Revealing Secrets Hiding in Plain Sight: Advances in Multi-scale Multi-modal Imaging

A grand challenge of modern biology is to understand how molecular, cellular and tissue physiology plays out across a daunting range of spatial and temporal scales. Current imaging methods leave significant gaps in our knowledge, limiting our ability to connect information across scales. How multiple methods are now being combined to fill and help bridge critical gaps will be shared; including where recent advances to multi-tilt electron tomography (mtEMT) and development of new probes for correlated light (LM), x-ray microCT (XRM), correlated multi-ion mass spectroscopy imaging (MIMS) and EM (MIMS-EM) and state-of-the-art 3D EM technologies. Examples of biological questions being addressed in ongoing projects will be described to illustrate how development and application of new contrasting methods, imaging tools and data analysis strategies are allowing the observation of otherwise complex or hidden relationships between cellular, subcellular and molecular constituents of cells. For example, how advances in methods apply to ongoing studies on the intact normal brain and to analyze brain cells and synapses during learning (or when cells and issues respond to stressors inducing degenerative brain disorders like Alzheimer’s or Parkinson’s) will be shown. Recent accomplishments to be summarized include determination of the higher order structure and functional organization of chromatin of intact cell nuclei; the analysis of actin-associated structures within specific brain postsynaptic structures “dendritic spines”; as well as analysis of the extracellular matrix (ECM) around multiple types of synapses of mammalian brains. The ECM work explores Roger Tsien’s theory (2013, PNAS) postulating that the brain stores life-long memories by locally managing the activity of extracellular proteases to edit ECM and thereby influences the locations and relative strengths of synapses over time scales as long as life-spans.