Necklace Cell: New Logic for Odor Information Processing

The taste of mowing, the taste of burning wood, the taste of newly paved asphalt roads, or the taste of mother cooking.

Is there a taste that instantly brings you back to a moment in your childhood? The author has recently been deeply immersed in Proust’s ambiguity, and there is such an experience about the “cake taste”:

It was dark and cloudy the next day, and my mood was very depressed. I accidentally took a spoonful of tea and sent it to my mouth. At first I had picked up a piece of “Little Madeleine” and put it into the tea to prepare it for softening. The spoonful of tea with the scum of scum touched my captain and suddenly made me stunned. I noticed a different change in my body. A kind of pleasant pleasure spread throughout the body, I feel super clean, but I don’t know why. I only think that in life, the glory and disgrace are all light and the robbing of the back is not a big problem. The so-called short life is just a momentary illusion; that situation is like the effect of love, it enriches me with a valuable spirit. Perhaps, this feeling is not from the outside world, it is my own. I no longer feel mediocre, wretched, and vulgar. Where did this strong thrill come from? I feel that it is related to the taste of tea and snacks, but it goes far beyond the taste and is definitely different from the nature of taste. So where does it come from? What does it mean? Where can I receive it?

Little Madeleine cake, picture from

How do we smell the taste? Classic theory from the 2004 Nobel Prize

To answer this question, we must first understand What are the receptors that feel the taste? . The next step is to know that the various receptors are How to encode different odor molecules And their How to tell the next level of neurons about odor information

The known human olfactory system, from [1]. The characteristics of Olfactory receptor cells are:Each cell expresses a specific olfactory GPCR receptor(GPCR: G-protein coupled receptor, the most common receiver category on cell membranes). Because various odor molecules can usually activate multiple receptors, the odor does not correspond to the olfactory cells;Different combinations of olfactory cells allow us to distinguish between taste types that are much larger than the number of olfactory cells.

So how does the downstream neural circuit decode the odor after the odorant activates the olfactory cell? The neural circuit from the nose to the sniffing ball is very interesting: An olfactory sensory cell expressing the same receptor will project to the same olfactory globule. This is called the “marking line” system. As shown above, each color represents a receptor, although the same color of olfactory cells are distributed at different locations in the nasal epithelium, and their axons project to the mitral valve cells in the same lower olfactory globule.

The discovery of olfactory receptors and this organizational principle of the olfactory system won the 2004 Nobel Prize in Physiology or Medicine for Richard Axel and Linda Buck.

Summary: Three classic principles of olfactory perception

1. Each cell expresses a specific olfactory receptor.

2. The olfactory receptor is a GPCR protein.

3. Marker line system: The olfactory sensory cells that express the same receptor will project to the same olfactory globule.

The olfactory system of mice: the story has just begun

Our understanding of the olfactory system is largely due to the model animals: especially mice, the rise of genetic tools allowed scientists to study specific cell types.

The picture is translated from Nilay Yapici’s summary, based on references [2, 3].

The olfactory cells in the previous section are only part of the mammalian olfactory system. For mice, there are three similar systems that are currently well studied: Olfactory sensory cells in the main olfactory epithelium Projecting onto the main olfactory bulb, conforming to a cell and a receptor and marker line principle, expressing the GPCR protein; Pear-nose neurons in the pear nose , projecting to the accessory olfactory bulb, also conforms to the principle of one cell and one receptor, expressing the GPCR protein; Olfactory sensory cell The same story.

The other two olfactory cells are unclear: in the main olfactory epithelium, in addition to the classical olfactory sensory cells, there is also a type of necklace cells; in the Grüneberg organ there is another class of cells expressing OMP; Are they also in line with the classic three principles of smell?

Necklace cells: heterogeneous in olfactory cells

The following is the topic, starting with this summer’s “Cell” “a class of non-GPCR chemoreceptors to define the new logic of mammalian sense of smell” [4].

Necklace cells are located in the main olfactory epithelium, and previous studies have shown that they can sense gases such as carbon dioxide, pheromones, plant odors, and some components in the urine. but Necklace cells do not express GPCR proteins.

So how do they perceive various odor molecules? Through RNA sequencing (inner translation: molecular biology black magic 1), the authors found Necklace cells specifically express the Ms4a gene family, encoding a class of transmembrane proteins (4 times transmembrane, long chain outside the membrane, in line with the characteristics of molecular receptors).

By observing transgenic human liver stem cells expressing GCaMP6s+Ms4a+ (I also translated it: this time is Black Magic 2), the authors found Different Ms4a proteins respond to different chemicals , as shown below (Fig. 3B):

At this point we know that necklace cells are likely to violate the traditional principle 2:The olfactory receptor is a GPCR protein.

Then the necklace cells comply with principle 1, Each cell expresses a specific olfactory receptor What?

Through the Black Magic 3 RNAscope, the authors found that each necklace cell not only expressed the same Ms4a protein (Fig. 4):

In the above figure, the RNA of different Ms4a receptors is marked with different colors, and many cells can be seen to contain multiple colors.

So are these receptors working? In other words, does the necklace cell really respond to the odor molecules that different receptors respond to?

To explore this issue, the authors used a two-photon microscope to observe the response of necklace cells to different odor molecules.

As shown in the figure above (Fig. 6). In Figure a, for each cell, each column is an odor. It can be seen that the responses of different cells are very similar. In Figure b, the degree of activity of the cells is color-coded, and each column is a scent molecule stimulus that acts on one cell per cell. It can be seen that many cells contain multiple odorants (responding to multiple odor molecules. Note that the Ms4a receptors for each row of odor molecules are different).

At this point, we found that the necklace cells really violated principle 1: Each cell expresses a specific olfactory receptor.

What about principle 3? The way in which the necklace cells and downstream neurons are projected is temporarily unclear. but It is difficult to imagine how necklace cells expressing multiple receptors adhere to the marking line principle.

Summary: Necklace cells and classical olfactory cells are different in sensory and coding methods.

Expression per cell Various Olfactory receptors.

2. The olfactory receptor is not a GPCR protein, but a new one. Ms4a protein (may be an ion channel!).

3. Marking line system: Although the projection method is not clear, Most likely different from the marking line system

Postscript: On the importance of genetic black magic

There have been many recent articles, including Magical “thirsty neuron” The common feature is In the very basic field, new discoveries continue to emerge . And these new discoveries are no exception Depends on new technologies, especially genetic technology

This is the best time.

Extended reading

More about the classic olfactory system:

How does human smell work? Zhao Sijia’s article

Human Smell: Why do you like this taste? Zhao Sijia’s article

Why do different aromas give people different feelings? Chen Xiaoyi’s answer

How is the smell felt by the nose? – Mr-HH’s answer

Thanks to Nilay Yapici for providing a summary of the mouse olfactory system.

[1] Rinaldi, A. (2007). The scent of life. The exquisite complexity of the sense of smell in animals and humans. EMBO Reports, 8(7), 629–33.

[2] Bargmann, C. I. (2006). Comparative chemosensation from receptors to ecology. Nature, 444(7117), 295–301.

[3] Munger, S. D., Leinders-Zufall, T., & Zufall, F. (2009). Subsystem Organization of the Mammalian Sense of Smell. Annual Review of Physiology, 71(1), 115–140.

[4] Greer, P. L., Bear, D. M., Lassance, J., Bloom, M. L., Tsukahara, T., Pashkovski, S. L., … Datta, S. R. (2016). A Family of non-GPCR Chemosensors Defines an Alternative Logic for Mammalian Olfaction. Cell, 165(7), 1734–1748.