神經新生與受損海馬迴之功能恢復

Abstract

海馬迴是腦中負責學習與記憶的重要部位，也是許多神經疾病的發病點，像是阿茲海莫症，失憶症，中風，癲癇，長期壓力等等。如果能找到方法來修復腦部的病變，將可造福很多人。在成人或成鼠的大腦裡有兩個地方可以持續的進行神經細胞新生，海馬迴的粒細胞是其中一個。之前我發展出一套雞尾酒治療方式(包含神經滋養分子，神經生長分子， 以及豐富有刺激的環境)來促進神經細胞新生及生存，並恢復海馬迴功能(Lai et. al., 2011a, submitted)。延續先前研究成果，本研究主要要利用我之前建立的模範系統來研究是否神經細胞新生在恢復腦部功能扮演一個非常重要的角色。這個研究主要包括下列四部份: (1)同時作雞尾酒治療並抑制神經細胞新生，看在沒有神經細胞新生的狀況下，是否雞尾酒治療仍能恢復海馬迴功能，若不能恢復海馬迴功能，表示在這種治療下，神經細胞新生是必須的；若仍能恢復海馬迴功能，表示可能透過促進既有神經的重新連結來達到治療效果(2)觀察並分析新神經細胞的分佈狀況及形態(長度，分枝及突觸)(3)在行為學習記憶測試完畢，短時間內利用分析具突觸活化專一性之immediate early gene 的表現來了解是否新神經細胞參與了行為學習記憶測試，也就是說新神經細胞是否已融入神經網路中 (4) 此雞尾酒治療是否對腦部未受傷之正常鼠也有效? 若是的話則可讓正常鼠在行為測試中表現的更好。移除腎上腺可以很專一的造成海馬迴粒細胞死亡而不影響腦部任何其他區域，我將以此作為研究系統來進行神經細胞新生並恢復腦部功能，並借此更加了解神經細胞新生並恢復腦部功能的機制。利用個體本身內生性”幹細胞”來再生細胞將可免除手術不便，幹細胞來源的問題，以及異體移植所產生的排斥。

The hippocampus is a brain region central to learning and memory and is a key target of many neurological diseases that have dramatic cognitive consequences, including Alzheimer’s and other forms of dementia, stroke, epilepsy, and chronic stress. Discovering methods that reverse damage would dramatically improve health for many people. Hippocampal granule cells are one of the two cell pools that produce new neurons continuously in adult mammalian brains. Previously, I used a simple mammalian model system for ablation and regeneration of specific neurons (granule cells) for studying the ability of regenerated neuron to restore cognitive and physiological functions of the hippocampus (Lai et. al. 2011a, b. submitted). In this proposal, I would like to take one step further to understand if neurogenesis plays a critic role in the function recovery of damaged hippocampus. Corticosterone, an adrenal stress hormone, is essential for the survival of granule cells. Bilateral removal of adrenal glands(ADX) leads to extensive granule cell death over a period of several weeks and gradually causes memory deficits, especially in spatial tests. This surgery is used to specifically eliminate granule cells in the hippocampus to study the regeneration of granule cells and restoration of functional brain circuitry. Many substances are known to accelerate neurogenesis, but there are few data regarding the restoration of functional brain network after increased neurogenesis. A cocktail treatment that I developed promoted neurogenesis and functional recovery of damaged hippocampus (Lai et. al. 2011a, submitted). The same model will be used in this proposal to address question further. To determine whether neurogenesis is essential for the cocktail treatment to be effective, neurogenesis blocking stretagies are used to decide if the deficit re-emerged when neurogenesis is blocked. The morphology of the new granule cells will be analyzed in detail after treatment, including length of neurites, density of mature spine, and post synaptic density. It is important for new granule cells to be integrated to the circuitry to be functional. Immediate early gene expression analysis is performed shortly after the behavior test to understand if the new granule cells are integrated in the network. To be specific, a synaptic-activation activated immediate early gene expression will be used as a marker. This is the first model system for studying the regeneration of selectively and gradually lost neurons, regrowth of synaptic connectivity, and recovery of cognitive function. This work offers the promise to repair brain damage through neural circuit regeneration.