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Director’s Blog: New Views into the Brain

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The physicist and mathematician Freeman Dyson once noted, “New directions in science are launched by new tools much more often than by new concepts.”1 This week marks the publication of a new tool that may alter the way we look at the brain. Karl Deisseroth and his colleagues at Stanford University have developed a method they call CLARITY. Yes, CLARITY is an acronym, for Clear Lipid-exchanged Anatomically Rigid Imaging/immunostaining-compatible Tissue hYdrogel. By replacing the brain’s fat with a clear gel, CLARITY turns the opaque and impenetrable brain into a transparent and permeable structure. Most important, the hydrogel holds the brain’s anatomy intact. And because the hydrogel is permeable, the brain can be stained to localize proteins, neurotransmitters, and genes at a high resolution (see images below). Unlike other recent breakthroughs in neuroanatomy, this one can be used in human brains.

This technique is only for post-mortem tissue. And it measures structure not function. But I predict this new tool will revolutionize neuropathology, opening a new era for studying the neural basis of mental disorders. Indeed, in this initial report Deisseroth and his colleagues describe findings from a brain of someone who had died with autism 6 years earlier. With CLARITY they detected an unusual pattern of bridging connections from a particular class of inhibitory cells in this brain. Of course, this finding from a single brain needs to be replicated. The beauty of CLARITY is that other brains can now be tested, even tissue that has been stored for years.

CLARITY arrives only a week into the new BRAIN Initiative, announced by President Obama on April 2nd. Yes, BRAIN is another acronym—for Brain Research for Advancing Innovative Neurotechnologies. With some 200 neuroscientists in the East Room of the White House, the President declared, “…there is this enormous mystery waiting to be unlocked, and the BRAIN Initiative will change that by giving scientists the tools they need to get a dynamic picture of the brain in action and better understand how we think and how we learn and how we remember. And that knowledge could be—will be—transformative.”

The President proposed $100 million for the first year of what he called “the next great American project.” NIH, the Defense Advanced Research Projects Agency, the National Science Foundation, and several private laboratories and foundations will be working to develop the next generation of tools for decoding the language of the brain. The NIH BRAIN Initiative  will begin with a planning process to identify the highest priorities and propose some specific short-term and long-term goals.

Recent investments have already built a foundation for this new initiative. As just one example, the Human Connectome Project  has increased the resolution of white matter imaging to provide the first detailed “wiring diagram” of the human brain. In one of the first reports from this project, scientists discovered a surprisingly simple 3-dimensional organization of fiber tracts in the human brain.2 The Human Connectome Project has already posted extensive imaging results and cognitive data on a reference cohort of 68 healthy volunteers, on its way to a database of 1200 subjects including 300 twin pairs. (Note to students and early stage scientists: this goldmine of data is waiting for you!)

The new BRAIN Initiative, building on these recent advances, could not come at a better time. Several recent reports have emphasized the increase in prevalence and the increasing costs of brain disorders, from autism to Alzheimer’s disease. The World Health Organization estimates that neuropsychiatric diseases in the developed world are already the leading source of medical disability.3 A recent report from the World Economic Forum projects that health care for mental disorders will account for the greatest expense among health care costs of all non-communicable diseases in the coming decades, greater than cancer, diabetes, and pulmonary disease put together. Given the contribution of mental disorders to these other medical diseases and recognizing our still limited understanding of the brain, you can see why the President called for “this next great American project.”

If CLARITY is a predictor, the next few years could be a period of rapid new insights into brain structure and function. As Dyson said, “new directions in science are launched by new tools.” One can barely begin to imagine how tools like CLARITY will change our concepts of how the brain works in health and disease.

Video

CLARITY provided this 3D view showing a thick slice of a mouse brain’s memory hub, or hippocampus. It reveals a few different types of cells: projecting neurons (green), connecting interneurons (red), and layers of support cells, or glia (blue). Conventional 2D methods require that brain tissue be thinly sliced, sacrificing the ability to analyze such intact components in relation to each other. CLARITY permits such typing of molecular and cellular components to be performed repeatedly in the same brain.
Source:
Kwanghun Chung, Ph.D., and Karl Deisseroth, M.D., Ph.D., Stanford University

CLARITY makes possible this 3D tour of an entire, intact mouse brain. It was imaged using a fluorescence technique that previously could only be performed with thinly-sliced brain tissue, making it difficult to relate micro-level findings to macro-level information about wiring and circuitry.
Source:
Kwanghun Chung, Ph.D., and Karl Deisseroth, M.D., Ph.D., Stanford University

References

 1Dyson F. Imagined Worlds. Cambridge, MA: Harvard University Press, 1997.

 2Wedeen VJ et al. The geometric structure of the brain fiber pathways. Science. 2012 Mar 30;335(6076):1628-34. doi: 10.1126/science.1215280.

 3The Global Burden of Disease: 2004 Update. Geneva, World Health Organization, 2008.

 4Bloom DE et al. The Global Economic Burden of Noncommunicable Diseases. Geneva: World Economic Forum, 2011.

See press release: Fat-Free See-Through Brain Bares All