Neuron: Professor Hailan Hu's team analyzes the regulation mechanism of the medial prefrontal cortex microcirculation in social competitive behavior

Neuron competition is one of the most common social behaviors in the animal world, and it is also the cause of social hierarchy, the basic way of social organization
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For groups, a stable hierarchical structure limits dissipative conflicts within ethnic groups, and is closely related to social stability and population continuity; for individuals, social hierarchy has a profound impact on their quality of life and is considered the best indicator of health
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So what is the neural mechanism behind social competition? In 2011, Hu Hailan’s team published an article in Science, introducing the “drill tube test” to study the social competition of mice: In a pipe that only allows one mouse to pass through, two mice meet in a narrow path, and if one does not advance, they retreat.
Contests are inevitable, and the dominant player will push the opponent out of the pipeline within 30 seconds
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Based on this paradigm, Hu Hailan’s team found in the early stage that enhancing or inhibiting the activity intensity of neurons in the medial prefrontal cortex can instantly change the mouse’s chance of winning in competition, thereby establishing the prefrontal cortex’s key role in controlling social competition consciousness and determining the success or failure of competition.
1,2
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However, questions such as the role of different cell types in the dorsal medial prefrontal cortex and the formation of cortical microloops in social hierarchy still need to be answered urgently
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On November 18, 2021, Beijing time, Professor Hu Hailan’s team from the School of Brain Science and Brain Medicine, Zhejiang University School of Medicine/The Frontier Science Center for Brain-Brain-Machine Fusion of the Ministry of Education published an online publication titled "Dynamics of a disinhibitory prefrontal microcircuit" in the internationally renowned journal Neuron "in controlling social competition" to further uncover the connection between different inhibitory neurons in the dorsal medial prefrontal cortex (dmPFC) and the pyramidal neuron (PYR), which is the main output of cortical signals The relationship with regulation, and its different functions in the social competitive behavior of mice
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The research focused on the three major inhibitory neurons, which account for about 80% of the inhibitory neurons in the mouse cortex, which are parvalbumin (PV) positive, vasoactive intestinal polypeptide (VIP) positive, and growth hormone inhibitory.
Somatostatin (SOM) positive neurons, it is found that the microcircuit composed of VIP-PV-PYR through the functional connection of inhibition and de-inhibition, in a social context, finely and collaboratively regulate the activity of dmPFC pyramidal neurons, thereby affecting The behavior of mice in the face of social competition
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Schematic diagram of the microcircuit inside mPFC Different types of neurons play different roles in social competition.
About 80% of the neurons in the cerebral cortex are excitatory pyramidal neurons, which are the main transmitters of information output to the downstream brain area.

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The rest are inhibitory neurons.
In addition to directly inhibiting excitatory neurons, they can also form more complex multi-level microloops by inhibiting other inhibitory interneurons, so as to more precise the dynamic changes of the neural network.
Regulation
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Researchers found that using optogenetic methods to activate PYR and VIP neurons in dmPFC, or inhibit PV neurons can make mice show more pushing behaviors in the drill tube test, allowing the originally weak mice to win
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Using drug genetic methods to inhibit PYR and VIP neurons, or activate PV neurons, will make mice cringe in the face of social competition and lose to mice that are weaker than themselves
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For another type of SOM neuron, no matter whether it is activated or inhibited, there is no obvious behavior change
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In order to study how these different types of neurons participate in social competition, the researchers conducted optical fiber recording to observe their fluorescent calcium activity in the process of social competition in real time
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The results showed that the activity of PYR neurons and VIP neurons increased during the pushing behavior, and decreased when the retreat behavior occurred
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In contrast, PV neurons rise when both pushing and retreating behaviors occur
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Interestingly, the activity changes of VIP neurons are earlier than PYR and PV during pushing, so it is very likely that VIP neurons initiated a series of changes in mPFC's social competitive pushing behavior
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VIP neurons may be the real "VIP" in the regulation of social competition neural circuits
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The miniature two-photon microscope assists the deconstruction of the function of the microcirculation nerve group.
In view of the calcium activity characteristics of VIP neurons and PV neurons in social competition, and their opposite effects in social competition
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The research team wants to explore how these two types of neurons affect the activity of mPFC
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So the research team cooperated with the team of Academician Cheng Heping of Peking University
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They developed a miniature two-photon microscope that can observe the level of individual neurons in the brain in waking animals.

