Analysis of Graph Invariants in Functional Neocortical Circuitry Reveals Generalized Features Common to Three Areas of Sensory Cortex

Correlations in local neocortical spiking activity can provide insight into the underlying organization of cortical microcircuitry. However, identifying structure in patterned multi-neuronal spiking remains a daunting task due to the high dimensionality of the activity. Using two-photon imaging, we monitored spontaneous circuit dynamics in large, densely sampled neuronal populations within slices of mouse primary auditory, somatosensory, and visual cortex. Using the lagged correlation of spiking activity between neurons, we generated functional wiring diagrams to gain insight into the underlying neocortical circuitry. By establishing the presence of graph invariants, which are label-independent characteristics common to all circuit topologies, our study revealed organizational features that generalized across functionally distinct cortical regions. Regardless of sensory area, random and -nearest neighbors null graphs failed to capture the structure of experimentally derived functional circuitry. These null models indicated that despite a bias in the data towards spatially proximal functional connections, functional circuit structure is best described by non-random and occasionally distal connections. Eigenvector centrality, which quantifies the importance of a neuron in the temporal flow of circuit activity, was highly related to feedforwardness in all functional circuits. The number of nodes participating in a functional circuit did not scale with the number of neurons imaged regardless of sensory area, indicating that circuit size is not tied to the sampling of neocortex. Local circuit flow comprehensively covered angular space regardless of the spatial scale that we tested, demonstrating that circuitry itself does not bias activity flow toward pia. Finally, analysis revealed that a minimal numerical sample size of neurons was necessary to capture at least 90 percent of functional circuit topology. These data and analyses indicated that functional circuitry exhibited rules of organization which generalized across three areas of sensory neocortex.     

Biological pattern generation: the cellular and computational logic of networks in motion

In 1900, Ramón y Cajal advanced the neuron doctrine, defining the neuron as the fundamental signaling unit of the nervous system. Over a century later, neurobiologists address the circuit doctrine: the logic of the core units of neuronal circuitry that control animal behavior. These are circuits that can be called into action for perceptual, conceptual, and motor tasks, and we now need to understand whether there are coherent and overriding principles that govern the design and function of these modules. The discovery of central motor programs has provided crucial insight into the logic of one prototypic set of neural circuits: those that generate motor patterns. In this review, I discuss the mode of operation of these pattern generator networks and consider the neural mechanisms through which they are selected and activated. In addition, I will outline the utility of computational models in analysis of the dynamic actions of these motor networks.     

Dense Neuron Clustering Explains Connectivity Statistics in Cortical Microcircuits

Local cortical circuits appear highly non-random, but the underlying connectivity rule remains elusive. Here, we analyze experimental data observed in layer 5 of rat neocortex and suggest a model for connectivity from which emerge essential observed non-random features of both wiring and weighting. These features include lognormal distributions of synaptic connection strength, anatomical clustering, and strong correlations between clustering and connection strength. Our model predicts that cortical microcircuits contain large groups of densely connected neurons which we call clusters. We show that such a cluster contains about one fifth of all excitatory neurons of a circuit which are very densely connected with stronger than average synapses. We demonstrate that such clustering plays an important role in the network dynamics, namely, it creates bistable neural spiking in small cortical circuits. Furthermore, introducing local clustering in large-scale networks leads to the emergence of various patterns of persistent local activity in an ongoing network activity. Thus, our results may bridge a gap between anatomical structure and persistent activity observed during working memory and other cognitive processes.     

Microstructure of the neocortex: Comparative aspects

The appearance of the neocortex, its expansion, and its differentiation in mammals, represents one of the principal episodes in the evolution of the vertebrate brain. One of the fundamental questions in neuroscience is what is special about the neocortex of humans and how does it differ from that of other species? It is clear that distinct cortical areas show important differences within both the same and different species, and this has led to some researchers emphasizing the similarities whereas others focus on the differences. In general, despite of the large number of different elements that contribute to neocortical circuits, it is thought that neocortical neurons are organized into multiple, small repeating microcircuits, based around pyramidal cells and their input-output connections. These inputs originate from extrinsic afferent systems, excitatory glutamatergic spiny cells (which include other pyramidal cells and spiny stellate cells), and inhibitory GABAergic interneurons. The problem is that the neuronal elements that make up the basic microcircuit are differentiated into subtypes, some of which are lacking or highly modified in different cortical areas or species. Furthermore, the number of neurons contained in a discrete vertical cylinder of cortical tissue varies across species. Additionally, it has been shown that the neuropil in different cortical areas of the human, rat and mouse has a characteristic layer specific synaptology. These variations most likely reflect functional differences in the specific cortical circuits. The laminar specific similarities between cortical areas and between species, with respect to the percentage, length and density of excitatory and inhibitory synapses, and to the number of synapses per neuron, might be considered as the basic cortical building bricks. In turn, the differences probably indicate the evolutionary adaptation of excitatory and inhibitory circuits to particular functions.     

