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Selected publications

​For all the publications by the PI, please see Google Scholar and Publons.com.

8. Electric Shock Causes a Fleeing-like Persistent Behavioral Response in the Nematode Caenorhabditis elegans . Tee LF, Young JJ, Maruyama K, Kimura S, Suzuki R, Endo Y, Kimura KD. Genetics (2023) 

- A few years ago, we published that worms make "decisions" according to the definition in the field of neuroscience ( https://doi.org/10.7554/eLife.21629 ). This time, we publish that nematodes may also have a prototype of "emotions." 

- A while ago we thought, "people use electrical stimulation as an 'aversive stimulus' in rodents, but what if we electrically stimulated C. elegans?" Then we found that worms started running at a speed we had never seen before. What was interesting was that even after we stopped the electrical stimulation, they continued running.

- Generally, when a stimulus stops, neural activity stops too. (Otherwise, you would still see light after you close your eyes or hear sounds even after it has stopped.) However, there are cases where neural activity continues even if the stimulus is only temporary, and this is related to interesting brain functions such as "memory," "decision-making," and "emotions." (Maybe it is easy to understand what "memory" is. The simplest explanation for "decision-making" is that "when we are wondering, the information needed for judgment is stored in our brain." As for "emotions," a momentary event can make us feel happy or depressed for a while.)

- The neural circuits that make up the brain of C. elegans are simple and easy to analyze, and the relationship with genes is easy to understand, so we thought it would be a good place to study the mechanism of sustained neural activity and decided to delve deeper into this research.

- As a result of conducting experiments on various genes, many unexpected things have come to light, such as none of the previously known 'stimulus-sensing genes' seem to be involved, the same gene (L-type VGCC) recently discovered in the electric-sensing organs of bony fish may be related to the perception of electrical stimuli, and dopamine and serotonin are not involved, but neuropeptides are necessary for the mechanism of 'appropriately ending a run.' Furthermore, since it satisfies three of the four "emotion primitives" announced about 10 years ago, perhaps we are looking at the prototype of emotion.

- There is no easy paper, and this one was also difficult. Ling Fei, a government-supported student from Malaysia, had no experience in neuroscience, genetics, or electrical circuit assembly but worked really hard. Jared, who came on sabbatical, managed to slip through the COVID-19 pandemic and conduct experiments with Ling Fei. Keisuke Maruyama and Sota Kimura persevered through the revisions that were going horribly wrong but finally made it work. I'd like to express my deep gratitude to Ryoga Suzuki, who worked hard in the early stages of the experiment at Nagoya City University, and Yuto Endo and Yuka Tsuda, who contributed to the exploration phase at Osaka University.

- This paper is just the beginning. We really look forward to seeing how it develops.

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7. Neural Mechanism of Experience-Dependent Sensory Gain Control in C. elegans . Ikejiri Y, Tanimoto Y, Fujita K, Hiramatsu F, Yamazaki SJ, Endo Y, Iwatani Y, Fujimoto K, Kimura KD. Neurosci Res (2023) 

- This paper shows that the activity patterns of sensory neurons change depending on experience and that by using a mathematical model, it was possible to predict to some extent the molecular mechanisms of the change, at least to some extent.

- We previously showed that ASH and AWB sensory neurons respond to 2-nonanone, an odor that C. elegans avoids, and that ASH neurons show temporal differentiation-like patterns to increases in odor concentration, while AWB neurons leaky integration-like patterns to decreases in odor concentration. Since we also showed that the response behavior to 2-nonanone was stronger (running farther in the same amount of time) when the worms were preexposed to 2-nonanone in advance, we investigated whether the responsiveness of ASH neurons and AWB neurons also changed.

- We found that, while AWB did not change, an interesting change occurred in ASH. Although ASH in naive worms responds similarly to both slight and large increases in odor intensity, we found that after the odor exposure, its responsiveness changed to "respond less to slight odor increments, but more to large odor increments." (This type of change in responsiveness is called "gain control.") When we examined the correlation with behavioral level, it seemed that it was running away farther in the same amount of time by using a strategy such as "ignoring the yellow light and running through it."

