Cell: Pu Muming published a single -cell transcription group, connection group and nerve regulation articles for the long -term brain

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Cell: Pu Muming published a single -cell transcription group, connection group and nerve regulation articles for the long -term brain

2022-06-24 06:09:39 6 ℃

The analysis of the single -cell transcription group promotes the identification of cell types in the brain and the drawing of the cell -type specific connection group, which helps to clarify the neural circuit of the brain function and treat brain diseases through nerve regulation. However, we lack the definition of consensus on neurons type/subtype, and also lack a clear understanding of causality in complex interconnected networks.

On June 21, 2022, the Chinese Academy of Sciences Brain Science and Intelligent Technology Excellence Innovation Center (Institute of Neuroscience)/ Shanghai Brain Science and Brain Technology Center Pu Muming published in Cell entitled "Transcriptome, Connectome and Neuromodulation of the Primate Brain". Commenting articles, the article focuses on the study and connection group research of the long -term animal brain, and accurate nerve regulation through physical means to regulate the specific nerve circuit behind various brain function and dysfunction.

Since Ramon Y Cajal proposed neurons as the basic unit of neurological system, identifying all neurons types and drawing their connection maps in the brain have always been an imminent task of neurobiologists. A lot of information based on cell form, electrical characteristics, gene expression spectrum, and connection mode has generated a lot of information. The latest progress of single cell RNA sequencing technology has greatly accelerated the pace of cell classification based on transcription groups. The emergence of cell -type specific virus vectors and optical imaging technology also allows drawing the MESOSCOPIC Connectomes, including the projection mode ("projection group") of the axis whole brain, and all input nerve connections received by a single neuron ("Input group"). In the classification of the transcription group and the connection -based group, the number of cell types increases with the resolution of the analysis, so each cell may eventually become a category. This requires our consensus to define the standards of cell types and subtypes. It is best to be a standard that can integrate the information obtained by various classification schemes.

Although it has not yet reached consensus on cell typing standards, in the past ten years, it has made great progress in studying the single -cell transcription and connection group of mice brain, as well as information from epigenetics, physiology and behavior research. Scientists are trying to extend the study of single-cell transcription groups from rats to non-human spiritual long animals (NHP) and human brains. However, the single -cell connection group in NHP is still in the early stages. This comment focuses on the study and connection group research of spiritual long animal brain, as well as accurate nerve regulation through physical means to regulate the activity of specific neural circuits behind various brain function and dysfunction.

Single cell transcription group of spiritual brain

It is now obtaining a large amount of data on single cell transcription from NHP and human brains. Conservative and differentiated gene expression patterns were found in homologous areas of embryo and adult mice and human brains. Like mice, it is necessary to integrate single -cell data in the brain, electrical characteristics, and gene expression patterns in the brain of spiritual long animals. For the glutamic acid in the human cortex, Berg and others do have discovered some correspondence between their transcription group mode and form and physiological characteristics. With the further progress of this work, we are increasingly needed to unify the types and subtypes of the cells, which can be used as the basis for integrating the information obtained by various classification methods.

A neurons type or subtype should have some unique features as marks, and these features must be relatively stable in the entire life cycle of the entire neuron; while continuous gene expression, physiological characteristics and forms continuously in the short -term scale// morphology/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form/ form. Changes in connection can be considered different states of neurons. The obtained stable and uniquely expressed genes will help define the type of cells, but so far, the analysis of most single -cell transcription groups generally lacks information about the time change of the transition group mode. It is known that the expression of different transcription factor groups during the early nerve occurring determines the fate of the main neurons type, namely glutamate neurons, GABA can neurons, and quality regulatory neurons. By conducting parallel markers on the ancestral cells to track the spectral relationship and transcription group characteristics during the mouse's front brain development, Bandler and others found that the differentiation of the leather GABA can be different from the level of the ancestral cells in 2022. It is unclear to how much the heterogeneity in the ancestral cell group of each major neuron type can explain the subtype diversity of its descendants, and whether the internal spectrum dependencies are determined by all neurons in different brain areas. The dominant role in subtypes.

