Principles of connectivity among morphologically defined cell types in adult neocortex.
Principles of connectivity among morphologically defined cell types in adult neocortex.
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DOI：
10.1126/science.aac9462
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发表时间：
2015-11-27
期刊：
影响因子：
--
通讯作者：
Tolias AS
中科院分区：
文献类型：
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作者：
Jiang X;Shen S;Cadwell CR;Berens P;Sinz F;Ecker AS;Patel S;Tolias AS
大脑皮层复杂的微电路被认为是哺乳动物大脑令人惊叹的能力所依赖的关键基础。到目前为止，我们对新皮层微电路中定型连接的了解是从对少数神经元细胞类型之间连接的个别研究拼凑起来的。在这里，我们提供了对神经元细胞类型和连接的无偏、大规模分析，以揭示皮层的基本构建模块以及支配它们组装成皮层电路的原理。利用先进的组织切片技术、多个同时的全细胞记录以及形态重建技术，我们能够全面了解成年动物中不同类型神经元之间的连接，特别是释放γ - 氨基丁酸（GABAergic）的中间神经元类型之间的连接。
我们利用一种制备高质量成年组织切片的方法，并将该技术与八重同时全细胞记录相结合，随后采用一种改进的染色方法，能够详细恢复轴突和树突分支的形态。这些数据使我们能够对新皮层第1、2/3和5层（分别为L1、L23和L5）中形态学和电生理学定义的神经元类型（主要是GABAergic中间神经元）进行普查，并观察它们在成年动物中的连接模式。
我们对新皮层神经元进行的大规模、全面分析区分出了15种主要的中间神经元类型，此外还有两种按层定义的锥体神经元类型（L23和L5）。皮层中间神经元在L1层包括两种类型（eNGC和SBC - 样），在L23层有七种（L23MC、L23NGC、BTC、BPC、DBC、L23BC和ChC），在L5层有六种（L5MC、L5NGC、L5BC、SC、HEC和DC）（见图）。每种类型都有定型的电生理特性和形态特征，并且可以通过细胞类型特异性的轴突几何形状和轴突投射模式与其他所有类型区分开来。重要的是，每种类型的神经元都有其自身特有的输入 - 输出连接模式，在突触后靶点、层位和突触特性方面与其他组成神经元类型以不同程度的特异性相连接。尽管每种细胞类型都有特定的连接模式，但我们发现少数简单的连接模式在各层和细胞类型中重复出现，定义了一种典型的皮层微电路。
我们对成年新皮层中神经元细胞类型和连接的全面分析提供了迄今为止新皮层微电路最完整的连接图。与当前用于细胞类别的基因标记（这些标记对皮层进行大致描绘）相比，我们对形态学和电生理学特性的分析揭示了新的细胞类别，并使我们能够推导出少数在各层和细胞类型中重复的简单连接规则。这种皮层连接的详细蓝图应该有助于在脑部疾病的动物模型中识别特定的电路异常，并最终可能为开发基于全面电路的、针对细胞类型的干预措施提供一条途径。
成年新皮层中形态学定义的细胞类型之间的连接。（A）同时进行八重全细胞记录以研究连接，随后进行形态重建。（B）形态不同的神经元类型之间的突触连接，包括锥体（P）神经元。（C）神经胶质样细胞（NGCs）与其他细胞类型的连接。这种连接被认为是非突触的，由容积传递介导。马蒂诺蒂细胞，MC；篮状细胞，BC；单束状细胞样细胞，SBC - 样；双极细胞，BTC；双极细胞，BPC；双束状细胞，DBC；吊灯样细胞，ChC；灌木细胞，SC；水平伸长细胞，HEC；深投射细胞，DC
The intricate microcircuitry of the cerebral cortex is thought to be a critical substrate from which arise the impressive capabilities of the mammalian brain. Until now, our knowledge of the stereotypical connectivity in neocortical microcircuits has been pieced together from individual studies of the connectivity between small numbers of neuronal cell types. Here, we provide unbiased, large-scale profiling of neuronal cell types and connections to reveal the essential building blocks of the cortex and the principles governing their assembly into cortical circuits. Using advanced techniques for tissue slicing, multiple simultaneous whole-cell recording, and morphological reconstruction, we are able to provide a comprehensive view of the connectivity between diverse types of neurons, particularly among types of γ-aminobutyric acid–releasing (GABAergic) interneurons, in the adult animal. We took advantage of a method for preparing high-quality slices of adult tissue and combined this technique with octuple simultaneous, whole-cell recordings followed by an improved staining method that allowed detailed recovery of axonal and dendritic arbor morphology. These data allowed us to perform a census of morphologically and electrophysiologically defined neuronal types (primarily GABAergic interneurons) in neocortical layers 1, 2/3, and 5 (L1, L23, and L5, respectively) and to observe their connectivity patterns in adult animals. Our large-scale, comprehensive profiling of neocortical neurons differentiated 15 major types of interneurons, in addition to two lamina-defined types of pyramidal neurons (L23 and L5). Cortical interneurons comprise two types in L1 (eNGC and SBC-like), seven in L23 (L23MC, L23NGC, BTC, BPC, DBC, L23BC, and ChC), and six in L5 (L5MC, L5NGC, L5BC, SC, HEC, and DC) (see the figure). Each type has stereotypical electrophysiological properties and morphological features and can be differentiated from all others by cell type-specific axonal geometry and axonal projection patterns. Importantly, each type of neuron has its own characteristic input-output connectivity profile, connecting with other constituent neuronal types with varying degrees of specificity in postsynaptic targets, laminar location, and synaptic characteristics. Despite specific connection patterns for each cell type, we found that a small number of simple connectivity motifs are repeated across layers and cell types defining a canonical cortical microcircuit. Our comprehensive profiling of neuronal cell types and connections in adult neocortex provides the most complete wiring diagram of neocortical microcircuits to date. Compared with current genetic labels for cell class, which paint the cortex in broad strokes, our analysis of morphological and electrophysiological properties revealed new cell classes and allowed us to derive a small number of simple connectivity rules that were repeated across layers and cell types. This detailed blueprint of cortical wiring should aid efforts to identify specific circuit abnormalities in animal models of brain disease and may eventually provide a path toward the development of comprehensive circuit-based, cell type-specific interventions. Connectivity among morphologically defined cell types in adult neocortex. (A) Simultaneous octuple whole-cell recording to study connectivity followed by morphological reconstruction. (B) Synaptic connectivity between morphologically distinct types of neurons, including pyramidal (P) neurons. (C) Connectivity from neurogliaform cells (NGCs) to other cell types. This connectivity is believed to be nonsynaptic and mediated by volume transmission. Martinotti cell, MC; basket cell, BC; single-bouquet celllike cell, SBC-like; bitufted cell, BTC; bipolar cell, BPC, double-bouquet cell, DBC; chandelier cell, ChC; shrub cell, SC; horizontally elongated cell, HEC; deep-projecting cell, DC.