Diverse 'connectomes' hint at genes' limits in the nervous system

February 10, 2009
Axons in the connectomes of the left and right interscutularis muscles of a 1-month old animal were color-coded based on the rank-order of their motor unit sizes (the number of muscle fibers innervated by each axon) in each connectome. Thus each axon and its contralateral counterpart can be identified in the connectomes, and subsequently their morphologies can be compared. Credit: Ju Lu/Harvard University

Genetics may play a surprisingly small role in determining the precise wiring of the mammalian nervous system, according to painstaking mapping of every neuron projecting to a small muscle mice use to move their ears. These first-ever mammalian "connectomes," or complete neural circuit diagrams, reveal that neural wiring can vary widely even in paired tissues on the left and right sides of the same animal.

Scientists at Harvard University and the Massachusetts Institute of Technology describe the work this week in the journal PLoS Biology, accompanied by vivid images depicting neurons that are strikingly treelike, but also tremendously varied.

"We had expected to find a great degree of neural symmetry in the same mouse's two interscutularis muscles, but this isn't even close to true," says Jeff W. Lichtman, professor of molecular and cellular biology in Harvard's Faculty of Arts and Sciences.

In order to understand how each nerve cell integrates into the functional organization of a neural circuit, it is necessary to obtain the complete wiring diagram (connectome) of the circuit by tracing out all the neural processes in the sample. We used confocal laser scanning microscopy to image all the axons that innervate a small ear muscle in transgenic mice that express fluorescent protein in motor neurons. Shown here is one of the reconstructed image stacks containing branches of ~ 10 axons. Each axon was traced out in a semi-automated image processing program and rendered in 3D with a distinct color. This image stack is representative of the hundreds of image stacks from which the entire connectome was reconstructed. Credit: Ju Lu/Harvard University

"It looks like the mammalian nervous system may be a bit like a football game," he adds. "Even when the rules are the same, every single outcome is unique."

Curiously, the connectome of the mouse interscutularis -- a muscle also found in dogs, rats, and other mammals that readily move their ears -- reveals that some of its neurons are as much as 25 percent longer than is necessary. This casts doubt on a longstanding assumption among neuroscientists that neural wiring length is generally minimized to conserve space, energy, and resources.

"This well-known hypothesis that wiring length should be minimized has been in the scientific literature for decades," says Ju Lu, a postdoctoral researcher in molecular and cellular biology at Harvard. "It's very surprising, frankly, to find so much excess wiring in the mammalian nervous system."

Lichtman and Lu's work represents only the second connectome to date, following one for the worm Caenorhabditis elegans. While their task initially appeared manageable -- the entire interscutularis muscle is but a few millimeters in length -- teasing out the muscle's tangle of about 15 intricately branched and intertwined axons proved fiendishly complex.

"It's a bit like taking a giant plate of spaghetti and, without unraveling it, trying to figure out which strand goes where," says Lu. "Except in this case, each strand of spaghetti has up to 37 branches."

Working with mice containing a gene that causes motor neurons to fluoresce, Lichtman and Lu used an automated microscope to gather tens of thousands of images. These images were analyzed with semi-automated tracing tools, although the need for frequent corrections and manual editing by Lu slowed the pace of the mapping to a scant half-millimeter per hour.

Connectomes from a mouse's two interscutularis muscles depict dramatically different neural circuitry even within mirror-image tissues from the same animal.

"Comparison of each neuron and its counterpart on the opposite side of the animal revealed that each connectome was unique," Lichtman says, "demonstrating wiring diagrams that differ substantially in form, even within a common genetic background."

Lichtman says the research suggests the mammalian nervous system is in some ways unexpectedly primitive, its freeform structure lacking the regimentation seen in insects and worms. But, he adds, this seeming randomness may be advantageous.

"This may explain why humans and other mammals can quickly adapt their behaviors to a changing environment," Lichtman says. "We may be less perfected in our genetic evolution, but our flexible neural wiring may allow us to undergo behavioral evolution at a very rapid rate."

Such variation in the nervous system, he adds, could help explain why different humans, each equipped with the same neural building blocks, excel at tasks ranging from dancing to mathematical computations, and from crossword puzzles to bowling.

Source: Harvard University

Explore further: Range of diseases may result when brain self-regulation goes awry, researchers say

Related Stories

Range of diseases may result when brain self-regulation goes awry, researchers say

September 28, 2017
After making many thousands of measurements in experiments spanning more than 10 years, scientists at UC San Francisco have discovered that two molecular partners interact at synapses to maintain stable neuronal function. ...

