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Structural and molecular interrogation of intact biological systems.

Obtaining high-resolution information from a complex system, while maintaining the global perspective needed to understand system function, represents a key challenge in biology. Here we address this challenge with a method (termed CLARITY) for the transformation of intact tissue into a nanoporous hydrogel-hybridized form (crosslinked to a three-dimensional network of hydrophilic polymers) that is fully assembled but optically transparent and macromolecule-permeable. Using mouse brains, we show intact-tissue imaging of long-range projections, local circuit wiring, cellular relationships, subcellular structures, protein complexes, nucleic acids and neurotransmitters. CLARITY also enables intact-tissue in situ hybridization, immunohistochemistry with multiple rounds of staining and de-staining in non-sectioned tissue, and antibody labelling throughout the intact adult mouse brain. Finally, we show that CLARITY enables fine structural analysis of clinical samples, including non-sectioned human tissue from a neuropsychiatric-disease setting, establishing a path for the transmutation of human tissue into a stable, intact and accessible form suitable for probing structural and molecular underpinnings of physiological function and disease.

Pubmed ID: 23575631

Authors

  • Chung K
  • Wallace J
  • Kim SY
  • 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

Journal

Nature

Publication Data

May 16, 2013

Associated Grants

  • Agency: NIH HHS, Id: DP1 OD000616
  • Agency: NIDA NIH HHS, Id: R01 DA020794
  • Agency: NIMH NIH HHS, Id: R01 MH099647
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Brain
  • Cross-Linking Reagents
  • Formaldehyde
  • Humans
  • Hydrogel
  • Imaging, Three-Dimensional
  • In Situ Hybridization
  • Lipids
  • Mice
  • Molecular Imaging
  • Permeability
  • Phenotype
  • Scattering, Radiation