Slc13A5 在小鼠行為及海馬迴神經結構的影響

The effect of Slc13A5 knockout on behavior and hippocampal neuron morphology in mice

蔡依璇(Yi-Hsuan Tsai)

指導教授 ： 王培育

國立臺灣大學/醫學院/腦與心智科學研究所/碩士(2016年)

https://doi.org/10.6342/NTU201601557

摘要

許多研究證實果蠅的基因 Indy (I’m not dead yet 的縮寫)能藉由影響代謝而調節壽命，與卡路里節制(calorie restriction, CR)有一樣的效果，而卡路里節制對於許多物種上面被指出能夠延長壽命並且改善認知功能。
在這個研究當中，主要聚焦於哺乳類上面 Indy 的同源基因Slc13A5，利用一系列的行為學實驗來觀察 Slc13A5 在全身上面對於小鼠行為的影響，並且針對大腦做分析。本實驗利用新奇事物認知測試(novel object recognition)評估小鼠的記憶功能，發現在 Slc13A5 全身基因剔除的小鼠上面能顯著提升辨識記憶。更進一步，利用被動型躲避學習記憶實驗(passive avoidance)以及三室社交行為測試平台(three chamber test)，在恐懼記憶以及社會辨識記憶能力上面，Slc13A5 全身基因剔除的小鼠與卡路里節制的小鼠都具有促進記憶功能上的提升。
記憶力的形成可能源自於腦神經結構上的改變，為了探討 Slc13A5 基因剔除以及卡路里節制在認知功能上的改變與形象學上面的關聯，本實驗利用高基氏染色(Golgi-Cox staining)重建與記憶相關的腦區，海馬迴中齒狀迴以及 CA1 當中的神經細胞，不只是在神經樹突上的分析，並且分析在樹突上與訊息傳遞、認知功能相關的突觸脊。本實驗發現在 Slc13A5 基因剔除以及卡路里節制的相似在於突觸脊密度上有上升的現象。

關鍵字

鈉離子依賴二羧酸蛋白 ； 卡路里節制 ； 記憶學習 ； 海馬迴 ； 高基氏染色 ； 神經結構

並列摘要

The Drosophila gene Indy (for I’m not dead yet) was proposed to regulate life span via an effect on metabolism that could overlap with calorie restriction (CR), which is the most widely recognized lifespan-extending and cognitive-improving intervention in a variety of species. In this study, I aim to investigate the function of mammalian homolog of Indy (mIndy), Slc13A5 in the brain. I evaluated the cognitive functions of Slc13A5 knockout mice through a series of behavior tests. I found that Slc13A5 knockout mice could significantly enhance the recognition memory performance of mice by novel object recognition (NOR) tasks. Furthermore, the improvement of fear memory and social recognition memory in Slc13A5 knockout mice is similar to CR-induced memory enhancement by passive avoidance test and three chamber test.These results imply that Slc13A5 knockout mice could induce memory enhancement similar to CR.
Since evidence for the memory formation is generally related to molecular and structural alterations, the dendritic structures of granule cells and pyramidal neurons in hippocampus are econstructed by using Golgi-Cox staining to discuss how CR and Slc13A5 knockout regulate cognitive function. The structural similarity between CR and Slc13A5 knockout were observed at the spine density in DG granule cells.

並列關鍵字

I’m not dead yet ； mIndy ； calorie restriction ； memory ； hippocampus ； Golgi-Cox staining ； neuron structure

參考文獻

Andrade, J.P., Lukoyanov, N.V., and Paula-Barbosa, M.M. (2002). Chronic food restriction is associated with subtle dendritic alterations in granule cells of the rat hippocampal formation. Hippocampus 12, 149-164.

Anson, R.M., Guo, Z., de Cabo, R., Iyun, T., Rios, M., Hagepanos, A., Ingram, D.K., Lane, M.A., and Mattson, M.P. (2003). Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proceedings of the National Academy of Sciences of the United States of America 100, 6216-6220.

Anton, S., and Leeuwenburgh, C. (2013). Fasting or caloric restriction for healthy aging. Experimental gerontology 48, 1003-1005.

Barker, G.R., Bird, F., Alexander, V., and Warburton, E.C. (2007). Recognition memory for objects, place, and temporal order: a disconnection analysis of the role of the medial prefrontal cortex and perirhinal cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 27, 2948-2957.

Birkenfeld, A.L., Lee, H.Y., Guebre-Egziabher, F., Alves, T.C., Jurczak, M.J., Jornayvaz, F.R., Zhang, D., Hsiao, J.J., Martin-Montalvo, A., Fischer-Rosinsky, A., et al. (2011). Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell metabolism 14, 184-195.