We can reasonably expect that the stable gene expression mode of differentiated neuron subtypes should be matched with its functional requirements in neural networks, and the function of neurons is often determined by its specific connection, and the matching process Beginning with a specified site in the brain after the filament is divided and the synapse connection is formed. Shibata et al. In 2021, the mouse's brain discovered the gradient of the front and rear brain regions of the cloakic acid and the expression of its matching receptor, and the active activity of cloakic acid was necessary to establish a churchyle cortex connection. Therefore, the gene expression of time and space programming during the early nerve occurring may not only determine the "base state" of the neurons (named "(named" (named by Fishell and Heinz) after-divorced, but also defines the main neurons type, but also instructs the migration of neurons, axis/ axis/ Dendrobes grow and branches, as well as initial neurons connectivity. The subsequent interaction with the local environment and the trimming and consolidation of the nerve connection that depends on electrical activities will give it the final mode of the stable gene expression of the neuron subtype of the unique form and physiological characteristics of it. Therefore, a method that can integrate the subtype classification based on the transcription group and the connection group is to find a set of unique and stable expression genes in each type of neurons. At the same time, these neurons also show unique connection connections Group mode. In the long -term leather of spiritual animals, in view of the long -term proliferation and more complex inter -cytoplasm of its ancestral cells, people are expected to have more neuronal subtypes than rodents. In addition, stability -based neurons type/subtype classification standards must be applied to long -term memory brought by experience, because these memories involve long -term stable gene expression and changes in synapses. Long -term memory, especially those potential long -level cognitive functions, such as facial recognition and language processing, involve creating different neuron subtypes? The rapid development of spatial transcription analysis is now allowed to draw the genetic expression spatial distribution map of the entire brain by single -cell resolution. Large-scale "STEREO-SEQ" technology is now applied to the entire macaque brain to determine the spatial distribution of cell types defined by transcription group mode in the cortex and cortex. This spatial transcription group analysis will also have human brain tissues applied to or autopsy, and provide more accurate spatial positioning of specific gene expression. This information understands the basis of the various functional and functional disorders of the human brain. Combined with histological and MRI -based information, the analysis of the spatial transcription group can also help produce a more fine brain segmentation and provide the foundation for drawing the neuron connection diagram of all neurons in the long -term brain.

Analysis of space transcription groups in the entire life cycle of animals represents a very meaningful new research direction, which will allow us to solve many important issues of the evolution, development, and aging of the brain of spiritual long animals. In order to answer these questions, we not only need to identify the genes that are specially expressed in the long -categorian animals, but also need to understand the regulatory components of the long -term specialty gene expression. These components determine the unique expression of conservative genes and spiritual long -class specific genes. The patterns, as well as their dependence on inter -cytopenic interaction and apparent genetic factors in the tissue environment. The formation of the extension of human brain development, the occurrence of cortex folds, and the formation of complex networks of human specific functions (such as language) can greatly benefit the knowledge when specific genes, where, and how to express. Some of these problems can be solved by applying genetic and gene editing technology to NHP.

The Jiuyou Brain's Brain -Gimmaking Connection Group

Although the analysis of the single -cell transcription group of the human brain can be performed in the samples and autopsy tissues obtained during the operation, the mapping of the human brain media is much more difficult. Virus expression is great difficulty to track neuridity connection, as well as high -throughput imaging and remote projection of large -scale reconstruction under single -cell resolution. The drawing of the media connection group in NHP, such as monkeys and macaques, is currently more realistic. Recently, by rebuilding the fluorescent microscopic image of the entire brain's ultra -thin slice, or the optical imaging of the improved optical transparent tissue block, it has confirmed the ability of the macaque brain to remotely track a single neuron projection under micron resolution. The data collection and processing of each macaque brain is huge, but it seems to be within a feasible range. On the other hand, it is a more difficult challenge to clarify the local network connection in different brain areas and drawing each type of neurons.

In the past, anatomical work has been widely studied using retrograde fluorescent beads to conduct extensive research on the leather-leather projection in the brain of the macaques. The genes that identify different cell types in different cortex areas and brain areas in different cortex regions and brain areas, and further clarify that specific promoters/enhancers that express these genes will cause development to draw cell -type specific nerve connection groups for cellular types. Molecular tracer. This connection group information provides a basis for further research on neurons/circuit -specific activities related to different brain functions. Macro brain imaging (for example, magnetic resonance imaging, MRI) has generated a lot of information about structure and functional connection in NHP, normal human subjects, and patients with brain diseases. The relatively low space and time resolution, the change of the image collection and analysis program, and the individual differences limit the usefulness of these imaging data in the clinical environment. The analysis of the NHP brain's media connection group, combined with the previous animal's structure and FMRI imaging, will help explain the macro "structure connection group" inferred from the diffusion image imaging. The optical imaging and optical generic operation of specific neurons in specific brain areas will further help explain the "functional connection group" inferred by MRI research and inference. Nervous regulation for the treatment of brain diseases

