In the essay, Selkoe and colleagues outline key developments that followed the first description of the disease by Alois Alzheimer in 1907.  They explain how the discoveries of tau and amyloid β-protein precursor in the late 1980s and early 1990s brought Alzheimer research into sync with basic research in molecular genetics and protein chemistry.  Furthermore, the recognition of Alzheimer disease as a common disorder – currently estimated to affect 20-25 million people worldwide – has helped define it as an urgent problem in biomedical research.

But beyond that, Selkoe and colleagues describe how tackling a complicated disease – and one that affects the most human qualities of memory, reasoning, language, and emotion – can be intellectually rewarding. “The complexity of the problem and the diverse ways in which one might think about approaching it make for a fascinating adventure in biomedical research,” they write.

For more on Alzheimer research – including discussion of competing ideas between “BAPtists” and “TAUists” – read the complete essay here.

Initial methods to analyze behavioral phenotypes in C. elegans relied on human observation, and were therefore subjective and imprecise. Terms like “sluggish” or “loopy” were used to describe the uncoordinated activity of some mutants. And the procedures were often time-consuming, as the observer was required to monitor worm behavior in real time.

But, as described by Bill Schafer and colleagues in the current issue of Cold Spring Harbor Protocols, automated microscopy and image analysis systems for recording and analyzing worm behavior are much more robust.  They allow for precise quantitative definitions of behavioral phenotypes, and permit the analysis of behaviors that occur over long time periods or are difficult to detect by eye.

In the issue, Schafer and colleagues provide protocols for preparing media and worms for automated tracking and image analysis, describe high-throughput worm behavior analysis using Multiworm Tracker, and offer strategies for obtaining uniform illumination during worm tracking.  They also compare and contrast single- and multi-worm tracking approaches, and describe how comparisons of wild-type and genetically modified worms can be used to functionally dissect the molecular mechanisms behind specific behaviors.

The editors, Dennis Selkoe, Eckhard Mandelkow, and David Holtzman, chose leading researchers in Alzheimer biology to contribute chapters on topics in which they have deep expertise. The 25 chapters include contributions covering all aspects of Alzheimer disease, from our current molecular understanding of it to therapeutic agents that could be used to treat and prevent it.

Additionally, the first and last chapters provide the editors’ perspectives on the disease, its challenges and prospects for developing effective treatments. “[We] have tried to step back from the wealth of details and convey a sense of what has motivated the global quest to understand the biology of AD, how sometimes competing concepts and lines of inquiry have proceeded, and, most importantly, where we believe this scientifically rich and therapeutically promising field is headed,” they write.

The book is a vital reference for neurobiologists, cell biologists, pathologists, and other scientists pursuing the biological basis of Alzheimer disease, as well as investigators, clinicians, and students interested in its pathogenesis, treatment, and prevention.  For more details, click here.

The July issue of Cold Spring Harbor Protocols features an article by Jeff Lichtman, Joshua Sanes, and colleagues, who developed the Brainbow technique.  The article describes currently available Brainbow cassettes and transgenic mice, as well as the elements necessary for creating Brainbow transgenes from scratch.  An accompanying protocol provides step-by-step details for introducing Brainbow transgenes into mice, fixing samples from Brainbow animals, and acquiring and analyzing multichannel images from Brainbow samples.

The cover of the July issue shows motor neurons in the spinal cord of a young adult transgenic Brainbow mouse.  For more on the July issue, click here.

“Directly seeing the nervous system in action—be it a vesicle releasing transmitter, a neuron integrating synaptic input in its dendrites, or a neuronal population generating patterns of activity—is always a fascinating experience and provides us with a sense of immediate and credible understanding.” –Fritjof Helmchen and Arthur Konnerth (Imaging in Neuroscience: A Laboratory Manual)

The latest addition to our fleet of imaging manuals provides neuroscience researchers with a comprehensive set of methods for imaging cells, synapses, neuromolecules, circuits, and brain function in health and disease.  Imaging in Neuroscience covers basic techniques, such as maintaining live cells and tissue slices during imaging, as well as cutting-edge techniques, such as optogenetics, uncaging, calcium imaging, and imaging neuronal activity.

Edited by Fritjof Helmchen (University of Zurich) and Arthur Konnerth (Technical University, Munich), Imaging in Neuroscience includes 92 chapters with step-by-step protocols and background information for visualizing neural dynamics.  The book also features a set of appendices with a glossary of imaging terms and other useful information on spectra, lenses, filters, and safe handling of imaging equipment.

