Olfaction, or the sense of smell, is fundamentally different from the senses of vision, audition, touch and taste. Unlike the latter four, the sense of smell is mediated not just by a few, but by many hundreds – in the case of mice even more than a thousand – different receptors. Unlike the other senses, the stimuli that enter via these olfactory receptors are not “translated" in the thalamus before reaching the cerebral cortex. Instead, they are rapidly transmitted from the olfactory bulb at the base of the brain to deeper layers of the cortex and the limbic system, which in turn are closely linked to emotions and memories. In another deviation from audition and vision, once here, this olfactory information is neither topographically represented nor hierarchically organized, but decentrally stored in a closely linked network. By decoding this dynamic pattern of odor processing, neuroscientists hope to obtain a better understanding of how the brain experiences space, thereby gaining new insights into its general functional principles. Prof. Dr. Tobias Ackels has made significant strides in this field: He has proven that olfaction is a four-dimensional sense capable of perceiving even the smallest time differences, and using these to generate spatial information.

Even though our sense of smell has atrophied in the course of evolution compared to that of many animals, we humans are able to distinguish between at least 10,000 different smells, which we store deep in our memory as an experiential impression with associated feelings. Sometimes memories we thought long forgotten suddenly resurface when we reencounter the smell once associated with them. This extraordinary differentiation capacity of smell was first explained in 1991 – a decade before the working version of the human genome was published – by neurophysiologists Linda Buck and Richard Axel from Columbia University in New York, following their discovery that this capacity emanates from a very large group of genes that code for the expression of G-protein coupled receptors (GPCRs), which act as receiving antennas for odor signals on the olfactory cells. In mice, these genes make up three percent of their genome and contain the blueprints for more than 1,000 olfactory receptors. Although the human genome has only around 350 olfactory receptors, for us humans, too, there is no other vital function aside from smell that requires such a large number of GPCR genes.

From the nose to the olfactory bulb
Based on this fundamental discovery, Buck and Axel spent the next decade independently and extensively researching the manner in which the olfactory system is organized; their comprehensive research findings were recognized in 2004 with the Nobel Prize in Physiology or Medicine. Briefly put, their research showed that there are millions of olfactory cells located far up in the mucous membrane of the nose each expecting different incoming odors, whereby every individual olfactory cell expresses only one type of odorant receptor. Each type, in turn, can be found on around 10,000 olfactory cells. Rather than being specialized on just one odorant, the receptor can be activated by many odors, albeit with different sensitivities. This means the olfactory spectrum of all receptor types overlaps. The impulses of an activated olfactory cell travel via its output cable (axon) to tiny tangles (glomeruli) in the olfactory bulb at the base of the brain, where they are converted to mitral and tufted cells. A mouse, for example, has about 2,000 glomeruli. Given that each glomerulus only receives information from olfactory cells of the same receptor type, the specificity of individual receptor types is initially retained in the input signals of both the mitral and tufted cells. Only once they leave the olfactory bulb are they mixed into dynamic patterns of olfactory sensation.

Nerve cells that renew themselves for a lifetime
Buck and Axel's findings brought the olfactory system of mammals into the spotlight of neurobiology, yielding completely surprising insights into its plasticity and flexibility – the result of so-called interneurons in the circuits connecting the olfactory bulb's glomeruli with deep cortical regions. Contrary to the once prevailing dogma that nerve cells cannot renew themselves in adults, here, they are in fact able to divide throughout life and have therefore acquired the reputation of being conductors of thought and feeling. At the same time, quite a few neurobiological research groups appeared somewhat reluctant to place the sense of smell at the center of their own research – and not just because the field seemed to have been exhausted after the Nobel Prize, but first and foremost due to the fact that the questions it raises can be difficult to elucidate methodologically. That is also why it took until 2023 for the structure of an olfactory receptor to be clarified for the first time: it is that difficult to isolate such receptors and propagate them heterologously in cell cultures, which in turn makes them accessible for analysis by cryo-electron microscopy. Another great challenge consists of reproducing in experiments the neurological effect of natural odors, which swirl around in clouds of scent. Tobias Ackels has mastered this challenge with remarkable success. The material on which this success is based is a temporal odor delivery device, which he built to control the release of different odorants – either individually or mixed – in extremely precise temporal impulses.

