2026 Kosaka Top Basic Science Abstract Award Winner Interview: Mitsukuni Yoshida, MD, PhD

Whole-Brain Single-Cell Resolution Activity Mapping Identifies Mammillary Body Circuit Failure Underlying Aging, Arousal Instability, and Potential Perioperative Cognitive Risk

Mitsukuni Yoshida, MD, PhD, knew from an early age that he would pursue science. He conducted his first experiment in the fourth grade and that marked the beginning of his journey as an inquisitive and fearless scientist. At the age of 14, he moved by himself to the United States with the aspiration to become a scientist. His initial experiment and the experience of moving to a new country taught him resilience, independence, and the willingness to take risks when chasing something meaningful. As a resident and fellow at Washington University School of Medicine in St. Louis, the same mindset still drives how he approaches research today: being comfortable with uncertainty, asking difficult questions, and staying committed to long-term goals even when the path is not straightforward. As he concludes his residency and fellowship in August, the data from this fortitude show positive results. Throughout his research career, Dr. Yoshida has steadfastly committed to uncovering answers to how systemic aging translates into functional decline across organs, which led to a fascination around the brain as a central regulator of aging. Rather than starting with predefined assumptions, he and his collaborators are using an unbiased whole-brain approach to identify the neuronal populations that are naturally most affected by aging. His hope is to move from descriptive aging phenotypes to a mechanistic circuit-level understanding that can inform perioperative brain health and delirium prevention. At the Kosaka Best Abstracts Award Session on Sunday, May 3 at the 2026 Annual Meeting, presented by IARS and SOCCA, Dr. Yoshida’s scientific progress was recognized for the second year in a row as the Kosaka Top Basic Science Research Abstract Award recipient  for his current research on “Whole-Brain Single-Cell Resolution Activity Mapping Identifies Mammillary Body Circuit Failure Underlying Aging, Arousal Instability, and Potential Perioperative Cognitive Risk.” For Dr. Yoshida, this validation of his research journey reflects on the exceptional training, mentorship and scientific guidance he has received over the years and reinforces the importance of seeking mechanistic, high-risk questions that connect fundamental biology with clinical problems that clinicians and scientists face every day. Below, he contemplates the evolution of his research, how this recognition proves significant during a challenging year navigating the transition from training to a faculty position, and his future aims for this important area of study.

1. For this research, you are…

Principal Investigator

2. What inspired you to pursue this area of research, and how has your focus evolved over time?

I have been interested in the biology of aging for much of my scientific career, particularly in understanding how systemic aging translates into functional decline across organs. During my PhD, I focused on metabolic regulation of aging and longevity, especially NAD+ biology and inter-tissue communication. That work taught me how strongly systemic physiology can be shaped by signals originating from specific cellular hubs. Over time, I became increasingly interested in the brain as a central regulator of aging. While many studies focus on predefined brain regions or known pathways, I wanted to take a more unbiased approach to ask which neuronal populations are naturally the most vulnerable during aging, rather than assuming where dysfunction begins. Since completing my PhD, I have been exploring ways to map whole-brain neuronal activity at high resolution under native behavioral conditions. During clinical training in anesthesiology, especially while caring for older surgical patients with postoperative delirium and cognitive vulnerability, this question became even more clinically relevant. That experience pushed my research focus from general longevity mechanisms toward identifying specific neural circuits that govern aging-related brain vulnerability and delirium.

3. What key question or challenge does your current research aim to address?

The central question of my current research is: which specific neuronal populations become dysfunctional during aging, and what behaviors do they control? Aging affects the brain broadly, but not all neural circuits are equally vulnerable. We still do not fully understand which neuronal subsets fail first, how that dysfunction alters arousal, cognition, and behavioral resilience, and why this increases susceptibility to conditions like postoperative delirium. Rather than starting with predefined assumptions, we are using an unbiased whole-brain approach to identify the neuronal populations that are naturally most affected by aging. Once we identify those vulnerable hubs, we can ask what behaviors they regulate and whether restoring their function can improve brain resilience. Ultimately, the goal is to move from descriptive aging phenotypes to a mechanistic circuit-level understanding that can inform perioperative brain health and delirium prevention.

4. What are the most important findings or insights from your work so far?

One of the most important findings from our work so far is that acute dysfunction of the mammillary body appears sufficient to drive several features of aging-related brain dysfunction and delirium-like phenotypes. The mammillary body is often overlooked outside of classical memory circuitry, but our unbiased whole-brain activity mapping identified it as a particularly vulnerable neural hub during aging. When we acutely suppressed mammillary body function, we observed phenotypes that resembled aging-associated cognitive vulnerability, including impaired arousal regulation, disrupted vigilance-state stability, and delirium-like behavioral features. This suggests that aging-related brain dysfunction may not simply reflect diffuse global decline, but instead may arise from failure of specific neural hubs that organize cognitive stability and wakefulness. That shift in perspective is important because it creates a much more precise framework for understanding, and eventually treating perioperative delirium and aging-related cognitive decline.

5. How could your research, whether through direct clinical application or by advancing foundational knowledge, impact the field of anesthesiology and ultimately improve patient care?

