SUMMARY The stereotyped features of neuronal circuits are those most likely to explain the remarkable capacity of the brain to process information and govern behaviors, yet it has not been possible to comprehensively quantify neuronal distributions across animals or genders due to the size and complexity of the mammalian brain. Here we apply our quantitative brain-wide (qBrain) mapping platform to document the stereotyped distributions of mainly inhibitory cell types. We discover an unexpected cortical organizing principle: sensory-motor areas are dominated by output-modulating parvalbumin-positive interneurons, whereas association, including frontal, areas are dominated by input-modulating somatostatin-positive interneurons. Furthermore, we identify local cell type distributions with more cells in the female brain in seven out of eight sexually dimorphic subcortical areas, in contrast to the overall larger brains in males. The qBrain resource can be further mined to link stereotyped aspects of neuronal distributions to known and unknown functions of diverse brain regions.

Cognition presumably emerges from neural activity in the network of association connections between cortical regions that is modulated by inputs from sensory and state systems and directs voluntary behavior by outputs to the motor system. To reveal global architectural features of the cortical association connectome, network analysis was performed on >16,000 reports of histologically defined axonal connections between cortical regions in rat. The network analysis reveals an organization into four asymmetrically interconnected modules involving the entire cortex in a topographic and topologic core-shell arrangement. There is also a topographically continuous U-shaped band of cortical areas that are highly connected with each other as well as with the rest of the cortex extending through all four modules, with the temporal pole of this band (entorhinal area) having the most cortical association connections of all. These results provide a starting point for compiling a mammalian nervous system connectome that could ultimately reveal novel correlations between genome-wide association studies and connectome-wide association studies, leading to new insights into the cellular architecture supporting cognition.T he cerebral cortex is the core of the brain's cognitive system (1, 2). Emerging evidence suggests that misdirected and/or dysfunctional cortical connections established during neurodevelopment, or degenerative events later in life, are fundamental to cognitive alterations associated with brain disorders like Alzheimer's disease, autism spectrum disorder, and schizophrenia (3). Presumably, an understanding of biological mechanisms underlying cognition and the control of voluntary behavior rests at least partly on the structure-function wiring diagram of the cortex. Design principles of this neural circuitry are based on a network of interactions between distributed nervous system regions, and on the underlying function of their constituent neuron populations, and individual neurons.Unfortunately, a global structure-function wiring diagram of the cortex has not yet been elaborated (4). A necessary, but not sufficient, prerequisite for establishing this basic plan is a comprehensive structural model of cortical connectivity (5-7). Such a "roadmap" could then be used as a database scaffolding for molecular, cellular, physiological, behavioral, and cognitive data and for modeling (8)-analogous to a Google Maps for the brain. The research strategy described here provides the starting point for such a model, as well as a framework, benchmark, and infrastructure for developing a global account of nervous system structural network organization as a whole.The conceptual framework underlying our strategy to analyze global nervous system connection architecture is twofold. First, because of considerable complexity-for example, human isocortex on one side has 6-9 billion neurons (9-11) interconnected by orders-of-magnitude-more synapses-three hierarchical (nested) levels analysis are considered (12, 13). A macroconnection be...

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is critical, however, for both basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brainwide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brainwide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open-access data repository; compatibility with existing resources; and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.

Strains of mice, through breeding or the disruption of normal genetic pathways, are widely used to model human diseases. Atlases are an invaluable aid in understanding the impact of such manipulations by providing a standard for comparison. We have developed a digital atlas of the adult C57BL/6J mouse brain as a comprehensive framework for storing and accessing the myriad types of information about the mouse brain. Our implementation was constructed using several different imaging techniques: magnetic resonance microscopy, blockface imaging, classical histology and immunohistochemistry. Along with raw and annotated images, it contains database management systems and a set of tools for comparing information from different techniques. The framework allows facile correlation of results from different animals, investigators or laboratories by establishing a canonical representation of the mouse brain and providing the tools for the insertion of independent data into the same space as the atlas. This tool will aid in managing the increasingly complex and voluminous amounts of information about the mammalian brain. It provides a framework that encompasses genetic information in the context of anatomical imaging and holds tremendous promise for producing new insights into the relationship between genotype and phenotype. We describe a suite of tools that enables the independent entry of other types of data, facile retrieval of information and straightforward display of images. Thus, the atlas becomes a framework for managing complex genetic and epigenetic information about the mouse brain. The atlas and associated tools may be accessed at

