Nature. Bohai/Hu Wei/Zhong Yi collaborated to report on the new mechanism of brain-spleen neural loop control antibody immune response.

On April 29, 2020, Qi Hai research group of Institute of immunology of Tsinghua University, Hu Ji research group of Shanghai University of science and technology, and Zhong Yi research group of McGovern Institute of brain science and technology of Tsinghua University published online the paper brain control of human immune responses amenable to behavioral in nature The brain activity affected by behavior regulates humoral immune response.through the mouse model, this study found a neural pathway from the CRH neurons in the amygdala and paraventricular nucleus to the spleen; this pathway promotes the antibody immune response induced by vaccination and regulates the immune response in response to somatic behavioral stimuli.according to the author, this is the first anatomically clear pathway, which is not mediated by endocrine hormones, but is anatomically clear, and the central nervous system regulates the adaptive immune response. Its discovery opens up a new direction for the research of neuroimmunology.Title: the nucleus and loop of central nervous system for frequent movement and immune enhancement. Firstly, the authors developed a new operation to remove the spleen nerve in mice. It was found that the number of plasma cells (antibody secreting cells) produced by the mice after vaccination was obviously deficient, suggesting that the splenic nerve impulse signal can promote the response of B cells.through pharmacological and genetic experiments, they further found that the expression of acetylcholine 9 receptor on B cells is indispensable for the promotion of spleen nerve.through in vivo cell elimination experiments, the authors found that the most likely "exchange" between adrenergic splenic nerves and B cells that need to sense acetylcholine is the recently discovered T cells that can sense norepinephrine and secrete acetylcholine. In addition, the authors found that the splenic nerve was connected with the paraventricular nucleus (PVN) and the central amygdala (CEA) by retrograde tracing of pseudorabies virus.the function of these two regions is closely related to stress and fear reaction. The common type of neurons in the two regions is CRH (adrenocorticotropic hormone releasing hormone) expressing neurons.CRH neurons are the upstream neurons that control the pituitary adrenal axis. Their activation can lead to a large amount of glucocorticoids released from the adrenal gland, regulate the body's stress and inhibit the activities of the immune system.the known endocrine function of immunosuppression can not explain the phenomenon of immune enhancement seen by the author.but can CRH neurons also directly manipulate the splenic nerve and promote the production of plasma cells by transmitting immune enhanced signals through neural pathways? In order to test this hypothesis, the authors found that the electrical signal of splenic nerve was significantly enhanced in a few seconds after stimulation of CRH neurons of CEA / PVN, which proved that there was a pathway connection between CEA / PVN and spleen (Fig. 1). In addition, the authors demonstrated that the activity of CRH neurons in CEA / PVN regulated the production of plasma cells in response to B cells in spleen by eliminating CRH neurons, inhibiting and activating dreamd chemical genetics.fig-1: photogenetic experiments showed that the connection between CEA / PVN CRH neurons and splenic nerve was affected by external environment and behavior.so, is there any behavior that can stimulate this brain spleen nerve axis to enhance immune response? By monitoring the activity of CRH neurons in CEA / PVN under different behavioral paradigms, the authors found that a newly developed "isolated platform standing" behavior could activate CRH neurons in both nuclei at the same time.figure-2: isolated high platform standing mode video: isolated high platform behavior that can enhance the antibody response intensity of mice. More importantly, in the second week after vaccination, mice can increase antigen-specific antibody by ~ 70% after experiencing this behavior pattern twice a day.the effect of this behavior on antibody response is dependent on CRH neurons, spleen nerves and acetylcholine receptors expressed by B cells.although standing on a high platform can be regarded as a stress paradigm, not all behaviors leading to stress can enhance immunity.the author tested the binding model commonly used in neurobiology research, and found that this paradigm strongly and persistently activated the CRH neurons of PVN, but inhibited the CRH neurons of CEA, resulting in the body continuously producing high levels of glucocorticoid, which inhibited the immune response.so far, in this study, the authors identified and proved a brain spleen nerve axis which can enhance adaptive immunity, and revealed the dual immunomodulatory function of CRH neurons: the classical known pituitary adrenal neuroendocrine immunosuppressive effect and the newly discovered immunoregulation effect of the newly discovered neural loop on the spleen. neuroimmunology is in the ascendant. At present, the main directions include: Taking CNS and peripheral nerve as target organs, studying the role of innate microglia and recruited immune cells in the system homeostasis and pathological changes; studying the signal interaction and interaction of innate immune cells (macrophages, ILC, etc.) in Central and peripheral nerves and lymphoid organs and barrier tissues (intestinal epithelium, etc.) Function intermodulation, etc. this new work just published makes us realize that lymphocyte mediated adaptive immune response can also be directly regulated by central peripheral nerve loop, and a biological basis for positive regulation of immune response through somatic behavior. in view of the last point, Professor Qi Hai specially pointed out that exercise (physical exercise) can enhance "immunity", which is a common sense conclusion accepted by almost all people more or less, but the scientific basis behind it is far from clear. he believes that the brain spleen axis they found may provide an explanation in terms of circuit. moderate exercise may stimulate the CRH neurons of CEA and PVN, and enhance the production of plasma cells and anti infective antibodies. on the contrary, people tend to catch cold after frequent marathon running, which may be that the immunosuppression caused by excessive stress exceeds the effect of immune enhancement. Professor Qi Hai speculated that further research on neuroimmunology in the future should be possible to quantitatively describe and evaluate different exercise methods, different body movement forms and even different types of specific neurons and neural circuits The influence of the process of "meditation" and "meditation" on the immune system provides us with a more clear scientific basis for correctly choosing exercise or other ways of practice to strengthen our "immunity". this is the vision expressed by his title "frequently moving". it is reported that Zhang Xu, 2013 doctoral student of Tsinghua University Life Science Joint Center, Lei Bo, 2016 doctoral student of Tsinghua Institute of life, Yuan Yuan, 2015 doctoral student of Shanghai University of science and technology, and Zhang Li, 2016 doctoral student of Tsinghua PTN project, are the co first authors of this paper. in addition, Xu Fuqiang, Wuhan Institute of mathematical physics, Chinese Academy of Sciences, Liao Xuebin, School of pharmacy, Tsinghua University, and sun Wenzhi of Capital Medical University have made important contributions to the smooth development and completion of this study. original link: plate maker: Ke