Local, reflex, and central communication 局部、反射和中枢通信
Megan Sammons, ^(1,5){ }^{1,5} Miranda C. Popescu, ^(2,3,5){ }^{2,3,5} Jingyi Chi, ^(4,5){ }^{4,5} Stephen D. Liberles, ^(4,6){ }^{4,6} Nadine Gogolla, ^(2,6){ }^{2,6} and Asya Rolls ^(1,6,**){ }^{1,6, *} Megan Sammons、 ^(1,5){ }^{1,5} Miranda C. Popescu、 ^(2,3,5){ }^{2,3,5} Jingyi Chi、 ^(4,5){ }^{4,5} Stephen D. Liberles、 ^(4,6){ }^{4,6} Nadine Gogolla、 ^(2,6){ }^{2,6} and Asya Rolls ^(1,6,**){ }^{1,6, *}^(1){ }^{1} Rappaport School of Medicine, Technion, Haifa, Israel ^(1){ }^{1} 以色列海法 Technion 拉帕波特医学院^(2){ }^{2} Emotion Research Department, Max Planck Institute of Psychiatry, Munich, Germany ^(2){ }^{2} 德国慕尼黑马克斯-普朗克精神病学研究所情感研究部^(3){ }^{3} International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany ^(3){ }^{3} 国际马克斯-普朗克转化精神病学研究学院（IMPRS-TP），德国慕尼黑^(4){ }^{4} Howard Hughes Medical Institute, Department of Cell Biology, Harvard Medical School, Boston, MA, USA ^(4){ }^{4} 美国马萨诸塞州波士顿哈佛医学院细胞生物学系霍华德-休斯医学研究所^(5){ }^{5} These authors contributed equally ^(5){ }^{5} 这些作者的贡献相同^(6){ }^{6} These authors contributed equally ^(6){ }^{6} 这些作者的贡献相同*Correspondence: rolls.asya@gmail.com *通信：rolls.asya@gmail.comhttps://doi.org/10.1016/j.cell.2024.08.050
SUMMARY 摘要
Behavior is tightly synchronized with bodily physiology. Internal needs from the body drive behavior selection, while optimal behavior performance requires a coordinated physiological response. Internal state is dynamically represented by the nervous system to influence mood and emotion, and body-brain signals also direct responses to external sensory cues, enabling the organism to adapt and pursue its goals within an ever-changing environment. In this review, we examine the anatomy and function of the brain-body connection, manifested across local, reflex, and central regulation levels. We explore these hierarchical loops in the context of the immune system, specifically through the lens of immunoception, and discuss the impact of its dysregulation on human health. 行为与身体生理紧密同步。来自身体的内部需求驱动着行为选择，而最佳的行为表现则需要协调的生理反应。内部状态通过神经系统动态地表现出来，从而影响情绪和情感，而身体-大脑信号也引导着对外部感官线索的反应，使生物体能够在不断变化的环境中适应并追求自己的目标。在这篇综述中，我们将研究大脑与身体之间联系的解剖结构和功能，这些联系体现在局部、反射和中枢调节三个层面。我们以免疫系统为背景，特别是通过免疫感知的视角来探讨这些分级循环，并讨论其失调对人类健康的影响。
As we deepen our understanding of organism physiology, it becomes apparent that we are missing an important piece of the puzzle. The organism does not act as a mere sum of its compo-nents-rather, new properties emerge when we observe the organism as an integrated entity. There is a remarkable synchronization at play-each organ tunes its function in rhythm with other physiological systems and contributes its unique inputs and needs, with the brain and nervous system orchestrating the entire symphony. 随着我们对生物体生理学认识的加深，我们显然缺少了拼图中重要的一块。有机体并不仅仅是其组成部分的总和--相反，当我们把有机体作为一个整体来观察时，新的特性就会出现。在大脑和神经系统的协调下，整个交响乐演奏出了非凡的同步性--每个器官都根据其他生理系统的节奏调整自己的功能，并贡献自己独特的输入和需求。
Brain-body communication is bidirectional. On the one hand, the central nervous system can respond to physiological demands by evoking the behaviors that may fulfill them. For instance, an organism might seek warmth when its body temperature drops or crave specific foods when nutrients are deficient. On the other hand, physiology must adapt to mental and behavioral needs, allowing the organism to effectively execute its goals, such as the increase in heart rate during a flight from a predator attack. Even the very belief that a meal is imminent triggers brain-body signals that prepare the digestive system for food intake, as Pavlov first described. ^(1){ }^{1} 大脑与身体的交流是双向的。一方面，中枢神经系统可以通过唤起行为来满足生理需求。例如，当体温下降时，生物体可能会寻求温暖；当缺乏营养时，生物体可能会渴求特定的食物。另一方面，生理机能必须适应心理和行为需求，使生物体能够有效地实现其目标，例如在躲避捕食者攻击时心跳加速。正如巴甫洛夫首次描述的那样，即使是认为即将进餐这一信念本身也会触发大脑-身体信号，使消化系统为摄入食物做好准备。 ^(1){ }^{1}
The connections between mental and physiological states manifest in modern medicine in the epidemiological correlation between elevated stress levels and the emergence of disease ^(2,3){ }^{2,3} or in the improved physiological state in patients receiving a placebo pill. Interventions aimed at the brain-body connection, such as breathing practices, meditation and relaxation techniques, and exercise, are supported by an emerging body of correlative evidence for the benefit of treating a patient’s emotional, psychological, and cognitive needs. ^(4){ }^{4} Nevertheless, we do not understand how these therapies work, leaving us 心理状态与生理状态之间的联系在现代医学中表现为压力水平升高与疾病发生 ^(2,3){ }^{2,3} 之间的流行病学相关性，或服用安慰剂药片后患者生理状态的改善。越来越多的相关证据表明，针对患者情绪、心理和认知需求的干预措施，如呼吸练习、冥想和放松技巧以及运动等，对治疗患者的情绪、心理和认知需求大有裨益。 ^(4){ }^{4} 然而，我们并不了解这些疗法是如何发挥作用的，这让我们
with a significant challenge to uncover the underlying mechanisms of brain-body communication in health and disease. 揭示健康和疾病中脑-体交流的内在机制是一项重大挑战。
The segregation between the brain and the body that has come to dominate modern medicine is motivated by the need to understand the causal mechanisms of physiological phenomena. It required dissecting the underpinning of each physiological system in isolation to gain a detailed understanding of its components. This contrasts with Eastern medical practices, which are governed by an integrated mind-body perception. However, modern science and medicine have reached a point in which emerging evidence in fields ranging from immunology, reproduction, cardiovascular disease, microbiology, and others highlights the relevance of interconnections between these systems. In seeking to reunite our understanding of the brain and body, science has provided evidence for interactions between the nervous system and other physiological systems at multiple levels of interaction. We will define these interactions as a set of hierarchical loops: local, reflexive, and central (Figure 1). This conceptual segregation, although artificial, will allow us to discuss each loop with its own set of parameters and specific regulation and to define how they synchronize in the overall scheme of brain-body integration. Finally, we will exemplify how these concepts apply to the interaction of the brain with one essential peripheral system, the immune system, and the concept of immunoception. 现代医学之所以将大脑和身体分开，是因为需要了解生理现象的因果机制。它要求孤立地剖析每个生理系统的基础，以获得对其组成部分的详细了解。这与东方医学的做法形成了鲜明对比，东方医学受身心一体化观念的支配。然而，现代科学和医学已经发展到了这样一个阶段：免疫学、生殖学、心血管疾病、微生物学等领域的新证据凸显了这些系统之间相互联系的重要性。在寻求重新认识大脑和身体的过程中，科学提供了神经系统与其他生理系统在多个相互作用层面上的相互作用的证据。我们将把这些相互作用定义为一系列分级循环：局部循环、反射循环和中心循环（图 1）。这种概念上的划分虽然是人为的，但却能让我们讨论每个环路各自的参数和具体调节方式，并确定它们如何在脑体整合的整体计划中同步。最后，我们将举例说明这些概念如何应用于大脑与一个重要的外周系统--免疫系统--的相互作用，以及免疫感知的概念。
INPUTS TO THE NERVOUS SYSTEM 神经系统的输入
The nervous system constantly senses and evaluates the physiological condition of the body. The brain receives information in 神经系统不断感知和评估人体的生理状况。大脑通过以下方式接收信息
two primary forms: soluble molecules that reach circumventricular organs (CVOs) and other brain borders (see Box 1), and sensory neurons, which serve as direct information highways from the body (Figure 2). Sensory neurons include cranial nerves, with the vagus and glossopharyngeal nerves providing dominant innervation of organs in the abdomen and thorax, as well as spinal nerves from the dorsal root ganglia (DRGs). 主要有两种形式：一种是到达脑室周围器官（CVO）和其他大脑边界的可溶性分子（见方框 1），另一种是作为身体直接信息高速公路的感觉神经元（图 2）。感觉神经元包括颅神经（迷走神经和舌咽神经是腹部和胸部器官的主要神经支配神经）以及来自背根神经节（DRGs）的脊神经。
The vagus nerve collectively innervates a variety of organs in the gut as well as the airways (lungs, trachea, and larynx), 迷走神经共同支配着肠道内的多个器官以及呼吸道（肺、气管和喉）、
Figure 1. Overview of hierarchical loops of brain-body communication 图 1.脑体交流的分层回路概览
