Hwai-Jong Cheng Lab 程淮榮 實驗室
Institute of Molecular Biology, Academia Sinica, Taiwan
Hwai-Jong Cheng Lab 程淮榮 實驗室
Institute of Molecular Biology, Academia Sinica, Taiwan
Institute of Molecular Biology, Academia Sinica, Taiwan
Institute of Molecular Biology, Academia Sinica, Taiwan
We are interested in axon guidance, a research field that deals with everything about how the neuronal network in our brain is built and refined during early development, and how this network matures and changes throughout the entire lifetime. In adult mammalian brain, the subgranular zone of the hippocampal dentate gyrus retains the capacity for neurogenesis throughout life. These adult-born neurons are functionally integrated into the existing hippocampal circuitry, where they are involved in learning and memory. Disruptions to such adult hippocampal neurogenesis (AHN) are implicated in human neurological disorders, including Alzheimer’s disease, depression, epilepsy, and age-related cognitive decline.
Our objective is to understand why AHN becomes less efficient with age and how aging process changes the new axonal connections in adult hippocampus. Like their mature counterparts, newborn dentate granule cells (GCs) in the adult brain receive synaptic inputs from the perforant pathway and send axonal projections along the mossy fiber pathway into stratum lucidum of the CA3 subfield. In CA3, the newborn mossy fiber boutons (MFBs) establish synaptic contacts with large spiny structures termed thorny excrescences at the proximal dendrites of mature CA3 pyramidal cells. We and others have shown that it takes about eight weeks for newborn GCs in young adult mouse hippocampus to form mature MFB contacts with CA3 pyramidal cells. Adult-born MFBs establish novel synaptic contacts in two main patterns: 1) de novo synaptogenesis and 2) replacement of preexisting contacts through a progressive encroachment on postsynaptic territory. The mechanisms underlying such development are unknown.
We combine mouse genetics, confocal and electron microscopic imaging, and array tomography-based molecular phenotyping to delineate how newborn GCs change with age and to elucidate the underlying mechanisms that control the generation and synaptic integration of newborn GCs in aged mice.
我們致力於研究神經軸突連結如何形成 (axon guidance)。此領域探索所有與大腦神經細胞連結與連結後修飾的所有細節；從早期發育到個體成熟， 終其一生，迴路的連結不斷變化。在成年的哺乳類大腦，海馬迴齒狀迴(hippocampal dentate gyrus) 內的下顆粒層區域 (subgranular zone) 始終保留神經新生 (neurogenesis) 的能力。在成年時才新生的神經細胞會被整合進已發育成熟的神經迴路，參與學習與記憶的功能。許多研究顯示，如果海馬迴神經新生功能異常，將造成阿茲海默失智症、憂鬱、癲癇以及老化相關的認知功能退化。
我們研究團隊的目標是釐清在大腦老化過程中，海馬迴神經細胞新生能力退化的原因，以及老化如何改變海馬迴新生神經細胞的軸突連結。如同已成熟的齒狀迴顆粒細胞 (granule cell)，成年時才新生的顆粒細胞也會接受來自貫通纖維 (perforant pathway) 的軸突輸入訊息，再由顆粒細胞軸突聚集成的苔狀纖維 (mossy fiber pathway)，將訊息送到成熟 CA3 錐狀細胞 (pyramidal cell) 的近端樹突。我們與其他研究團隊都發現，在剛成年的個體，新生顆粒細胞生成的苔狀纖維，其軸突末端 ( 膨體 (bouton)) 要在 CA3 錐狀細胞上的巨大棘突 (thorny excrescences) 形成突觸 (synapse) 需為期 8 週。成年新生苔狀纖維膨體形成突觸有兩種形式：1) 從無到有的突觸生成 (de novo synaptogenesis)；2) 漸進式地侵入已有的突觸，取代原有的膨體。但其中的發育機制還不明瞭。
我們結合小鼠基因學、共軛焦顯微影像、電子顯微影像及分子陣列層析成像 (array tomography-based molecular phenotyping) 等技術，勾勒出成年新生的海馬迴顆粒細胞隨年齡的改變過程，並解開老年時新生的顆粒細胞如何產生， 以致整合進原有的神經網絡。
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