“When I was choosing a postdoc topic, I was wondering if there was a field that could combine my personal interests and laboratory advantages and make everyone think of me when they mention it 10 years later. So, I started to study a relative aspect in the brain. Less attention has been paid to the brain region: the function of thalamus and its role in brain diseases, said Zhang Ying, postdoctoral fellow at MIT (MIT) McGovern Institute for Brain Science.
Picture | Zhang Ying (Source: Zhang Ying)
Recently, his paper as first author and correspondent was published in Nature. In the research, she found a thalamic brain area. By regulating different types of neurons in this brain area, the movement and depression-like symptoms of Parkinson's disease can be improved.
It is worth noting that for these different thalamic neuron types, Zhang Ying also screened out corresponding molecular targets. Through stimulators or antagonist , the activity of thalamic neuron circuits can be successfully regulated, thereby improving Parkinson's disease. disease phenotype.
The reviewer found this study interesting and useful, and said that the team has produced exciting discoveries in the neuronal composition of the parafascial nucleus of the thalamus. In the study, the research team used a series of novel circuit manipulation techniques to explore in detail a rarely studied area of the thalamus.
The most interesting thing is that they found that a neuron in the parafascial nucleus of the thalamus can specifically project to parvalbumin-positive neurons in the downstream subthalamic nucleus and participate in the motor learning function of healthy mice. At the same time, they also found that this group of parvalbumin-positive neurons turned out to be excitatory long-projection neurons.
"The reviewers agreed that our study has made an outstanding contribution to further understanding the neuronal composition and function of different basal ganglia nuclei. In addition, we regulate brain tracts by acting on different cholinergic receptors Paranucleus neuronal circuits can improve the motor and non-motor functions of Parkinson's disease, which has important guiding significance for the treatment of Parkinson's disease," Zhang Ying said.
Recently, a related paper titled "Targeting thalamic circuits rescues motor and mood deficits in PD mice" was published on Nature[1].
Figure | Related papers (Source: Nature)
Professor Feng Guoping, Chair Professor of MIT McGovern Institute for Brain Science and Academician of the American Academy of Arts and Sciences, and Dheeraj S. Postdoctoral Fellow at MIT and Harvard Broad Institute . Roy) serves as the co-corresponding author of .
Picture丨Feng Guoping (Source: Data map)
is expected to be transformed into primates
Currently, the world is entering an aging society, and the academic community is also deeply engaged in research in the field of aging. Zhang Ying’s postdoctoral work mainly focused on two aging-related neurological diseases: Alzheimer’s disease and Parkinson’s disease.
Parkinson's disease may be known to everyone. It is a disease related to movement. Patients mainly manifest abnormal movement functions. However, most Parkinson's patients actually experience some non-motor symptoms, such as depression, sleep disorders, etc. At present, most research focuses on improving patients' motor functions, such as deep electrical stimulation of the subthalamic nucleus.
These treatments can indeed effectively improve patients' motor functions, but they have little effect on non-motor symptoms such as depression. Therefore, the team imagined that if they find a brain area that can regulate both motor function and depression and other emotional disorders, it will surely play a guiding role in the treatment of Parkinson's disease. “When I was choosing a postdoc topic, I was wondering if there was a field that could combine my personal interests and laboratory advantages and make everyone think of me when they mention it 10 years later. So, I started to study a relative aspect in the brain. Less attention has been paid to the brain region: the function of thalamus and its role in brain diseases, said Zhang Ying, postdoctoral fellow at MIT (MIT) McGovern Institute for Brain Science. Picture | Zhang Ying (Source: Zhang Ying)
Recently, his paper as first author and correspondent was published in Nature. In the research, she found a thalamic brain area. By regulating different types of neurons in this brain area, the movement and depression-like symptoms of Parkinson's disease can be improved.
It is worth noting that for these different thalamic neuron types, Zhang Ying also screened out corresponding molecular targets. Through stimulators or antagonist , the activity of thalamic neuron circuits can be successfully regulated, thereby improving Parkinson's disease. disease phenotype.
The reviewer found this study interesting and useful, and said that the team has produced exciting discoveries in the neuronal composition of the parafascial nucleus of the thalamus. In the study, the research team used a series of novel circuit manipulation techniques to explore in detail a rarely studied area of the thalamus.
The most interesting thing is that they found that a neuron in the parafascial nucleus of the thalamus can specifically project to parvalbumin-positive neurons in the downstream subthalamic nucleus and participate in the motor learning function of healthy mice. At the same time, they also found that this group of parvalbumin-positive neurons turned out to be excitatory long-projection neurons.