The nervous system communicates with every physiological system in the body through multiple interconnected levels. These levels form control loops, with higher levels regulating lower ones to achieve adaptive bodily control. Top: central, adaptive regulation, and immunoception involve higher-order brain structures integrating interoceptive information with external sensory data, past experiences, motivational drives, and emotions to form a complex representation. This integration allows adaptive modulation of the internal physiological state, including of the immune system, across different contexts and timescales, enabling prospective and goal-directed regulation of physiology. This regulation includes adjusting the homeostatic set points and modulating body phyisiology directly and indirectly through adjustments in motivation and behavior. Adaptive control is guided by cortical regions (darker blue) such as the alC, ACC, vmPFC, and OFC, while subcortical regions (lighter blue) like the CeA, BNST, hypothalamus, VS, PAG, and PBN implement the integrated adjustments in physiology, motivation, and behavior. Middle: reflexive control is a quick, reactive system that integrates at subcortical sites (green), such as the hypothalamus or the NTS and AP in the brainstem. Here, current bodily state information is compared to predefined homeostatic set points, and if a deviation is sensed, hard-wired responses regulate physiology to return to its set point, such as during inflammation. The autonomic nerves, including the sympathetic and parasympathetic branches, carry instructions from the brain and exert differential effects on inflammation. Bottom: local modulation occurs in a bidirectional manner between sensory neurons innervating peripheral sites and local cells, including immune cells. These interactions influence inflammation by modulating cytokine or neuropeptide secretion (right side). alC, anterior insular cortex; ACC, anterior cingulate cortex; vmPFC, ventromedial prefrontal cortex; OFC, orbitofrontal cortex; CeA, central nucleus of the amygdala; BNST, bed nucleus of the stria terminalis; VS, ventral striatum; PAG, periaqueductal gray; PBN, parabrachial nucleus; NTS, nucleus of the solitary tract; AP, area postrema. 神经系统通过多个相互关联的层次与身体的每个生理系统进行交流。这些层次形成控制回路，由较高层次调节较低层次，以实现对身体的适应性控制。上图：中枢、适应性调节和免疫感知涉及高阶大脑结构，它们将内部感知信息与外部感官数据、过往经验、动机驱动和情绪整合在一起，形成一个复杂的表征。这种整合可以在不同的环境和时间范围内对内部生理状态（包括免疫系统）进行适应性调节，从而实现前瞻性的、以目标为导向的生理调节。这种调节包括通过调整动机和行为，直接或间接地调整体内平衡设置点和调节人体生理状态。适应性控制由 alC、ACC、vmPFC 和 OFC 等皮层区域（深蓝色）引导，而 CeA、BNST、下丘脑、VS、PAG 和 PBN 等皮层下区域（浅蓝色）则实现生理、动机和行为的综合调整。中间：反射性控制是一种快速反应系统，在皮层下部位（绿色）进行整合，如下丘脑或脑干的 NTS 和 AP。在这里，当前的身体状态信息会与预先设定的平衡设定点进行比较，如果感觉到偏差，硬连线反应就会调节生理机能，使其恢复到设定点，例如在炎症期间。包括交感神经和副交感神经分支在内的自律神经传达来自大脑的指令，并对炎症产生不同的影响。 下图：支配外周部位的感觉神经元与包括免疫细胞在内的局部细胞之间以双向方式进行局部调节。这些相互作用通过调节细胞因子或神经肽的分泌来影响炎症（右侧）。alC，前岛叶皮层；ACC，前扣带回皮层；vmPFC，腹外侧前额叶皮层；OFC，眶额叶皮层；CeA，杏仁核中央核；BNST，纹状体末端床核；VS，腹侧纹状体；PAG，uctal periaqueductal gray；PBN，胫旁核；NTS，孤束核；AP，后区。
vasculature (heart, arteries), and other abdominal and thoracic sites. Vagal sensory neurons include first-order sensors that directly sense stimuli, as well as second-order neurons that receive inputs from upstream sentinel cells like enteroendocrine cells in the intestine, glomus cells in the vasculature, neuroepithelial bodies in the lung, taste cells in the larynx, and immune cells. ^(9){ }^{9} Some are chemosensory neurons, specialized to detect hypoxic or hypercapnic conditions, ingestion of nutrients or nausea-inducing toxins, inhalation of certain cough-inducing irritants, or infection by sickness-causing pathogens. Others are mechanosensory neurons that detect changes in blood pressure or blood volume, airway closure, and stretch of organs like the lungs, stomach, heart, esophagus, and intestine. Single-cell atlases of vagal sensory neurons ^(10-12){ }^{10-12} revealed 血管（心脏、动脉）以及其他腹部和胸部部位。迷走感觉神经元包括直接感受刺激的一阶传感器，以及接收来自上游哨兵细胞（如肠道中的肠内分泌细胞、血管中的胶质细胞、肺中的神经上皮体、喉中的味觉细胞和免疫细胞）输入的二阶神经元。 ^(9){ }^{9} 有些是化学感觉神经元，专门检测缺氧或高碳酸血症、摄入营养物质或引起恶心的毒素、吸入某些引起咳嗽的刺激物或感染致病病原体。还有一些是机械感觉神经元，它们能检测到血压或血容量的变化、气道关闭以及肺、胃、心脏、食道和肠道等器官的伸展。迷走感觉神经元 ^(10-12){ }^{10-12} 的单细胞图谱显示
cytokines in the brain 大脑中的细胞因子
Abstract 摘要
The brain is nearly impenetrable, guarded closely by the restrictive blood-brain barrier. Bloodborne cells and large macromolecules are intentionally excluded from the brain to safeguard it from infection and damage. Yet, there is valuable information in the blood stream in the form of hormones and cytokines that can provide insights into the internal physiological status. The brain has specialized structures called CVOs with fenestrated capillaries and a reduced blood-brain barrier, where the presence of bloodborne chemicals can be detected. The area postrema is one CVO that acts as a hotspot for neuroimmune interactions. Cytokines like growth differentiation factor 15 (GDF15) trigger area postrema (AP) responses, leading to sickness and nausea as well as autonomic and immunological changes. Cytokines can affect brain activity by directly interacting with neurons, glia, and/or ependymal cells. Another example is the adipocyte hormone leptin that can access neurons in the hypothalamus to control feeding behavior. Single-cell sequencing has revealed a diversity of sensory neurons across CVOs, and additional studies are needed to understand the biology of many of these brain-resident sensory neurons and their roles in body-brain communication. ^(5-7){ }^{5-7} The secretory CVOs are release sites for neurohormones that control body physiology and include the subcommissural organ (SCO), pituitary gland, median eminence, and pineal gland. The choroid plexus produces cerebrospinal fluid (CSF) but, notably, lacks neurons. It is crucial for neurohumoral modulation by regulating the exchange of molecules between the blood and CSF, secreting CSF, and transporting hormones, cytokines, and nutrients. It also serves as an immunological interface, producing signaling molecules that modulate immune responses within the central nervous system. ^(8){ }^{8} 大脑几乎坚不可摧，受到血脑屏障的严密保护。血源性细胞和大分子物质被有意排除在大脑之外，以保护大脑免受感染和损害。然而，血流中以激素和细胞因子的形式存在着宝贵的信息，可以让人了解大脑内部的生理状况。大脑有专门的结构，称为 "CVO"，其中的毛细血管呈栅栏状，血脑屏障减弱，可以检测到血液中的化学物质。脑后区是一个 CVO，是神经免疫相互作用的热点。细胞因子（如生长分化因子 15 (GDF15)）会引发后遗区（AP）反应，导致恶心、呕吐以及自主神经和免疫学变化。细胞因子可直接与神经元、胶质细胞和/或上皮细胞相互作用，从而影响大脑活动。另一个例子是脂肪细胞激素瘦素，它可以进入下丘脑的神经元控制进食行为。单细胞测序揭示了整个CVO中感觉神经元的多样性，还需要更多的研究来了解这些驻脑感觉神经元的生物学特性及其在体脑交流中的作用。 ^(5-7){ }^{5-7} 分泌型CVO是控制人体生理机能的神经激素的释放场所，包括副神经丛器官（SCO）、垂体、正中突起和松果体。脉络丛产生脑脊液（CSF），但缺乏神经元。它通过调节血液和脑脊液之间的分子交换、分泌脑脊液以及运输激素、细胞因子和营养物质，对神经体液调节起着至关重要的作用。 它还是免疫界面，产生调节中枢神经系统内免疫反应的信号分子。 ^(8){ }^{8}
incredible cell diversity, with dozens of distinct cell types, far more than the number of known vagal reflexes. Furthermore, genetic and anatomical mapping approaches revealed many vagal terminal morphologies with unknown sensory properties. Thus, there are additional capabilities of the vagus nerve that await characterization. 令人难以置信的细胞多样性，有数十种不同的细胞类型，远远超过已知迷走神经反射的数量。此外，遗传学和解剖学绘图方法揭示了许多具有未知感觉特性的迷走神经末端形态。因此，迷走神经还有更多的功能有待鉴定。
Vagal axons enter the brain bilaterally through the jugular foramina, and those from the largest vagal ganglion (the nodose ganglion) target the brainstem at the nucleus of the solitary tract (NTS), with some also projecting to the area postrema (AP). Vagal neurons of the jugular ganglion instead target the spinal trigeminal tract. ^(9){ }^{9} A topographic organization of visceral sensory input arises in the NTS from disordered representations in peripheral ganglia, ^(13){ }^{13} and is generally maintained in higher-order nuclei, such as the viscerosensory nuclei of the thalamus and insular cortex (IC). ^(14){ }^{14} 迷走神经轴突通过双侧颈静脉孔进入大脑，来自最大迷走神经节（结节神经节）的迷走神经轴突以脑干孤束核（NTS）为目标，其中一些还投射到后遗区（AP）。颈神经节的迷走神经元则以脊髓三叉神经束为目标。 ^(9){ }^{9} 内脏感觉输入的拓扑组织在NTS中产生于外周神经节的无序表象， ^(13){ }^{13} 并通常保持在高阶核团中，如丘脑和岛叶皮层（IC）的粘感觉核团。 ^(14){ }^{14}
DRG neurons that innervate internal organs are even less well understood. DRG neurons are classically known to detect stimuli associated with sensations of touch, proprioception (movement and location of body muscles), nociception (pain and itch), and temperature and send axonal inputs to the dorsal horn of the spinal cord. Signals are then further transmitted through spino-thalamic-cortical pathways, where they synapse with higher-order neurons. Single-cell transcriptomics identified 17 distinct types of mouse DRG neurons, most of which are conserved in humans. ^(15,16){ }^{15,16} Many neuron types respond to classical stimuli associated with touch, heat, cold, and itch, while the functions of others are not yet fully understood. In addition to their classical 对支配内脏器官的 DRG 神经元的了解就更少了。众所周知，DRG 神经元能检测与触觉、本体感觉（身体肌肉的运动和位置）、痛觉（痛和痒）和温度相关的刺激，并将轴突输入脊髓背角。然后，信号通过脊髓丘脑-皮层通路进一步传递，并与高阶神经元发生突触。单细胞转录组学发现了17种不同类型的小鼠DRG神经元，其中大部分在人类中是保守的。 ^(15,16){ }^{15,16} 许多神经元类型会对与触摸、热、冷和痒相关的经典刺激做出反应，而其他类型的神经元的功能尚不完全清楚。除了经典的