Neuroanatomy: uninhibited connectivity in neocortex?

The mouse neocortex is now the focus of research using twenty-first century techniques of circuit analyses, which are revealing different wiring strategies for excitatory and inhibitory connections and providing important insights into the possible computations of cortical circuits.     

Development and evolution of the pallium

The neocortex is the most representative and elaborated structure of the mammalian brain and is related to the achievement of complex cognitive capabilities, which are disturbed following malformation or lesion. Searching for the evolutionary origin of this structure continues to be one of the most important and challenging questions in comparative neurobiology. However, this is extremely difficult because of the highly divergent evolution of the pallium in different vertebrates, which has obscured the comparison. Herein, we review developmental neurobiology data for trying to understand the genetic factors that define and underlie the parcellation of homologous pallial subdivisions in different vertebrates. According to these data, the pallium in all tetrapods parcellates during development into four major histogenetic subdivisions, which are homologous as fields across species. The neocortex derives from the dorsal pallium and, as such, is only comparable to the sauropsidian dorsal pallium (avian hyperpallium and lizard/turtle dorsal cortex). We also tried to identify developmental changes in phylogeny that may be responsible of pallial divergent evolution. In particular, we point out to evolutionary differences regarding the cortical hem (an important signaling center for pallial patterning, that also is a source of Cajal–Retzius cells, which are involved in cortical lamination), which may be behind the distinct organization of the pallium in mammals and non-mammals. In addition, we mention recent data suggesting a correlation between the appearance and elaboration of the subventricular zone (a new germinative cell layer of the developing neocortex), and the evolution of novel cell layers (the supragranular layers) and interneuron subtypes. Finally, we comment on epigenetic factors that modulate the developmental programs, leading to changes in the formation of functional areas in the pallium (within some constraints).     

Specificity and randomness: structure-function relationships in neural circuits

A fundamental but unsolved problem in neuroscience is how connections between neurons might underlie information processing in central circuits. Building wiring diagrams of neural networks may accelerate our understanding of how they compute. But even if we had wiring diagrams, it is critical to know what neurons in a circuit are doing: their physiology. In both the retina and cerebral cortex, a great deal is known about topographic specificity, such as lamination and cell-type specificity of connections. Little, however, is known about connections as they relate to function. Here, we review how advances in functional imaging and electron microscopy have recently allowed the examination of relationships between sensory physiology and synaptic connections in cortical and retinal circuits.     

Microcircuits in visual cortex

The microcircuitry of the neocortex is bewildering in its anatomical detail, but seen through the filters of physiology, some simple circuits have been suggested. Intensive investigations of the cortical representation of orientation, however, show how difficult it is to achieve any consensus on what the circuits are, how they develop, and how they work. New developments in modeling allied with powerful experimental tools are changing this. Experimental work combining optical imaging with anatomy and physiology has revealed a rich local cortical circuitry. Whereas older models of cortical circuits have concentrated on simple 'feedforward' circuits, newer theoretical work has explored more the role of the recurrent cortical circuits, which are more realistic representations of the actual circuits and are computationally richer.     

Dendritic spines and linear networks

The function of the cortical microcircuitry is still mysterious. Using a bottom-up analysis based on the biophysics and connectivity of cortical neurons, we propose the hypothesis that the neocortex is essentially a linear integrator of inputs. Dendritic spines would slow the neuron and contribute to linearize input summation. Since excitatory axons are relatively straight, they appeared designed to help disperse information to a large number of recipient neurons, generating a distributed circuit. A linear summation regime will ensure the full benefit of a distributed connectivity matrix. Linear integration could also help the neocortex decode the sensory world and may have additional computational advantages. In this view, spines would be the anatomical signature of linear networks.     

