Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Brain Connectome, Mesoscale Connectome of Mouse Brain


Nature  508, 207–214 (10 April 2014)

A mesoscale connectome of the mouse brain

Seung Wook Oh,

Allen Institute for Brain Science, Seattle, Washington 98103, USA

Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, Maryland 20892, USA


Comprehensive knowledge of the brain’s wiring diagram is fundamental for understanding how the nervous system processes information at both local and global scales. However, with the singular exception of the C. elegans microscale connectome, there are no complete connectivity data sets in other species. Here we report a brain-wide, cellular-level, mesoscale connectome for the mouse. The Allen Mouse Brain Connectivity Atlas uses enhanced green fluorescent protein (EGFP)-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain. This systematic and standardized approach allows spatial registration of individual experiments into a common three dimensional (3D) reference space, resulting in a whole-brain connectivity matrix. A computational model yields insights into connectional strength distribution, symmetry and other network properties. Virtual tractography illustrates 3D topography among interconnected regions. Cortico-thalamic pathway analysis demonstrates segregation and integration of parallel pathways. The Allen Mouse Brain Connectivity Atlas is a freely available, foundational resource for structural and functional investigations into the neural circuits that support behavioural and cognitive processes in health and disease.

A central principle of neuroscience is that the nervous system is a network of diverse types of neurons and supporting cells communicating with each other mainly through synaptic connections. This overall brain architecture is thought to be composed of four systems—motor, sensory, behavioural state and cognitive—with parallel, distributed and/or hierarchical sub-networks within each system and similarly complex, integrative interconnections between different systems. Specific groups of neurons with diverse anatomical and physiological properties populate each node of these sub- and supra-networks, and form extraordinarily intricate connections with other neurons located near and far. Neuronal connectivity forms the structural foundation underlying neural function, and bridges genotypes and behavioural phenotypes. Connectivity patterns also reflect the evolutionary conservation and divergence in brain organization and function across species, as well as both the commonality among individuals within a given species and the uniqueness of each individual brain.

Despite the fundamental importance of neuronal connectivity, our knowledge of it remains remarkably incomplete. C. elegans is the only species for which an essentially complete wiring diagram of its 302 neurons has been obtained through electron microscopy. Histological tract tracing studies in a wide range of animal species has generated a rich body of knowledge that forms the foundation of our current understanding of brain architecture, such as the powerful idea of multi-hierarchical processing in sensory cortical systems. However, much of these data are qualitative, incomplete, variable, scattered and difficult to retrieve. Thus, our knowledge of whole-brain connectivity is fragmented, without a cohesive and comprehensive understanding in any single vertebrate animal species (see for example the BAMS database for the rat brain). With recent advances in both computing power and optical imaging techniques, it is now feasible to systematically map connectivity throughout the entire brain. A salient example of this is the ongoing effort in mapping connections in the Drosophila brain.

The connectome refers to a comprehensive description of neuronal connections, for example, the wiring diagram of the entire brain. Given the enormous range of connectivity in the mammalian brain and the relative inaccessibility of the human brain, such descriptions can exist at multiple levels: macro-, meso- or microscale. At the macroscale, long-range, region-to-region connections can be inferred from imaging white-matter fibre tracts through diffusion tensor imaging (DTI) in the living brain. However, this is far from cellular-level resolution, given the size of single volume elements (voxels >1mm3). At the microscale, connectivity is described at the level of individual synapses, for example, through electron microscopic reconstruction at the nanometer scale. At present, the enormous time and resources required for this approach makes it best suited for relatively small volumes of tissue (<1mm3). At the mesoscale, both long-range and local connections can be described using a sampling approach with various neuroanatomical tracers that enable whole-brain mapping in a reasonable time frame across many animals. In addition, cell-type-specific mesoscale projects have the potential to dramatically enhance our understanding of the brain’s organization and function because cell types are fundamental cellular units often conserved across species.

Here we present a mesoscale connectome of the adult mouse brain, The Allen Mouse Brain Connectivity Atlas. Axonal projections from regions throughout the brain are mapped into a common 3D space using a standardized platform to generate a comprehensive and quantitative database of inter-areal and cell-type-specific projections. This Connectivity Atlas has all the desired features summarized in a mesoscale connectome position essay: brain-wide coverage, validated and versatile experimental techniques, a single standardized data format, a quantifiable and integrated neuroinformatics resource and an open-access public online database.

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