roles in somatosensation, some also innervate internal organs, including the bladder, colon, heart, and spleen. ^(17-20){ }^{17-20} Still, the diversity of somatosensory neuron types involved in visceral representations, as well as their functions, response properties, and signaling mechanisms, remain largely unknown. ^(17,18){ }^{17,18} Moreover, we are lacking functional studies to understand the division of labor between sensory pathways of cranial nerves, spinal nerves, and CVOs. ^(17-20){ }^{17-20} 在躯体感觉中发挥作用的神经元中，有些还支配着内脏器官，包括膀胱、结肠、心脏和脾脏。 ^(17-20){ }^{17-20} 尽管如此，参与内脏表征的躯体感觉神经元类型的多样性，以及它们的功能、反应特性和信号机制在很大程度上仍然是未知的。 ^(17,18){ }^{17,18} 此外，我们还缺乏功能研究来了解颅神经、脊神经和中枢神经的感觉通路之间的分工。
OUTPUTS OF THE NERVOUS SYSTEM 神经系统的输出
As sensory information is received by the brain, communication with the body occurs through major humoral and neuronal pathways. The endocrine system secretes hormones into the bloodstream, while the somatic nervous system controls voluntary muscle movement, and the autonomic nervous system regulates a variety of internal organ functions, which we focus on here. The autonomic nervous system is broadly divided into two main programs: the sympathetic and parasympathetic systems. The sympathetic nervous system is widely recognized for triggering the “fight or flight” response, a term coined by Walter B. Cannon in the early 20th century to describe a series of rapid and powerful physiological adjustments to prepare the body for facing or escaping urgent threats. By contrast, the parasympathetic nervous system is often associated with the “rest and digest” state, supporting essential bodily functions during more tranquil times. The autonomic nervous system not only adjusts physiological processes during emotional states and behaviors but is also integral in our daily lives for maintaining homeostasis, i.e., ensuring the constancy of organ physiology amid ever-changing internal and external conditions. 大脑接收感官信息后，通过主要的体液和神经元通路与身体进行交流。内分泌系统向血液中分泌激素，躯体神经系统控制肌肉的自主运动，而自律神经系统则调节各种内脏器官的功能，我们在此重点介绍自律神经系统。自律神经系统大致分为两大系统：交感神经系统和副交感神经系统。交感神经系统因触发 "战斗或逃跑 "反应而广为人知。"战斗或逃跑 "反应是沃尔特-B-坎农（Walter B. Cannon）在 20 世纪初创造的一个术语，用来描述一系列快速而有力的生理调整，使身体为面对或逃离紧急威胁做好准备。相比之下，副交感神经系统通常与 "休息和消化 "状态有关，在较为平静的时期支持身体的基本功能。自律神经系统不仅在情绪状态和行为中调整生理过程，而且在我们的日常生活中也是维持平衡不可或缺的一部分，即在不断变化的内部和外部条件下确保器官生理的恒定性。
The sympathetic and parasympathetic nervous systems are often partners in the same dance, with opposing but coordinated motions that maintain a delicate physiological balance. The baroreceptor reflex exemplifies this coordination, ensuring real-time stabilization of the cardiovascular system. Baroreceptor sensory neurons alert the brain to changes in blood pressure through PIEZO-dependent detection of arterial distension, triggering responses that adjust heart rate and vascular resistance by engagement of parasympathetic outflow and simultaneous disengagement of sympathetic outflow. ^(21){ }^{21} These systems exhibit dynamic sensitivity, with central circuits adapting during physiological states such as exercise. Similar antagonistic functions of the sympathetic and parasympathetic systems have been described across physiological systems, from respiration to digestion. Understanding this yin-yang hallmark of brainbody communication in the context of the immune system and whether the systems truly have opposing roles has become an emerging area of research. ^(22){ }^{22} 交感神经系统和副交感神经系统通常是同一支舞蹈中的舞伴，它们的动作相互对立但又相互协调，从而维持着微妙的生理平衡。气压感受器反射就是这种协调的典范，它确保了心血管系统的实时稳定。气压感受器感觉神经元通过对动脉扩张的 PIEZO 依赖性检测，提醒大脑注意血压的变化，并通过副交感神经外流的参与和交感神经外流的同时脱离，触发调整心率和血管阻力的反应。 ^(21){ }^{21} 这些系统表现出动态敏感性，在运动等生理状态下，中枢回路会进行调整。交感神经和副交感神经系统的类似拮抗功能已在从呼吸到消化的各个生理系统中得到描述。了解免疫系统中脑体交流的这种阴阳特征，以及这两个系统是否真的具有对立作用，已成为一个新兴的研究领域。 ^(22){ }^{22}
Autonomic outflow involves a characteristic two-neuron relay, with preganglionic neurons in the central nervous system and postganglionic neurons typically in peripheral ganglia. The preganglionic neuron has a motor axon that targets peripheral ganglia in the body, and the postganglionic neuron relays descending motor commands directly to a target organ (Figure 2). Some sympathetic preganglionic neurons also target hormone-producing cells of the adrenal medulla. Sympathetic preganglionic neurons are situated in the thoracic and upper 自主神经外流涉及一种特征性的双神经元中继，节前神经元位于中枢神经系统，节后神经元通常位于外周神经节。节前神经元有一条运动轴突，目标是体内的外周神经节，而节后神经元则直接向目标器官转达下行运动指令（图 2）。一些交感神经节前神经元还以肾上腺髓质的激素分泌细胞为目标。交感神经节前神经元位于胸腔和上腹部。
Figure 2. Peripheral anatomy facilitating brain-body communication 图 2.促进脑体交流的外周解剖结构
Left: Internal sensory information reaches the brain through major humoral and neuronal pathways (afferent pathways). 左图：内部感觉信息通过主要的体液和神经元通路（传入通路）到达大脑。
Right:The autonomic nervous system is broadly divided into two main programs: the sympathetic and parasympathetic systems (efferent pathways). 右图：自律神经系统大致分为两个主要程序：交感神经系统和副交感神经系统（传出通路）。
All these pathways are present bilaterally in the body and are illustrated according to human anatomy. Left panel illustrates the afferent pathways, composed of vagal (left) and spinal (right) afferents. Vagal afferents are pseudounipolar sensory neurons in the nodose or jugular ganglia (vagal ganglion in figure). These sensory neurons send a peripheral branch to innervate organs and a central branch to the brainstem. Nodose neurons synapse in the NTS and sometimes in the AP, while jugular neurons synapse in the SPV. This internal sensory information is then transmitted from these brainstem sites to higher-order neurons. Spinal afferents are pseudounipolar neurons in the dorsal root ganglia (DRGs). DRG neurons extend a peripheral branch to innervate organs and a central branch to the dorsal horn of the spinal cord, and occasionally to the DCN in the brainstem. This sensory information is subsequently relayed to higher-order neurons. Right panel illustrates the efferent pathways-parasympathetic and sympathetic nervous systems. Descending neuronal signals reach areas in the brainstem such as the DMV and the nAmb, where parasympathetic preganglionic neurons reside. These neurons send projections to the periphery through the motor arm of the vagus nerve. Parasympathetic preganglionic neurons synapse with postganglionic neurons located in ganglia close to or within target organs. The preganglionic neurons release ACh to communicate with postganglionic neurons, which in turn secrete acetylcholine or other molecules to regulate the function of target organs. Central output reaches sympathetic preganglionic neurons in the spinal cord. These preganglionic neurons send short axons to synapse on postganglionic neurons in the paravertebral or prevertebral sympathetic ganglia. A population of sympathetic preganglionic neurons project directly to the adrenal 所有这些通路都存在于人体的双侧，并根据人体解剖学进行了说明。左图为由迷走神经（左）和脊髓（右）传入组成的传入通路。迷走神经传入是结节或颈静脉神经节（图中为迷走神经节）中的假两极感觉神经元。这些感觉神经元发出外周支支配器官，发出中枢支支配脑干。结节神经元在 NTS，有时也在 AP 中进行突触，而颈神经元则在 SPV 中进行突触。这些内部感觉信息随后从这些脑干部位传递到高阶神经元。脊髓传入是背根神经节（DRGs）中的假极神经元。背根神经节神经元的外周分支支配器官，中央分支支配脊髓背角，偶尔也支配脑干的 DCN。这些感觉信息随后被传递给高阶神经元。右图显示传出路径--副交感神经系统和交感神经系统。下行神经元信号到达脑干中的 DMV 和 nAmb 等区域，副交感神经节前神经元就位于这些区域。这些神经元通过迷走神经的运动臂向外周发出投射。副交感神经节前神经元与位于目标器官附近或内部神经节的节后神经元发生突触。节前神经元释放乙酰胆碱与节后神经元沟通，节后神经元则分泌乙酰胆碱或其他分子来调节目标器官的功能。中枢输出到达脊髓的交感神经节前神经元。这些节前神经元发出短轴突，与椎旁或椎前交感神经节中的节后神经元发生突触。交感神经节前神经元群直接投射到肾上腺
