Wiring for smell sets up early, then persists

April 10, 2014, Brown University
Native neurons (green) that express the odorant receptor MOR28 attach to known glomeruli (above). Neurons expressing engineered MOR28 (red) may attach to other glomeruli. Growing side-by-side, the red neurons could redirect some of the green, but only in the perinatal period. Neuron wiring established early remained stable in adults. Credit: Barnea lab/Brown University

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 journal Science shows that the system's flexibility, or plasticity, has its limits. Working in mice, Brown University scientists found that the fundamental neural wiring map between the nose and the brain becomes established in a critical period of early development and then regenerates the same map thereafter.

The findings not only reveal a key moment with lifelong consequences in the development of a vital sensory system, but also may provide a "heads up" for bioengineers and doctors looking to develop regenerative therapies for the . As flexible as the brain is, it also has mechanisms—at least in the olfactory system—to ensure that the connections established early will be maintained for life.

"Our experiments enabled us to reveal that the system has some 'memory'," said Gilad Barnea, the Robert and Nancy Carney Assistant Professor of Neuroscience and corresponding author of the study.

Tracking connections

Lead author Lulu Tsai, now a postdoctoral fellow at Drexel University, conducted the experiments under Barnea's supervision while she was a graduate student at Brown. Tsai and Barnea are the paper's only authors.

"Lulu really sweated for this," Barnea said. "These experiments were very complicated."

Tsai and Barnea sought to track the development of sensory neurons that express an odorant receptor, MOR28, through space and time in the mouse olfactory system. They did so by engineering a version of the receptor that could be expressed or suppressed at key developmental times. Neurons that express the engineered version of MOR28 would glow red under the microscope. In addition, the researchers tweaked the native version of the receptor gene such that neurons that express it would glow green.

n a typical mammalian olfactory system, neurons expressing a receptor gene like MOR28 will be found randomly sprinkled around the lining of the nose, but their long, wiry axons will all connect to just two symmetrical pairs of structures called glomeruli within the brain's olfactory bulb. The glomeruli relay odor signals to the rest of the brain.

Barnea and Tsai's developed similarly, with most native MOR28-expressing neurons connecting their axons into the typical glomeruli during . But when the researchers let the engineered MOR28 become expressed, those connected into other nearby glomeruli. Significantly, native MOR28 axons sometimes ended up becoming rerouted to these alternate glomeruli with their engineered brethren. Under the microscope, green mixed with red.

It's a novel finding that some engineered MOR28-expressing neurons could reroute native MOR28-expressing neurons to join them outside the standard four MOR28 glomeruli. It suggests that influence each other during early development as they find their way to glomeruli and don't, as current neurodevelopmental models suggest, do so autonomously.

Timing is everything

But the main finding of a critical period where wiring becomes locked in came about as Tsai controlled the timing of engineered MOR28 receptor expression. She induced that on the day some mice were born, a week later in other mice, and two weeks later in still others. In mice where engineered MOR28 expression was allowed at birth, one in nine mice showed rerouting of native MOR28 axons to glomeruli with engineered MOR28. A week out only one in 17 mice showed any rerouting. After two weeks it never happened.

"We conclude that there is a critical period for the formation of rerouted-MOR28 glomeruli that ends at birth or shortly thereafter," Tsai and Barnea wrote in Science.

The researchers also looked at this in other ways. In one experiment, they found that they didn't need to maintain expression of the engineered MOR28 for the rerouted connections to persist into adulthood. Once established, they remained.

They also tested whether the rerouting seen in developing mice could occur in adults. They let native MOR28-expressing axons grow alone, and then wiped them out. Then they let native and engineered MOR28-expressing neurons regrow fresh connections to the together when the mice were adults. They never saw rerouting in the adult mice as connections regrew, suggesting that the ability to reroute is lost in adulthood.

In yet another experiment, they found that if they let rerouted glomeruli become established and then wiped out olfactory neurons, the regrowing connections would return to the rerouted glomeruli even when the engineered receptor was no longer expressed. So although adults can't create new rerouted glomeruli, they will restore existing ones.

All of the experiments together showed that the fundamental wiring diagram of the is laid out and implemented early in life. Whatever pattern is established then stays there for life.

These observations suggest that the course of early development has lifelong consequences, Barnea said, providing insight into understanding of neurodevelopmental and psychiatric disorders.

These observations may also have implications for regenerative medicine, Barnea said. Once neural circuits are established, it may be difficult to induce subsequent fundamental alterations to them. On the other hand, learning more about the differences between early development and the adult system may help to devise better regenerative strategies.