Better way to culture central nervous cells found

January 29, 2013
A protein associated with neuron damage in people with Alzheimer's disease is surprisingly useful in promoting neuron growth in the lab, according to a new study by engineering researchers at Brown University. The findings, ...

Research showcases most comprehensive wiring diagram of mammalian brain to date

April 2, 2014
Researchers from the Allen Institute for Brain Science have published the first comprehensive, large-scale data set on how the brain of a mammal is wired, providing a groundbreaking data resource and fresh insights into how ...

Wiring for smell sets up early, then persists

April 10, 2014
To accommodate a lifetime of scents and aromas, mammals have hundreds of genes that each produce a different odorant receptor. The complex and diverse olfactory system they build remains adaptable, but a new study in the ...

Making connections in the eye: Wiring diagram of retinal neurons is first step toward mapping the human brain

August 7, 2013
The human brain has 100 billion neurons, connected to each other in networks that allow us to interpret the world around us, plan for the future, and control our actions and movements. MIT neuroscientist Sebastian Seung wants ...

Rethinking things past: Both Hebbian plasticity and neuromodulation essential to memory formation

December 30, 2014
(Medical Xpress)—In 1949, Donald O. Hebb (often called the father of neuropsychology and neural networks) published The Organization of Behavior: A Neuropsychological Theory1, connecting the two previously distinct areas ...

Recommended for you

New approach to studying chromosomes' centers may reveal link to Down syndrome and more

November 20, 2017
Some scientists call it the "final frontier" of our DNA—even though it lies at the center of every X-shaped chromosome in nearly every one of our cells.

Genome editing enhances T-cells for cancer immunotherapy

November 20, 2017
Researchers at Cardiff University have found a way to boost the cancer-destroying ability of the immune system's T-cells, offering new hope in the fight against a wide range of cancers.

A math concept from the engineering world points to a way of making massive transcriptome studies more efficient

November 17, 2017
To most people, data compression refers to shrinking existing data—say from a song or picture's raw digital recording—by removing some data, but not so much as to render it unrecognizable (think MP3 or JPEG files). Now, ...

Genetic mutation in extended Amish family in Indiana protects against aging and increases longevity (Update)

November 15, 2017
The first genetic mutation that appears to protect against multiple aspects of biological aging in humans has been discovered in an extended family of Old Order Amish living in the vicinity of Berne, Indiana, report Northwestern ...

US scientists try first gene editing in the body

November 15, 2017
Scientists for the first time have tried editing a gene inside the body in a bold attempt to permanently change a person's DNA to try to cure a disease.

Genetic variant prompts cells to store fat, fueling obesity

November 13, 2017
Obesity is often attributed to a simple equation: People are eating too much and exercising too little. But evidence is growing that at least some of the weight gain that plagues modern humans is predetermined. New research ...


Adjust slider to filter visible comments by rank

Display comments: newest first

not rated yet Feb 10, 2009
A wierd result. It'll be interesting to see if this conclusion is confirmed, and if the conclusion then drawn withstands scrutiny. I'm sure they must have considered it, but what are the odds that a particular set of genetics may precisely encode left and right muscular controls separately and differently for different purposes, like "left-handedness" etc.?
1 / 5 (1) Feb 10, 2009
What else are they wrong about???

Think about that for a few seconds within the context of all other sciences as well.

Many entire edifices of science need be torn down and re-started, is the final result-when something new is found-instead of the usual desire to slam square pegs into round holes. We see children doing this as they sit on the floor at home or in day-care-every day.

Never fail to understand that this established pattern still sits there--in the mind even in the tenured scientist at the age of 60. It is just waiting to be activated at it's base root, which is emotion. Oh. Emotion and the autonomous system rules the base formation of logic. Fancy that.

These things are done --as the proponents do not want to change their ways. Too emotionally difficult.

Too bad that science is SUPPOSED to be logic.
1 / 5 (1) Feb 10, 2009
I'm not impressed.

As lengould100 pointed out handedness could explain some of the dissimilarities, the right and left sides of the nervous system are obviously wired differently.

Also, this process doesn't appear to require precise wiring. More critical processes could still be much more precisely controlled.

As for the apparently messy wiring, the extra meandering could be to reduce stress on the wires caused by the flexibility of the surrounding tissue. Just look at the wiring harness between your car body and the door.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.