lumbar segments of the spinal cord, with sympathetic ganglia comprising either the sympathetic chain adjacent to the vertebrae or prevertebral sympathetic ganglia. Sympathetic preganglionic neurons release acetylcholine, which acts on nicotinic receptors to excite postganglionic neurons or adrenal chromaffin cells. The postganglionic neurons then typically release norepinephrine or, in rare cases, acetylcholine and other secreted molecules to regulate specific tissue functions. Adrenal chromaffin cells, on the other hand, directly secrete catecholamines such as epinephrine and norepinephrine into the bloodstream, thereby more broadly influencing organ function. Cellular responses to norepinephrine are notably dose-dependent and influenced by perfusion efficiency at receptor sites, meaning that nerves innervating specific targets can create higher local norepinephrine concentrations and trigger distinct reactions compared with systemic norepinephrine. ^(23){ }^{23} 交感神经节是脊髓腰段的神经元，交感神经节由毗邻脊椎的交感神经链或椎体前交感神经节组成。交感神经节前神经元释放乙酰胆碱，乙酰胆碱作用于烟碱受体，从而兴奋节后神经元或肾上腺绒毛细胞。然后，节后神经元通常会释放去甲肾上腺素，或在极少数情况下释放乙酰胆碱和其他分泌分子，以调节特定的组织功能。另一方面，肾上腺绒毛膜细胞会直接分泌儿茶酚胺（如肾上腺素和去甲肾上腺素）进入血液，从而更广泛地影响器官功能。细胞对去甲肾上腺素的反应具有明显的剂量依赖性，并受受体部位灌注效率的影响，这意味着支配特定靶点的神经可产生更高的局部去甲肾上腺素浓度，并引发与全身去甲肾上腺素不同的反应。 ^(23){ }^{23}
Parasympathetic preganglionic neurons instead reside directly in the brainstem, in motor nuclei associated with cranial nerves (III, VII, IX, and X), or in sacral segments of the spinal cord. Postganglionic parasympathetic neurons are located near or within target organs; for example, postganglionic parasympathetic neurons in the gut are part of the enteric nervous system. Acetylcholine is the primary neurotransmitter used at both preganglionic and postganglionic synapses of the parasympathetic system. Peripheral neurons (parasympathetic and sympathetic) can sometimes co-release neuropeptides or nitric oxide together with amines. 副交感神经节前神经元则直接位于脑干、与颅神经（III、VII、IX 和 X）相关的运动神经核或脊髓骶段。节后副交感神经元位于目标器官附近或内部；例如，肠道中的节后副交感神经元是肠道神经系统的一部分。乙酰胆碱是副交感神经系统节前和节后突触的主要神经递质。外周神经元（副交感神经和交感神经）有时会与胺类物质共同释放神经肽或一氧化氮。
Recent studies using single-cell RNA sequencing have revealed a surprising diversity within the sympathetic and parasympathetic systems, challenging the old view of these systems as providing uniform “all-or-nothing” responses. ^(24-27){ }^{24-27} Cellular atlases have provided markers enabling the development of genetic tools for selective mapping and control of molecularly defined neurons, revealing that transcriptional diversity likely underlies functional diversity. For instance, transcriptomic analysis has revealed a diversity of vagal preganglionic neurons, with at least seven neuron subtypes within the dorsal motor nucleus of the vagus (DMV) and a smaller group within the nucleus ambiguous (nAmb). ^(24,25){ }^{24,25} These neuron subtypes exhibit distinct connectivity patterns within the body, and early studies suggest a functional division of labor. Different neuronal subtypes within the nAmb mediate the baroreceptor reflex, the dive reflex, and motor control over the esophagus. ^(25,28){ }^{25,28} Each neuron type potentially exerts differential and nuanced physiological control rather than a singular, all-or-nothing, rest and digest response. Together, these findings indicate that transcriptional diversity is a crucial organizational principle in parasympathetic preganglionic neurons, with each neuron type assuming a unique projection pattern and specific function. 最近利用单细胞RNA测序技术进行的研究揭示了交感神经和副交感神经系统内部令人惊讶的多样性，挑战了这些系统提供统一的 "全有或全无 "反应的旧观点。 ^(24-27){ }^{24-27} 细胞图谱提供了标记，有助于开发用于选择性映射和控制分子定义神经元的遗传工具，揭示了转录多样性可能是功能多样性的基础。例如，转录组分析揭示了迷走神经节前神经元的多样性，在迷走神经背侧运动核（DMV）中至少有七个神经元亚型，在模糊核（nAmb）中还有一个较小的亚型。 ^(24,25){ }^{24,25} 这些神经元亚型在体内表现出不同的连接模式，早期研究表明它们存在功能分工。nAmb 中的不同神经元亚型介导了气压感受器反射、下潜反射和对食道的运动控制。 ^(25,28){ }^{25,28} 每种神经元类型都可能发挥不同的、细微的生理控制作用，而不是单一的、全有或全无的休息和消化反应。这些发现共同表明，转录多样性是副交感神经节前神经元的重要组织原则，每种神经元类型都具有独特的投射模式和特定功能。
Similar approaches are starting to shed light on the transcriptional diversity of the sympathetic nervous system, corroborating early histology and electrophysiology studies that observed differences in soma size, dendrite morphology, response property, 类似的方法开始揭示交感神经系统转录的多样性，证实了早期组织学和电生理学研究观察到的体节大小、树突形态和反应特性的差异、
and neuropeptide expression. Single-cell analyses identified 16 types of cholinergic preganglionic neurons that comprise the thoracolumbar and sacral outflows, ^(27){ }^{27} and five to seven subtypes in the superior cervical, stellate, and thoracic ganglia. ^(26,29){ }^{26,29} These studies reveal expression of numerous genes encoding neuropeptides and hormone receptors, suggesting more complex communication mechanisms and modulatory mechanisms beyond canonical aminergic transmission. Moreover, these rich datasets enable an unprecedented opportunity to study the intricate mechanisms of signal transduction and neuron modulation in the sympathetic nervous system and will potentially reveal new organizational features and functions. Genetic access to molecularly defined autonomic neurons will provide a road map to link transcriptional profiles, morphological features, projection patterns, response properties, and functions. Pharmacological tools that target specific neuronal populations may provide tailored control of physiology and new therapeutic opportunities for selective adjustment of autonomic tone. This neuronal diversity also highlights precise and complex mechanisms during neural development to ensure proper wiring and function, as well as exciting developmental and mechanistic questions that await further investigation. 和神经肽的表达。单细胞分析确定了构成胸腰椎和骶神经外流的16种类型的胆碱能节前神经元， ^(27){ }^{27} 以及上颈神经节、星状神经节和胸神经节中的5到7种亚型。 ^(26,29){ }^{26,29} 这些研究揭示了编码神经肽和激素受体的大量基因的表达，表明除了典型的胺能传导外，还有更复杂的交流机制和调节机制。此外，这些丰富的数据集为研究交感神经系统复杂的信号转导和神经元调节机制提供了前所未有的机会，并有可能揭示新的组织特征和功能。通过基因获取分子定义的自律神经元将为连接转录特征、形态特征、投射模式、反应特性和功能提供路线图。以特定神经元群为靶点的药理学工具可提供量身定制的生理学控制，并为选择性调节自律神经张力提供新的治疗机会。神经元的多样性还突显了神经发育过程中确保正确布线和功能的精确而复杂的机制，以及有待进一步研究的令人兴奋的发育和机制问题。
NEURONAL REGULATION ACROSS HIERARCHIES: THE INTERCONNECTEDNESS OF LOCAL, REFLEXIVE, AND CENTRAL REGULATION 跨层次的神经元调控：局部调节、反射调节和中枢调节的相互联系
The intricate and interwoven architecture of the nervous system is characterized by a series of hierarchical controls of bodily physiology that, as described in the previous section, connect the peripheral to the central nervous system. This complex network is a continuum, fine-tuned by integrating local, reflexive, and central regulatory levels to coordinate the body’s interactions with its environment and promote homeostasis on both a short and long timescale. 神经系统的结构错综复杂、相互交织，其特点是对身体生理机能进行一系列分级控制，如上一节所述，这些分级控制将外周神经系统与中枢神经系统连接起来。这个复杂的网络是一个连续体，通过整合局部、反射和中枢调控水平进行微调，以协调人体与环境的相互作用，并促进短期和长期的平衡。
Local control 地方控制
Peripheral sensory neurons are deeply embedded within tissues. ^(30){ }^{30} In addition to transmitting sensory information to the central nervous system, sensory neurons and/or their communication partners, like enteroendocrine cells in the gut, can in some cases have more local functions, releasing peptides that elicit direct physiological effects on peripheral tissues. ^(9,31){ }^{9,31} It should be noted, however, that the existence of local responses does not exclude the routing of relevant information through the brain. 外周感觉神经元深藏于组织内部。 ^(30){ }^{30} 除了向中枢神经系统传递感觉信息外，感觉神经元和/或它们的通讯伙伴（如肠道中的肠内分泌细胞）在某些情况下还能发挥更多的局部功能，释放肽类物质，对外周组织产生直接的生理效应。 ^(9,31){ }^{9,31} 不过，应该注意的是，局部反应的存在并不排除相关信息通过大脑传递。
These local effects of sensory neurons were demonstrated in the context of immunity. Peripheral sensory neurons innervate tissues inhabited by immune cells. These neurons can directly sense the presence of pathogens or changes in immune activity via cytokine receptors or pattern recognition receptors that detect pathogen-derived component. ^(32){ }^{32} In addition to transmitting this immune-related sensory information to the central nervous system, these sensory neurons can also locally modulate 感觉神经元的这些局部效应在免疫方面得到了证实。外周感觉神经元支配着免疫细胞居住的组织。这些神经元可以通过细胞因子受体或模式识别受体直接感知病原体的存在或免疫活动的变化，而细胞因子受体或模式识别受体可以检测到病原体衍生的成分。 ^(32){ }^{32} 除了向中枢神经系统传递这种与免疫有关的感觉信息外，这些感觉神经元还能在局部调节
