思想、感情和行為都來自于復(fù)雜回路中多種腦細(xì)胞產(chǎn)生的電信號。研究人員在這種基本水平上嘗試解釋思維，但缺乏研究抑郁癥,、帕金森氏癥等疾病病因的工具。最近,，斯坦福大學(xué)等單位的研究人員發(fā)明出一種利用光對腦細(xì)胞活性進(jìn)行直接控制的新技術(shù),，為研究神經(jīng)回路和治療神經(jīng)系統(tǒng)疾病提供了一臂之力。詳細(xì)內(nèi)容刊登于4月5日《Nature》,。
神經(jīng)紅綠燈
為了對神經(jīng)元進(jìn)行選擇性控制,，研究人員利用病毒將編碼光敏蛋白的基因插入目的細(xì)胞。Karl Deisseroth等在2005年《Nature Neuroscience》一篇文章中報(bào)道：將來源于海藻的基因ChR2插入神經(jīng)元后,，神經(jīng)元在藍(lán)光照射下活性上升,。本周《Nature》文章報(bào)道：來自于古細(xì)菌（archaebacterium）的另一種NpHR能夠使神經(jīng)元在黃光照射下活性下降。將這兩種基因結(jié)合起來,，使神經(jīng)元如同汽車遵從交通信號燈一樣遵從光波：藍(lán)色代表“通行”（發(fā)射信號），黃色代表“停止”（不發(fā)射信號）,。
文章報(bào)道,，這種技術(shù)能夠在活體生物中產(chǎn)生直接的觀察效果。斯坦福小組的德國同事他們將NpHR插入線蟲的運(yùn)動神經(jīng)元后,，線蟲在顯微鏡聚焦的黃光照射下停止游泳,。某些實(shí)驗(yàn)中，遺傳改變的線蟲暴露于藍(lán)光后,，會在非前進(jìn)方向上搖擺,，光關(guān)閉后恢復(fù)正常行為。
與此同時(shí),，斯坦福大學(xué)研究人員在小鼠活腦組織提取物中進(jìn)行實(shí)驗(yàn),，利用這種技術(shù)使神經(jīng)元在毫米級時(shí)間內(nèi)發(fā)射信號或停止發(fā)射信號（與自然條件下相同）。其它實(shí)驗(yàn)顯示,，這些光對細(xì)胞沒有副作用,，關(guān)閉后細(xì)胞恢復(fù)正常功能。
潛在應(yīng)用價(jià)值
光神經(jīng)元控制的最直接應(yīng)用是,，在神經(jīng)回路中尋找細(xì)胞異常的原因,。腦深部電刺激能夠幫助帕金森氏癥患者,，但確切機(jī)理不明。通過選擇性刺激或破壞不同腦神經(jīng),，新技術(shù)能夠確定對深部腦刺激有反應(yīng)的神經(jīng)元,。這有助于發(fā)展副作用小的電治療法。
另一潛力是模擬神經(jīng)網(wǎng)絡(luò)通信的實(shí)驗(yàn),。神經(jīng)網(wǎng)絡(luò)通信產(chǎn)生的信號模式——有時(shí)開啟有時(shí)關(guān)閉,，如同二進(jìn)制計(jì)算機(jī)的“0”和“1”，模式中的藍(lán)光和黃光迫使神經(jīng)元釋放信號,。利用這種技術(shù),，研究人員有望對研究相對透徹的神經(jīng)元的行為進(jìn)行檢測和精細(xì)調(diào)節(jié)，通過人為刺激神經(jīng)元發(fā)射運(yùn)動指令等信號使癱瘓人士恢復(fù)運(yùn)動能力,。
最終,，此技術(shù)可用于開發(fā)大腦的潛在功能。文章作者,、研究生Feng Zhang說：“終有一天我們會知道大腦的組裝方式,。不同類型的細(xì)胞是怎樣互相交流以實(shí)現(xiàn)情緒等復(fù)雜工作的，或者說人們是怎樣做出決定的,？”,。
部分英文原文：
Nature 446, 633-639 (5 April 2007) | doi:10.1038/nature05744; Received 23 December 2006; Accepted 14 March 2007
Multimodal fast optical interrogation of neural circuitry
Feng Zhang1, Li-Ping Wang1, Martin Brauner2, Jana F. Liewald2, Kenneth Kay1, Natalie Watzke4, Phillip G. Wood4, Ernst Bamberg3,4, Georg Nagel4,5, Alexander Gottschalk2 & Karl Deisseroth1
Department of Bioengineering, Stanford University, Stanford, California 94305, USA
Institute of Biochemistry, and,
Institute of Biophysical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Johann Wolfgang Goethe-University, Frankfurt Biocenter N220, Max-von-Laue Strae 9, D-60438 Frankfurt, Germany
Max-Planck-Institute of Biophysics, Max-von-Laue-Strae 3, D-60438 Frankfurt am Main, Germany
University Wuerzburg, Botanik I, Julius-von-Sachs-Platz 2, D-97082 Wuerzburg, Germany
Correspondence to: Karl Deisseroth1 Correspondence and requests for materials should be addressed to K.D. (Email: [email protected]).
Abstract
Our understanding of the cellular implementation of systems-level neural processes like action, thought and emotion has been limited by the availability of tools to interrogate specific classes of neural cells within intact, living brain tissue. Here we identify and develop an archaeal light-driven chloride pump (NpHR) from Natronomonas pharaonis for temporally precise optical inhibition of neural activity. NpHR allows either knockout of single action potentials, or sustained blockade of spiking. NpHR is compatible with ChR2, the previous optical excitation technology we have described, in that the two opposing probes operate at similar light powers but with well-separated action spectra. NpHR, like ChR2, functions in mammals without exogenous cofactors, and the two probes can be integrated with calcium imaging in mammalian brain tissue for bidirectional optical modulation and readout of neural activity. Likewise, NpHR and ChR2 can be targeted together to Caenorhabditis elegans muscle and cholinergic motor neurons to control locomotion bidirectionally. NpHR and ChR2 form a complete system for multimodal, high-speed, genetically targeted, all-optical interrogation of living neural circuits.
