Nature: (with expert insight) non-classical pathways for spleen-brain regulatory immune function.

Understanding the latest progress in neuroscience ● click on the blue word to focus on us ● the interaction between emotion and body function has always been a well-known but unknown phenomenon. To explain the mechanism of this phenomenon is also one of the interests of scientists and philosophers for centuries.ancient Greek medical master Galen put forward that excessive secretion of black bile by the spleen is one of the causes of depression and anxiety. In traditional Chinese medicine, it is also believed that anger, joy, thinking, sadness and fear also have a profound impact on the functions of the five viscera.current scientific research also attempts to explain the interaction between the brain and peripheral functions from various aspects of health, including the regulation of emotion on the immune system.in 2016, it was found that activating the ventral tegmental area (VTA) in the reward circuit of the brain by genetic methods can increase the activity of monocytes and macrophages, and the T cell response of delayed hypersensitivity mouse model is enhanced [1], which provides evidence for emotion regulation and immune function.but the function of immune system is complex and diverse. One important aspect is the acquired immune response, which is also an important mechanism for the body to resist the invasion of various pathogens.published in the main issue of nature on April 29, 2020, the paper "brain control of human immune responses amenable to behavioral modulation" published by Qi Hai research group of Tsinghua University, Zhong Yi research group and Hu Ji research group of Shanghai University of science and technology [2] explained the neurochemical and loop mechanism of the regulation of spleen plasma cell production by Shenjing system in humoral immunity.in humoral immunity, B cells, which play a specific role in humoral immunity, are stimulated by helper T cells and dendritic cells in lymph nodes and spleen and differentiate into mature B cells and memory B cells that can produce specific antibodies. After stimulation, a part of B cells directly become plasma cells that can secrete antibodies The other part will concentrate and proliferate to form germinal center (GC) and be further screened to differentiate into plasma cells.the maturation process of B cells is shown in Fig. [5] in this paper, we innovatively used alcohol to ablate the splenic nerve, and found that after the loss of innervation, a large number of spleen plasma cells (SPPC) were produced by antigen immunization, but the GC was not reduced.the main neurotransmitters of peripheral nerves, norepinephrine (NE) and acetylcholine (ACh), were injected intravenously into animals. It was found that SPPC increased significantly after immunization. Acetylcholinesterase anchored on B cell expression membrane could block the increase, indicating that ACh was a substance directly promoting SPPC production.subsequently, the researchers found that SPPC highly expressed acetylcholine receptor containing α 9 subunit. Through the construction of chimeric animals, it was found that B cell specific knockout of chrna9 (coding gene of acetylcholine receptor α 9 subunit, which lacks the acetylcholine receptor of α 9 subunit) in all B cells of knockout mice, could reduce SPPC production induced by immune, indicating that splenic nerve activity increased by activating nAChRs of B cells The generation of strong SPPC.it has been reported that T cells can secrete ACh [3] under ne activation, and researchers express choline acetyltransferase (choline acetyltransferase) by constructing chimeric animal specific markers It was found that NE nerve fibers and SPPC were densely distributed around the T cells of transferase (ChAT). After these T cells were specifically killed by chemical genetics combined with diphtheria toxin, the SPPC induced by immunity decreased, but the GC remained unchanged, which indicated that these T cells might mediate the regulation of SPPC production by secreting acetylcholine.following the discovery of the peripheral regulation of SPPC production by the splenic nerve, the researchers tried to find the neural connections between the splenic nerve and the brain.a large number of signals were found in spinal cord, brainstem and hypothalamus by retrograde trans multistage pseudorabies virus tracing.a large number of neurons in the central nucleus of the amygdala (CEA) and the stress-related paraventricular nucleus of the hypothalamus (PVN), which are closely related to the physiological and behavioral responses of anxiety and fear, are labeled by the virus.both CEA and PVN contain a large number of CRH neurons [4]. After inactivation or inhibition of CEA and PVN neurons by virus strategy, researchers found that SPPC induced by immunity decreased; these neurons were activated by chemical genetics, and SPPC increased, which could be eliminated by splenic nerve ablation.these results indicate that CRH neurons of CEA and PVN regulate SPPC production through splenic nerve.since there is a direct anatomical and functional relationship between the SPPC generation of the brain and the spleen, can behaviors and emotions also affect immune function through the brain? Because both CEA and PVN are related to stress, the researchers tested the effects of severe and mild stress on immune function. it was found that repeated standing on high platform for a short time can increase the production of SPPC secreting specific antibodies by activating PVN and CEA at the same time, and the immune effect after mild stimulation can last up to one month. so far, this paper suggests that appropriate pressure may enhance the body's humoral immune function and provide neurobiological basis for the application of translational medicine. from flurin cathomas & amp; Scott J. Russo. Nature. 