medulla. Communication between preganglionic and postganglionic neurons is mediated by acetylcholine. The postganglionic neurons extend axons to target organs and primarily release norepinephrine to modulate physiological functions. Adrenal chromaffin cells within the adrenal medulla secrete catecholamines such as epinephrine and norepinephrine into the circulation. NTS, nucleus of the solitary tract; AP, area postrema; SPV, spinal trigeminal nucleus; DCN, dorsal column nuclei; DMV, dorsal motor nucleus of the vagus; nAmb, nucleus ambiguus; ACh, acetylcholine. 髓质。节前神经元和节后神经元之间的交流由乙酰胆碱介导。节后神经元将轴突延伸至靶器官，主要释放去甲肾上腺素以调节生理功能。肾上腺髓质内的肾上腺绒毛细胞分泌儿茶酚胺，如肾上腺素和去甲肾上腺素，进入血液循环。NTS，孤束核；AP，后遗区；SPV，脊髓三叉神经核；DCN，背柱核；DMV，迷走神经背运动核；nAmb，伏隔核；ACh，乙酰胆碱。
Figure 3. Reflexive control of inflammation Reflex circuits play a critical role in maintaining homeostasis. During inflammation, these circuits can be engaged by peripheral signals such as cytokines. Brainstem areas including the NTS, AP, and DMV are activated by these signals to reduce inflammation or mediate behaviors. (The anti-inflammatory re- 图 3.炎症的反射性控制 反射回路在维持体内平衡方面发挥着关键作用。在炎症期间，细胞因子等外周信号会激活这些回路。包括 NTS、AP 和 DMV 在内的脑干区域会被这些信号激活，以减轻炎症或调节行为。(抗炎再
the immune response. They can secrete regulatory factors such as calcitonin gene-related peptide (CGRP), substance PP (SP), and vasoactive intestinal peptide (VIP). ^(33){ }^{33} Accordingly, sensory neurons were implicated in suppressing inflammation, driving it, and mediating resistance to infections. ^(34,35-37){ }^{34,35-37} Local interactions between somatosensory neurons and immune cells are particularly evident in nociceptive mechanisms, where immune cells release inflammatory mediators that sensitize or activate sensory neurons, contributing to the onset and maintenance of pain and sickness behavior. ^(38,39){ }^{38,39} Mast cells, neutrophils, and macrophages contribute to this interaction by playing discrete roles in affecting neurons, mediating pain and itch. ^(40,41,42){ }^{40,41,42} These local mechanisms are evident and further complicated in clinical settings, where damage to nerves has been associated with improvement to psoriasis, ^(43){ }^{43} whereas a genetic mutation that results in the lack of somatosensory neurons is associated with more bacterial infections. ^(44){ }^{44} Yet, it is important to note that some of these effects can take place also at reflexive and central regulatory levels. 免疫反应。它们可以分泌降钙素基因相关肽（CGRP）、物质 PP （SP）和血管活性肠肽（VIP）等调节因子。 ^(33){ }^{33} 因此，感觉神经元与抑制炎症、驱动炎症和介导抗感染有关。 ^(34,35-37){ }^{34,35-37} 躯体感觉神经元和免疫细胞之间的局部相互作用在痛觉机制中尤为明显，免疫细胞释放炎症介质，使感觉神经元敏感或激活，从而导致疼痛和疾病行为的发生和维持。 ^(38,39){ }^{38,39} 肥大细胞、中性粒细胞和巨噬细胞在影响神经元、介导疼痛和瘙痒方面发挥着不同的作用，从而促进了这种相互作用。 ^(40,41,42){ }^{40,41,42} 这些局部机制在临床环境中显而易见并进一步复杂化，神经损伤与牛皮癣的好转有关， ^(43){ }^{43} 而导致躯体感觉神经元缺乏的基因突变与更多的细菌感染有关。 ^(44){ }^{44} 然而，值得注意的是，其中一些影响也可能发生在反射和中枢调节层面。
The connection between pain and inflammation serves an important adaptive role across all these levels. Pain sensitization leads to modified behavior to protect affected areas and avoid pressure on an inflamed spot. According to this line of reasoning, one can expect that pro-inflammatory cytokines will exacerbate pain while anti-inflammatory cytokines help alleviate it. However, the activity programs of sensory neurons are not as discrete, and variations in the activating pathogens (e.g., bacteria vs. virus), the affected tissue, the specific types of sensory neurons involved, and the prevailing condition of the tissue. All highlight a major gap in our understanding of the local interactions between pain and immunity. 疼痛与炎症之间的联系在所有这些层面上都发挥着重要的适应作用。痛觉敏化会改变人们的行为，以保护受影响的部位，避免对发炎部位施加压力。根据这一推理，我们可以认为促炎细胞因子会加剧疼痛，而抗炎细胞因子则有助于减轻疼痛。然而，感觉神经元的活动程序并不那么独立，激活的病原体（如细菌与病毒）、受影响的组织、涉及的特定类型的感觉神经元以及组织的普遍状况都存在差异。所有这些都凸显了我们对疼痛与免疫之间局部相互作用的理解存在重大差距。
Another conceptual gap that highlights the importance of further research in this direction is the understanding of why sensory neurons secrete immune mediators despite the presence of other tissue cells, such as epithelial subsets, which are capable of fulfilling this role. One possibility is that these local sensory neurons possess some level of integrative capacity that manifests in their differential effects on the local immune response. 另一个凸显在这一方向开展进一步研究重要性的概念性空白是了解为什么感觉神经元会分泌免疫介质，尽管存在其他组织细胞，如上皮亚群，它们能够发挥这一作用。一种可能性是，这些局部感觉神经元具有某种程度的整合能力，表现为对局部免疫反应的不同影响。
Reflexive control 反射控制
Beyond the local sensory response, a pathway followed by a reflexive activity, known as the reflex arc, typically involves a sensory neuron that detects the stimulus and a motor neuron that carries out the response (Figure 3). However, reflexive activities can involve more complex pathways, including additional neuronal relays. This additional processing of information within the spinal cord or brainstem may lead to more nuanced responses based on other sensory stimuli or the physiological state of the tissue or organism. 除了局部感觉反应之外，反射活动所遵循的路径（称为反射弧）通常包括检测刺激的感觉神经元和执行反应的运动神经元（图 3）。不过，反射活动可能涉及更复杂的路径，包括额外的神经元中继。脊髓或脑干对信息的这种额外处理可能会根据其他感官刺激或组织或机体的生理状态产生更细微的反应。
flex, which ultimately reduces inflammation, consists of splenic projecting postganglionic neurons from the DMV that secrete NE, which acts on B2AR on T cells. These T cells then secrete ACh, which helps to reduce inflammation. ^(45){ }^{45} Similar circuits can be deliberately engaged to reduce inflammation by electrostimulation. For example, stimulating the acupuncture point ST36 activates the DMV, which projects to the adrenal gland. ^(46){ }^{46} Here, neuropeptide Y (NPY)+ chromaffin cells secrete ACh, reducing inflammation. CG, celiac ganglion; NE, norepinephrine; B2AR, beta2\beta 2-adrenergic receptors. 挠性神经元最终会减轻炎症，它由来自 DMV 的脾投射节后神经元组成，这些神经元会分泌 NE，NE 会作用于 T 细胞上的 B2AR。然后，这些 T 细胞会分泌 ACh，从而帮助减轻炎症。 ^(45){ }^{45} 通过电刺激，可以有意识地调动类似的回路来减轻炎症。例如，刺激穴位 ST36 可激活 DMV，DMV 投射到肾上腺。 ^(46){ }^{46} 在这里，神经肽 Y（NPY）+ 绒毛膜细胞分泌 ACh，从而减轻炎症。CG，腹腔神经节；NE，去甲肾上腺素；B2AR， beta2\beta 2 肾上腺素能受体。
Reflex circuits are heavily involved in regulating homeostasis, the delicate balance of maintaining physiological conditions within a narrow set point. ^(47){ }^{47} This set point encompasses constants like core body temperature, blood pressure, and systemic sugar levels, which can be largely regulated by physiological reflex arcs without the involvement of higher brain areas. These types of classical reflex arcs are reactive systems that provide direct negative feedback control by triggering stereotypical compensatory actions when physiological parameters deviate from their predefined set points. ^(47){ }^{47} More complex reflex arcs also allow for dynamic changes in physiological set points; for example, exercise dampens the baroreceptor reflex to allow heart rate and blood pressure to remain elevated as needed. 反射回路在很大程度上参与调节体内平衡，即在一个狭窄的设定点内维持生理状态的微妙平衡。 ^(47){ }^{47} 这个设定点包括核心体温、血压和全身血糖水平等常量，它们在很大程度上可以由生理反射弧调节，而无需高级脑区的参与。这些类型的经典反射弧是一种反应系统，当生理参数偏离预定的设定点时，它们会触发刻板的补偿动作，从而提供直接的负反馈控制。 ^(47){ }^{47} 更复杂的反射弧还允许生理设定点发生动态变化；例如，运动会抑制气压感受器反射，使心率和血压根据需要保持升高。
One example of a reflex response at the neuro-immune axis is the inflammatory reflex (Figure 3). It was initially observed that electrical stimulation of the vagus nerve dampens the systemic immune response to endotoxin shock ^(45){ }^{45} (the specific mediators that activate this response are still not fully elucidated). Vagal motor neurons were proposed to innervate spleen-projecting postganglionic neurons located in the celiac-superior mesenteric ganglia of the sympathetic prevertebral ganglia. Postganglionic neurons then release noradrenaline in the spleen, which signals to cholinergic T cells through 32 -adrenergic receptors. T cell-derived acetylcholine subsequently acts via a nicotinic receptor ( alpha7nAChR\alpha 7 \mathrm{nAChR} ) on macrophages, suppressing the inflammatory cytokine response. This neuronal mechanism facilitates a rapid, system-wide response essential for survival. ^(48){ }^{48} 神经-免疫轴反射反应的一个例子是炎症反射（图 3）。最初观察到，电刺激迷走神经可抑制对内毒素休克的全身免疫反应 ^(45){ }^{45} （激活这种反应的特定介质仍未完全阐明）。有人认为迷走运动神经元支配位于交感神经椎前神经节腹腔肠系膜上神经节的脾脏投射节后神经元。节后神经元随后在脾脏释放去甲肾上腺素，通过 32 - 肾上腺素能受体向胆碱能 T 细胞发出信号。T 细胞衍生的乙酰胆碱随后通过巨噬细胞上的烟碱受体（ alpha7nAChR\alpha 7 \mathrm{nAChR} ）发挥作用，抑制炎症细胞因子反应。这种神经元机制促进了对生存至关重要的快速、全系统反应。 ^(48){ }^{48}