"It is clear that there is much more for us to learn about the of neural circuits," he said.

Explore further: Mice have distinct subsystem to handle smell associated with fear

More information: "A Critical Period Defined by Axon-Targeting Mechanisms in the Murine Olfactory Bulb," by L. Tsai et al. Science, 2014.

Related: Finding the target: How timing is critical in establishing an olfactory wiring map

Related Stories

Mice have distinct subsystem to handle smell associated with fear

July 23, 2012
A new study finds that mice have a distinct neural subsystem that links the nose to the brain and is associated with instinctually important smells such as those emitted by predators. That insight, published online this week ...

A protein in neurons in the nose controls the sensitivity of mice to smells in their environment

October 4, 2013
Information about odorant molecules in the environment helps animals to find food, select mates and avoid predators. Yoshihiro Yoshihara and colleagues from the RIKEN Brain Science Institute have now identified a protein ...

New model show how the brain is organized to process odor information

March 19, 2012
Just like a road atlas faithfully maps real-word locations, our brain maps many aspects of our physical world: Sensory inputs from our fingers are mapped next to each other in the somatosensory cortex; the auditory system ...

Recommended for you

Brain zaps may help curb tics of Tourette syndrome

January 16, 2018
Electric zaps can help rewire the brains of Tourette syndrome patients, effectively reducing their uncontrollable vocal and motor tics, a new study shows.

A 'touching sight': How babies' brains process touch builds foundations for learning

January 16, 2018
Touch is the first of the five senses to develop, yet scientists know far less about the baby's brain response to touch than to, say, the sight of mom's face, or the sound of her voice.

Researchers identify protein involved in cocaine addiction

January 16, 2018
Mount Sinai researchers have identified a protein produced by the immune system—granulocyte-colony stimulating factor (G-CSF)—that could be responsible for the development of cocaine addiction.

Neuroscientists suggest a model for how we gain volitional control of what we hold in our minds

January 16, 2018
Working memory is a sort of "mental sketchpad" that allows you to accomplish everyday tasks such as calling in your hungry family's takeout order and finding the bathroom you were just told "will be the third door on the ...

Brain imaging predicts language learning in deaf children

January 15, 2018
In a new international collaborative study between The Chinese University of Hong Kong and Ann & Robert H. Lurie Children's Hospital of Chicago, researchers created a machine learning algorithm that uses brain scans to predict ...

Preterm babies may suffer setbacks in auditory brain development, speech

January 15, 2018
Preterm babies born early in the third trimester of pregnancy are likely to experience delays in the development of the auditory cortex, a brain region essential to hearing and understanding sound, a new study reveals. Such ...

2 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

JVK
1 / 5 (1) Apr 10, 2014
Ecological variation leads to ecological adaptations via conserved molecular mechanisms in:

Nutrient-dependent/pheromone-controlled adaptive evolution: a model.
Kohl JV. Socioaffect Neurosci Psychol. 2013 Jun 14;3:20553. eCollection 2013. Review.
http://www.ncbi.n...24693353

Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors. Kohl JV. Socioaffect Neurosci Psychol. 2012 Mar 15;2:17338. doi: 10.3402/snp.v2i0.17338. eCollection 2012.
http://www.socioa...38/20758

Human pheromones: integrating neuroendocrinology and ethology.
Kohl JV, Atzmueller M, Fink B, Grammer K. Neuro Endocrinol Lett. 2001 Oct;22(5):309-21. Review. http://www.nel.ed...view.htm

From fertilization to adult sexual behavior. Diamond M, Binstock T, Kohl JV.
Horm Behav. 1996 Dec;30(4):333-53. http://www.hawaii...ion.html
JVK
1 / 5 (1) Apr 10, 2014
Re: critical periods

"The epigenetic effects of nutrients on evolved differences in the diet and starch digestion of dogs and wolves (Axelsson et al., 2013) were detailed at the same time differences in the socialization of these subspecies were attributed to explorations involving only chemosensory input in 3 to 4-week-old wolf pups. For comparison, differences in starch digestion and exploration involving multisensory input in dogs begin a mere 2 weeks later (Lord, 2013). The differences in nutrient-dependent pheromone-controlled socialization, however, extend across a life-time of more aggressive behavior in wolves that have not been domesticated because less digested starch from their diet genetically predisposes infants to first respond to olfactory/pheromonal cues as they initially explore their postnatal environment." http://www.socioa...53/27989

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.