The nervous system can be viewed as a biological computer whose genetically determined macrocircuitry has two basic classes of parts: gray matter regions interconnected by fiber pathways. We describe here the basic features of an online knowledge management system for storing and inferring relationships between data about the structural organization of nervous system circuitry. It is called the Brain architecture management system (BAMS; http://brancusi.usc.edu/bkms) and it stores and analyzes data specifically concerned with nomenclature and its hierarchical taxonomy, with axonal connections between regions, and with the neuronal cell types that form regions and fiber pathways.

A systematic account of neuron cell types is a basic prerequisite for determining the vertebrate nervous system global wiring diagram. With comprehensive lineage and phylogenetic information unavailable, a general ontology based on structure-function taxonomy is proposed and implemented in a knowledge management system, and a prototype analysis of select regions (including retina, cerebellum, and hypothalamus) presented. The supporting Brain Architecture Knowledge Management System (BAMS) Neuron ontology is online and its user interface allows queries about terms and their definitions, classification criteria based on the original literature and "Petilla Convention" guidelines, hierarchies, and relations-with annotations documenting each ontology entry. Combined with three BAMS modules for neural regions, connections between regions and neuron types, and molecules, the Neuron ontology provides a general framework for physical descriptions and computational modeling of neural systems. The knowledge management system interacts with other web resources, is accessible in both XML and RDF/OWL, is extendible to the whole body, and awaits large-scale data population requiring community participation for timely implementation.

The brain's structural organization is so complex that 2,500 years of analysis leaves pervasive uncertainty about (i) the identity of its basic parts (regions with their neuronal cell types and pathways interconnecting them), (ii) nomenclature, (iii) systematic classification of the parts with respect to topographic relationships and functional systems and (iv) the reliability of the connectional data itself. Here we present a prototype knowledge management system (http://brancusi.usc.edu/bkms/) for analyzing the architecture of brain networks in a systematic, interactive and extendable way. It supports alternative interpretations and models, is based on fully referenced and annotated data and can interact with genomic and functional knowledge management systems through web services protocols.

The nervous system is a biological computer integrating the body's reflex and voluntary environmental interactions (behavior) with a relatively constant internal state (homeostasis)-promoting survival of the individual and species. The wiring diagram of the nervous system's structural connectivity provides an obligatory foundational model for understanding functional localization at molecular, cellular, systems, and behavioral organization levels. This paper provides a high-level, downwardly extendible, conceptual framework-like a compass and map-for describing and exploring in neuroinformatics systems (such as our Brain Architecture Knowledge Management System) the structural architecture of the nervous system's basic wiring diagram. For this, the Foundational Model of Connectivity's universe of discourse is the structural architecture of nervous system connectivity in all animals at all resolutions, and the model includes two key elements-a set of basic principles and an internally consistent set of concepts (defined vocabulary of standard terms)-arranged in an explicitly defined schema (set of relationships between concepts) allowing automatic inferences. In addition, rules and procedures for creating and modifying the foundational model are considered. Controlled vocabularies with broad community support typically are managed by standing committees of experts that create and refine boundary conditions, and a set of rules that are available on the Web.There is no set of organs, in the formation of which, we find so perfect a gradation from the simple to the compound, as in the. . .nervous system; in fact, this system is established on a uniform plan in the whole animal scale." Friedrich Tiedemann (1).