This is important because immune cells communicate via dispersed chemical signals, resulting in a slower, localized response. This is crucial for carefully regulating immune reactions. However, when a faster and more systemic response is required (e.g., sepsis), the nervous system can bridge the gap. These are hard-wired programs crucial for survial. For example, neurons in the caudal NTS respond indirectly to cytokines secreted during inflammation and work to suppress the inflammation. ^(49){ }^{49} 这一点非常重要，因为免疫细胞通过分散的化学信号进行交流，从而产生较慢的局部反应。这对于仔细调节免疫反应至关重要。然而，当需要更快、更系统的反应时（如败血症），神经系统就能弥补这一差距。这些都是对生存至关重要的硬连接程序。例如，尾部 NTS 的神经元会对炎症期间分泌的细胞因子做出间接反应，并抑制炎症。 ^(49){ }^{49}
Another component of inflammation, sickness behavior, has also been shown to be mediated by neurons in the NTS and AP. ^(5,50){ }^{5,50} The AP is directly activated by certain cytokines, like GDF15, and mediates sickness-related behaviors such as nausea. ^(5,6){ }^{5,6} While these behaviors also involve higher brain structures and require complex processing by the brain, direct reflex loops between immune signals reaching the AP and autonomic responses have been demonstrated (Figure 3). 炎症的另一个组成部分--疾病行为，也被证明是由 NTS 和 AP 的神经元介导的。 ^(5,50){ }^{5,50} AP直接被某些细胞因子（如GDF15）激活，并介导恶心等与疾病相关的行为。 ^(5,6){ }^{5,6} 虽然这些行为也涉及较高的大脑结构，需要大脑进行复杂的处理，但到达 AP 的免疫信号与自律神经反应之间的直接反射回路已被证实（图 3）。
An intriguing variation of neuroimmune reflexes has been reported in studies involving electroacupuncture stimulation (ES). These studies found that stimulation of specific subsets of peripheral sensory neurons at acupuncture points can result in vagal-adrenal activation, which induces an anti-inflammatory effect (Figure 3). ^(51){ }^{51} Notably, one study demonstrated that this is intensity-dependent: high-intensity ES activates a different mechanism via the spinal-sympathetic axis, which may drive inflammation. ^(46){ }^{46} These findings highlight an important gap in this field, raising questions about potential sympathetic reflex loops. Additionally, they underscore our incomplete understanding of the interactions between the two components of the autonomic nervous system. 在涉及电针刺激（ES）的研究中，报道了神经免疫反射的一种有趣变异。这些研究发现，刺激穴位处的特定外周感觉神经元亚群可导致迷走神经-肾上腺激活，从而诱发抗炎作用（图3）。 ^(51){ }^{51} 值得注意的是，一项研究表明这与强度有关：高强度的ES通过脊髓-交感轴激活了一种不同的机制，这可能会驱动炎症。 ^(46){ }^{46} 这些发现凸显了该领域的一个重要空白，提出了有关潜在交感神经反射回路的问题。此外，它们还强调了我们对自律神经系统两个组成部分之间相互作用的不完全理解。
A promising application of the inflammatory reflex is the use of vagal nerve stimulation (VNS) for reducing inflammation in diseases such as inflammatory bowel disease (IBD), pancreatitis, kidney injury, and rheumatoid arthritis. ^(48,52){ }^{48,52} Notably, VNS has been effective in calming gut inflammation by acting directly on specific immune cells in the gut rather than through the spleen or T cells. ^(53){ }^{53} However, the broad activation of vagal sensory and motor neurons by VNS limits the generalization of this approach. More selective targeting of specific neuronal populations could improve efficacy while limiting side effects. Understanding which specific motor neurons interact with the immune system, along with the corresponding sensory pathways they receive information from, is crucial. This research prompts critical questions about the benefits of anti-inflammatory neural circuits and the broader implications for functions governed by similar reflexes. It also highlights the communication between these regulatory loops; while these networks initiate responses at the brainstem level, they result in a more complex set of behaviors regulated by central and interoceptive pathways. 炎症反射的一个有前途的应用是利用迷走神经刺激（VNS）减轻炎症性肠病（IBD）、胰腺炎、肾损伤和类风湿性关节炎等疾病的炎症反应。 ^(48,52){ }^{48,52} 值得注意的是，VNS通过直接作用于肠道中的特定免疫细胞，而不是通过脾脏或T细胞，从而有效缓解肠道炎症。 ^(53){ }^{53} 然而，VNS 对迷走神经感觉和运动神经元的广泛激活限制了这种方法的推广。更有选择性地靶向特定神经元群可以提高疗效，同时限制副作用。了解哪些特定的运动神经元与免疫系统相互作用，以及它们从哪些相应的感觉通路接收信息至关重要。这项研究提出了一些关键问题，涉及抗炎神经回路的益处以及对类似反射所支配功能的广泛影响。它还强调了这些调节环路之间的交流；虽然这些网络在脑干水平上启动了反应，但它们导致了一系列由中枢和感知间通路调节的更复杂的行为。
Central regulation and immunoception 中枢调节和免疫感知
Local and reflexive levels of control provide fast and direct reactive regulation of bodily physiology through hard-wired action programs. Higher-order brain areas act more adaptively, synchronizing changes across physiological systems and timescales, adjusting bodily functions in real time during behavior, and proactively initiating central regulatory actions. They integrate information about the current state of different bodily systems and environmental conditions with evolutionarily selected programs, prior experience, and motivational state. This processing enables the brain to anticipate future states and adjust bodily functions to meet incoming needs or challenges. ^(47){ }^{47} To achieve such adjustments, higher-order brain areas exert topdown control of physiology, including temporary alterations of the homeostatic set points to accommodate expected states, as well as of motivational drives and behavior (Figure 1). Central circuits of the interoceptive nervous system are thus essential for adapting body physiology in dynamic environments (Figure 4). ^(47,54){ }^{47,54} Emerging theories propose that adaptive homeostasis is central to brain function and provide working models for interoception and bodily regulation (Box 2). 局部和反射性的控制水平通过硬连线的行动程序对身体生理进行快速、直接的反应性调节。高阶脑区的行为更具适应性，它们同步生理系统和时间尺度的变化，在行为过程中实时调整身体机能，并主动启动中枢调节行动。它们将不同身体系统和环境条件的当前状态信息与进化选择程序、先前经验和动机状态整合在一起。这种处理过程使大脑能够预测未来状态，并调整身体机能，以应对即将到来的需求或挑战。 ^(47){ }^{47} 为了实现这种调整，高阶脑区对生理机能进行自上而下的控制，包括暂时改变稳态设定点以适应预期状态，以及改变动机驱动和行为（图1）。因此，感知间神经系统的中枢回路对于在动态环境中调整人体生理机能至关重要（图 4）。 ^(47,54){ }^{47,54} 新出现的理论认为，适应性平衡是大脑功能的核心，并为内感知和身体调节提供了工作模型（方框 2）。
Interoceptive brain areas integrate visceral information ascending from vagal and spinal afferents, passing through the NTS, parabrachial nucleus (PBN), and interoceptive thalamic nuclei, and ultimately reaching the posterior IC (pIC), the anterior cingulate cortex (ACC), and the somatosensory cortices. ^(55,64){ }^{55,64} In parallel, bloodborne molecules are sensed by CVOs and other border regions (Box 1), which also ultimately relay information to cortical regions, including the IC and ACC. Cortical sites receiving interoceptive information are interconnected with visceromotor cortical regions, such as the anterior IC (aIC), ACC, ventromedial prefrontal, and orbitofrontal cortices, which are thought to mediate adaptive homeostatic control (Box 2). ^(59)At{ }^{59} \mathrm{At} this level, a more complex multisensory integration is performed, as well as processing in the context of prior experience, motivational drives, emotion, and cognition. As a result, these brain areas are thought to compute interoceptive predictions, based on which coordinated autonomic, motivated behavioral, 内感知脑区整合了从迷走神经和脊髓传入的内脏信息，这些信息通过NTS、腋旁核（PBN）和丘脑内感知核，最终到达后部IC（pIC）、前扣带回皮层（ACC）和躯体感觉皮层。 ^(55,64){ }^{55,64} 与此同时，CVO 和其他边界区域（方框 1）也会感知血载分子，这些区域最终也会将信息传递到皮层区域，包括 IC 和 ACC。接收内感知信息的皮层部位与内视运动皮层区域相互连接，如前 IC（aIC）、ACC、腹内侧前额叶和眶额叶皮层，这些皮层区域被认为介导适应性同调控制（方框 2）。 ^(59)At{ }^{59} \mathrm{At} 在这一层次，会进行更复杂的多感官整合，并结合先前的经验、动机驱动、情绪和认知进行处理。因此，这些脑区被认为可以计算感知间预测，并在此基础上协调自律神经和动机行为、
Figure 4. Central networks of bodily physiology and immunoception 图 4.身体生理和免疫感知的中心网络