The general goal of the analysis of the single -cell transcription group and the connection group is to provide the foundation for monitoring and manipulating specific neurons types and circuit activities. However, the specific neurons and circuits of brain diseases are difficult to recognize, especially for mental diseases such as autism, depression, and schizophrenia. These diseases involve network abnormalities that change with individual genetic background and development history. In the neural network connected to each other, especially in neural networks in association and leaf cortex, it is difficult to decipher the causal relationship between related activities related to multiple brain areas, and it is difficult to determine whether the neural circuit is dominating or only regulating a specific specific. Brain function. In addition, abnormal neural circuits originated from the abnormal connection of neurons, and these neurons are also included in many other normal circuit connections. Therefore, the drugs of targeted molecular and cell signals are inevitable. People are increasingly hoping that the network that regulates functional disorders through physical, physiological, and psychological means (hereinafter referred to as "Neuromodulation") can provide non -drug treatment of brain diseases.

The development of drugs or nerve regulation methods requires more suitable animal models. So far, rodent models that generally use brain diseases have performed clinical efficacy testing for candidate drugs, but there are few drugs that can be passed through clinical trials in the end. Because NHP is close to humans in many anatomy and physiological characteristics, the disease model of monkey and macaques may be proven to be valuable and irreplaceable. Many non -invasive nerve regulatory tools, such as through the craniotomy magnetic stimulation (TMS), direct or AC electrocomputer stimulus (TDCS or TACS), and ultrasonic stimuli with low space resolution and poor target specificity. This problem can be used through The larger size NHP brain is partially solved. GM and gene editing methods for making mouse models are now expanding to NHP. The most recent example is the macaque model of day and night rhythm disorders generated by deleting the core day and night rhythmic gene BMAL1 in the macaque embryo. The lack of monkeys in BMAL1 show a variety of symptoms, including sleep disorders, anxiety/depression behavior and schizophrenia -like electrocardycrus characteristics. It is currently being used to test the effects of drugs and nerve regulation to relieve the symptoms of specific mental illness.

Ideally, the clinical treatment of neurotic regulation should be based on the understanding of specific dysfunction neurons and circuits of specific brain diseases. At present, this situation cannot be achieved to a large extent. On the other hand, even if you do not know the "cause" of brain diseases, you can use nerve regulation to correct the "influence" (observed disease phenotype), provided that the cause and impact may be mutually For cause and effect. For example, based on observing the decrease in gamma oscillation in the Martorell and others in the Gamma oscillation in the Martore model, it shows that inducing gamma oscillations through visual or auditory stimulation can reduce the starch protein spots of the entire new cortex. Blocks and improve memory functions.

Research on the clinical nerve regulation of invasiveness (for example, deep brain stimulation, DBS) and non -invasiveness (for example, TDCS and TMS) methods show that there are great differences in the treatment effect of patients, just as several items about the movement defects of patients with stroke patients in TDCS treatment stroke patients As shown in the charm analysis. This variability can be attributed to the differences in parameters used in various studies, such as strength, time, duration, and regulatory parts, and the difference in specific skull anatomy and neural circuit differences in patients. In the clinical application of nerve regulation, the importance of the time of kong has not received enough attention. A recent study of the macaque stroke model shows that the low -frequency duct Film Stimulation (ACS) can cause synchronous discharge of neurons -related neurons -related neurons in the cortex around the lesion, thereby improving the flexibility of the monkey's grasp after stroke. This can be attributed to the ACS applied by the gripping campaign to enhance the nerve circuit of the grip movement. Therefore, when the target behavior initiated or treated with patients is carried out at the same time, the relatively non -specific nerve regulation may enhance the treatment effect, even if the exact potential nerve circuit is still unclear. Considering the individual differences between the anatomical structure and nerve circuit configuration of the skull, the impact of each subject's brain needs to be quantitatively simulated or measured to achieve more accurate and effective nerve modulation. For example, the clinical response to a series of focus stimulation can help determine the effective personalized stimulus parameters when using DBS to treat severe depression. In non -invasive TCS and TMS treatments, individual specific modeling distributed in intracranial electric fields based on structural MRI data can more accurately identify the amplitude of the current and regulate the brain area. The dynamic changes of the induced, online monitoring brain network. Calculating modeling to assist calibration stimulus parameters, as well as brain state changes caused by regulatory control or instant clinical response of individual patients, and online adjustment parameters can provide effective and accurate nerve regulation for the treatment of brain diseases.