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Interview with the first author, Dongdong Zhang: Unveiling the neuro-arterial ‘bridge’ for the first time – Breakthrough on neurovascular coupling

   |  March 27, 2024

This article focuses on “Changes in the Life Sciences Industry.” Starting from an introduction of our partners, we will introduce to you stories of the research team and their laboratory, methodologies and tools they used to inspire researchers and spark thinking.

Not long ago, Jiemin Jia’s team from Westlake University published a research paper titled Synaptic-like transmission between neural axons and arteriolar smooth muscle cells drives cerebral neurovascular coupling in the journal of Nature Neuroscience, demonstrating that single glutamatergic axons dilate their innervating arterioles via synaptic-like transmission between neural-arteriolar smooth muscle cells (aSMCs). These findings reveal a “novel bridge” for direct communication between neurons and cerebral blood vessels, providing new understandings to the rapid and precise regulation of cerebral circulation.

We interviewed Dr. Dongdong Zhang, the first author of the paper, to understand the mechanism of neurovascular coupling.

Break through previous limitations and dare to explore new mechanisms of cerebral blood flow regulation

Blood supply powers neural computations in the brain. Fluctuations in computational activity produce commensurate alterations in the regional cerebral blood flow (CBF) within seconds, termed neurovascular coupling (NVC). Impaired NVC function can lead to cerebral microcirculation ischemia and hypoxia, affect local nerve signal conduction, cause and aggravate cerebral small vessel disease, and may even lead to cognitive dysfunction and dementia.

Energy, required by neuronal activation and metabolism, comes from blood supply since it cannot be stored in the brain. Dr. Zhang told us, “Since blood supply is vital for brain activity, how do neurons convey information to the blood flow after being activated?” This became the starting point for the research team’s exploration.

Although the regulatory mechanism of neuronal activation on blood flow has been studied for more than 130 years, more information is still needed to this end. “How do activated neurons regulate cerebral blood flow? What messages are transmitted during this process? When do such transmission occur? Are there other unknown circulatory regulation mechanisms beyond our existing knowledge?” The first author, when talking about the original aspiration of the experiment, added, “There is still a lot we can do about NVC.”

Breakthrough innovations co-generated by advanced equipment and relentless research

To explore the structural basis of the regulatory mechanism, the research team used serial block face scanning electron microscopy (SBF-SEM) and three-dimensional (3D) reconstruction of volumetric correlative light electron microscopy (EM) to analyze the spatial correlation between the artery and other cells in its surrounding tissues.

Long, long had been the road of scientific exploration and far, far was the journey.

Dr. Dongdong Zhang started this experimental research in 2017, and it took 6 years to achieve today’s results. “Structure determines function”, and in studying the structure of arteries and their surrounding vascular tissues and cells, he could not help but sigh with motion: “We have collected nearly 30 T of EM data, and have been analyzing and reconstructing brain tissue, cell ultrastructure and blood vessel structure. This process alone took us two to three years, and the workload was extremely heavy. “

This study is the first in the world to analyze the spatial relationship between astrocytic endfeet and penetrating arterioles. According to Zhang, results from 3D EM scanning revealed “gaps” between the two structures. And pre-synaptic daughter boutons pass through these gaps and contact physically with the vasculature, establishing a “new bridge” for neurovascular communication that has not been shown previously.

During basic functional verification, the research team used the laser speckle contrast imaging (LSCI) system (RFLSI III, RWD Life Sciences). The interviewee told us that this instrument displayed changes in cerebral blood flow over a wide range whereby contacts between axonal boutons and SMCs were discovered, which regulate blood flow and arteriolar diastole.

The research team used the laser speckle contrast imaging (LSCI) system (RFLSI III, RWD Life Sciences) to record blood flow changes

“I am very grateful to the RWD LSCI system. It is very helpful in our research for cerebral blood flow monitoring that may impact physiological functions. Given us a great hand.”

In addition, other RWD products are also installed in his laboratory, such as surgical instruments, stereotaxic frames, and mobile anesthesia ventilators. “We have positive user experience with all these tools.” Dr. Dongdong Zhang once again recognized RWD’s solutions and put forward valuable suggestions for optimization of some.

RWD Laser Speckle Imaging System in Westlake University

Fear no failure in research, value methodologies, and keep being enthusiastic

In 2017, when Westlake University was called Zhejiang West Lake Institute for Advanced Study, Dr. Zhang was among the first batch of doctoral students at that time. Before that, his master’s dissertation focused on stroke, which best matched the research direction of Professor Jia, one of the five PIs in the Life Sciences Department of the Institute. Considering his future research and personal development, he successfully joined Professor Jia’s team.

“When I first got here, my supervisor did not ask me to stay for a few more years, but emphasized what scientific discoveries I may make during my PhD program, what scientific questions I may address, and what value I could bring to the field and even to the society. Those are the most important things.”

Our interviewee was deeply inspired by Professor Jia. “So, just like that, I became her first student.”

The first author of this research, doctoral candidate of class 2017 Dongdong Zhang (left) and his supervisor Professor Jiemin Jia (right) (taken in 2017)

Scientific research requires a lot of time, energy, and enthusiasm for repetitive work. It is necessary to maintain sufficient interest and a high degree of concentration to gain. Dr. Zhang has already made up his mind to go for research and his pursuing of a Ph.D. was for the joy and happiness brought by scientific exploration. “Originally, I could publish a paper and successfully graduate in three years with a doctorate degree, but I chose to investigate for five years, and it has now been seven years. As Professor Jia said at the time, compared with graduating as a doctor, what matters more is the topics studied during these years.”

In the end, it was the inner driving force that kept Dr. Dongdong Zhang firm in his belief from beginning to end, and he is willing to face the difficulties and challenges along the journey of research.

“To engage in scientific research, you first have to ask yourself why you want to do the research in the first place and whether you are really interested in it.” Dr. Zhang does not succumb to repeated and boring experiments day after day. Exploring the unknown and satisfying curiosity is what he feels about research and where the fun lies.

“Secondly, experiments sometimes do fail. It is vital what kind of mindset you hold when being defeated. You must be courageous enough to stand up after the fall.” For researchers, such courage to brave failures is the prerequisite for real success.

Since Dr. Zhang was Prof. Jia’s first student, and many platforms at Westlake had not yet been established at that time, he conducted most of the experiments by himself. Mentioning some then unfamiliar experimental methods and technologies, he also extended his gratitude for the help offered by professionals.

“When you encounter difficulties, it is very important to learn to humbly ask experts in some fields for advice. Even if you start from scratch, it is conducive to solving problems simply by asking.” Regarding how to overcome obstacles during experiments, the first author also shared his own experience with us.

With time and personal efforts, Dr. Zhang has achieved fruitful results in his own research field and has his own opinions on scientific exploration. When asked about the current promising area of NVC, he continued our dialogue.

The neurovascular coupling mechanism has been studied for more than 130 years. During this period, researchers have been asking the same question — how neurons regulate the coupling. “But at a deeper level, in addition to regulating energy metabolism, do they also regulate some other physiological behaviors? This is a very interesting topic.”

“Since activated neurons modulate blood flow, will changes in blood flow in turn regulate some neuronal functions? This is another intriguing question that Professor Jia’s team is keen to answer.”

The journey of scientific research may be long and arduous, but with sustained actions, we will eventually reach our destination. We look forward to Dr. Dongdong Zhang’s continuous dedication in the field he specializes in and bringing greater value to the industry and even society.

Please refer to our previous article: Nature Neuroscience: New breakthrough in neurovascular coupling theory!

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