By Daniel Dunaief

Brain cells don’t always have easily discovered roles, the way various instruments do in an orchestra.

Sometimes, different cells share a function, making it possible to perform various tasks or to process information from the environment, while other times, different cells play their own part in making it possible for an organism to optimize its circuitry to act and react on the world.

So it is for the tufted and mitral cells of land based vertebrates, which are part of the olfactory system, sending signals to the brain about the odors and triggering thoughts about moving towards a desired food or away from the scent of a predator. In many studies, the names have been used interchangeably, as scientists were not sure how to separate them.

Researchers have spent considerable time studying mitral cells, which project into a region of the brain called the piriform cortex. These cells are nicely organized into one layer, which makes them easy to identify and are bigger in size compared to tufted cells.

Mitral cells, which have been the celebrated stars of the olfactory system, are easier to see and sort out than their nasal cousins, the tufted cells which, by contrast, are slightly smaller.

Recently, two scientists at Cold Spring Harbor Laboratory, Florin Albeanu, an Associate Professor, and Arkarup  Banerjee, an Assistant Professor, published a study that suggested there’s more than meets the eye, or, maybe, the nose, with these tufted cells.

Tufted cells, it turns out, are better at recognizing smells than mitral cells and are critical for one of two parallel neural circuit loops that help the brain process different odor features, according to a study the scientists published in the journal Neuron at the end of September.

“People had assumed mitral cells were very good at” differentiating odor, but “tufted cells are better,” Albeanu said. “How they interact with each other and what the mitral cells are computing in behaving animals remains to be seen.”

Albeanu and Arkarup, who had performed his PhD research in Albeanu’s lab before returning to CSHL in 2020, exposed mice to different odors, from fresh mint to bananas and at different concentrations. They chose these compounds because there are no known toxic effects. The scientists also screened for compounds that elicited strong responses on the dorsal surface of the olfactory bulb that they could access using optical imaging tools.

It is hard to distinguish mitral and tufted cells when doing recordings. Optical imaging, however, enabled them to see through layers and shapes, if they were recording activity in a particular type of cell.

So, Albeanu asked rhetorically, “why is this exciting?”

As it turns out, these two types of cells project to different regions of the brain. Mitral cells travel to the piriform cortex, while tufted cells travel to the anterior olfactory nucleus.

It appears at this point that tufted cells are more likely to share information with other tufted cells, while mitral cells communicate with other mitral cells, as if the olfactory system had two parallel networks. There may yet be cross interactions, Albeanu said.

Mitral cells may be part of a loop that helps enhance and predict smells that are important for an animal to learn. Tufted cells, however, appear superior to mitral cells in representing changes in odor identity and intensity. By flagging the tufted cells as sources of olfactory information, the researchers were able to suggest a different combination of cells through which animals detect smells.

“A large fraction of people in the field would expect that mitral cells and the piriform complex are representing odor identity more so than the tufted cells and the anterior olfactory nucleus, so this is the surprise,” Albeanu explained in an email. Thus far, the reaction in the research community has been positive, he added. 

Throughout the review process, the researchers encountered natural skepticism.

“It remains to be determined how the findings we put forward hold when mice are engaged in odor trigger behavior” as odors are associated with particular meaning such as a reward, an lead to specific actions,” Albeanu explained. “This is what we are currently doing.”

Albeanu added that a few different streams of information may be supported by tufted and mitral cells, depending on the needs of the moment.

The study that led to this work started when Banerjee was a PhD student in Albeanu’s lab. Albeanu said that a postdoctoral fellow in his lab, Honggoo Chae, provided complementary work to the efforts of Banerjee in terms of data acquisition and analysis, which is why they are both co-first authors on the study.

For Banerjee, the work with these olfactory cells was an “echo from the past,” Albeanu added. 

As for where the research goes from here, Albeanu said future questions and experiments could take numerous approaches.

Researchers are currently looking for markers or genes that are expressed specifically and differentially in mitral or tufted cells and they have found a few potential candidates. While some markers have been found, these do not sharply label all mitral only versus all tufted cells only.

One of the confounding elements to this search, however, is that these cells have subtypes, which means that not every mitral cell has the same genetic blueprint as other mitral cells.

Another option is to inject an agent like a virus into the piriform cortex and assess whether boosting or suppressing activity in that region in the midst of olfaction alters the behavioral response.

Additionally, researchers could use tools to alter the activity of neurons during behavior using optogenetic approaches, inducing or suppressing activity with cell type specificity and millisecond resolution.

Albeanu would like to test speculation about the roles of these cells in action, while a mice is sampling smells he presents.

By observing the reactions to these smells, he could determine an association between rewards and punishment and anything else he might want to include.

The upshot of this study, Albeanu said, is that an objective observer would have much less trouble extracting information about the identity and intensity of a smell from a tufted cell as compared with a mitral cell.

Tufted cells had been “slightly more mysterious” up until the current study.