2022饶毅北大讲课视频｜《生物学概念与途径》11（下）：整合

11    还原与整合    (下）

11.9    整合：视网膜

视觉认知是逐步整合的结果。

视网膜神经信息传递的三级细胞（感光细胞、双极细胞、视神经节细胞）有整合，视网膜内还有其他细胞（如水平细胞、无突细胞）也参与调节、整合。

美国生理学家Keffer Hartline（1903-1983）于1932年记录到马蹄蟹单根视神经的动作电位，发现视觉刺激强弱影响其发放频率，但不影响其形状（Hartline and Graham，1932）。

更多的脊椎动物视神经研究显示，有些视神经对恒定的光照有稳定的反应，有些对给光有反应（on response），有些视神经是撤光的时候反应最强（off response），有些视神经是给光和撤光的时候反应都强（on-off response），有些视神经只对撤光有反应，光线的运动也能影响一些视神经的反应（Hartline，1938，1940a，1940b）。Hartline称：“单个神经细胞不会独立行动，视觉系统所有单位行动的整合才能产生视觉”（Hartline，1942）。

Stephen Kuffler（1903-1980）研究猫的视网膜时发现，RGC的感受野不是简单的对光反应，而有特定模式。有些RGC的感受野是中心为On反应、周边为Off反应（称为“On中心”感受野）。有些相反，中心为Off 反应、周围On 反应（称为“Off中心”感受野）， 而且用光同时刺激中心和周边区域可以抑制神经元的反应（Kuffler，1953）。英国的Horace Barlow（1921-，达尔文的曾孙）研究蛙的视网膜得到类似发现（Barlow，1953；Barlow，FitzHugh and Kuffler，1957）。这些发现显示视觉传递到RGC时经过了视觉加工处理。

哺乳动物的RGC送出神经纤维投射到外侧膝状体（LGN），双侧各有一个LGN，分六层，2、3、5层接受同侧视网膜的RGC投射，1、4、6接受对侧视网膜的RGC投射。LGN的神经投射到大脑皮层枕叶的初级视皮层（V1）。

11.10    视皮层研究的基础

对初级视皮层的研究，是神经信息整合为认知的一次突破。加拿大旅美科学家David Hubel（1926-2013）和瑞典旅美科学家Torsten Weisel（1924-）的合作为核心内容(Hubel and Wiesel，1998，2005)。1958年，Wiesel是霍普金斯大学眼科研究所Kuffler的博士后，Hubel来加入生理系Vernon Mountcastle（1918-2015）实验室，但因生理系拥挤安排不过来，Kuffler建议Hubel与Wiesel合作九个月等空间。这一合作延续25年，而且前五年就已硕果累累。Kuffler和Barlow等已经研究视网膜的信号，Hubel和Wiesel研究视皮层。

在技术上，Kuffler的合作者发明了较好的仪器（Talbot and Kuffler，1952），可以固定头和眼睛，而且可以局部给光刺激视网膜较小的区域，改进了此前常用的弥散给光。Hubel本人发明了用钨丝电极记录皮层电位（Hubel，1957），很快成为皮层电生理研究的常用工具，它的尖足够小（直径0.5到0.05微米）可以较好记录单细胞放电，而柔韧性足够强，相对不易断。Hubel还发明了微推进器，将微电极插入脑内（Hubel，1959）。工欲善其事必先利其器的Hubel综合多种实验方法，设计建立了研究途径：发明电极，用微推进器将之插入视皮层，用Talbot和Kuffler发明的仪器局部给光刺激视网膜后记录视皮层的信号，然后用电流损毁电极所在部位，电生理实验完成后可以通过解剖观察损毁部位而确定电极插入的部位（Hubel，1959）。

在科学上，Vernon Mountcastle在体躯感觉皮层的研究是Hubel和Wiesel研究的基础之一。

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Mountcastle发现了皮层功能柱（cortical columns）：功能柱垂直于皮层表面，其中不同层的神经细胞都对同样的体躯部位产生感觉反应（Mountcastle，1957，1997）。他当时可以分四种感觉模式：皮肤的毛发位移、皮肤压力、深部压力和关节转动。他发现功能柱内部的神经元都对同一种感觉刺激起反应，而不对其他起反应（Mountcastle，1957）。当时已有对皮层纵切的实验，它们对皮层功能影响很小（Lorente De Nó，1949；Sperry, Minor and Myers，1955），Mountcastle推测这些是由于对纵向功能柱影响较小的缘故。