Postoperative delirium remains one of the most common and devastating complications we encounter in perioperative medicine, particularly in older adults, yet we still lack objective biomarkers and effective targeted therapies. Much of our current management remains reactive rather than preventive. Our goal is to build a mechanistically faithful model of delirium that captures the neurophysiologic and behavioral features seen in patients. If we can further validate that our model truly recapitulates the clinical syndrome, it creates an opportunity to identify molecular and phenotypic biomarkers that allow us to objectively recognize patients at risk before delirium develops. From there, we can use the model to test targeted interventions, whether pharmacologic, metabolic, or circuit-based, to prevent or reverse vulnerability. Ultimately, I hope this work helps shift anesthesiology from managing delirium after it occurs to predicting, preventing, and treating it with precision, improving recovery, functional outcomes, and quality of life for our aging surgical patients.

6. What does presenting in the Kosaka Best Abstract Awards Session and at the IARS Annual Meeting mean to you?

Presenting at the Kosaka Best Abstract Awards Session and at the International Anesthesia Research Society Annual Meeting is incredibly meaningful to me because it represents the intersection of my clinical and scientific identity. As anesthesiologists, we care for some of the most vulnerable patients during periods of major physiologic stress. As a scientist, I am motivated by understanding the mechanisms that drive those vulnerabilities. This work on aging, neural circuit dysfunction, and delirium sits exactly at that intersection. The IARS meeting has always been a place where translational ideas are taken seriously, and the Kosaka session is particularly special because it highlights research that can shape the future of our field. Being able to share this work there is both an honor and an opportunity to engage with mentors, collaborators, and peers who are pushing anesthesiology forward.

7. How do you feel about receiving the Kosaka Best Abstract Award, and what does this recognition mean for your work and career?

Receiving the Kosaka Best Abstract Award is both humbling and deeply encouraging. Research can often feel like a long process of uncertainty, failed experiments, and incremental progress, so recognition like this is meaningful because it validates that the questions we are asking matter. This is especially meaningful to me because this is the second time I have received the Kosaka Award. I was also honored with it last year. Receiving it again feels less like an individual achievement and more like a reflection of the exceptional training, mentorship, and scientific guidance I have been fortunate to receive over the years. For me, it reinforces the importance of pursuing mechanistic, high-risk questions that connect fundamental biology with clinical problems we face every day, such as aging-related brain vulnerability and postoperative delirium. This year has also been a particularly challenging and transitional one as I finish my training and navigate the faculty job search process. In that context, this recognition carries even greater meaning. I hope it reflects the excellence of the physician-scientist training environment I have had at Washington University School of Medicine and serves as validation of the investment that institutional leaders are making in my next position and future career development. I also hope it affirms their confidence and foresight in supporting the kind of translational, high-risk science that can ultimately shape the future of perioperative medicine.

8. What are the next steps for your research, and how do you see this work evolving?

The immediate next step is to further establish whether the neural and behavioral phenotypes we observe truly reflect clinically relevant delirium rather than general cognitive decline or nonspecific aging effects. That means integrating EEG signatures, sleep-wake architecture, behavioral assays, and circuit-level mapping to define the syndrome more precisely. We are particularly interested in identifying specific vulnerable neural hubs that may drive aging-related susceptibility. Our current data point toward previously underappreciated regions of the brain that may serve as central regulators of arousal stability and cognitive resilience. Long term, I see this work expanding into translational studies that connect these preclinical findings with patient biomarkers, whether EEG-based, imaging-based, or molecular, and eventually informing perioperative interventions that can be tested clinically. The broader goal is to make perioperative brain health a more measurable, predictable, and treatable part of anesthetic care.

9. Is there anyone you would like to acknowledge as part of this work?

Absolutely. This work would not be possible without the mentorship and support of my current mentor, Rajendra Apte, who has unconditionally supported my pursuit of scientific curiosity and encouraged me to ask ambitious questions across disciplines. I am also deeply grateful to my PhD mentor, Shin-ichiro Imai, who introduced me to the field of aging biology. I also want to acknowledge my gap-year mentor, Sohail Tavazoie, who has continuously supported my path toward becoming a physician-scientist and taught me the importance of pursuing bold and mechanistically meaningful questions.

I would also like to express my sincere gratitude to Warren Sandberg for offering me the opportunity to continue this work as a faculty member and for supporting my long-term development as a physician-scientist. Having institutional leadership that believes in both the science and the person behind it is incredibly meaningful during such an important transition in my career.

Finally, without the support of the McDonnell Center for Systems Neuroscience, I would never have been able to pursue a project as risky and unconventional as this one. Their willingness to support high-risk, high-reward science made this work possible. I hope the success of this project can serve as a reminder of how important it is to invest in research that may be uncertain at the beginning, but has the potential to fundamentally move the field forward.

10. Outside of your research, what is something colleagues might be surprised to learn about you?

People are often surprised to learn that I started conducting scientific experiments in fourth grade. From a very early age, I knew I wanted to pursue science seriously. I moved to the United States by myself at 14 years old to pursue that path, with the goal of building a career as a scientist. Looking back, I think that experience shaped much of how I approach both science and medicine: it taught me resilience, independence, and the willingness to take risks when pursuing something meaningful. In many ways, the same mindset still drives how I approach research today: being comfortable with uncertainty, asking difficult questions, and staying committed to long-term goals even when the path is not straightforward.