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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 閔明源 | zh_TW |
| dc.contributor.advisor | Ming-Yuan Min | en |
| dc.contributor.author | 洪瑋辰 | zh_TW |
| dc.contributor.author | Wei-Chen Hung | en |
| dc.date.accessioned | 2025-09-10T16:07:55Z | - |
| dc.date.available | 2025-09-11 | - |
| dc.date.copyright | 2025-09-10 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-08-04 | - |
| dc.identifier.citation | Agashkov, K., Krotov, V., Krasniakova, M., Shevchuk, D., Andrianov, Y., Zabenko, Y., Safronov, B. V., Voitenko, N., & Belan, P. (2019). Distinct mechanisms of signal processing by lamina I spino-parabrachial neurons. Sci Rep, 9(1), 19231. https://doi.org/10.1038/s41598-019-55462-7
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99387 | - |
| dc.description.abstract | 神經迴路的調節對於感覺處理、喚醒狀態以及疼痛知覺具有關鍵影響。本論文探討兩種調控機制:腦幹區域的膠質細胞與神經元之間的溝通，以及脊髓中突觸可塑性的變化。
第一部分研究聚焦於藍斑核（locus coeruleus, LC），該區域為中樞神經系統中去甲腎上腺素的主要來源，與喚醒與認知功能密切相關。雖然過去研究指出膠質細胞可能參與調控LC活性，但缺乏直接的功能性證據顯示膠質細胞與LC去甲腎上腺素能（NA）神經元之間存在訊息傳遞。本研究透過選擇性光遺傳活化表現Aldh1l1的星狀膠質細胞，發現其活化會在LC-NA神經元中誘發明顯的內向電流(inward current, IAsc)與自發性興奮性突觸電流（sEPSC）頻率增加。此效應主要由星狀膠質細胞釋放的麩胺酸(glutamate)所引發，並透過活化AMPA與NMDA受體達成，其中包括活化突觸外NMDA受體所產生的慢性內向電流（slow inward currents, SICs）。本研究首次提供星狀膠質細胞透過麩胺酸釋放調控LC去甲腎上腺素能神經元興奮性的電生理證據，揭示膠質細胞參與調節喚醒相關神經活動的機制。 第二部分研究則針對脊髓背角（dorsal horn, DH）中在神經病理性疼痛狀態下的突觸變化。我發現表現Nav1.8的痛覺神經元與脊髓背角第一層（lamina I）中脊髓丘腦傳導神經元（lamina I spinothalamic tract neurons, L1-STTNs）之間的突觸傳遞變化。我們結合光遺傳與逆行追蹤技術，在脊髓切片中進行選擇性刺激與記錄，發現神經損傷（spared nerve injury, SNI）會增強Nav1.8+神經元對L1-STTN的訊息傳遞。此變化伴隨失敗率(failure rate)下降與paired pulse ratio (PPR)改變，顯示為突觸前調節(presynaptic regulation)，但未觀察到AMPA/NMDA受體比例改變或單一量子電流振幅變化，亦即未見明顯的突觸後改變。僅有少部分L1-STTN在SNI後顯示ERK磷酸化增加，顯示其突觸後興奮性提升幅度有限。本研究結果指出，神經病理性疼痛狀態下，Nav1.8+傷害感受器與L1-STTNs之間的突觸會產生選擇性的突觸前增強，而非全面性的神經元過度興奮，進一步了解慢性疼痛相關突觸可塑性機制。綜合而言，透過光遺傳學、電生理記錄與神經迴路層級的實驗設計，本研究提供對中樞神經系統適應性與病態狀態下可塑性機制的深入理解。 | zh_TW |
| dc.description.abstract | The modulation of neuronal excitability is essential for regulating sensory processing, arousal, and pain perception. This thesis explores two complementary mechanisms—glial-to-neuronal communication in the brainstem and synaptic plasticity in the spinal cord—that shape excitability within key circuits involved in arousal and nociception.
