34
4.7. Dorsal MCs did not participate in mediating avoidance behaviors 36
4.8. Elevating MC activity decreased avoidance behaviors in chronic pain 37
4.9. Gating model for MC-mediated anxiolytic effects 39
5. DISCUSSION 40
5.1. Summary 40
5.2. Potential explanation of the discrepancy in observation and manipulation results 40
5.3. Limitation of fiber photometry measurement and data interpretation 41
5.4. Relevance of GABAergic transmission to MC-mediated anxiolytic effects 42
5.5. Potential network mechanisms of CA1 outputs control on avoidance behaviors 43
5.6. Pathway-specific subcortical neuromodulatory drives for MC activation 44
5.7. Morphological, physiological, and functional dichotomy between dorsal and ventral MCs 45
5.8. MC-mediated anxiety regulation and hippocampal oscillations 46
5.9. Parallel pathways gating the anxiety representation in the ventral CA1 47
5.10. Minimum effect of environmental novelty-induced MC activity changes in the EPM test 48
5.11. Implication of adult neurogenesis in MC-mediated anxiolytic effects 49
6. FIGURES AND TABLES 51
6.1. Figure 1. Wiring diagrams of the hippocampus and hippocampal DG. 51
6.2. Figure 2. Anatomical and physiological properties of MCs. 52
6.3. Figure 3. Majority of viral-expressing MCs in Crlr-Cre mouse are GluR2/3 immunoreactive. 54
6.4. Figure 4. Increased MC activity during open-arm exploration. 55
6.5. Figure 5. Activity of ventral MCs did not correlate with locomotion speed. 57
6.6. Figure 6. Increased MC activity during open-arm exploration the EZM and modified EPM tests. 59
6.7. Figure 7. MC activation recruited GABAergic INs and suppressed GCs. 61
6.8. Figure 8. Light stimulation alone did not show off-target effects. 64
6.9. Figure 9. Optogenetic activation of MCs suppressed CA1 PCs. 65
6.10. Figure 10. Optogenetic activation of MCs suppressed CA1 PCs in awake mice. 66
6.11. Figure 11. Elevating ventral MC activity decreased avoidance behaviors. 67
6.12. Figure 12. Chemogenetic inhibition of ventral MCs had no effect on avoidance behaviors. 69
6.13. Figure 13. Optogenetic inhibition of ventral MCs had no effect on avoidance behaviors. 70
6.14. Figure 14. Either chemogenetic activation or inhibition of dorsal MCs had little effect on avoidance behaviors. 72
6.15. Figure 15. A FM-like mouse model displayed comorbid anxiety. 74
6.16. Figure 16. Enhancing MC activity alleviated heightened avoidance behavior in chronic pain. 75
6.17. Figure 17. MC gates in anxiety-related information routing along hippocampal circuits. 77
6.18. Table 1. MC activation on avoidance behaviors of male and female mice. 78
6.19. Table 2. Resources table 79
7. SUPPLEMENTARY FIGURES 81
7.1. Figure S1. Similar results obtained from different serotypes of viruses. 81
7.2. Figure S2. Increased MC activity during open-arm exploration in five consecutive EPM tests. 82
8. REFERENCES 84
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