人的大脑皮层约2600平方厘米，从脑膜紧邻的第一层到邻接脑室的第六层，其中功能柱从第2层到第6层，每个功能微柱（minicolumn）一般含80-100个神经元（纹状皮层2.5倍于此），多个微柱组成直径为300到600微妙的功能柱（cortical column）（Peters and Sethares，1996；Mountcastle，1997）。听觉皮层、运动皮层也一样有功能柱，听觉皮层的功能柱与声波的频率等相关（Mountcastle，1997）。功能柱可能与发育过程中神经细胞前体的起源和迁移有关（Rakic，1972，1995）。

11.11    整合：初级视皮层

在Hubel和Wiesel之前，极少研究视皮层。他们起初研究猫的视皮层，后研究猴的视皮层。

在仅有的视皮层研究中，德国佛莱堡大学的Jung等用了弥散的光作为刺激，作用于整个视网膜，记录到百分之五十的V1细胞对光有反应，其反应类似视网膜的RGCs（Jung，1953，1958；Jung and Baumgartner，1955）。

1959年，Hubel比较了弥散光和点光，发现V1的细胞基本对弥散光不反应，而对局限光反应很强，On反应和Off反应都有。存在对移动的光有反应的V1细胞，其中多数只对一个方向移动的光有反应，有些对于静止的光无反应（Hubel，1959）。这一研究看起来是用新的记录电极和给光方法，重复Jung的研究，但却有新发现。事后分析，Jung等的研究不仅给光方法不佳，而且记录有问题，估计是记录到了LGN投射到视皮层V1的纤维，而不是V1内部的细胞，所以记录到的反应类似视网膜的RGC。

Hubel和Wiesel最初预测在视皮层也发现类似RGC的反应，On中心反应、Off中心反应（Hubel and Wiesel，1998）。但他们发现了差别：中心不是圆的，而是“拉长了的圆“（Hubel and Wiesel，1959）。他们称这种细胞为“简单细胞”。

他们提出这些细胞是对直线有反应。按这样的想法，他们进一步实验确定V1确实有对直线有反应的细胞，对而且直线的朝向有要求，只有特定朝向（orientation）的直线才能引起特定V1细胞的反应，所以是“朝向选择性细胞”。

Hubel和Wiesel还发现，V1的细胞一般主要对一侧眼的刺激有反应，因此有眼优势细胞。对运动有反应的细胞对直线运动方向（direction）有选择性（Hubel and Wiesel，1959）。

他们还发现，视皮层也有功能柱，而且同一个功能柱的细胞都对同一个方向的线有反应，既朝向选择性功能柱（orientation selective columns），也有主要对一侧眼有反应的功能柱，眼优势柱（ocular dominance columns）(Hubel and Wiesel，1962，1963a)。因此，皮层的功能柱是普遍的规律，而不限于体躯感觉皮层（Mountcastle，1957），相邻的朝向功能柱偏好的朝向相近，逐渐变化。

在发现这些事实的基础上，Hubel和Wiesel提出V1之所以有这种识别线的简单细胞是因为他们接受了按一定朝向排列的LGN识别点的细胞的神经投射（Hubel and Wiesel，1962）。

这是对认知现象提出大脑皮层神经生理学解释的优美范例。

Hubel和Wiesel对于简单细胞的解释简单而优美，很快认为可能是对的。但不容易检验。因为需要检测投射到同一个V1线识别细胞的LGN神经纤维末梢到底对什么有反应。1990年代中期才有实验似乎支持LGN投射与V1细胞反应的关系（Reid and Alonso，1995；Ferster，Chung and Wheat，1996；Hubel，1996）。为了分离LGN投射的神经末梢电位与V1局部神经元网络的电位，Ferster等用全细胞膜片钳方法，记录V1细胞的膜电位，并通过降温大幅度减少V1神经元网络的活动，他们发现，V1神经元的膜电位仍然保持朝向选择性。由于冷冻V1后V1神经元的膜电位主要来自LGN投射，这就证明V1简单细胞的朝向选择性的确可以由LGN的传入产生，这就支持了Hubel和Wiesel的模型（Ferster，Chung and Wheat，1996；Hubel，1996）。Reid等人同时在LGN和V1进行单细胞微电极记录，并使用脉冲相关分析判定LGN细胞与V1简单细胞之间是否存在单突触连接，他们发现，与V1细胞有单突触连接的那些LGN细胞，其感受野的确按V1简单细胞的感受野朝向排列。当然，V1局部网络对V1简单细胞的反应也有贡献。