哺乳动物大脑中神经活动如何改变突触

大脑最基本性质是快速适应周围环境改变的能力,这主要是通过改变各个神经细胞之间的连接来实现的。有多种不同机制可以调节突触的强度,包括突触效率的稳态调节、突触增强和减弱的形态学表现以及钙在其中的作用。当开始了解这些突触改变的细胞生物学机制的时候,也应该考虑这种突触可塑性在完整大脑中的功能意义。因此,应用最新的成像手段来研究经验如何影响皮层环路中突触的改变,尤其是在体双光子显微技术可以在新皮层的单个神经元水平上研究形态和功能可塑性。这些实验将逐渐填补传统的细胞水平和系统水平研究之间的空白,并将有助于更全面充分地理解突触可塑性这种现象及其在皮层功能乃至动物行为中所起的作用。     

Early network activity propagates bidirectionally between hippocampus and cortex

Spontaneous activity in the developing brain helps refine neuronal connections before the arrival of sensory‐driven neuronal activity. In mouse neocortex during the first postnatal week, waves of spontaneous activity originating from pacemaker regions in the septal nucleus and piriform cortex propagate through the neocortex. Using high‐speed Ca²⁺ imaging to resolve the spatiotemporal dynamics of wave propagation in parasagittal mouse brain slices, we show that the hippocampus can act as an additional source of neocortical waves. Some waves that originate in the hippocampus remain restricted to that structure, while others pause at the hippocampus‐neocortex boundary and then propagate into the neocortex. Blocking GABAergic neurotransmission decreases the likelihood of wave propagation into neocortex, whereas blocking glutamatergic neurotransmission eliminates spontaneous and evoked hippocampal waves. A subset of hippocampal and cortical waves trigger Ca²⁺ waves in astrocytic networks after a brief delay. Hippocampal waves accompanied by Ca²⁺ elevation in astrocytes are more likely to propagate into the neocortex. Finally, we show that two structures in our preparation that initiate waves—the hippocampus and the piriform cortex—can be electrically stimulated to initiate propagating waves at lower thresholds than the neocortex, indicating that the intrinsic circuit properties of those regions are responsible for their pacemaker function. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 661–672, 2016     

Primal-size neural circuits in meta-periodic interaction

Experimental observations of simultaneous activity in large cortical areas have seemed to justify a large network approach in early studies of neural information codes and memory capacity. This approach has overlooked, however, the segregated nature of cortical structure and functionality. Employing graph-theoretic results, we show that, given the estimated number of neurons in the human brain, there are only a few primal sizes that can be attributed to neural circuits under probabilistically sparse connectivity. The significance of this finding is that neural circuits of relatively small primal sizes in cyclic interaction, implied by inhibitory interneuron potentiation and excitatory inter-circuit potentiation, generate relatively long non-repetitious sequences of asynchronous primal-length periods. The meta-periodic nature of such circuit interaction translates into meta-periodic firing-rate dynamics, representing cortical information. It is finally shown that interacting neural circuits of primal sizes 7 or less exhaust most of the capacity of the human brain, with relatively little room to spare for circuits of larger primal sizes. This also appears to ratify experimental findings on the human working memory capacity.     

Two-step wiring plasticity--a mechanism for estrogen-induced rewiring of cortical circuits

Estrogens have been shown to exert powerful effects on cognitive behaviors mediated by several areas of the brain including the cortex. Remodeling of spiny synapses is a key step in the rewiring of neuronal circuitry thought to underlie the processing and storage of information in the forebrain. Whereas estrogen has been shown to regulate synapse structure and function, we are only just starting to understand the molecular and cellular underpinnings of how estrogens can modulate neuronal circuits. Here I will review recent molecular and cellular work that offers a potential mechanism of how estrogen may modulate synapse structure and function of cortical neurons. This mechanism allows cortical neurons to respond to activity-dependent stimuli with greater efficacy in a cellular model termed "Two-Step Wiring Plasticity". This novel form of spine plasticity thus provides insight into how estrogens may modulate the rewiring of neuronal circuits, underlying its ability to influencing cortically based behaviors. This article is part of a Special Issue entitled 'Neurosteroids'.     

