Month: November 2013

http://www.pnas.org/content/110/45/E4266

Worcester Polytechnic Institute and Rockefeller University researcher in have developed a system to image brain activity in multiple awake and unconstrained worms. The technology makes it possible to study the genetics and neural circuitry associated with animal behavior.  It can also be used as a high-throughput screening tool for drug development targeting autism, anxiety, depression, schizophrenia, and other brain disorders.

Numerous studies have been done by “worm labs” around the world exploring various neurological processes in C. elegans. These have typically been done using one worm at a time, with the animal’s body fixed in place on a slide. In his paper, Professor Dirk Albrecht’s team details how they imaged, recorded, and analyzed specific neurons in multiple animals as they wormed their way around a custom-designed microfluidic array, called an arena, where they were exposed to favorable or hostile sensory cues.

The team engineered a strain of worms with neurons near the head that would glow when they sensed food odors. In experiments involving up to 23 worms at a time, Albrecht’s team infused pulses of attractive or repulsive odors into the arena and watched how the worms reacted. In general, the worms moved towards the positive odors and away from the negative odors, but the behaviors did not always follow this pattern.

In addition to watching the head neurons light up as they picked up odor cues, the new system can trace signaling through “interneurons.” These are pathways that connect external sensors to the rest of the network (the “worm brain”) and send signals to muscle cells that adjust the worm’s movement based on the cues. Numerous brain disorders in people are believed to arise when neural networks malfunction. In some cases the malfunction is dramatic overreaction to a routine stimulus, while in others it is a lack of appropriate reactions to important cues. Since C. elegans and humans share many of the same genes, discovering genetic causes for differing neuronal responses in worms could be applicable to human physiology. Experimental compounds designed to modulate the action of nerve cells and neuronal networks could be tested first on worms using Albrecht’s new system. The compounds would be infused in the worm arena, along with other stimuli, and the reaction of the worms’ nervous systems could be imaged and analyzed.

http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.3572.html

Last year Johns Hopkins researchers reported that brain cells known as parvalbumin-expressing interneurons instruct nearby stem cells not to divide by releasing a chemical signal called GABA.

In a new study, Professors Hongiun Song and Guo-li Ming wanted to find out how GABA from surrounding neurons affects the newborn neurons that stem cells produce. Many of these newborn neurons naturally die soon after their “birth,” Song says; if they do survive, the new cells migrate to a permanent home in the brain and forge connections called synapses with other cells.

To learn whether GABA is a factor in the newborn neurons’ survival and behavior, the research team tagged newborn neurons from mouse brains with a fluorescent protein and then watched their response to GABA.

“We didn’t expect these immature neurons to form synapses, so we were surprised to see that they had built synapses from surrounding interneurons and that GABA was getting to them that way,” Song says. In the earlier study, the team had found that GABA was getting to the synapse-less stem cells by a less direct route, drifting across the spaces between cells.

The team engineered the interneurons to be either stimulated or suppressed by light. When stimulated, the cells would indeed activate nearby newborn neurons, the researchers found. They next tried the light-stimulation trick in live mice, and found that when the specialized interneurons were stimulated and gave off
more GABA, the mice’s newborn neurons survived in greater numbers than otherwise. This was in contrast to the response of the stem cells, which go dormant when they detect GABA.

“This appears to be a very efficient system for tuning the brain’s response to its environment,” says Song. “When you have a high level of brain activity, you need more newborn neurons, and when you don’t have high activity, you don’t need newborn neurons, but you need to prepare yourself by keeping the stem cells active. It’s all regulated by the same signal.”

Song notes that parvalbumin-expressing interneurons have been found by others to behave abnormally in neurodegenerative diseases such as Alzheimer’s and mental illnesses such as schizophrenia.