- 學位論文
大鼠視丘腹基核轉接神經元的興奮性突觸傳導與可塑性
Excitatory Synaptic Transmission and Plasticity of Relay Neurons in The Ventrobasal Nucleus of Rat Thalamus
若您是本文的作者，可授權文章由華藝線上圖書館中協助推廣。
摘要
視丘腹基核(Thalamic ventrobasal nucleus)是體感覺訊息由脊髓上行之內側蹄系路徑(medial lemniscal pathway, ML pathway)傳往大腦皮質的主要轉運站，同時也接受皮質-視丘路徑(corticothalamic pathway, CT pathway)的皮質回饋。儘管這是一個感覺與知覺生理學中樞處理研究中的重要模式系統，許多興奮性突觸傳導與可塑性的基本性質卻付之闕如。此外，視丘轉接神經元(relay neuron)會依據生理條件的不同，放射不同模式的動作電位，在現象上，平行於視丘-皮質系統依據個體意識狀態的不同，呈現出不同的計算特性。動作電位模式的二元性一直被猜測是這種系統狀態相關(state-dependent)的感覺訊息處理的細胞學基礎，但是在突觸與細胞生理層次，不同的神經元活化模式對於其突觸強度動態調節的了解仍然非常不足。 本研究採用標準的全細胞膜片箝制記錄(whole-cell patch-clamp recording)與細胞組織化學呈色法，以系統性的方法與比較性的觀點探討腹基核皮質(CT)與感覺(蹄系)(ML)突觸的突觸傳導與可塑性。皮質與感覺突觸在興奮性突觸後電流(EPSC)大小對電刺激強度的關係與短期可塑性(short-term plasticity)上相當不同：皮質ESPC表現出線性的輸入-輸出關係，其強度在成對的高頻率刺激時增強(paired-pulse facilitation)；感覺EPSC則表現出全有全無(all-or-none)的輸入-輸出關係，其強度在成對高頻率刺激時則衰減(paired-pulse depression)。更有趣的是，離子通道型麩氨酸受體(ionotropic glutamate receptor)的組成有很大的不同。皮質路徑的NMDA受體電流與非NMDA受體電流的比值較高，同時也選擇性地表現透鈣性AMPA受體(CaP-AMPAR)。許多研究顯示，這些受體的活化在長期突觸可塑性的引發(induction)與表現(expression)上扮演重要的角色，促使我們進一步比較突觸可塑性在這兩個路徑上的不同。皮質突觸可以表現依賴NMDA受體的長期增益(long-term potentiation, LTP)以及依賴L型電壓閘控鈣離子通道(L-type voltage-gated calcium channel)的長期衰減(long-term depression, LTD)；相對而言，同樣的實驗條件無法在感覺突觸誘發長期可塑性的表現。在不同的實驗誘發條件同時被滿足的情況下，皮質突觸的連結強度則能對多重興奮性活動進行整合性的回應。我們接著嘗試運用實驗與雜訊分析(noise analysis)技術探討離子通道型麩氨酸受體在皮質突觸長期可塑性中扮演的角色。我們發現，NMDA受體與透鈣性AMPA受體皆未參與皮質突觸長期衰減的引發與表現。我們的證據更進一步顯示其表現機制主要牽涉突觸前機制的變化。 為了對突觸可塑性引發的生理條件有更深刻的了解，我們測試了數種不同的神經元放電(spiking)與配對(pairing)模式對突觸連結強度的影響。我們發現轉接神經元連續型的動作電位放電(continuous spiking)能夠誘發皮質突觸依賴於L型鈣離子通道的長期突觸衰減，但高頻率爆炸式的動作電位放電(burst spiking)則無法誘發其可塑性。儘管如此，若以特定時序(時間差)對突觸前輸入與突觸後神經元進行重覆性、低頻率的配對活化，爆炸式的放電模式則能誘發皮質突觸的長期增益，且該現象依賴於低閾值電位(low threshold potential)的存在，顯示T型電壓閘控鈣離子通道(T-type voltage-gated calcium channel)對於此種可塑性的重要性。 根據上述發現，我提出了一個視丘訊息處理與傳遞的動態模型，並據此提出可驗證的假設與值得繼續研究的方向。縱觀而言，本研究詳細探討了視丘轉接神經元上感覺與皮質突觸的基本差異，並指出皮質突觸連結強度有強烈的傾向回應不同的經驗而產生相應的變化，此種變化可能是個體調節視丘感覺訊息處理的生理與細胞學基礎。這些基礎知識在我們對於活體感覺訊息處理時，視丘-大腦皮質交互作用的深入理解與其相關的應用上是不可或缺的。
並列摘要
Thalamus is regarded as the gateway for sensory information relay from periphery to higher cortical areas, and has been suggested to play pivotal roles in state-dependent information processing and several different types of neurological disorders. Relay neurons in the ventrobasal nucleus (VBN) of the thalamus transmit somatosensory information to the cerebral cortex and receive sensory and cortical (feedback) synaptic inputs via, respectively, medial lemniscal (ML) and corticothalamic (CT) fibres. Despite an invaluable model for studying central processes of sensation and perception, this system has not been well characterized in terms of basic details of the excitatory synaptic transmission and plasticity. With more functional relevance, changes of the synaptic transmission, especially in response to physiological patterned activities, have critical implications for the computation of the thalamo-cortico-thalamic network, but this aspect is rarely studied. For example, the duality of spiking modes, burst and continuous, was thought to underlie state dependence of thalamic information transfer, but the impact of different firing patterns on synaptic weight is not explored. Our work applies standard whole-cell patch-clamp electrophysiology and cellular histochemistry to study the fast excitatory synaptic transmission and plasticity of relay neurons in the ventrobasal nucleus of rat thalamus in a systematic and comparative manner. CT and ML synapses had distinct properties in terms of stimulus-response relationships and short-term plasticity: CT excitatory postsynaptic current (EPSC) had linear input-output relationship and paired-pulse facilitation, while