Nav: Home

iMT: Creating a blueprint for cortical connectivity

January 28, 2019

With a bit of light, a few photo sensitive compounds and specialized paper, the blueprint was born. As the favored type of technical drawing for over a century, architects used this crucial tool for its fast reproducibility as well as its capacity for detailed documentation. For workers on a build site, the document was equally essential as it contained all the necessary design information, the specific types of components included, and served as a guide detailing how everything fit together. If there was ever any doubt, more often than not a quick consult with the blueprint resolved questions and progressed stalled construction forward.

But what happens when neuroscientists have questions about the brain and the intricate connections within? Is there even such a thing as a brain blueprint? Despite an ever-growing body of work uncovering how neurons in the brain form connections, researchers still lack a comprehensive diagram detailing their wiring. Establishing this would have the potential to dramatically improve our understanding of the brain, uncovering how the unique circuitry of individual structures endow us with extraordinary abilities like language, sensory perception and cognition.

Taking the first step towards actualizing a blueprint of the brain, researchers from the Max Planck Florida Institute for Neuroscience (MPFI), have developed a novel technique capable of tracing intricate neural connections with unprecedented sensitivity. In a recent publication in Nature Neuroscience, researchers in the lab of Dr. Hiroki Taniguchi, have demonstrated both the unparalleled specificity and high throughput nature of the approach. By innovatively combining cutting-edge genetic tools with the established technique of monosynaptic tracing, the Taniguchi Lab has created a powerful new tool named intersectional monosynaptic tracing (iMT), capable of unraveling the elaborate circuits within the brain.

Studying a specialized class of brain cell known as inhibitory interneurons, the Taniguchi Lab is interested in looking into how these diverse cells assemble into circuits in various regions of the cerebral cortex. Normally, these cells act to refine, shape and balance information processing, but their dysfunction has been implicated in diseases such as autism, schizophrenia and epilepsy. Elucidating how these inhibitory circuits function, will pioneer novel approaches for the diagnosis and treatment of brain disorders. One challenging aspect hindering the elucidation of cortical circuits, is the sheer diversity of neurons in the brain.

Dr. Taniguchi explains, "While cellular diversity makes the brain so unique, it also conveys a great difficulty in the study of individual circuits. Take for instance the typical inhibitory circuit that we study in the lab; one excitatory principal neuron that transmits information over long distances from one brain region to another, and multiple inhibitory neurons that form connections with it. At first glance this model seems fairly simple but in reality, there are many diverse types of principal and inhibitory interneurons. Each individual type of interneuron is thought to make very specific connections depending on a principal neuron's location, function, and depth within the cortex. Without the ability to take a look at the specific connections formed by each subpopulation of inhibitory neuron, an accurate picture of the circuit cannot be formed.

Dr. Michael Yetman, a Postdoctoral Researcher in the Taniguchi Lab and first author of the paper notes that they wanted a technique that could cut through the cellular diversity of the brain, and only target specific subtypes of neurons. "This way, we could compare and contrast the connections of each unique subtype and study the types of circuits they form," explains Yetman.

iMT was developed with this goal in mind, overcoming limitations of previously used methods to trace connections within the brain. Techniques such as electrical stimulation and monosynaptic tracing, were either too inefficient or lacked the sensitivity necessary to precisely trace connections from many different cell types found in the brain. iMT builds upon its predecessor, but with an innovative twist that is critical for conveying the technique's sensitivity.

"Monosynaptic tracing utilizes a modified form of the rabies virus that lacks a necessary protein, restricting the virus to a single, starter cell and preventing infection of other cells around it," explains Yetman. "But if the protein along with the virus is expressed in only the starter cell, then the virus has the ability to jump and infect nearby cells. For studying neurons within the brain, we can express the virus and protein in a principal neuron and watch as the virus jumps the synaptic connections to only the interneurons directly connected. Once there, the virus in a sense gets stuck without the necessary protein and tells the neuron to start expressing fluorescent protein. With microscopy, we can see the cells that are directly connected to our starter neuron. The limitation is that we could only visualize the connected interneurons as a whole, missing the unique properties of individual subtypes."

To overcome this limitation, the team has added an additional genetic component that reliably and specifically targets single subtypes of interneurons. Once the virus reaches a cell subtype that contains this component, a second new fluorescent protein is expressed. Now scientists have the ability to visualize the interneuron connections as a whole as well as connections of specific interneuron subtypes. Already iMT has proved groundbreaking, revealing dramatic differences in the interneuron circuit design of key inhibitory subtypes as well those of the same subtype that form connections with principal neurons of different brain areas.

"Though iMT is only in the first stages of development, it has the potential to provide a more detailed, brain-wide circuit diagram that will be essential for combating prominent brain disorders," notes Yetman. "In the future we hope to further the technique to include the capability of studying the functional, and not just physical, connections of neural circuits."

iMT and the neuroscientists at MPFI, are taking us one step closer to achieving the construction of a concrete cortical blueprint.

Max Planck Florida Institute for Neuroscience

Related Neurons Articles:

How do we get so many different types of neurons in our brain?
SMU (Southern Methodist University) researchers have discovered another layer of complexity in gene expression, which could help explain how we're able to have so many billions of neurons in our brain.
These neurons affect how much you do, or don't, want to eat
University of Arizona researchers have identified a network of neurons that coordinate with other brain regions to influence eating behaviors.
Mood neurons mature during adolescence
Researchers have discovered a mysterious group of neurons in the amygdala -- a key center for emotional processing in the brain -- that stay in an immature, prenatal developmental state throughout childhood.
Astrocytes protect neurons from toxic buildup
Neurons off-load toxic by-products to astrocytes, which process and recycle them.
Connecting neurons in the brain
Leuven researchers uncover new mechanisms of brain development that determine when, where and how strongly distinct brain cells interconnect.
More Neurons News and Neurons Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...