但还有不同于Hubel和Wiesel的解释：V1细胞有计算功能，或V1不同功能柱之间可以横向相互作用，也可以解释V1简单细胞的反应。而复杂细胞和高复杂细胞，就可能更复杂。在鼠进行双光子成像，通过钙离子浓度反映神经细胞的兴奋性（Jia et al., 2010）。在小鼠视皮层单细胞树突进行光学成像辅以电生理记录发现：同一根树突上，接受不同朝向直线刺激的输入，而无论细胞的输出朝向，其输入都有多种朝向，从而支持V1细胞不是依赖输入的相似性决定其输出，而是单个细胞可以计算其多种输入信号，整合后得到单一输出信号（Jia et al., 2010）。

所以，前级神经纤维投射确定V1简单细胞朝向选择性的机理并非已经证明。认知的神经机理，可能比以前想象的要复杂。

Hubel和Wiesel还发现猫的17区（猴的V1）有对更复杂型式反应的细胞：对运动的线，对运动的边界，对特殊的形状。他们称之为“复杂细胞”（没有On和Off区域，有位置不变性）（Hubel and Wiesel，1962）。在猫的18区（猴的V2），他们发现90%的细胞是复杂细胞，在猫的19区（猴的V3），他们发现42%为复杂细胞、58%为“超复杂”细胞（后者反应的图形需要有非连续性，亦称end-stop）（Hubel and Wiesel，1965a）。V2和V3的一个功能柱可同时含有复杂细胞和超复杂细胞。V2和V3的细胞多数为双眼驱动。从V1到V3越来越复杂，而且解剖上，他们观察到V1对于V2和V3有投射。Hubel和Wiesel提出复杂细胞接受简单细胞的投射从而解析更复杂的视觉刺激（Hubel and Wiesel，1965a）。当时很容易认为视觉认知从此都由简单的投射法则而解决。

以上实验是用猫做的。Hubel和Wiesel此后在猴做了同类实验（Hubel and Wiesel，1968）。在猴的V1，他们发现有简单、复杂和超复杂细胞，简单细胞多于复杂和超复杂细胞。猴V1也有朝向选择功能柱和眼优势功能柱，而且相互独立。第II和第III层的浅层2/3只有复杂和超复杂细胞，没有简单细胞，双眼驱动。第III深层的1/3、IVa和IVb层有简单细胞，其中IVb主要是简单细胞、几乎无复杂细胞。第IV层细胞基本都是单眼驱动。第V和VI层主要是复杂和超复杂细胞，双眼驱动。因为视皮层的第IV层接受丘脑LGN输入，提示IV层简单加工后，再在其他层曾进一步加工。

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11.12    结语

生物学研究，与其他自然科学一样，迄今以还原为主，取得了很大的进展。还原的途径在可以预见的未来会继续发挥很大作用。但是，整合也是明显需要的，在少数领域，整合取得了一定的进展，虽然远不如还原。显然，在生物学研究成功应用还原的范围和例子都超过整合的原因是技术性，而不是理念性。在分子交互作用、在细胞内部、细胞之间、组织、系统等层面，更多的整合有待进一步研究。

研究神经系统对整合需求最为明显，因为没有整合，只有细胞层面的反应，不能形成认知。虽然视觉系统的整合加工仍然是认知的重要模型，其他认知如嗅觉、听觉的神经生物学也有很大进展，与我们对视觉的理解相辅相成。而情绪、语言、思维等更高级的脑功能，需要更多地从整合层面进行研究和理解。

注1：Mountcastle和两位同事的结果最初于1955年在美国生理学会宣读（Davis, Berman and Mountcastle，1955；Mountcastle, Berman and Davis，1955），但等到1957年发表文章的时候，两位合作者不敢接受Mountcastle的功能柱概念，因此文章仅Mountcastle一位作者（Snyder，2015）。

注2：Hubel和Wiesel初期工作在霍普金斯大学，1959年他们随Kuffler到哈佛医学院药理系，1966年哈佛建立由Kuffler主持的世界上第一个神经生物学系，主要以Kuffler从霍普金斯带到哈佛的人为主，用生理、生化等多学科研究神经生物学问题。

注3：Hubel和Wiesel有一系列视觉发育的研究（Wiesel and Hubel，1963a,1963b, 1965a, 1965b; Hubel and Wiesel,1963b, 1965, 1970），一个主要发现是视觉发育的关键期，在关键期没有视觉经历对视觉的影响特别大，而关键期之前或者之后闭眼影响就小很多。

