Thirty-seven scientists from Cold Spring Harbor Laboratory (CSHL) and 20 other major research institutions in the U.S. and Europe have issued a major challenge to the neuroscience community.
At long last, the time has come, they argue in a just-published paper, to assemble a comprehensive map of the major neural circuits in the mammalian brain.
In an age in which the genomes of many organisms, including that of humans, have been fully sequenced and can be accessed instantly by anyone with a computer, anywhere in the world, it is astonishing to consider that "we have, as yet, not been able to compile a whole-brain map of the circuitry that underlies the functioning of our own brains," notes Professor Partha P. Mitra, Ph.D., senior author of the paper and leader of the ongoing Brain Architecture Project at CSHL, funded by the WM Keck Foundation. To help address this knowledge gap, Mitra organized a series of meetings at the CSHL Banbury Center in 2007 and 2008, from which this proposal grew.
The neuroscience community's "sparse knowledge" of mammalian neuroanatomical circuitry is "perhaps the largest lacuna in our knowledge about nervous system structure," Mitra and colleagues observe in their paper, which appears in the March issue of PLoS Computational Biology .
The case for committing resources to assembly of a whole-brain circuit map is particularly strong, they say, because it almost certainly will provide insights about what goes wrong in brain dysfunctions spanning a range of neurodevelopmental illnesses including autism, schizophrenia, and perhaps mood disorders such as depression, bipolar illness, and obsessive-compulsive disorder (OCD). Further, the authors argue that technological advances along with decreasing computational and data-storage costs have made such an effort feasible now, when it could only be dreamt of even in the recent past.
A community-wide project to prepare a 'first draft'
Mitra and his co-authors therefore advocate for "a concerted effort" to complete a first-draft circuit map of the entire mouse brain within two to three years, as a first step to mapping vertebrate brain architecture across species. The proposed project would ideally be pursued simultaneously by neuroscientists at multiple institutions according to standardized protocols. "In this respect," says Jason Bohland, Ph.D., a postdoctoral neuroscience researcher at CSHL and the paper's lead author, "it would be analogous to the multi-institution effort to sequence the human genome, with the important distinction that our brain-circuit map could be completed much more rapidly and would cost a small fraction of the genome project – as little as a few million dollars ranging up to perhaps $20 million, depending on the redundancy in coverage that we commit to."
To date, research on the brains of mammals – typically, rodents and non-human primates – has described, using a multitude of different techniques, only a small fraction of the total set of neuronal pathways, in an unsystematic manner. Although spectacular advances have been made in neuroscientists' ability to examine and measure the output of individual neurons in the brains of living animals, such studies have shed little light on how the brain as a whole is wired together. In much the same way that the study of the genome has shifted to emphasize networks of interacting genes, neuroscientists are beginning to understand the importance of circuit-level properties in the normal and dysfunctional brain.
This, says Mitra, is notable in part because "the defining architectural feature of the nervous system is precisely that it forms a circuit." One critical question, therefore, is at what level of resolution to attempt a whole-brain circuit diagram. Mitra and co-authors are proposing to map the circuit in the mouse brain at what they call a "mesoscopic scale." Somewhere between the micro- and macroscopic, this intermediate level corresponds with the basic architectural organization of the mouse brain, in terms of its observed cellular, chemical, and genetic makeup. Most importantly, the authors expect this to be the level at which the pattern of connections in individual animals will have a significant degree of commonality, ultimately providing a meaningful and tractable description of the brain's structure.
Tracing the inputs and outputs of each area
Brain organization at the macroscopic level – the level of entire structural-functional systems and major nerve-fiber bundles – is somewhat understood, but provides an insufficient level of description of the overall wiring diagram. Some scientists have argued that it would be best to map mouse brain structure at the micro-level of individual synapses – the myriad gaps across which individual neurons communicate, with the help of neurotransmitters and modulators such as glutamate, GABA, acetylcholine, dopamine and serotonin. But this isn't technologically feasible to do on a brain-wide scale for a mouse, let alone larger vertebrate brains. Data storage at such a scale, which would involve storing nanometer-resolution images made with electron microscopes, could cost as much as one billion dollars, Mitra says.
In contrast, the proposed project is "both technologically and economically practical, involving techniques that are well proven," according to Mitra. All measurements will be made in standard lab mice of precisely the same developmental age – 56 days, as in the Allen Brain Atlas project; each mouse will be injected in one brain area with one or more tracers, which are actively transported within individual nerve cells. These tracers may be "conventional" molecules that have been used by neuroanatomists over the last several decades, or engineered viruses that infect cells at the injection site, marking their extent through the expression of a fluorescent protein. The utility of these techniques is in tracing projection neurons either from axon terminals to potentially distant cell bodies or vice-versa.
Together, the tracers will provide a view of the pattern of inputs and outputs for a given site in the brain. These patterns will be mapped from images of thinly sectioned brain slices obtained using light microscopy, taking advantage of recently available technologies to rapidly and automatically scan and digitize a set of slides.