In the first part of this study, I explored how astrocytes influence noradrenergic (NA) neurons in the locus coeruleus (LC), a brainstem region known as the main source of noradrenaline in the central nervous system and a key player in arousal and cognitive regulation. While earlier studies have hinted that astrocyte activity in the LC may be linked to emotional disturbances and could potentially affect NA neurons by altering extracellular ions or releasing gliotransmitters, direct evidence of astrocyte-to-neuron communication in this area has been lacking. To address this gap, I selectively activated Aldh1l1-expressing astrocytes using optogenetics and recorded the resulting responses in LC-NA neurons. Upon photostimulation, I observed large inward currents and a marked increase in spontaneous EPSC frequency in NA neurons. These effects were driven by astrocyte-derived glutamate, acting primarily through AMPA and NMDA receptors. Notably, there was also an increase in the frequency of slow inward currents (SICs) and a rise in spontaneous phasic firing during and after stimulation, lasting up to 20 minutes. Supporting the role of NMDA receptors in this process, application of the antagonist DL-AP5 significantly reduced SIC activity. Taken together, these findings provide new evidence that astrocytes in the LC can modulate the excitability and synaptic activity of NA neurons through glutamatergic signaling, revealing a previously unrecognized form of astrocyte-to-neuron interaction in this nucleus. In the second part of this study, I examined how synaptic function changes in the dorsal horn (DH) of the spinal cord under neuropathic pain. While it's well accepted that altered synaptic transmission in the DH plays a role in pain sensitization, the specific types of synapses involved are still not fully understood. To explore this, I used optogenetic stimulation and retrograde tracing in spinal cord slices to activate first-order nociceptors expressing Nav1.8 (NRsNav1.8) and recorded from lamina I spinothalamic tract neurons (L1-STTNs). After spared nerve injury (SNI), I found that the EPSCs evoked by NRsNav1.8 (Nav1.8-STTN EPSCs) became stronger. This was associated with a lower synaptic failure rate and changes in paired-pulse ratio, pointing to a presynaptic mechanism. I also noticed an increase in the frequency of spontaneous EPSCs in L1-STTNs, but their amplitude didn’t change. Interestingly, the AMPA/NMDA ratio and the size of unitary EPSCs in Sr²⁺ conditions stayed the same. Apart from these, a small number of L1-STTNs showed increased pERK expression and slightly reduced action potential thresholds after SNI. These results suggest that SNI leads to a selective enhancement of synaptic inputs from NRsNav1.8 onto L1-STTNs, mainly through presynaptic changes, and this may contribute to abnormal sensory transmission in neuropathic pain. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-09-10T16:07:55Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-09-10T16:07:55Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 中文摘要 iii Abstract v 目次 vii 圖次 x 表次 xiii Chapter 1 1 Study of Cell-Specific Contributions in Adult Neural Circuits 1 Chapter 2: 5 Glutamate-Mediated Astrocyte-to-Neuron Signaling in the Locus Coeruleus: Mechanisms and Long-Term Modulation 5 2.1. Introduction 5 2.1.1 Introduction to the Purpose of the Study 5 2.1.2 Background 7 2.1.3 Study Aim 18 2.2 Materials and Methods 21 2.2.1 Animals 21 2.2.2 Animals and stereotaxic surgery for viral vector injection in the LC 21 2.2.3 Tamoxifen Administration and Induction Protocol 22 2.2.4 Preparation of brain slices and electrophysiology 22 2.2.5 Photostimulation of optogenetic experiments 24 2.2.6 Ca²⁺ imaging 25 2.2.7 EPSCs and SICs analysis 26 2.2.8 Immunohistochemistry (IHC) 26 2.2.9 Pharmacological Agents 28 2.2.10 Statistical analysis 29 2.3 Results 30 2.3.1 Selective Optogenetic Activation of Astrocytes in the Locus Coeruleus 30 2.3.2 Astrocyte-Induced Excitation of LC Noradrenergic Neurons 31 2.3.3 Glutamate Release Underlie Astrocyte-to-Noradrenergic Neuron Communication 34 2.3.4 Calcium-Dependent Mechanisms Dominate Astrocytic Glutamate Release 35 2.3.5 Astrocyte Photostimulation Enhances spontaneous EPSCs but not miniature EPSCs Activity in LC-NA Neurons. 