There’s been a lot of interest in the last couple weeks in a new big science proposal coming from the Obama administration called the brain activity map (BAM) project. The idea, which I’ve discussed here and here, is to fund a coordinated effort of neuroscientists and nanoscientists to develop methods that would allow us to understand the dynamic dance of neural activity within behaviorally relevant circuits. This could begin in less complex animals, but would have the ultimate goal of beginning to reveal the neural substrate of human thought, perception and action. Several of the techniques proposed in the project are essentially science fiction, but other elements of the plan build on imaging and electrophysiology methods that have been developed in the last decade or so. One of the researchers that has been developing these approaches is Rafael Yuste, and he is also one of the architects of the BAM proposal. I would love to hear what Rafa (as his friends call him) has to say about some of the criticisms that have been aimed at the project in the media, but I don’t know him.
Fortunately, I do know Jason MacLean, a brilliant scientist who joined the faculty at the University of Chicago while I was working on my PhD there. After doing some amazing work in invertebrate neuroscience with Ron Harris-Warrick, MacLean joined Yuste’s lab at Columbia University, where he helped advance several of the techniques now proposed as the basis for the BAM proposal. One of these methods, called calcium imaging, involves using very sensitive microscope-mounted cameras to record the activity of many neurons at the same time. This technique is most effectively used in brain slice experiments, but can be adapted to experiments with behaving animals as well. When MacLean joined Yuste’s lab, they were doing experiments which followed the activity of upwards of 300 cells, but he helped push the technology toward simultaneous monitoring of 1,000 cells. Now in his own lab, he records routinely from around 1,500 cells at a time. MacLean also developed techniques for simultaneously recording electrical activity from large numbers of neurons in tandem with calcium imaging.
I asked MacLean about some of the promise and limitations of the techniques outlined in the BAM proposals (Note, since I’m not a real journalist, and I don’t know how to turn my notes on this conversation into accurate direct quotes, I’m just going to stick with a synopsis in the third person, trying as much as possible to relay the tone and content of his comments. Any mistakes, omissions or factual errors are most likely the result of my journalistic ineptitude.)
At the center of the proposal is the idea of recording all the neural activity of a circuit in a behaving animal. What is the state of the current methods for monitoring the activity of circuit-sized groups of cells?
In addition to his own work, MacLean referenced work by such scientists as Ken Harris, where electrode-based techniques can be used to record from tens to the low-hundreds of neurons in behaving rats, while scientists like Mark Churchland and Nicho Hatsopoulos1 record from similar cell counts in primates. He added that Mark Schnitzer’s lab at Stanford has also been pushing calcium imaging in behaving mice from about 100 cells to 300 cells. MacLean points out that there are some limitations to these technologies that may or may not be overcome with the increased funding proposed by the BAM project. The basic physics of light diffraction, for example, means that calcium imaging in behaving animals is typically limited to a single cortical layer at one time, and there are also limits to the temporal precision of this technique.
Can these technologies (or the other more fanciful methods suggested by the BAM project) be scaled up to achieve the goals of recording from entire neural circuits?
MacLean is optimistic that these methods could reach the goal of analyzing discrete circuits, at least in some model organisms. He believes that many of the newer methods are very close to producing fruitful results. He argues (as the BAM scientists do) that, while single neuron analysis may continue to produce some useful insights, multicellular analysis is essential to truly understanding how brains represent and process information. This point-of-view, he notes, had actually been proposed beginning in the 1970s, but only recently has experimental technology been available to actually accomplish the goal. MacLean also points out that the analytical tools to deal with large multi-cellular data sets are still inadequate, though there many people working on new approaches (for example, Liam Paninski and Byron Yu). The analysis amounts to understanding the interaction in large networks of neurons, but this process is more difficult than analyzing gene networks (for example), where it is possible to experimentally eliminate individual elements and observe the effect of the rest of the system.
Could knowledge gained from the BAM project help with diseases like Alzheimer’s and Parkinson’s, as suggested by the proponents?
MacLean noted that some recent work has suggested some circuit-level changes in activity associated with the proteins thought to underlie Alzheimer’s disease, but he thinks that the BAM project could really be useful for understanding and treating major psychiatric disorders, though the fact that these are often broad-spectrum conditions means that developing appropriate animal models is often difficult.
Should BAM be funded?
He acknowledges that since his research interests and priorities overlap with those of the proposed project, he may not be completely unbiased. MacLean is also reluctant to weigh in on the big vs. small science question, but his experience with NIH funding opportunities to date leads him to think that the current emphasis of safe, incremental research will not produce major advances. He believes that funding riskier research with an emphasis on multi-neuronal analysis is not only essential to understand the emergent behavior of neural systems, but will eventually provide a robust return on the taxpayer’s investment.
1. In the interest of disclosure, Nicho Hatsopoulos was a member of my dissertation committee.
Photo Credit (Creative Commons): A Brainbow image from flickr user judy_breck.