Shown here is the visual reconstruction of synapses in part of the mouse cortex that responds to whisker stimulation. Neurons are depicted in green. Multicolored dots represent separate synapses— about one billion of them per cubic millimeter of tissue. Credit: Stephen Smith

The cortex of the human brain holds more than 100 trillion neural connections, or synapses, packed into a layer of tissue just 2 to 4 millimeters thick. Visualizing these densely packed units individually has proved extremely challenging. Synapses in the brain are crowded in so close together that they cannot be reliably resolved by even the best of traditional light microscopes, explains Stanford neuroscientist Stephen Smith in a press release from the university.

Smith and collaborators have developed a new technology that highlights all the synapses in the mouse cortex. "Now we can actually count them and, in the bargain, catalog each of them according to its type," he says.

The ability to study synapses en masse could help scientists understand Alzheimer's disease, autism and other neurological and developmental disorders. Many of these have been shown to be linked to dysfunction or degeneration of the synapses.

Smith and collaborators first sliced thin pieces of brain tissue and then stained the slices with groups of three different antibodies. Each antibody was designed to bind to a specific type of protein found in different types of synapses and to glow a certain color, with 17 different antibodies in all.

Sections of neurons are shown in green. The protruding bulbs are the parts of the neuron that receives a connection from another cell, highlighted in blue, yellow and pink.

After each application huge numbers of extremely high-resolution photographs were automatically generated to record the locations of different fluorescing colors associated with antibodies to different synaptic proteins. The antibodies were then chemically rinsed away and the procedure was repeated with the next set of three antibodies, and so forth. Each individual synapse thus acquired its own protein-composition "signature," enabling the compilation of a very fine-grained catalog of the brain's varied synaptic types.

These individual pictures were then stitched together using specialized software also designed in Smith's lab, creating a three-dimensional image of the section of brain tissue. The research was published this week in the journal Neuron.

The researchers were able to "travel" through the resulting 3-D mosaic and observe different colors corresponding to different synaptic types. Observed in this manner, the brain's overall complexity is almost beyond belief, said Smith. "One synapse, by itself, is more like a microprocessor —with both memory-storage and information-processing elements — than a mere on/off switch. In fact, one synapse may contain on the order of 1,000 molecular-scale switches. A single human brain has more switches than all the computers and routers and Internet connections on Earth," he said.

His group is now focused on using array tomography to tease out more such distinctions, which should accelerate neuroscientists' progress in, for example, identifying how many of which subtypes are gained or lost during the learning process, after an experience such as traumatic pain, or in neurodegenerative disorders such as Alzheimer's. With support from the National Institutes of Health, Smith's lab is using array tomography to examine tissue samples from Alzheimer's brains obtained from Stanford and the University of Pennsylvania.

"I anticipate that within a few years, array tomography will have become an important mainline clinical pathology technique, and a drug-research tool," Smith said. He and Micheva are founding a company that is now gathering investor funding for further work along these lines.

Electrical engineers in Debdeep Jena's lab at the University of Notre Dame have found a way to make two nitride semiconductors conduct electricity better, which may make them useful for building more effective ultraviolet (UV) lasers and light-emitting diodes (LEDs). These devices could enable a wide range of applications such as high-density optical data storage, water treatment, sterilization of medical equipment, UV-enabled security marks on credit cards and paper money, and biological imaging.

A prototype UV LED made using Jena's technique for growing nitride semiconductors. Credit: AAAS

Nitride semiconductors such as aluminum gallium nitride and gallium nitride have the widest spectral range of band gaps--the energy required to move electrons through the material--among all semiconductors, ranging from the infrared through the visible and into the deep UV range. This makes them excellent for use in short-wavelength lasers and in LEDs for solid-state lighting, but it also makes it hard for engineers to design energy-efficient devices.

Like all semiconductors, nitrides need to be "doped" with foreign materials to conduct electricity efficiently. This either provides the material with charge-carrying electrons, or electron vacancies--called holes--that allow electrons to move freely. But the energy barriers in gallium nitride (GaN), for instance, are so large that even devices made with magnesium (the most commonly used hole-dopant for GaN) don't work well at room temperature, making them extremely inefficient.

In a paper published in the January 1, 2010, issue of Science, Jena and his colleagues describe growing graded layers of aluminum gallium nitride (doped with magnesium) on the nitride surface of gallium nitride crystals. This means that the proportion of aluminum to gallium in the top layer increased as its thickness grew. Experiments testing this material's conductivity showed that making the semiconductor this way efficiently activated the magnesium doping atoms at room temperature.

Jena's group also built prototype UV LEDs using both the graded aluminum gallium nitride (AlGaN) material and regular maginesium-doped GaN. The AlGaN LEDs were both more efficient and brighter than the GaN devices. Jena believes that this should make nitride semiconductors much more practical alternatives for any device requiring UV light.

Researchers at the Lawrence Berkeley National Laboratory have used advanced imaging techniques to solve the structure of one of nature's most important molecular machines. A clearer picture of this motor-like protein, which spins along strands of bacterial messenger RNA to read and translate it into proteins, may help pharmaceutical researchers develop new antibiotics. The researchers studied a version of the protein called Rho from E. coli bacteria. This type of protein, called a transcription factor, is also important in human development and disease.

In the video below, Rho, which is shaped like a hexagon with a hole in the center, is shown in cross section as it walks along the RNA strand, shown in orange. Rho spirals in such a way that it can only move in one direction along the RNA strand, which is crucial to making proteins properly.

In order to get a better picture of Rho, the Berkeley researchers used the lab's Advanced Light Source, which accelerates electrons to very high energies in order to create some of the brightest x-rays in the world. Using these x-rays, they were able to see a part of Rho's structure that was previously not very well understood.