37 2.3.6 Recording of Slow Inward Currents (SICs) in LC-NA neurons. 39 2.3.7 Long-term enhancement (LTE) of SICs 42 2.3.9 NMDA Receptor Activation Is Required for the Induction of LTE-SICs 46 2.3.10 Astrocytic NMDA Receptors Mediate Autocrine Signalling for LTE-SIC Induction 48 2.3.12 Astrocytic Calcium Dynamics and Its Potential Role in LTC-SIC Induction 52 2.4 Discussion 54 2.4.1 Astrocyte-Mediated Glutamate Signaling in the LC. 55 2.4.2 Comparison with Tang et al. (2014): L-Lactate vs. Glutamate Signaling 58 2.4.3 Mechanism of Astrocytic Glutamate Release. 60 2.4.4 SICs in LC-NA Neurons: A Comparison to Other Brain Regions 62 2.4.5 Long-Term Enhancement of SICs (LTE-SICs) 64 2.4.6 Autocrine Activation via NMDA Receptors on Astrocytes 68 2. 4.7 Future Directions 70 2.5 Conclusion 80 2.6 Figures 81 Chapter 3 124 Spared Nerve Injury Enhances Synaptic Transmission of Nociceptors expressing Nav1.8 onto Lamina-I Spinothalamic Tract Neurones in Mice 124 3.1 Introduction 124 3.1.1 Clinical Background of Neuropathic Pain 124 3.1.2 Animal Models for Neuropathic Pain and Rationale for Using the SNI Model 126 3.1.3 Synaptic Plasticity, Central Sensitization, and Knowledge Gaps in Neuropathic Pain 129 3.1.4 Aims 131 3.2 Materials and Methods 133 3.2.1 Animals 133 3.2.2 Animal preparation and stereotaxic tracer injection 133 3.2.3 Behavioral testing 134 3.2.4 Spared nerve injury (SNI) and sham surgery 135 3.2.5 Preparation of spinal cord slices and electrophysiological recordings 136 3.2.6 Optogenetic stimulation 138 3.2.7 Histochemistry 139 3.2.9 Statistical analysis 142 3.3 Results 144 3.3.1 Anatomical characterization of L1-STTNs 144 3.3.2 Selective Labeling of L1-STTNs for Whole-Cell Recording and Post Hoc Morphological Examination. 145 3.3.3 Monosynaptic input from Nav1.8-expressing afferents 147 3.3.6 Presynaptic modulation of Nav1.8-STTN EPSCs by SNI. 151 3.3.7 Enhancement of Nav1.8-STTN EPSCs by SNI does not involve postsynaptic modulation. 154 3.3.9 SNI changes the percentage of L1-STTN subtypes categorized based on firing patterns. 158 3.4 Discussion 162 3.4.1 Possible presynaptic mechanisms: role of presynaptic NMDARs 163 3.4.3 Potential mechanisms underlying firing pattern changes 167 3.5 Conclusion 171 3.6 Figures 173 References 191 | - |
| dc.language.iso | en | - |
| dc.subject | 藍斑核 | zh_TW |
| dc.subject | 星狀膠質細胞 | zh_TW |
| dc.subject | 光遺傳活化 | zh_TW |
| dc.subject | 脊髓 | zh_TW |
| dc.subject | 痛覺神經元 | zh_TW |
| dc.subject | 突觸可塑性 | zh_TW |
| dc.subject | optogenetics | en |
| dc.subject | locus coeruleus | en |
| dc.subject | plasticity | en |
| dc.subject | nociceptors | en |
| dc.subject | dorsal horn | en |
| dc.subject | astrocyte | en |
| dc.title | 神經元與膠質細胞對神經細胞興奮性的調控： 對藍斑核與脊髓疼痛迴路的電生理研究 | zh_TW |
| dc.title | Neuronal and Glial Modulation of Excitability: Electrophysiological Studies of the Locus Coeruleus and Spinal Pain Circuit | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 陳示國;徐經倫;吳玉威;楊琇雯;姚皓傑 | zh_TW |
| dc.contributor.oralexamcommittee | Shih-Kuo Chen;Ching-Lung Hsu;Yu-Wei Wu;Hsiu-Wen Yang;Hau-Jie Yau | en |
| dc.subject.keyword | 藍斑核,星狀膠質細胞,光遺傳活化,脊髓,痛覺神經元,突觸可塑性, | zh_TW |
| dc.subject.keyword | locus coeruleus,astrocyte,optogenetics,dorsal horn,nociceptors,plasticity, | en |
| dc.relation.page | 213 | - |
| dc.identifier.doi | 10.6342/NTU202503170 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2025-08-06 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生命科學系 | - |
| dc.date.embargo-lift | N/A | - |
| Appears in Collections: | 生命科學系 | |
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| File | Size | Format | |
|---|---|---|---|
| ntu-113-2.pdf Restricted Access | 7.02 MB | Adobe PDF |
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