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饶毅 （2020）脸识别

脸识别

同种动物之间相互识别脸既是很高级的视觉认知，也是社会认知。对此，科学发掘了很多现象，也有一些机理研究，但理解有限。

初级视皮层V1继续投射到更高的区域，分为识别where（物体空间位置）的背侧通路和识别what（物体本征）的腹侧通路。

腹侧通路从V1到V2、V4、及更远的区域，其可分辨的图像特征越来越复杂（Kobatake and Tanaka，1994）。颞下皮层（inferotemporal cortex，IT）可以识别更复杂的图形，如：圆、方块、多刺圆、手等（Gross, Bender and Rocha-Miranda，1969；Gross, Rocha-Miranda and Bender，1972）。

普林斯顿大学心理系科学家在猴的IT（Gross, Rocha-Miranda and Bender，1972；Perret et al., 1982；Desimone et al., 1984）和颞上回（superior temporal sulcus，STS）（Bruce et al., 1981）发现了识别脸的细胞，其中IT的脸识别细胞几乎都对脸特异反应，而对其他物体没有反应（Desimone et al., 1984）。

人识别脸的能力强于黑猩猩和猴（Rosenfeld and van Hoesen，1979；Parr，2011）。黑猩猩、猴、绵羊、鸟类（鸡和鸽）、狗等动物也有脸识别细胞（Kendrick and Baldwin，1987；Ryan and Lea，1994；Kendrick et al.,1996；Pascalis and Kelly，2009）。绵羊不仅有识别绵羊脸的细胞，还有识别人脸、狗脸的细胞（Kendrick and Baldwin，1987）。羊羔一到两个月认识母亲的脸（Kendrick et al.，1998）。雌绵羊还对雄绵羊的脸有偏好（Kendrick et al., 1995）。低等动物一般依赖嗅觉，但有两种蜂（wasps，Polistes fuscatus和Polistes metricus），P fuscatu是群居的、P metricus是独居的，前者有识别个体脸的能力，后者没有（Sheehan and Tibbets, 2011）。

用行为检测显示人对脸的关注在出生很早期就可能出现：9分钟左右就对脸的反应大于其他（Goren，Sarty and Wu，1975），5周就注视脸（Haith, Bergman and Moore, 1977），对脸是否好看也有不同的反应（Slater，1998，2000）。在4天区分不带围巾的母亲与其他人的脸、35天区分带围巾的母亲和其他人的脸（Bushnell，Sai and Mullin，1989；Walton，Bower and Bower，1992；Pascalis et al., 1995；Bruce et al., 2000；Bartrip，Morton and De Schonen，2001）。3个月识别熟悉的脸（De Haan et al.，2001）。用fMRI检测观察到，两个月的婴儿的对脸反应脑区被脸激活情况类似成人，但脸还激活婴儿的语言区域（Tzourio-Mazoyer et al.，2002）。脸激活与成人一样在9岁儿童（Gathers et al.，2004）、或12岁（Golarai et al.，2007）。黑猩猩在4周左右识别母亲的脸（Myowa-Yamakoshia，2005）。

1980年代的一系列电生理实验证明猴的神经元对脸有特异反应（Bruce，Desimone and Gross,1981;Perret, Rolls and Caan,1982; Desimone et al., 1984; Perrett et al., 1984, 1985a, 1985, 1988b; Rolls, Baylis and Leonard, 1985; Saito et al., 1986; Perret, Mistlin and Chitty, 1987）。STS多感觉区域有只对脸反应的细胞（Bruce et al., 1981）。例如，记录497个STS细胞，48个只对脸反应，被脸持续激活，28个细胞在脸有转向、或颜色、大小、距离变化后反应不变（Perret，Rolls and Caan，1982）。早期在IT一次记录中，41个没有反应，110个有反应的细胞中，66个有选择性反应，其中20对形状反应、2个对手反应、3个对脸有选择性反应（Desimone et al., 1984）。可以比较对脸和物体、脸和身体的反应，找到对这三种分别有选择性反应的细胞（Pinsk et al., 2005）。通过fMRI辅助确定电生理电极插入位置，可以找到特定区域内97%的细胞都对脸有选择性反应（Tsao et al., 2006; Friewald, Tsao and Livingston, 2007），说明有脸特异区块（patch）。用脑表面光学成像观察，可以看到对脸呈现有选择性反应的脑区紧密相连（Wang, Tanaka and Tanifuji, 1996, 1998）。从而提出可能有脸朝向的功能柱（Tanaka，2003）。功能核磁共振实验也支持具有相似朝向选择性的面孔细胞在皮层上聚集（Dubois et al., 2015）。