"The reviewers agreed that our study has made an outstanding contribution to further understanding the neuronal composition and function of different basal ganglia nuclei. In addition, we regulate brain tracts by acting on different cholinergic receptors Paranucleus neuronal circuits can improve the motor and non-motor functions of Parkinson's disease, which has important guiding significance for the treatment of Parkinson's disease," Zhang Ying said.
Recently, a related paper titled "Targeting thalamic circuits rescues motor and mood deficits in PD mice" was published on Nature[1].
Figure | Related papers (Source: Nature)
Professor Feng Guoping, Chair Professor of MIT McGovern Institute for Brain Science and Academician of the American Academy of Arts and Sciences, and Dheeraj S. Postdoctoral Fellow at MIT and Harvard Broad Institute . Roy) serves as the co-corresponding author of .
Picture丨Feng Guoping (Source: Data map)
is expected to be transformed into primates
Currently, the world is entering an aging society, and the academic community is also deeply engaged in research in the field of aging. Zhang Ying’s postdoctoral work mainly focused on two aging-related neurological diseases: Alzheimer’s disease and Parkinson’s disease.
Parkinson's disease may be known to everyone. It is a disease related to movement. Patients mainly manifest abnormal movement functions. However, most Parkinson's patients actually experience some non-motor symptoms, such as depression, sleep disorders, etc. At present, most research focuses on improving patients' motor functions, such as deep electrical stimulation of the subthalamic nucleus.
These treatments can indeed effectively improve patients' motor functions, but they have little effect on non-motor symptoms such as depression. Therefore, the team imagined that if they find a brain area that can regulate both motor function and depression and other emotional disorders, it will surely play a guiding role in the treatment of Parkinson's disease.
The research team initially paid attention to the parafascial nucleus of the thalamus because this nucleus can serve as an upstream nucleus to regulate different basal ganglia brain areas. At the same time, it can also regulate depression-related brain areas including , nucleus accumbens, and .
(Source: Nature)
Previously, a scientific research team specifically detected abnormalities in the parafascial nucleus of the thalamus in the brains of Parkinson's patients. These studies suggest that the parafascicular nucleus of the thalamus may play a role in both motor and non-motor processes. At the same time, it may also be involved in the pathogenesis of Parkinson's disease.
Therefore, the team used a series of systems biology research methods and found that there are three different neuron subtypes in the parafascial nucleus of the thalamus, which respectively regulate movement, motor learning, and depression-like phenotypes. By regulating these three different thalamic parafascial nucleus circuits through optogenetic or pharmacogenetic methods, the movement and depression-like abnormalities in Parkinson's mouse models can be improved.
In addition, they also found corresponding to three different acetylcholine receptors as drug targets, using their antagonists or agonists to improve motor and non-motor symptoms in Parkinson's disease mice. It is worth noting that the three drug targets also have corresponding nuclei expressed in the brains of macaques, which shows that this research has great hope of being translated into primates .
While studying the parafascial nucleus circuit of the thalamus, the research team accidentally discovered a group of parvalbumin-positive neurons located in the subthalamic nucleus. It is generally believed that parvalbumin-positive neurons are inhibitory neurons of a local circuit and play a regulatory role by projecting to excitatory neurons in the nucleus.
Through rigorous biochemical experiments and electrophysiological experiments, Zhang Ying and colleagues confirmed that this group of parvalbumin-positive neurons located in the subthalamic nucleus is a type of excitatory long-projection neurons. At the same time, this special group of parvalbumin-positive neurons receives projections from the parafascial nucleus of the thalamus and participates in motor learning activities in mice.
In order to find a brain area that can regulate both motor symptoms and non-motor symptoms in patients with Parkinson's disease, the team also explored the circuit and function of the parafascial nucleus of the thalamus, and found in its downstream nucleus, the subthalamic nucleus. A new type of parvalbumin-positive neurons was discovered, and the corresponding molecular target was also found, which can be used to treat Parkinson's disease movement and depression symptoms.
(Source: Nature)
Become a voice for a small field
In fact, as far as the entire brain is concerned, there are some brain areas such as the cortex and hippocampus, given their important functions in cognition and other aspects, and their relatively mature research Tools, a large number of scientists have been gathered to study them before, and relatively complete research results have been produced.
For the thalamus, although it plays a very important "transduction center" function in the brain, it is still a relatively unknown brain area due to its relatively complex structure and lack of corresponding research tools.