Monitoring Individual Molecules with Quantum Dots

The first article details the use of nanometer-sized quantum dots (QDs) to track the motion of individual membrane molecules over time.  QDs possess strong fluorescence and photostability, permitting extended recording times compared to other methods.  In the article, authors Sabine Lévi, Maxime Dahan, and Antoine Triller (Ecole Normale Supérieure, Paris) provide step-by-step methods to stain neurons with QDs and to track QD-labeled molecules using single-fluorophore epifluorescence, as well as guidance for interpreting the data and reconstructing the trajectory of individual QD-labeled molecules.  These methods have been successfully used to follow the diffusion of individual glycine receptors, GABA receptors, NMDA receptors, lipid raft markers, glycophosphatidylinositol-anchored green fluorescent protein (GPI-GFP), and other molecules of interest.

Studying Specific Neural Activities with Microbial Opsins

The second article describes characteristics of various microbial opsins that are used in optogenetics.  Optogenetics is a revolutionary technology that combines optics and genetics to study very specific events, such as action potentials, in their natural context—even in freely moving mammals.  Microbial opsins are light-sensing proteins that regulate ion fluxes to control biological activities, and their corresponding genes can be expressed in mammalian neurons to enable millisecond-precision optical control of neural activity.  The authors of the article, Karl Diesseroth and colleagues (Stanford) and Peter Hegemann (Humboldt-Universität, Berlin), describe the diversity of microbial opsin genes, including those for bacteriorhodopsins, proteorhodopsins, halorhodopsins, and channelrhodopsins, and the structure-function properties of their corresponding proteins.  This overview will be useful to those looking to employ optogenetics as a research tool.

I had a hand in putting these books together, and I’m always pleased when we manage to publish books that I know I would have found incredibly helpful in my previous incarnation as a bench scientist. These two hit home as I was a postdoc in an imaging lab. While that was ten (10!!!) years ago, it’s almost shocking to realize that there weren’t any comprehensive lab manuals out there that really covered the whole of bio-imaging, from the basics of optics to the most current, bleeding-edge techniques. Consider that problem solved, courtesy of series editor Rafa Yuste.

The new series spins off from a previous set of publications. In 2000, CSHL Press published Imaging Neurons, based on a CSHL laboratory course. The book was a few years ahead of its time, and the methods had really caught on by the time the sequel, Imaging in Neuroscience and Development was released in 2005. Five years later, and there’s been far too many new applications developed to fit into one volume, hence the release of the new series.

Imaging: A Laboratory Manual is the flagship of the series. It offers all the basics: optics, confocal, multi-photon, lasers, cameras, staining cells, etc. The manual goes on from there though, through labeling and indicators to advanced techniques like photoactivation, light sheet imaging, array tomography, fast imaging, molecular imaging, superresolution imaging and every acronym you can think of (FRET, FLIM, FRAP, FIONA, PALM, STORM, BiFC, AFM, TIRFM to name a sampling). If you have a microscope in your lab or if you spend any time in your local imaging center, this is the book you need.

Imaging in Developmental Biology: A Laboratory Manual is the second book in the series, just released. We old-school developmental biologists used to have to look at fixed sectioned specimens taken from different time points, and try to piece together the big picture of what was really happening as an embryo developed. New techniques have revolutionized our understanding of dynamic processes, as they allow for real-time imaging, often over the entire course of an organism’s development. Like the preceding volume, the book starts with the basics, methods for visualizing development in laboratory standard model organisms (C. elegans, Drosophila, zebrafish, Xenopus, avians and mouse) and then step by step brings the reader to the cutting edge of imaging technology.

The supplemental movies from both books are freely available through Cold Spring Harbor Protocols. Look for a third volume in March, on Imaging in Neuroscience, which will offer an astounding 90-plus chapters for analyzing every aspect of the nervous system in detail.

Of these methods, PALM (Photoactivated Localization Microscopy) provides the highest shown resolution in biological samples (approximately 10 nanometers) and allows for the assessment of individual molecules. In the December issue of Cold Spring Harbor Protocols, Oregon Health Science University’s Haining Zhong presents Photoactivated Localization Microscopy (PALM): An Optical Technique for Achieving ~10-nm Resolution. The article provides an overview of the basic principles of PALM, its implementation and the potential applications in neuroscience.

Caenorhabditis elegans has been a key organism for understanding cellular differentiation and development. The fate of every one of the worm’s somatic cells has been mapped out, and its short developmental time, transparent shell, and nonpigmented cells makes C. elegans an ideal subject for imaging studies. Timothy Walston from Truman State University and Jeff Hardin from the University of Wisconsin-Madison provide An Agar Mount for Observation of Caenorhabditis elegans Embryos, an easy way to prepare live C. elegans embryos for microscopic visualization. The method involves embedding the embryo in agar to hold it in place,providing a fixed orientation for consistent imaging. Embryos prepared this way are amenable to both light microscopy and confocal microscopy. As one of our featured articles, the protocol is freely available to subscribers and non-subscribers alike.