ML EPSC all-or-none and paired-pulse depression. More interestingly, the compositions of ionotropic glutamate receptors differed. CT synapses showed higher NMDAR / non-NMDAR peak current ratio than ML synapses, and preferentially expressed calcium-permeable AMPA receptors (CaP-AMPARs). Activation of these receptors has been widely implicated in the induction and / or expression of synaptic plasticity, which motivated the comparison of synaptic plasticity between these two synapses. NMDAR-dependent long-term potentiation (LTP) and L-type voltage-gated calcium channel(VGCC)-dependent long-term depression (LTD) were readily induced at CT synapses, but not ML synapses, under the induction protocols tested. In addition, CT synaptic strength could be modulated in response to pre- and postsynaptic activities in an integrative manner while multiple induction conditions were met concurrently. Efforts were then made to elucidate the role of ionotropic glutamate receptors in long-term plasticity of CT synapses by experimental and analytical approaches. We found that activation of CaP-AMPARs and NMDARs contributed to neither induction nor expression of LTD at CT synapses, and evidence further suggested that the expression of LTD mainly involves presynaptic modification. In order to get insights into the physiological conditions for induction of synaptic plasticity, several protocols involving different spiking and pairing patterns were tested under current-clamp recording. Intriguingly, LTD was induced at CT synapses in response to repetitive continuous spiking, rather than burst spiking, of VBN relay neuron. Furthermore, we showed that LTP at CT synapses could be induced by repetitive, low-frequency pairing of CT EPSP with burst spiking of relay neuron, but not by pairing of CT EPSP with high-frequency spiking (without LTS) which mimicked the fast Na+ action potentials riding on the LTS of natural burst spiking, suggesting a critical role of T-type VGCCs in the induction of STDP at CT synapses. In light of our discovery, I propose a working model of dynamic thalamic information relay, and generate testable ideas for future research. Taken together, this study unveils the fundamental functional differences between sensory and cortical inputs onto thalamic relay neurons, and shows that the strength of corticothalamic pathway is preferentially subjected to use-dependent modifications, which can be a cellular substrate for dynamic regulation of thalamic information relay, and therefore instrumental to our in-depth interpretation and understanding of the ongoing in-vivo sensory processes within the thalamocortical system at synaptic and cellular levels.
參考文獻
Adermark L, Lovinger DM (2007) Combined activation of L-type Ca2+ channels and synaptic transmission is sufficient to induce striatal long-term depression. J Neurosci 27(25):6781-6787
Andersen P, Morris R, Amaral D, Bliss T, O'Keefe J (2007) Historical perspective: proposed functions, biological characteristics, and neurobiological models of the hippocampus. In The Hippocampus Book. Oxford University Press, New York
Andersen P, Sundberg SH, Sveen O, Wigstrom H (1977) Specific long-lasting potentiation of synaptic transmission in hippocampal slices. Nature 266:736-737
Andersen TF, Tikhonov DB, Bølcho U, Bolshakov K, Nelson JK, Pluteanu F, Mellor IR, Egebjerg J, Strømgaard K (2006) Uncompetitive antagonism of AMPA receptors: mechanistic insights from studies of polyamine toxin derivatives. J Med Chem 49:5414-5423
Antal K, Emri Z, Tóth TI, Crunelli V (1996) Model of a thalamocortical neurone with dendritic voltage-gated ion channels. Neuroreport 7:2655-2658