In vivo imaging of neural circuit formation in the neonatal mouse barrel cortex

Higher brain function in mammals primarily relies on complex yet sophisticated neuronal circuits in the neocortex. In early developmental stages, neocortical circuits are coarse. Mostly postnatally, the circuits are reorganized to establish mature precise connectivity, in an activity-dependent manner. These connections underlie adult brain function. The rodent somatosensory cortex (barrel cortex) contains a barrel map in layer 4 (L4) and has been considered an ideal model for the study of postnatal neuronal circuit formation since the first report of barrels in 1970. Recently, two-photon microscopy has been used for analyses of neuronal circuit formation in the mammalian brain during early postnatal development. These studies have further highlighted the mouse barrel cortex as an ideal model. In particular, the unique dendritic projection pattern of barrel cortex L4 spiny stellate neurons (barrel neurons) is key for the precise one-to-one functional relationship between whiskers and barrels and thus an important target of studies. In this article, I will review the morphological aspects of postnatal development of neocortical circuits revealed by recent two-photon in vivo imaging studies of the mouse barrel cortex and other related works. The focus of this review will be on barrel neuron dendritic refinement during neonatal development.     

Coilin, more than a molecular marker of the cajal (coiled) body

The Cajal (coiled) body is a discrete nuclear organelle that was first described in mammalian neurons in 1903. Because the molecular composition, structure, and function of Cajal bodies were unknown, these enigmatic structures were largely ignored for most of the last century. The Cajal body has now regained the interest of biologists, due to the isolation of a protein marker, coilin. Despite current widespread use of coilin to identify Cajal bodies in various cell types, its structure and function are still little understood. Here, I would like to discuss what we have learned about coilin and suggest a possible role for coilin in RNA processing and cellular trafficking, especially in relation to Cajal bodies and nucleoli. Although coilin has been investigated primarily in somatic cells, I will emphasize the advantages of using the amphibian oocyte to study nuclear proteins and organelles.     

Gene expression profiling of primate neocortex: molecular neuroanatomy of cortical areas

One hundred years have passed since Brodmann's mapping of the mammalian neocortex. Solely on the basis of morphological observations, he envisaged the conservation and differentiation of cortical areal structures across various species. We now know that neurochemical, connectional and functional heterogeneity of the neocortex accompanies the morphological divergence observed in such cytoarchitectonic studies. Nevertheless, we are yet far from fully understanding the biological significance of this cortical heterogeneity. In this article, we review our past works on the gene expression profiling of the postnatal primate cortical areas, by quantitative real-time polymerase chain reaction (PCR), DNA array, differential display PCR and in situ hybridization analyses. These studies revealed both the overall homogeneity of gene expression across different cortical areas and the presence of a small number of genes that show markedly area-specific expression patterns. In situ hybridization showed that, among such genes, occ1 and retinol-binding protein (RBP) mRNAs are selectively expressed in the neuronal populations that seem to be involved in distinct neural processing such as sensory reception (for occ1 ) and associative function (for RBP). Such a molecular neuroanatomical approach has the promise to provide an important link between structure and function of the cerebral cortex.     

Interneurons of the neocortical inhibitory system

Mammals adapt to a rapidly changing world because of the sophisticated cognitive functions that are supported by the neocortex. The neocortex, which forms almost 80% of the human brain, seems to have arisen from repeated duplication of a stereotypical microcircuit template with subtle specializations for different brain regions and species. The quest to unravel the blueprint of this template started more than a century ago and has revealed an immensely intricate design. The largest obstacle is the daunting variety of inhibitory interneurons that are found in the circuit. This review focuses on the organizing principles that govern the diversity of inhibitory interneurons and their circuits.     

How does the cerebral cortex work? Learning, attention, and grouping by the laminar circuits of visual cortex

The organization of neocortex into layers is one of its most salient anatomical features. These layers include circuits that form functional columns in cortical maps. A major unsolved problem concerns how bottom-up, top-down, and horizontal interactions are organized within cortical layers to generate adaptive behaviors. This article models how these interactions help visual cortex to realize: (i) the binding process whereby cortex groups distributed data into coherent object representations; (ii) the attentional process whereby cortex selectively processes important events; and (iii) the developmental and learning processes whereby cortex shapes its circuits to match environmental constraints. New computational ideas about feedback systems suggest how neocortex develops and learns in a stable way, and why top-down attention requires converging bottom-up inputs to fully activate cortical cells, whereas perceptual groupings do not.