Information from the periphery, including immune signals, is relayed to the brain through vagal and spinal afferents. These pathways converge in the NTS and PBN, ascend via the thalamus (e.g., ventromedial and ventroposterior lateral nuclei), and reach cortical areas such as the posterior IC, ACC, S1, and S2. ^(55){ }^{55} Humoral information detected by CVOs (e.g., IL-6) is also transmitted through neural pathways to higher brain regions. Visceromotor cortices, including the alC, ACC, vmPFC, and OFC, mediate the contextual and adaptive regulation of physiology, initiating coordinated responses across physiological systems and behavior. These responses are recruited by interconnected subcortical structures, with the hypothalamus (e.g., PVN and LHA) playing a crucial role in sensing physiological needs and mediating homeostatic control by engaging autonomic, neuroendocrine, immune, and motivated behavioral responses as needed. The CeA and BNST are involved in processing emotions and stress and in recruiting the physiological responses associated with their expression. Additional regions contributing to adaptive physiological changes include the VS and VTA, which process reward and motivation, the PAG, which coordinates integrated behavioralautonomic responses, and autonomic nuclei such as the DMV and VLM. Central bodily regulation among these and other brain regions involves numerous feedforward and feedback modulatory connections across different levels of the neural hierarchy to process and control the internal physiological state. Abbreviations in violet correspond to brain regions located deeper in the brain with respect to the views provided in the illustration. NTS, nucleus of the solitary tract; AP, area postrema; PBN, parabrachial nucleus; PAG, periaqueductal gray; TH, thalamus; IC, insular cortex; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; OFC, orbitofrontal cortex; VLM, ventrolateral medulla; DMV, dorsal motor nucleus of the vagus; CeA, central nucleus of the amygdala; VTA, ventral tegmental area; HT, hypothalamus; PVN, paraventricular nucleus of the hypothalamus; LHA, lateral hypothalamic area; BNST, bed nucleus of the stria terminalis; VS, ventral striatum; ACC, anterior cingulate cortex; vmPFC, ventromedial prefrontal cortex. 来自外周的信息，包括免疫信号，通过迷走神经和脊髓传入神经传递到大脑。这些通路在 NTS 和 PBN 汇合，经丘脑（如腹内侧核和腹后外侧核）上升，到达后 IC、ACC、S1 和 S2 等皮质区域。 ^(55){ }^{55} CVO检测到的体液信息（如IL-6）也会通过神经通路传递到高级脑区。内视运动皮层，包括 alC、ACC、vmPFC 和 OFC，介导生理的情境和适应性调节，启动跨生理系统和行为的协调反应。这些反应由相互关联的皮层下结构调用，其中下丘脑（如 PVN 和 LHA）在感知生理需求和通过根据需要调动自律神经、神经内分泌、免疫和动机行为反应来介导稳态控制方面起着至关重要的作用。CeA 和 BNST 参与处理情绪和压力，并调动与之相关的生理反应。对适应性生理变化做出贡献的其他区域包括处理奖赏和动机的 VS 和 VTA、协调综合行为和自律神经反应的 PAG 以及 DMV 和 VLM 等自律神经核。这些脑区和其他脑区之间的中枢身体调节涉及神经层次结构中不同层次的大量前馈和反馈调节连接，以处理和控制内部生理状态。相对于插图中提供的视图，紫色缩写对应于位于大脑更深处的脑区。 NTS，孤束核；AP，后遗区；PBN，腋旁核；PAG，丘脑下部灰质周围；TH，丘脑；IC，岛叶皮层；S1，初级躯体感觉皮层；S2，次级躯体感觉皮层；OFC，眶额皮层；VLM，外侧髓质；DMV，迷走神经背运动核；CeA，杏仁核中央核；VTA，腹侧被盖区；HT，下丘脑；PVN，下丘脑室旁核；LHA，下丘脑外侧区；BNST，纹状体末端床核；VS，腹侧纹状体；ACC，前扣带回皮层；vmPFC，腹外侧前额叶皮层。
neuroendocrine, and immune commands are generated to ensure an optimal contextual adaptation of the organism’s physiology. Coordinated visceromotor predictions are broadcast to subcortical structures that recruit the adaptive reactions, such as the hypothalamus, central amygdala (CeA), bed nucleus of the stria terminalis (BNST), periaqueductal gay (PAG), PBN, and autonomic motor nuclei, including the DMV and ventrolateral medulla (VLM) (Figure 4). Motor cortices, including M1, M2, and the supplemental motor area, also contribute through striatal muscle control and sympathetic modulation. ^(65,66){ }^{65,66} 神经内分泌和免疫指令的产生，确保了机体生理的最佳环境适应。协调的粘液运动预测会转播到皮层下结构，这些结构会招募适应性反应，如下丘脑、中央杏仁核（CeA）、纹状体末端床核（BNST）、腹腔周围基质（PAG）、PBN 和自主运动核，包括 DMV 和延髓外侧（VLM）（图 4）。运动皮层，包括 M1、M2 和补充运动区，也通过纹状体肌肉控制和交感神经调节发挥作用。 ^(65,66){ }^{65,66}
While the described pathways outline a general axis for interoception and central regulation, the cortical and subcortical regions involved are highly interconnected. Most of these structures process interoceptive information and act as visceromotor centers, forming hierarchical control loops with multiple feedfor- 虽然所描述的路径勾勒出了内感知和中枢调节的一般轴线，但所涉及的皮层和皮层下区域是高度相互关联的。这些结构大多处理内感知信息并充当视觉运动中枢，形成具有多重反馈的分层控制回路。
ward and feedback mechanisms between the different levels of control (Figures 1 and 4). ^(64,67){ }^{64,67} The NTS and PBN have direct bidirectional connections to hypothalamic nuclei, such as the paraventricular hypothalamic nucleus (PVN) and lateral hypothalamic area (LHA), the CeA, BNST, and PAG. ^(64,68-71){ }^{64,68-71} These projections are involved, for example, in modulating emotion states and motivated behaviors during inflammation and pain, ^(70,72,73){ }^{70,72,73} or in regulating systemic immune activity in response to pro-inflammatory signals. ^(71){ }^{71} 不同控制水平之间的联系和反馈机制（图1和图4）。 ^(64,67){ }^{64,67} NTS和PBN与下丘脑核有直接的双向联系，如下丘脑室旁核（PVN）和下丘脑外侧区（LHA）、CeA、BNST和PAG。 ^(64,68-71){ }^{64,68-71} 例如，这些投射参与调节炎症和疼痛时的情绪状态和动机行为， ^(70,72,73){ }^{70,72,73} 或参与调节系统免疫活动以应对促炎症信号。 ^(71){ }^{71}
The maintenance of fluid balance serves as an excellent example to conceptualize how the brain coordinates reactive control with anticipatory regulation, driving adaptive changes upon processing of internal sensory information. ^(74){ }^{74} When the body detects changes in blood volume, a cascade of compensatory actions is recruited to restore fluid homeostasis through 维持体液平衡是一个很好的例子，它可以让我们概念化大脑是如何协调反应性控制和预期性调节，在处理内部感官信息时推动适应性变化的。 ^(74){ }^{74} 当人体检测到血容量发生变化时，就会通过一系列代偿行动来恢复体液平衡。
Abstract 摘要
Interoception stands as a key process through which the brain integrates and interprets signals from within the body to maintain homeostasis and promote adaptive changes in physiology. Two prominent theoretical frameworks that describe how the brain balances reactive and proactive bodily control are “homeostatic reinforcement learning” (HRL) ^(56){ }^{56} and “interoceptive active inference” (IAI). ^(57-60){ }^{57-60} Under certain assumptions, these frameworks converge in many aspects. ^(47,56,61){ }^{47,56,61} Both emphasize the brain’s predictive capabilities in actively controlling bodily processes to shift the current observed internal state toward a desired, predicted state. Central to these models is the concept that internal states optimal for survival in various contexts are re-experienced, becoming likely, predicted, and functioning as homeostatic (predefined) or adaptive set points. 内感知是大脑整合和解释来自身体内部的信号以维持体内平衡和促进生理适应性变化的一个关键过程。描述大脑如何平衡反应性和主动性身体控制的两个著名理论框架是 "稳态强化学习"（HRL） ^(56){ }^{56} 和 "感知间主动推理"（IAI）。 ^(57-60){ }^{57-60} 在某些假设条件下，这些框架在许多方面趋于一致。 ^(47,56,61){ }^{47,56,61} 两者都强调大脑的预测能力，即积极控制身体过程，将当前观察到的内部状态转变为期望的、预测的状态。这些模型的核心概念是，在各种情况下，最适合生存的内部状态会被重新体验、变得可能、被预测，并作为同态（预定义）或适应性设定点发挥作用。
HRL proposes that organisms aim to align their current physiological state with a desired set point, reducing homeostatic imbalances to maximize expected rewards in the long term. Behaviors that move the physiological state closer to this set point are reinforced. IAI suggests that the brain operates based on an internal model of the organism within the environment. It contextually infers the body’s internal state and generates predictions, which are then compared with actual sensory input, and errors are signaled when they do not match. A central function of the brain is minimizing these prediction errors, either by revising the internal model or by recruiting regulatory actions to reduce discrepancies. IAI assumes a hierarchical architecture where models exist at each level and predictions are transmitted via top-down connections, while prediction errors are relayed through bottom-up signals. In IAI, predictions at increasingly higher levels in the neural hierarchy guide increasingly complex responses. ^(47){ }^{47} Lowerlevel predictions address immediate reflexive needs by acting as set points, while higher-level predictions integrate interoceptive signals with more complex inputs, managing longer-term, goal-directed regulation and adapting set points accordingly. ^(60){ }^{60} This framework ensures stable internal models and efficient regulation across different timescales. ^(57,58,60){ }^{57,58,60} HRL 提出，生物体的目标是使其当前的生理状态与期望的设定点保持一致，减少同态失衡，从而最大限度地提高长期预期回报。使生理状态更接近这一设定点的行为会得到强化。IAI 认为，大脑是根据环境中生物体的内部模型运作的。它根据上下文推断机体的内部状态并做出预测，然后与实际的感官输入进行比较，当两者不一致时就会发出错误信号。大脑的一个核心功能就是通过修改内部模型或采取调节行动来减少这些预测误差。IAI 假设了一种分层结构，在这种结构中，模型存在于每个层次，预测通过自上而下的连接进行传递，而预测错误则通过自下而上的信号进行传递。在 IAI 中，神经层次结构中越来越高层次的预测会指导越来越复杂的反应。 ^(47){ }^{47} 较低层次的预测通过作为设定点来满足即时的反射性需求，而较高层次的预测则将内感知信号与更复杂的输入进行整合，管理长期的、以目标为导向的调节，并相应地调整设定点。 ^(60){ }^{60} 这一框架确保了稳定的内部模型和不同时间尺度的高效调节。 ^(57,58,60){ }^{57,58,60}
