Imaging the Brain with Sculpted Light

Perhaps the biggest goal in neuroscience is to understand how individual neurons interact with each other in both space and time.  The more detailed our understanding of complex neural networks is, the more we can understand how an organism’s nervous system processes information to generate behavior.  To achieve this goal, neuroscience research has focused on obtaining detailed anatomical wiring maps, such as those produced by the Human Connectome ProjectHowever, enormous efforts have also been made to map neural activity and how these networks engage in dynamic activities.  Classically, this has been achieved using electrophysiology, in which the activity of single neurons is recorded in real time.  With the advent of optogenetics and advanced imaging techniques, researchers have been able to monitor the activity of many neurons at once.  Most recently, a group of Austrian scientists developed a new, high speed imaging technique that allowed for the 3-dimensional imaging of the brain of C. elegans (described in the September issue of Nature Methods).

C. elegans Knowing Neurons

One of the simplest model organisms used in neuroscience research is the nematode C. elegans.  With 302 neurons and 8000 synapses, it’s the only animal for which the complete nervous system has been anatomically mapped.  The researchers chose to study this animal in the hopes that they could establish a complete map of structure-function relationships in an entire intact nervous system.  This has not been done before because of the limitations of conventional imaging, which has an inherent tradeoff between spatial or temporal accuracy and the size of the brain region that can be studied.  In other words, if you can resolve the activity of a single cell with high precision, you cannot simultaneously look at the function of all the neurons in an entire brain.  To overcome these shortcomings, the research team developed a way to “sculpt” the 3-dimensional distribution of light into “discs” throughout the sample.  This way they could record the activity of 70% of all the nerve cells in the nematode head with high spatial and temporal resolution!

C. elegans brain Knowing Neurons
Watch this video to see this brain-wide imaging in action!

As amazing as this new microscopy method is, it’s only half the story.  In order to visualize the neurons, they were tagged with a fluorescent protein called GCaMP5, which lights up when it binds to calcium.  Since neural activity causes a rapid change in the amount of calcium in the cell, calcium indicators like GCaMP5 have been heavily used to image neural activity (Akerboom et al., 2012).

Armed with these microscopy and genetic tools, it seems even more conceivable that neuroscientists will be able to establish a functional map of the C. elegans nervous system as well as those of other model organisms.  Moreover, these techniques will allow neuroscientists to tackle even more complicated questions: how is sensory information processed at the level of the whole brain?  For now, let’s celebrate these methodological advances, as they will open the way to do experiments that were not possible before!

To read more about mapping the brain, check out the June 2013 Focus Issue from Nature.

For a laugh, check out these C. elegans doing the Harlem Shake:



Schrödel T., Prevedel R., Aumayr K., Zimmer M. & Vaziri A. (2013). Brain-wide 3D imaging of neuronal activity in Caenorhabditis elegans with sculpted light, Nature Methods, 10 (10) 1013-1020. DOI: 

Akerboom J., Chen T.W., Wardill T.J., Tian L., Marvin J.S., Mutlu S., Calderon N.C., Esposti F., Borghuis B.G., Sun X.R. & Gordus A. (2012). Optimization of a GCaMP Calcium Indicator for Neural Activity Imaging, Journal of Neuroscience, 32 (40) 13819-13840. DOI: 10.1523/JNEUROSCI.2601-12.2012

Images adapted from Simon Fraser Universitythe Hammerland Lab at Yale, and Worm Atlas.

Kate Fehlhaber

Kate graduated from Scripps College in 2009 with a Bachelor of Arts degree in Neuroscience, completing the cellular and molecular track with honors. As an undergraduate, she studied long-term plasticity in models of Parkinson’s disease in a neurobiology lab at University of California, Los Angeles. She continued this research as lab manager before entering the University of Southern California Neuroscience graduate program in 2011 and then transferring to UCLA in 2013. She completed her PhD in 2017, where her research focused on understanding the communication between neurons in the eye. Kate founded Knowing Neurons in 2011, and her passion for creative science communication has continued to grow.