Zhang Ying said: "Actually, to me, the more mysterious scientific research is, the more interesting it is. As long as I can find a research method to break through technical barriers and specifically regulate a thalamic nucleus, I will be the first A person who speaks for that small field. "
Picture from left to right: Dr. Dhiraj, Professor Feng Guoping, Dr. Zhang Ying (Source: Zhang Ying)
Next, she will perform a specific test on a thalamic brain area. sexual regulation and explore its functions. Scientists who have studied the thalamus all know that one of the special characteristics of the thalamus is that many tools that work in other brain areas do not work in the thalamus. Zhang Ying tried many tools and explored various experimental conditions, and finally found that using a reverse trans-synaptic rabies virus can well infect the parafascicular nucleus of the thalamus.
As long as she can specifically mark the thalamic parafascicular nucleus, it is like opening a door. Combining various latest optogenetic and pharmacological genetic methods, she found that there are three different types of neurons in the thalamic parafascicular nucleus. Movement, motor learning ability, and depression-like emotions can be regulated respectively.
"The ultimate goal of science is to serve society, so how can I use my research on the thalamus to solve the problem of brain diseases? The first thing we think of is Parkinson's disease, which is the most common disease caused by motor nerves in life. Diseases caused by system decline," Zhang Ying said.
It said that in addition to the deterioration of motor functions, Parkinson's disease patients actually also suffer from emotional problems. Existing treatments can significantly improve a patient's ability to exercise, but have no effect on mood problems such as depression.
By regulating three different types of neurons in the parafascial nucleus of the thalamus, the team successfully found that the movement and depression-like phenotypes of the Parkinson's mouse model were significantly improved. Finally, the question they have to think about is how to transform the results.
Previously, many teams have studied neural circuits and applied them to mouse models of neurological disease . The key question is, can studies in mice translate to primates?
Therefore, the research team cooperated with Professor Lu Zhonghua of Shenzhen Institute of Advanced Technology . Finally, they were delighted to find that the molecular therapeutic target found in mice was also specifically expressed in macaques . This evidence suggests that this research has good translational prospects.
"I tried my best but couldn't, but I am grateful for my efforts."
Zhang Ying said: "There are many things in the research that are still fresh in my mind when I look back. In the past few years, my biggest gain is that I have learned to reconcile with myself. When I first started working as a postdoc, I set a three-year postdoc period for myself based on my PhD experience. Guoping initially sent me a four-year contract, and I responded confidently that three years would be enough. That was enough for me. Guoping changed the contract with a smile. Later, of course, he chose to extend it. It is now almost five years and he is still "moving bricks" in the laboratory. "As the third year approaches, Zhang Ying's post-doctoral life is the most stressful. , is also the darkest year. At that time, she was faced with two choices: package the data at hand immediately, or grind it down. The result she expects is to completely solve a scientific problem within three years, so none of the above options is perfect.
"It's like a collapse of faith. The most fundamental reason is that I am not as good as I thought. It took me a long time to reconcile with myself. There are indeed many people in this world who can do it during the three-year postdoc period. I made a very important discovery. I tried my best but couldn't. I am grateful for my efforts in the first three years, and I am also grateful for the goals I set at the beginning. Because of this three-year appointment, I worked hard and failed. A waste of every minute of my life. When I mentioned this to my mentor, he said that he expected that I would renew my contract, but was unwilling to dampen my enthusiasm at the time. I also thanked my mentor for protecting my innermost feelings. Perseverance," she added.
According to reports, Zhang Ying is from Nantong, Jiangsu. He enrolled in the School of Life Sciences of Nanjing University in 2008. He always thought that he would join a company after graduating from undergraduate degree, so he joined many school clubs and a radio station during his freshman and sophomore years.
“While enjoying college life, I also hope to add some experience to my job search resume. Until my junior year, I took an elective neurobiology course taught by Professor Wang Jianjun. I was attracted by the complexity and wonder of the brain, and I also wanted to contribute to my resume. I wanted to make some contribution to the treatment of brain diseases, so I started to study professional knowledge seriously, visited the library, and finally brought the terrible grade point to the guaranteed research range," she said.
In 2012, Zhang Ying was successfully admitted to the laboratory of Li Xiaoming, currently executive vice president of Zhejiang University School of Medicine, and began to study the role of the neuromodulation system in a rare autism related disease - Rett syndrome. . She found that cholinergic neurons in different brain areas are involved in the pathogenesis of different symptoms of Rett syndrome. For example, cholinergic neurons in the base forebrain are involved in social functions, and cholinergic neurons in the striatum are involved in the pathogenesis of different symptoms of Rett syndrome. Neurons mediate learning functions.
At the same time, she also found corresponding molecular targets. By regulating these targets, the social and learning functions of Rett syndrome mice can be improved. Due to his strong interest in the pathogenesis of brain diseases, he entered the research group of Professor Feng Guoping at MIT in 2017 for postdoctoral research.