脸识别能力有倒置效应，对正立的脸敏感性远远大于倒置的脸（Yin，1969；Thompson，1980）。脸识别细胞对于脸的要求是一个圆加两点一杠（大体相当于脸、眼和嘴）（Kobatake and Tanaka，1994）。对脸有全面的识别和部件的敏感（Freiwald，Tsao and Livingston，2009）。在猴的脸识别细胞研究中，提出抑制性神经元可能对于脸识别很重要，去除GABA的抑制性作用后，原对脸（和其他物体）有特异反应的细胞失去反应特异性（Wang，Fujita and Murayama，2000）。用微电流刺激猴的面孔加工脑区50-200毫秒，可以增加其对脸的反应以及对个人面孔的识别（Afraz, Kiani and Esteky, 2006；Moelle et al., 2017）。

猕猴面孔脑区中较低级区域的神经元对面孔朝向非常敏感，而高级区域的神经元则可区分不同个体的面孔，且反应不依赖于面孔朝向，说明高级区域表征面孔个体这一抽象概念 (Freiwald and Tsao, 2010)。进一步的研究对面孔个体的具体编码方式进行了探索，用计算模型生成上千张参数化的面孔，给动物呈现面孔图片的同时记录猕猴的面孔脑区，发现面孔细胞的反应和面孔模型中的抽象特征呈简单的线性关系，从~200个细胞的反应可相当准确地重构呈现给动物的原始面孔 （Chang and Tsao, 2017）。

人对脸反应的脑区类似于猴（Tsao et al., 2003; Tsao, Moellet and Freiwald, 2008；Pinsk et al., 2009；Srihasam et al., 2012）。在开颅手术的病人经过允许能用颅内记录事件相关电位改变（Allison et al., 1999; McCarthy et al., 1999, Puce, Allison and McCarthy, 1999），记录到脸特异反应。也直接记录到神经细胞对脸反应（Kreiman, Koch and Fried，2000）。更多的是用正电子扫描（PET）（Sergent，Ohta and MacDonald，1992；Haxby et al., 1994）和fMRI（Malach et al., 1995；Puce et al., 1996; Clark et al., 1996; Kanwisher, McDermott and Chun，1997；McCarthy et al., 1997）。可以分别观察几个脑区（FFA、OFA和fSTS）对脸的部件和构型的敏感性（Liu, Harris and Kanwisher，2010）。跨颅磁刺激（TMS）是一种研究脑功能的方法（Walsh and Cowey，2000）。用TMS作用于特定脑区，可以观察到脸反应的变化（Pitcher et al., 2007, 2008, 2009）。FFA对脸的部件和构型都敏感，OFA和fSTS只对真的脸部件反应、对其构型不反应（Dzhelyova, Ellison and Atkinson, 2010）。

人类有不能识别脸的个体，诊断为脸盲（prosopagnosia，faceblind）（Bodamer，1947），分为先天型（发育型）和获得型。脸盲者可以识别其他物体，而不能识别脸（Farah, Levinson and Klein, 1995；Farah, 1996; Henke et al., 1998; Nunn, Postma and Pearson, 2001; Duchaine and Nakayama, 2005; Duchaine et al., 2006; Li and Song, 2007; Riddoch et al., 2008）。也有患者可以识别脸但不能识别其他物体（Feinberg et al., 1994; Moscovitch, Winocur and Behrmann，1997；McMullen，Fisk and Phillips，2000；Germine et al., 2011）。对于脸盲的机理，有多种解释，有些脸盲可能确实是脸识别能力的特异变化（Duchaine，2006）。

后天获得的脸识别异常，可以是病变或外伤（Yin, 1970; Meadow et al., 1974; Landis et al., 1986; Barton et al., 2002；Bouvier and Engel，2006；Schiltz et al., 2006； Steeves et al., 2006）。右脑单侧外伤就可以导致脸盲。如果可以在脑成像观察到病变部位，有助于了解参与脸识别的脑区（Riddoch et al.,2008）。这些可以与在正常人脑进行的核磁共振成像、外科手术人脑电生理记录相辅相成（Kanwisher, McDermott and Chun，1997；Tsao et al., 2003；Barraclouth and Perret，2011）。

双生子研究显示脸识别能力有高度遗传性（Polk et al., 2007；Wilmer et al.，2010；Zhu et al., 2010）。德国一个大学的调查显示2.47%脸盲率（Kennerknecht et al., 2006, 2007），中国香港大学的调查显示1.88%的脸盲率（Kennerknecht, Ho and Wong，2008）。遗传性脸盲在一些家系发现（McConachie，1976；Grueter et al., 2007；Duchaine，Germine and Nakayama，2007；Schmalzl，Palermo and Coltheart，2008；Lee et al., 2009）。这些表明经典遗传学和基因组学可以用于研究脸识别。

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