- Next, we investigated how this change occurs and found that the activity pattern of ASH neurons, which we had previously thought was "differential," can be expressed by the formula "the leaky integration of the sum of the first and second derivatives" of the odor concentration, and that only the second derivative term disappears when an odor is preexposed.

- So, what kind of genes are involved in this cellular activity? The previous research revealed that L-type voltage-gated calcium channels play a role in the leaky integration of the first derivative in AWB neurons. The gene that plays the role of the second derivative was not identified unfortunately, but we found that two genes involved in G protein signaling seem to be involved in the suppression of the odor experience-dependent second derivative term.

- Actually, we knew from a relatively early stage that the ASH activity can be modeled with "leaky integral of the sum of first and second derivatives," but the coefficients of each term were very different depending on how the odor stimulus was presented, and it took us a long time to solve this problem. Still, we were finally able to explain it quite clearly by adopting the idea that "the coefficients change depending on how the stimulus is presented (for example, the way ion channels open changes)." (We know experts in mathematical models looked unhappy with this...)

- This paper is like a culmination of my research at Osaka University. It brings together much data from the lab members of the early days, and Prof. Iwatani, who is a member of the innovative research group "Bionavigation", which supported our research at Osaka University, supported our initial mathematical model research. And, Prof. Fujimoto, who was my neighbor when we both started working at Osaka University as tenure-track associate professors, helped me put the finishing touches on the paper and taught us how to write a paper on mathematical biology in the first place. In many ways, this paper is very moving.

- This paper received much more attention than we expected. For example, it was featured in Nikkei, selected for the 2024 Best Paper Award in the NSR journal in which it was published (for all papers published in 2023), and chosen for an oral presentation at the Society of Quantitative Biology. The 1st author, Ikejiri-kun, was very persistent in working on the coefficients and had constant exchanges with Professor Iwatani and Fujimoto-san, so this paper made us realize once again that "good things can happen if you work hard."

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6. 3DeeCellTracker, a deep learning-based pipeline for segmenting and tracking cells in 3D time lapse images. Wen C, Miura T, Voleti V, Yamaguchi K, Tsutsumi M, Yamamoto K, Otomo K, Fujie Y, Teramoto T, Ishihara T, Aoki K, Nemoto T, Hillman EMC, *Kimura KD. eLife (2021) [Article] [EurekAlert!]

In modern basic life science research as well as in drug discovery, recording and analyzing the images of cells over time using 3D microscopy has become extremely important. Once the images have been recorded, the same cell in different images at different time points has to be accurately identified ("cell tracking") because the living cells captured in the images are in motion. However, tracking many cells automatically in 3D microscope videos has been considerably difficult.

Chentao Wen, a postdoc in our lab, and colleagues developed the 1st AI-based software called 3DeeCellTracker that can run on a desktop PC and automatically track cells in 3D microscope videos. Using the software, they were able to measure and analyze the activities of ~100 cells in the brain of a moving microscopic worm, in a naturally beating heart of a young small fish, and ~1000 cancer cells cultured in 3D under laboratory conditions, which were recorded with different types of cutting-edge microscope systems.

This versatile software can now be used across biology, medical research, and drug development to help monitor cell activities.

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5. STEFTR: A hybrid versatile method for state estimation and feature extraction from the trajectory of animal behavior. Yamazaki SJ, Ohara K, Ito K, Kokubun N, Kitanishi T, Takaichi D, Yamada Y, Ikejiri Y, Hiramatsu F, Fujita K, Tanimoto Y, Yamazoe-Umemoto A, Hashimoto K, Sato K, Yoda K, Takahashi A, Ishikawa, Y, Kamikouchi A, Hiryu S, Maekawa, Kimura KD. Front Neurosci (2019) [Article]

Recording the movements of people and animals has become easy because of small GPS devices and video cameras. However, the reasons for such movements remain difficult to infer. We have developed a flexible artificial intelligence technology to understand the movement of animals, ranging from roundworms in petri dishes to penguins in the Antarctic Ocean. This method will make it easier to understand animal movements as well as their underlying brain activities.