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Combining two-color imaging and optogenetic manipulation modules, the miniature two-photon microscope can manipulate specific groups of neurons while recording the changes in the activities of different groups of neurons
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Researchers have found that inhibiting PV neurons in dmPFC activates other neurons in dmPFC with pyramidal neurons as the main body
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Inhibiting VIP neurons in mPFC will cause other neurons in mPFC to produce an inhibitory effect, which will weaken the calcium activity in mPFC
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These results verify the inhibitory and excitatory effects of PV neurons and VIP neurons in regulating mPFC activity
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The sequential activation of VIP, PV and PYR neurons in social competition.
In order to further explore the connection between VIP, PV and PYR neurons, researchers thought of the in vivo optical labeling electrophysiological recording technology, which can be measured in milliseconds.
The time resolution records each action potential of the neuron
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When PV neurons are activated, about 90% of other neurons in mPFC are strongly inhibited
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When VIP neurons were activated, some interesting phenomena were discovered
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On the whole, activating VIP neurons that accounted for only about 2% of the cortex caused nearly 50% of mPFC neurons to be activated
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When the recorded different types of neurons are classified, it is found that more PV neurons are directly inhibited or first inhibited and then activated; while PYR neurons are more delayed activated by VIP neurons
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Through the in vivo photo-labeling of electrophysiological records in behavior, the researchers further observed that in the pushing behavior of social competition, the response of PV neurons is heterogeneous: the activation of PYR neurons is inhibited (mediated deinhibition) ), there are also groups that are activated at the same time as PYR (maintain EI steady state)
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 Research summary of mPFC's regulation of social competition behavior Finally, the research team summarized the working model of mPFC's regulation of social competition behavior
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When a mouse encounters a weak opponent, VIP neurons are the first to be activated.
By inhibiting PV neurons and de-inhibiting PYR neurons, the overall activity of mPFC is enhanced, and the mice show stronger competition
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When a mouse encounters a strong opponent, VIP neurons are inhibited, and the firing of PV neurons is significantly increased, inhibiting the activity of PYR neurons, reducing the overall activity of mPFC, and the mice appear to give up competition
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As a result, the team proposed for the first time a neural circuit model of dmPFC composed of VIP-PV-PYR neurons to inhibit microcircuits to regulate social competition behavior
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Professor Hu Hailan’s Laboratory Member, Zhejiang University School of Brain Science and Brain Medicine Professor Hu Hailan and former laboratory member Dr.
Zhu Hong (now Emory University Postdoctoral Fellow) are the co-corresponding authors of this article.
PhD students Zhang Chaoyi, Dr.
Zhu Hong and Ph.
D student Ni Zhe Yi is the co-first author.
In addition, post-doctoral fellows Xin Qiuhong, Dr.
Zhou Tingting, and Dr.
Wu Runlong of Peking University have also made important contributions
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The research is mainly supported by the key projects of the National Natural Science Foundation of China, the key field research and development plan of Guangdong Province, the Chinese Academy of Medical Sciences project, the national key research and development plan, the discipline innovation and talent introduction plan of colleges and universities of the Ministry of Education, the Zhenxi Life Science Foundation, the key research and development plan of Zhejiang Province, Supported by the Star Science Foundation of Shanghai Advanced Research Institute and other projects
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This research was also supported by Academician Heping Cheng and Professor Jue Zhang from the Institute of Frontier Interdisciplinary Studies of Peking University, Professor Guangping Gao from the School of Medicine of the University of Massachusetts, Professor Miao He from the Institute of Brain Science, Fudan University, and Brain Science and Brain Medicine, Zhejiang University.
The strong support of Professor Gao Zhihua, Professor Ma Huan and Professor Li Haohong of the school, as well as the micro two-photon imaging service provided by the Nanjing Institute of Translational Research of Molecular Medicine, Peking University-Nanjing Brain Observatory
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 Original link: https://doi.
org/10.
1016/j.
neuron.
2021.
10.
034 References: 1.
Zhou, T.
et al.
History of winning remodels thalamo-PFC circuit to reinforce social dominance.
Science 357, 162- 168, doi:10.
1126/science.
aak9726 (2017).
2.
Wang, F.
et al.
Bidirectional control of social hierarchy by synaptic efficacy in medial prefrontal cortex.
Science 334, 693-697, doi:10.
1126/science.
1209951 ( 2011).
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