Mice smell faster than they breathe...
Being able to deduce their exact location from temporally fluctuating scent clouds is particularly important for the survival of nocturnal animals. After all, this is the only way they can find food in the dark and avoid predators. But how can a mouse succeed in orienting itself to rapid odor fluctuations in its environment if, with each 100-millisecond breath, it only takes in a limited number of scents, which trigger relatively slow biochemical signaling cascades at the receptors of its olfactory cells? The hypothesis put forward by Tobias Ackels was that this is only possible because tens of thousands of identical receptor neurons converge in a glomerulus, which, he surmised, leads to an enormous amplification of the sensory signal – not least since the olfactory cells of one receptor type are widely distributed in the nose, i.e. they are never activated simultaneously. This results in a time-delayed convergence in the olfactory bulb: its nervous input reflects the entire reservoir stored in the nasal mucosa, making it receptive to rapidly changing stimuli that would otherwise be lost. Ackels initially tested this hypothesis in a computer simulation. He later also confirmed this hypothesis after exposing mice to individual odor stimuli lasting 10 or 25 milliseconds and, based on the calcium influx, measuring the activity in the axons of their olfactory cells using fluorescence microscopy.

...and sniff out space from tiny time intervals
If two odors are temporally correlated, i.e. they fluctuate in the same rhythm, then they most likely originate from the same place. By contrast, if they are not temporally correlated, they likely originate from different places. In an effort to test this postulate by John Hopfield (Nobel Prize in Physics 2024) as part of a behavioral research experiment, Ackels first had to determine whether mice perceive such correlation differences at all. To do so, he presented a group of thirsty mice with odors consisting of two scents that either flowed synchronously or asynchronously from the valves of his application device. The experiment took place in a large cage with a water dispenser installed on the top floor. Half the mice were rewarded with water after having recognized a synchronous stimulus, the other half after having recognized an asynchronous stimulus. If an animal was wrong, it could not quench its thirst there. Both groups of mice successfully learned to distinguish the correlation structure of the two odors up to a frequency of 40 Hertz. In the nervous output of the olfactory bulb, at the level of the mitral and tufted cells, this differentiation was also detectable with the aid of fluorescence microscopy. In the next step, Ackels and his team presented the mice with odor stimuli that actually emanated either from the same source or from two distant sources, controlling their degree of correlation by means of photoionization. The mice were actually able to distinguish the spatial origin of the stimuli.

The link between smell and memory
“It was surprising to discover that mammals' olfaction can distinguish between rapidly fluctuating odors," says Tobias Ackels, who – having now understood the process is asking “how" it emerges: How is information extracted from the olfactory bulb and transmitted to higher regions of the olfactory brain? What role do interneurons play in this process? To answer the latter question, he is expanding his behavioral research to incorporate an arena that to mice appears as big as a soccer pitch does to us. Inside this arena, the mice scour back and forth between different scent sources. Ackels measures which scents they encounter when, as they move back and forth, and uses hair-thin silicon probes to determine the workings of the nerve cells in their olfactory brain. Making this research possible is a European Research Council (ERC) Starting Grant. Ackels' findings will also advance our understanding of the functional principles of the human brain. After all, there are good reasons to believe that “the brain can be found in the nose", as a recent review article on the state of research into the olfactory system put it . For the vast majority of animals, smell is the most important sense, which is also why the structure of its neuronal circuits shapes their brain development in a primal way and could even contribute fundamental building blocks and functional elements to the entire brain architecture. However, given that humans are visually controlled beings, we tend to underestimate the importance of smell. Just how important olfaction is for our overall quality of life became evident during the coronavirus pandemic, when many people temporarily lost their sense of smell. The particularly deep connection between smell and memory is probably the reason why a link between olfactory deficits and the onset of dementia is becoming increasingly likely. There is increasing evidence that olfactory disorders precede structural changes, memory impairment and the clinical symptoms of dementia – meaning they could serve as biomarkers for the very early detection of dementia. For Tobias Ackels, this opens up the possibility of applying his basic research, an opportunity he is exploring in close consultations with clinicians at the Deutsches Zentrum für neurodegenerative Erkrankungen (DZNE, German Center for Neurodegenerative Diseases) in Bonn.