(Source: Nature)
During the period, she and her partners started from the two thalamic nuclei-the anterior thalamus and the parafascial nucleus of the thalamus, and studied their roles in autism, schizophrenia and Parkinson's disease. role. Autism, schizophrenia and other diseases are accompanied by the decline of cognitive function. During this period, they found that the frontal thalamus is involved in the cognitive function of mice. By regulating its function, cognitive abnormalities in different model mice can be improved.
As for another thalamic nucleus, the parafascial nucleus of the thalamus, Zhang Ying and her colleagues’ team discovered that it has three different subcell types. By regulating the activities of these cell subtypes through different cholinergic receptors, it can improve the function at the same time. Motor symptoms, and depressive symptoms in mouse models of Parkinson's disease.
In the future, Zhang Yinghe’s team has two main plans: First, observe in primate models of Parkinson’s disease and regulate the molecular therapeutic targets discovered this time to try to improve the treatment of monkeys with Parkinson’s disease. Exercise and symptoms of depression. She imagined that if there was an improvement, would it be accompanied by some side effects?
Meanwhile, men are 1.5 times more likely to develop Parkinson's disease than women, suggesting the existence of gender differences. So, can the circuits and targets they studied exist in both genders and be effective?
On the other hand, the research team will combine new gene therapy methods to achieve more convenient manipulation of the efficacy of the circuit. Previously, they used agonists and antagonists of different molecular targets. These drugs have certain specificity, but they still act on some non-target molecules.
Next, the team will use gene manipulation technologies such as CRISPR to specifically regulate molecules in different loops to achieve therapeutic effects. At the same time, it will also use the latest drug delivery strategies that effectively break through the blood-brain barrier to achieve the goal of blood injection to treat brain diseases.
Regarding career planning, Zhang Ying said: "I do have plans to return to China to work. In the past ten years, domestic universities have also produced more and more world-class original research. Coupled with the impact of the new crown on the world, I think there will be more and more More and more overseas scholars are joining the wave of returning to China. This is not only because we want to use what we have learned to contribute to the basic research of our motherland, but also because domestic universities already have relatively good scientific research platforms, which allow researchers to make contributions. Jobs that are more valuable to society. Because life in the United States is relatively boring, when choosing future job opportunities, I prefer domestic first-tier cities.” D.S., Zhu, Y. et al. Targeting thalamic circuits rescues motor and mood deficits in PD mice. Nature (2022). https://doi.org/10.1038/s41586-022-04806-x
As long as she can specifically mark the thalamic parafascicular nucleus, it is like opening a door. Combining various latest optogenetic and pharmacological genetic methods, she found that there are three different types of neurons in the thalamic parafascicular nucleus. Movement, motor learning ability, and depression-like emotions can be regulated respectively.
"The ultimate goal of science is to serve society, so how can I use my research on the thalamus to solve the problem of brain diseases? The first thing we think of is Parkinson's disease, which is the most common disease caused by motor nerves in life. Diseases caused by system decline," Zhang Ying said.
It said that in addition to the deterioration of motor functions, Parkinson's disease patients actually also suffer from emotional problems. Existing treatments can significantly improve a patient's ability to exercise, but have no effect on mood problems such as depression.
By regulating three different types of neurons in the parafascial nucleus of the thalamus, the team successfully found that the movement and depression-like phenotypes of the Parkinson's mouse model were significantly improved. Finally, the question they have to think about is how to transform the results.
Previously, many teams have studied neural circuits and applied them to mouse models of neurological disease . The key question is, can studies in mice translate to primates?
Therefore, the research team cooperated with Professor Lu Zhonghua of Shenzhen Institute of Advanced Technology . Finally, they were delighted to find that the molecular therapeutic target found in mice was also specifically expressed in macaques . This evidence suggests that this research has good translational prospects.
"I tried my best but couldn't, but I am grateful for my efforts."
Zhang Ying said: "There are many things in the research that are still fresh in my mind when I look back. In the past few years, my biggest gain is that I have learned to reconcile with myself. When I first started working as a postdoc, I set a three-year postdoc period for myself based on my PhD experience. Guoping initially sent me a four-year contract, and I responded confidently that three years would be enough. That was enough for me. Guoping changed the contract with a smile. Later, of course, he chose to extend it. It is now almost five years and he is still "moving bricks" in the laboratory. "As the third year approaches, Zhang Ying's post-doctoral life is the most stressful. , is also the darkest year. At that time, she was faced with two choices: package the data at hand immediately, or grind it down. The result she expects is to completely solve a scientific problem within three years, so none of the above options is perfect.
