ZOom^3: A three-dimensional super-resolution technique to map brain connectivity from millimeters to molecules

Abstract

In tauopathies such as Alzheimer's disease (AD), protein aggregates comprised of neurofibrillary tangles, are formed which may potentially impede axonal transport. Misfolded aggregates serve as templates for non-aggregated isoforms. In AD, these are initially intraneuronal fibrils composed of tau and of phosphotau epitopes, as observed by immunohistochemistry. If released at an impaired presynaptic ending, misfolded tau may be picked up by the postsynaptic dendritic. Early in the disease, tau aggregates are present in limbic regions, and later progress to the neocortex, including association areas. In hippocampal subregions, the CLARITY method provides sufficient volume and transparency for immunohistochemical characterization of local connections and for coherent mapping, along with defining neurospecificity. We now show the neuroanatomy and connectivity of the human hippocampus at an unprecedented level of spatial resolution integrating two state-of-the-art techniques: ex vivo high-field diffusion MRI and three-dimensional, two-photon microscopy of CLARITY-processed postmortem human hippocampal tissue. We perform both techniques in the same sample and demonstrate how to co-register the two data types that are spatially aligned so that data from each methodology are superimposed. For the first time, it is now possible with this new methodology called ZOom3, to superimpose cellular and molecular mechanisms that shape connectivity at the micron level with the systems level connectivity patterns observed at the millimeter level within the postmortem human brain. The strength of this method is that individual axons can be resolved microscopically, up to a depth of 8mm, and their trajectory can be mapped directly to the neuroimaging data. This technique will facilitate the future development of in vivo neuroimaging correlation of molecular biomarkers.

Additional details