Summary: The experience of every odor derives from precise circuitry in the brain.
Source: Columbia University
Rendering the invisible visible is among scientists’ favorite challenges.
The sea creature-like images accompanying this short feature are microscopic portraits of brain cells that make sense of otherwise invisible smells, such as the aroma of a rose or the stench of a rotten egg. The graceful red and green streaks reveal cells in a mouse brain’s smell center: its olfactory bulb.
The olfactory bulb is organized into hundreds, even thousands, of segregated clusters, called glomeruli, and each glomerulusresponds in a specific way to the thousands of odor chemicals floating in the air.
Each glomerulus receives signals from its own subset of olfactory neurons,which are randomly distributed in an animal’s nose, yet all tuned to detect odor the same way. Since the 1990s, researchers (notably, the Zuckerman Institute’s own Richard Axel, MD, among others)have known that each of these subsets of olfactory neurons bears a uniquely shaped receptor protein (thanks to a randomizing gene-based process) that latches specifically onto a different odor molecule.
And that presents quite the neuroscientific mystery: how can each randomly located, odor-detecting cell in the nose manage to send signals to just one specific glomeruluswithin the olfactory bulb?
This feat is akin to, say, 50 friends who are originally separated in random places in a city making their way to the same apartment without initially having the address. Somehow they inherently all know where to go.
A pivotal insight into how the olfactory system achieves its wiring precision appears to be in hand. In a study published today in Cell, Zuckerman Institute Principal Investigator Stavros Lomvardas, PhD, and MD-PhD candidate Hani Shayya led a team that teased out what they suspect is the central organizing process in mice between the nose’s sensory cells and their glomeruli targets in the brain’s olfactory bulb.
The heart of their discovery resides in the shape of each receptor proteinas it assumes its unique 3D form within a tubular component of the cell known as the endoplasmic reticulum (ER). Each protein’s shape is determined by the unique sequence of its amino acid components.
Each of these amino acid sequences,the researchers found, imposes a measurable degree of stress on the ER (imagine stuffing various objects into a sock). In ways not yet known, these different degrees of ER stress act like a dial setting.
Each setting triggers a gene-directed process by which the sensory cells effectively direct their axons (via patterns of “guidance molecules”) to their target glomeruli within the olfactory bulb.
This way, each subset of sensory cells with the same-shaped receptor protein ends up projecting its axons to the very same glomerulus. Without a receptor-glomerulus mapping of this kind, a rose could end up smelling like a rotten egg and vice versa.
“It is mind blowing,” said Dr. Lomvardas, also a professor of neuroscience and of biochemistry and molecular biophysics at Columbia’s Vagelos College of Physicians and Surgeons.
“This system found a way to create a genetically encoded, hard-wired means of transforming randomly-chosen receptor identity to a very precise target in the olfactory bulb.”
He pointed out that neurodegenerative diseases, including Alzheimer’s and Parkinson’s, often involve olfactory deficits early in the disease process. This suggests that early detection of disruptions in the olfactory system’s high-precision wiring could become “clinically important,” he said.
Shayya pointed to another tantalizing possibility. Perhaps, olfactory neurons are not alone in the way ER stress organizes their wiring with downstream neurons. “If it turns out that all neurons do this, this discovery could help us understand much more about the brain,” said Shayya.
ER stress transforms random olfactory receptor choice into axon targeting precision
Olfactory receptor (OR) protein sequences determine neuronal ER stress levels
ER stress levels correlate with axon guidance gene expression differences
Manipulation of ER stress levels alter axon targeting specificity
ER stress-responsive Ddit3 levels transform OR identity into targeting specificity
Olfactory sensory neurons (OSNs) convert the stochastic choice of one of >1,000 olfactory receptor (OR) genes into precise and stereotyped axon targeting of OR-specific glomeruli in the olfactory bulb. Here, we show that the PERK arm of the unfolded protein response (UPR) regulates both the glomerular coalescence of like axons and the specificity of their projections.
Subtle differences in OR protein sequences lead to distinct patterns of endoplasmic reticulum (ER) stress during OSN development, converting OR identity into distinct gene expression signatures. We identify the transcription factor Ddit3 as a key effector of PERK signaling that maps OR-dependent ER stress patterns to the transcriptional regulation of axon guidance and cell-adhesion genes, instructing targeting precision.
Our results extend the known functions of the UPR from a quality-control pathway that protects cells from misfolded proteins to a sensor of cellular identity that interprets physiological states to direct axon wiring.