2020, the brain, as the control center of body function, maintains the stability of physiological signs, guides the output of instinct behavior, emotion and cognition and other advanced behaviors. to a certain extent, the brain can adjust its internal function and homeostasis according to the input of external information. The state of brain can be reflected in physiological signs and behavioral emotions through multi-dimensional network, and there may be interaction between the networks regulating physiological signs and behavioral emotions. starting from the command function of the brain, it may be a new perspective for us to understand the integrity of the body as a system and to carry out holistic intervention after steady-state damage (sub-health, disease, etc.). Author: in order to further promote the communication of neural connections between brain and peripheral organs, Li Xuexue, Shenzhen Institute of advanced technology, Chinese Academy of Sciences, has set up a wechat group to communicate with each other. Welcome to the pit! Expert opinion Professor Xiang Hongbing, doctoral / Master's supervisor. graduated from the medical department of Tongji Medical University in 1991 and obtained a doctor's degree in anesthesiology from Huazhong University of science and technology in 2004. From 2009 to 2011, he was engaged in basic research on pain, pruritus, and central and peripheral organs and nerve circuits in Yale University and Oregon Health & amp; Science University. brain regulation of peripheral organ function is usually mediated by neuroendocrine immune network. although the spleen is known to play an important role in immune regulation, it has not been clear how the nervous system regulates immune function through the spleen. the cooperative research of Qi Hai / Hu Ji / Zhong Yi just fills in this gap. the significance of this study is: first, to deepen our understanding of spleen function. clinicians often pay attention to the pathological state of the spleen, such as hypersplenism. Due to the splenic docking circulation, its regulation of systemic blood components can explain the pathological mechanism of hepatosplenic syndrome and systemic inflammatory response. it has been found that the spleen is the functional hub of cholinergic anti-inflammatory pathway to realize the regulation of inflammatory response. Some studies have revealed the molecular mechanism of vagal spleen synergetic regulation on acute lung infection injury and renal ischemia-reperfusion injury. this new discovery focuses on the spleen in the normal state of function. Physical behavior stimulation, such as exercise, can directly act on the spleen through the brain spleen nerve circuit, playing a role in enhancing immune function, which expands a new field of vision for spleen neuroimmunology research. Second, the exploration process of splenic nerve activity in response to central stimulation will become the standard paradigm for the study of central intervention on peripheral organ function. how the central nervous system regulates the functions of circulation, respiration, urinary tract and digestion is a new interdisciplinary research hotspot, and many important scientific questions need to be answered. in this study, a viral retrograde tracing method was used to map the neural circuits connecting the spleen and the brain. This method relies on monitoring the expression of a virus encoded fluorescent protein, which can "jump" through the synapses connecting spleen brain neurons, and can track and determine that two key brain regions (amygdala and hypothalamic paraventricular nucleus) contain splenic nerves Brain network neurons. this provides important anatomical evidence for the brain spleen nerve connection. at the same time, photogenetic technology and electrophysiological recording provide important functional evidence for the response of splenic nerve activity to central stimulation. it is believed that the study of neural "dialogue" between peripheral organs and brain networks will usher in a great leap forward in the next few years. References: [1] Ben Shaanan, T. L. et al. Activation of the forward system boosts innate and adaptive immunity. NAT. Med. 22, 940 – 944 (2016) [2] Zhang, X., Lei, B., yuan, Y. et al. Brain control of human immune responses amenable to behavioral modulation. Nature 581, 204 – 208 (2020). [3] Rosas Ballina, M. et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334, 98–101 (2011)【4】Peng, J. et al. A quantitative analysis of the distribution of CRH neurons in whole mouse brain. Front. Neuroanat. 11, 63 (2017).【5】Stebegg M, Kumar SD, Silva-Cayetano A, Fonseca VR, Linterman MA, Graca L. Regulation of the Germinal Center Response. Front Immunol. 2018;9:2469. Published 2018 Oct 25. doi:10.3389/fimmu.2018.02469