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Subject: FAT-FREE SEE-THROUGH BRAIN BARES ALL

U.S. Department of Health and Human Services NATIONAL INSTITUTES OF HEALTH
NIH News National Institute of Mental Health
(NIMH)<http://www.nimh.nih.gov/> NIH Office of the Director
(OD)<http://www.nih.gov/icd/od/> Embargoed for Release: Tuesday, April 10,
2013, 1 p.m. EDT 

CONTACT: Jules Asher, 301-443-4536, <e-mail:[log in to unmask]>

FAT-FREE SEE-THROUGH BRAIN BARES ALL
Method enables 3-D analysis of fine structure and connections -- NIH-funded
study 

Slicing optional. Scientists can now study the brain's finer workings, while
preserving its 3-D structure and integrity of its circuitry and other
biological machinery.  

A breakthrough method, called CLARITY, developed by National Institutes of
Health-funded researchers, opens the intact postmortem brain to chemical,
genetic and optical analyses that previously could only be performed using
thin slices of tissue.  By replacing fat that normally holds the brain's
working components in place with a clear gel, they made its normally opaque
and impenetrable tissue see-through and permeable.  This made it possible to
image an intact mouse brain in high resolution down to the level of cells
and molecules.  The technique was even used successfully to study a human
brain.

"CLARITY has the potential to unmask fine details of brains from people with
brain disorders without losing larger-scale circuit perspective," said NIH
Director Francis S. Collins, M.D., Ph.D., whose NIH Director's
Transformative Research Award Program <https://commonfund.nih.gov/TRA/>
helped to fund the research, along with a grant from the National Institute
of Mental Health NIMH.

"CLARITY will help support integrative understanding of large-scale, intact
biological systems, explained Karl Deisseroth, M.D., Ph.D.
<http://www.stanford.edu/group/dlab/about_pi.html>, of Stanford University
in California.  "It provides access to subcellular proteins and molecules,
while preserving the continuity of intact neuronal structures such as
long-range circuit projections, local circuit wiring, and cellular spatial
relationships."

Deisseroth, Kwanghun Chung,
Ph.D.<http://med.stanford.edu/profiles/Kwanghun_Chung/>, and other Stanford
colleagues report on their findings April 10, 2013 in the journal Nature. 

"This feat of chemical engineering promises to transform the way we study
the brain's anatomy and how disease changes it," said NIMH Director Thomas
R. Insel, M.D. "No longer will the in-depth study of our most important
three-dimensional organ be constrained by two-dimensional methods."

Until now, researchers seeking to understand the brain's fine structure and
connections have been faced with tradeoffs.  To gain access to deeply buried
structures and achieve high enough resolution to study cells, molecules and
genes, they had to cut brain tissue into extremely thin sections (each a
fraction of a millimeter thick), deforming it.  Loss of an intact brain also
makes it difficult to relate such micro-level findings to more macro-level
information about wiring and circuitry, which cuts across slices.  

In tackling this challenge, the researchers saw opportunity in the fact that
the fats, or lipids, that physically support the brain's working components,
such as neurons and their connections, also block chemical probes and the
passage of light. So replacing the lipids with something clear and permeable
- that would also hold everything else in place - might make it possible to
perform the same tests in an intact brain that previously could only be done
with brain tissue slices.  

Deisseroth's team infused into brain a high-tech cocktail, including a
plastic-like material and formaldehyde.  When heated, it formed a
transparent, porous gel that biochemically integrated with, and physically
supported, the brain's working tissue - while excluding the lipids, which
were safely removed via an electrochemical process.  The result was a brain
transformed for optimal accessibility.  

They called the new method Clear Lipid-exchanged Anatomically Rigid
Imaging/immunostaining-compatible Tissue Hydrogel -- CLARITY, for short.

Using CLARITY, the researchers imaged the entire brain of a mouse that had
been genetically engineered to express a fluorescent protein. A conventional
microscope revealed glowing details, such as proteins embedded in cell
membranes and individual nerve fibers, while an electron microscope resolved
even ultra-fine structures, such as synapses, the connections between
neurons. 

In a series of experiments using CLARITY in mouse brain, the researchers
demonstrated that, for the first time, standard immune- and genetics-based
tests can be performed repeatedly in the same intact brain.  Tracer
molecules, such as antibodies, can be readily delivered for staining tissue
-- or removed -- leaving brain tissue undisturbed.  

The researchers found that CLARITY outperformed conventional methods across
a range of previously problematic technical challenges.

When they used CLARITY to analyze a post-mortem human brain of a person who
had autism, even though it had been hardening in formaldehyde for six years,
they were able to trace individual nerve fibers, neuronal cell bodies and
their extensions. 

Grant numbers: 1 R01 MH099647 01
<http://projectreporter.nih.gov/project_info_details.cfm?aid=8411909&icde=14
929669&ddparam=&ddvalue=&ddsub=&cr=4&csb=default&cs=ASC>

The mission of the NIMH is to transform the understanding and treatment of
mental illnesses through basic and clinical research, paving the way for
prevention, recovery and cure. For more information, visit
<http://www.nimh.nih.gov>.

The NIH Common Fund encourages collaboration and supports a series of
exceptionally high impact, trans-NIH programs. These new programs are funded
through the Common Fund, and managed by the NIH Office of the Director in
partnership with the various NIH Institutes, Centers and Offices. Common
Fund programs are designed to pursue major opportunities and gaps in
biomedical research that no single NIH Institute could tackle alone, but
that the agency as a whole can address to make the biggest impact possible
on the progress of medical research. Additional information about the NIH
Common Fund can be found at <http://commonfund.nih.gov>.

About the National Institutes of Health (NIH): NIH, the nation's medical
research agency, includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. NIH is the primary federal
agency conducting and supporting basic, clinical, and translational medical
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visit <www.nih.gov>.

NIH...Turning Discovery into Health -- Registered, U.S. Patent and Trademark
Office
------------
REFERENCE:Chung K, Wallace J, Kim S-Y, Kalyanasundaram S, Andalman AS,
Davidson TJ, Mirzabekov JJ,  Zalocusky KA, Mattis J, Denisin AK, Pak S,
Bernstein H,  Ramakrishnan C,  Grosenick L, Gradinaru V, Deisseroth K.
Structural and molecular interrogation of intact biological systems. Nature,
April 10, 2012. DOI: 10.1038/Nature12107.
------------
The htm of this news release contains two videos.

3D analysis of intact mouse hippocampus
<http://www.youtube.com/watch?v=wMuwc2MxLuw>
CAPTION:
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: Karl Deisseroth, Stanford University

3D tour of intact mouse brain
<http://www.youtube.com/watch?v=stPThgZ2Y5o>
CAPTION: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: Karl Deisseroth, Stanford University ###

This NIH News Release is available online at:
<http://www.nih.gov/news/health/apr2013/nimh-10.htm>.


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