One of scientists’ favorite problems is making the invisible visible. The sea creature-like illustrations that go with this short film are microscopic images of the brain cells that interpret smells that are otherwise invisible, like the scent of a rose or the stench of a rotten egg. The olfactory bulb of a mouse’s brain is revealed by the graceful red and green streaks. The olfactory bulb is divided into hundreds or even thousands of distinct clusters known as glomeruli, and each glomerulus reacts differently to the tens of thousands of odor chemicals that are present in the ambient air. A single glomerulus can be seen in the image above, where signal-carrying axons from sensory cells in the nose have converged.
The olfactory neurons in each glomerulus are tuned to detect odor in the same manner, despite being randomly distributed throughout the animal’s nose. Scientists, like Richard Axel, MD, of the Zuckerman Institute, have known since the 1990s that each of these subsets of olfactory neurons has a receptor protein with a different shape that binds to a different odor molecule. This happens because of how genes work.
And that raises a fascinating neuroscientific puzzle: how do odor-detecting cells that are distributed at random in the nose manage to communicate with only one particular glomerulus in the olfactory bulb? This feat is comparable to, say, 50 friends finding each other after being split up in different parts of a city without knowing the address. They all seem to have a natural sense of direction.
There seems to be a critical understanding of how the olfactory system achieves its wiring precision. Stavros Lomvardas, PhD, principal investigator at the Zuckerman Institute, and MD-PhD candidate Hani Shayya led a team that teased out what they believe to be the main organizing mechanism in mice between the sensory cells in the nose and their glomeruli targets in the brain’s olfactory bulb.
The endoplasmic reticulum (ER), a tubular component of the cell, which is where each receptor protein assumes its distinctive 3D form, is at the center of their discovery (ER). Because each protein’s amino acid sequence is different, so is its shape.
The researchers discovered that the ER is subjected to measurable stress from each of these amino acid sequences (imagine stuffing various objects into a sock). These different levels of ER stress function like a dial setting in ways that aren’t yet clear.
Each setting starts a gene-controlled process that allows the sensory cells’ axons to reach their target glomeruli in the olfactory bulb (via patterns of “guide molecules”).
By projecting their axons to the same glomerulus, each subset of sensory cells with the same-shaped receptor protein achieves its goal. A rose could end up smelling like a rotten egg without this type of receptor-glomerulus mapping, and vice versa.
Dr. Lomvardas, a professor of neuroscience, biochemistry, and molecular biophysics at Columbia University‘s Vagelos College of Physicians and Surgeons, described the research as “mind-blowing.” This system found a way to turn a randomly chosen receptor identity into a genetically encoded and hardwired target in the olfactory bulb.
He emphasized that olfactory deficits frequently occur early in the course of neurodegenerative diseases like Alzheimer’s and Parkinson’s. This means that finding changes early in the olfactory system’s very precise wiring may become “clinically important,” he said.
Shayya made mention of an additional intriguing possibility. It’s possible that olfactory neurons are not the only ones whose wiring with downstream neurons is organized by ER stress. Shayya says that this discovery could help us learn a lot more about the brain if it turns out that all neurons act in this way.