"It's like a collapse of faith. The most fundamental reason is that I am not as good as I thought. It took me a long time to reconcile with myself. There are indeed many people in this world who can do it during the three-year postdoc period. I made a very important discovery. I tried my best but couldn't. I am grateful for my efforts in the first three years, and I am also grateful for the goals I set at the beginning. Because of this three-year appointment, I worked hard and failed. A waste of every minute of my life. When I mentioned this to my mentor, he said that he expected that I would renew my contract, but was unwilling to dampen my enthusiasm at the time. I also thanked my mentor for protecting my innermost feelings. Perseverance," she added.
According to reports, Zhang Ying is from Nantong, Jiangsu. He enrolled in the School of Life Sciences of Nanjing University in 2008. He always thought that he would join a company after graduating from undergraduate degree, so he joined many school clubs and a radio station during his freshman and sophomore years.
“While enjoying college life, I also hope to add some experience to my job search resume. Until my junior year, I took an elective neurobiology course taught by Professor Wang Jianjun. I was attracted by the complexity and wonder of the brain, and I also wanted to contribute to my resume. I wanted to make some contribution to the treatment of brain diseases, so I started to study professional knowledge seriously, visited the library, and finally brought the terrible grade point to the guaranteed research range," she said.
In 2012, Zhang Ying was successfully admitted to the laboratory of Li Xiaoming, currently executive vice president of Zhejiang University School of Medicine, and began to study the role of the neuromodulation system in a rare autism related disease - Rett syndrome. . She found that cholinergic neurons in different brain areas are involved in the pathogenesis of different symptoms of Rett syndrome. For example, cholinergic neurons in the base forebrain are involved in social functions, and cholinergic neurons in the striatum are involved in the pathogenesis of different symptoms of Rett syndrome. Neurons mediate learning functions.
At the same time, she also found corresponding molecular targets. By regulating these targets, the social and learning functions of Rett syndrome mice can be improved. Due to his strong interest in the pathogenesis of brain diseases, he entered the research group of Professor Feng Guoping at MIT in 2017 for postdoctoral research.
(Source: Nature)
During the period, she and her partners started from the two thalamic nuclei-the anterior thalamus and the parafascial nucleus of the thalamus, and studied their roles in autism, schizophrenia and Parkinson's disease. role. Autism, schizophrenia and other diseases are accompanied by the decline of cognitive function. During this period, they found that the frontal thalamus is involved in the cognitive function of mice. By regulating its function, cognitive abnormalities in different model mice can be improved.
As for another thalamic nucleus, the parafascial nucleus of the thalamus, Zhang Ying and her colleagues’ team discovered that it has three different subcell types. By regulating the activities of these cell subtypes through different cholinergic receptors, it can improve the function at the same time. Motor symptoms, and depressive symptoms in mouse models of Parkinson's disease.
In the future, Zhang Yinghe’s team has two main plans: First, observe in primate models of Parkinson’s disease and regulate the molecular therapeutic targets discovered this time to try to improve the treatment of monkeys with Parkinson’s disease. Exercise and symptoms of depression. She imagined that if there was an improvement, would it be accompanied by some side effects?
Meanwhile, men are 1.5 times more likely to develop Parkinson's disease than women, suggesting the existence of gender differences. So, can the circuits and targets they studied exist in both genders and be effective?
On the other hand, the research team will combine new gene therapy methods to achieve more convenient manipulation of the efficacy of the circuit. Previously, they used agonists and antagonists of different molecular targets. These drugs have certain specificity, but they still act on some non-target molecules.
Next, the team will use gene manipulation technologies such as CRISPR to specifically regulate molecules in different loops to achieve therapeutic effects. At the same time, it will also use the latest drug delivery strategies that effectively break through the blood-brain barrier to achieve the goal of blood injection to treat brain diseases.
Regarding career planning, Zhang Ying said: "I do have plans to return to China to work. In the past ten years, domestic universities have also produced more and more world-class original research. Coupled with the impact of the new crown on the world, I think there will be more and more More and more overseas scholars are joining the wave of returning to China. This is not only because we want to use what we have learned to contribute to the basic research of our motherland, but also because domestic universities already have relatively good scientific research platforms, which allow researchers to make contributions. Jobs that are more valuable to society. Because life in the United States is relatively boring, when choosing future job opportunities, I prefer domestic first-tier cities.” D.S., Zhu, Y. et al. Targeting thalamic circuits rescues motor and mood deficits in PD mice. Nature (2022). https://doi.org/10.1038/s41586-022-04806-x