4. Calcium dynamics regulating the timing of decision-making in C. elegans. Tanimoto Y, Yamazoe-Umemoto A, Fujita K, Kawazoe Y, Miyanishi Y, Yamazaki SJ, Fei X, Busch KE, Gengyo-Ando K, Nakai J, Iino Y, Iwasaki Y, Hashimoto K, Kimura KD. eLife (2017)  [Article]

All animals make decisions according to information, but the detailed mechanism is not known. We found that, C. elegans chooses the direction in an odor space by mathematically integrating the information of odor concentration. Moreover, we also identified a gene responsible for the integration. Because integration of information has been known to be important for decision-making of more complex experimental animals such as monkeys, the gene for integration may also be important for decision-making even in humans.

3. In actio optophysiological analyses reveal functional diversification of dopaminergic neurons in the nematode C. elegans. Tanimoto Y, Zheng YG, Fei X, Fujie Y, Hashimoto K, Kimura KD. Sci Rep (2016) [Article]

    Many neuronal groups such as dopamine-releasing (dopaminergic) neurons are functionally divergent, although the details of such divergence are not well understood. In this study, we revealed functional divergence within the dopaminergic neurons of C. elegans. Because dopaminergic neurons of the animals were supposedly activated by mechanical stimulus upon entry into a lawn of their food bacteria, we developed a novel integrated microscope system that can auto-track a freely-moving (in actio) C. elegans to individually monitor and stimulate the neuronal activities of multiple neurons. We found that only head-dorsal pair of dopaminergic neurons (CEPD), but not head-ventral or posterior pairs, were preferentially activated upon food entry. In addition, the optogenetic activation of CEPD neurons alone exhibited effects similar to those observed upon food entry. Thus, our results demonstrated functional divergence in genetically similar dopaminergic neurons, which may provide a new entry point toward understanding the functional diversity of neurons beyond genetic terminal identification.

2. Modulation of different behavioral components by neuropeptide and dopamine signalings in non-associative odor learning of Caenorhabditis elegans. Yamazoe-Umemoto, A, Fujita, K, Iino, Y, Iwasaki, Y, Kimura, KD. Neurosci Res (2015) [Article]

    Multiple neuromodulators are involved in learning and memory. However, the differences and similarities in mechanisms underlying how each neuromodulator regulates behaviors in learning, are not well understood. We found that dopamine and neuropeptide signalings are both required for odor learning of the nematode C. elegans. Interestingly, quantitative behavioral and genetic analyses have indicated that neuropeptide and dopamine signalings are independently required for the acquisition and execution of memory, respectively. Such different roles of multiple neuromodulators in learning could be evolutionarily conserved.

1. Enhancement of odor-avoidance regulated by dopamine signaling. Kimura KD, Fujita K, Katsura I. J Neurosci (2010) [Article]

    Plasticity in sensory responses is one of the fundamentals of neural function in animals. To develop an original behavioral paradigm for understanding the molecular and cellular basis of neural function of C. elegans, we investigated plasticity of odor avoidance of the animals. We found that C. elegans exhibits an enhancement of avoidance behavior to a repulsive odor 2-nonanone after preexposure to the odor, which may be beneficial for the animals by protecting them from further disturbance. In addition, genetic and pharmacological analyses revealed that the enhancement of 2-nonanone avoidance requires dopamine signaling via D2-like dopamine receptor DOP-3, which functions in a pair of RIC interneurons to regulate the enhancement. These results demonstrate a new genetic and pharmacological paradigm for non-associative enhancement of neural responses that is regulated by dopamine signaling.

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