The embodied predictive interoception coding (EPIC) model ^(59){ }^{59} proposes how IAI might be implemented in the brain of humans and primates. According to the model, visceromotor, agranular cortices at the apex of the interoceptive hierarchy, such as the alC and ACC, generate higher-order interoceptive predictions, including both visceromotor and viscerosensory predictions. The viscerosensory predictions are then transmitted to the granular insular cortices, which serve as the primary interoceptive processing cortical centers. Here, prediction errors are calculated, and feedback is sent up the hierarchy to refine these predictions. Visceromotor predictions are conveyed to subcortical regions, including the amygdala, hypothalamus, VS, PAG, and other brainstem areas involved in homeostatic control. This communication helps to activate adaptive physiological responses aimed at aligning the internal state with the predicted state. Both prediction mechanisms work to minimize prediction errors, while active regulation is thought to play the main role in this process. 内感知预测编码（EPIC）模型 ^(59){ }^{59} 提出了内感知如何在人类和灵长类动物的大脑中实现。根据该模型，位于内感知层次结构顶端的内感知运动、粒状皮层（如 alC 和 ACC）会产生更高阶的内感知预测，包括内感知运动和内感知预测。然后，视觉感知预测会被传送到粒状岛叶皮层，而粒状岛叶皮层是主要的感知间处理皮层中心。在这里，预测误差会被计算出来，并向上传递反馈以完善这些预测。粘液运动预测会传递到皮层下区域，包括杏仁核、下丘脑、VS、PAG 和其他参与平衡控制的脑干区域。这种交流有助于激活适应性生理反应，使内部状态与预测状态保持一致。这两种预测机制都致力于最大限度地减少预测误差，而主动调节被认为在这一过程中发挥着主要作用。
While some anatomical and functional studies support these theories, ^(62,63){ }^{62,63} there is still a lack of clear biological evidence for the implementation in the brain of the processes and architecture assumed by the theories. Further research is needed to better understand the brain mechanisms involved in adaptive control. 虽然一些解剖学和功能研究支持这些理论，但 ^(62,63){ }^{62,63} 仍然缺乏明确的生物学证据来证明这些理论所假设的过程和结构在大脑中的实现。要想更好地了解自适应控制所涉及的大脑机制，还需要进一步的研究。
negative feedback loops. Following events such as severe dehydration, autonomic responses ensure substantial blood pressure and tissue irrigation by accelerating heart rate and inducing peripheral vasoconstriction, while hormonal adjustments preserve fluid volume. Different arms of the interoceptive nervous system collaborate to produce these complex responses, including baroreceptors in the cardiovascular system, hormones like angiotensin II, and osmolarity sensors in CVOs. Dehydration also activates specific neurons, promoting thirst perception and motivating water-seeking and drinking behaviors. These neurons indirectly relay information to the anterior regions of the cingulate cortex and the IC, important in thirst perception and driving these behaviors. ^(67,74-77){ }^{67,74-77} Importantly, anticipation of increased water need, such as during food consumption, or decreased water need immediately after drinking can adjust behavior and physiology. These changes occur prior to measurable changes in blood osmolarity, blood volume, or hormone levels, consistent with a role for central circuits in top-down physiological and behavioral control. ^(74,76,77){ }^{74,76,77} Pavlov’s salivating dogs provide another classical example illustrating a similar anticipatory central circuit modulation of bodily processes. 负反馈回路。在发生严重脱水等情况后，自律神经系统会通过加快心率和诱导外周血管收缩来确保大量的血压和组织灌溉，同时通过荷尔蒙调节来保持体液容量。感知间神经系统的不同分支协同产生这些复杂的反应，包括心血管系统中的气压感受器、血管紧张素 II 等激素以及 CVO 中的渗透压传感器。脱水也会激活特定的神经元，促进口渴感知并激发寻水和饮水行为。这些神经元间接地将信息传递给扣带回皮层的前部区域和集成电路，对口渴感知和驱动这些行为非常重要。 ^(67,74-77){ }^{67,74-77} 重要的是，预期需水量增加（如在进食时）或饮水后立即需水量减少会调整行为和生理。这些变化发生在血液渗透压、血容量或激素水平发生可测量的变化之前，这与中枢回路在自上而下的生理和行为控制中的作用是一致的。 ^(74,76,77){ }^{74,76,77} 巴甫洛夫的流涎狗提供了另一个经典例子，说明了类似的中枢回路对身体过程的预期调节。
The IC has long been recognized as the primary visceral cortex, receiving strong sensory input from multiple bodily systems and actively regulating physiology. ^(14,65,78,79){ }^{14,65,78,79} Accumulating evidence supports the role of the IC in integrating internal and external sensory inputs with anticipatory contextual information, shaping interoceptive representations, and regulating physiology directly or indirectly through changes in motivation and behavior. ^(79){ }^{79} In humans, the experience of thermal pain intensity 长期以来，人们一直认为内脏皮层是主要的内脏皮层，它接收来自多个身体系统的强烈感觉输入，并积极调节生理机能。 ^(14,65,78,79){ }^{14,65,78,79} 越来越多的证据表明，内脏皮层在整合内部和外部感觉输入与预期情境信息、形成内感知表征以及通过动机和行为变化直接或间接调节生理机能方面发挥作用。 ^(79){ }^{79} 在人类中，热痛强度的体验
and affective touch activates the mid IC and pIC, while their contextual or cue-evoked anticipation activates the alc…^(80,81)^{80,81} Predictions of breathing changes also modulate alC activity. ^(82){ }^{82} In rodents, similar “anticipatory” neurons in the IC respond to associative cues signaling the occurrence of sensory stimuli affecting the physiological state, such as food, water, or aversive foot-shock. ^(67,83,84){ }^{67,83,84} Anticipatory activity signaling the availability of food or water was found to depend strongly on the body’s need state. This need-dependent saliency of relevant cues is relayed from the hypothalamus through the paraventricular thalamus and basolateral amygdala, projecting to the IC. ^(85){ }^{85} IC anticipatory activity contributes to guiding motivated behaviors that promote homeostasis and to adaptively control physiology, such as during emotion states. Indeed, IC neurons responsive to food or water cues are necessary for motivated behaviors exhibited during anticipation, like approaching food, ^(83){ }^{83} or increasing action vigor for receiving water during thirst. ^(67){ }^{67} Illustrating the recruitment of adaptive bodily changes in the context of emotions, neurons projecting from the pIC to the CeA are active in anxiogenic contexts and induce an increase in breathing rate while also promoting avoidance or anxiety-like behavior. ^(79){ }^{79} These and other studies suggest that neurons in the IC may encode anticipatory signals related to the internal state, integrating bodily need states, and regulate emotional and motivational states alongside bodily physiology to form a coordinated response. ^(84){ }^{84} Importantly, this evidence highlights how emotions serve as an adaptive central mechanism for direct and indirect adjustments of physiology in contexts that are salient for survival. In turn, bodily reactions during emotion responses ^(80,81)^{80,81} 对呼吸变化的预测也会调节alC的活动。 ^(82){ }^{82} 在啮齿类动物中，IC中类似的 "预期 "神经元会对影响生理状态的感官刺激（如食物、水或厌恶性足部冲击）发生时的联想线索做出反应。 ^(67,83,84){ }^{67,83,84} 研究发现，发出食物或水可用性信号的预期活动在很大程度上取决于身体的需求状态。这种依赖于需求的相关线索的显著性从下丘脑通过丘脑室旁和杏仁核基底外侧传递到集成电路。 ^(85){ }^{85} 集成电路的预期活动有助于引导促进平衡的动机行为和适应性地控制生理机能，例如在情绪状态下。事实上，对食物或水线索做出反应的集成电路神经元是在预期过程中表现出的动机行为所必需的，如接近食物， ^(83){ }^{83} 或在口渴时为获得水而增加行动力度。 ^(67){ }^{67} 从pIC投射到CeA的神经元在焦虑情境中非常活跃，在促进回避或类似焦虑的行为的同时，还会诱发呼吸频率的增加，这说明了在情绪背景下身体适应性变化的招募。 ^(79){ }^{79} 这些研究和其他研究表明，集成电路中的神经元可能会编码与内部状态相关的预期信号，整合身体需求状态，并在调节身体生理机能的同时调节情绪和动机状态，从而形成协调的反应。 ^(84){ }^{84} 重要的是，这些证据强调了情绪是如何作为一种适应性中央机制，在对生存至关重要的情况下直接和间接地调整生理机能的。反过来，情绪反应时的身体反应
influence the persistence of emotion memories. ^(84){ }^{84} This bidirectional interaction is increasingly seen as fundamental to maintaining physiological and emotional homeostasis. 影响情绪记忆的持久性。 ^(84){ }^{84} 这种双向互动越来越被视为维持生理和情绪平衡的基础。
The brain does not only anticipate needs and physiological states but synchronizes them across multiple systems and throughout time. The brain’s unique ability to monitor time makes it a very effective synchronization mechanism. For example, our circadian rhythm synchronizes immune cell mobilization throughout the day. Also, bone growth and the movement of hematopoietic stem cells within the blood and bone marrow are timed to occur at night, synchronized by the release of growth hormone (GH)(\mathrm{GH}) and managed by sympathetic innervation to the bone marrow. ^(86){ }^{86} In addition to circadian rhythms coordinating physiological processes over the course of a day, time perception is also part of our interoceptive processes as we anticipate how long a certain process will take and orchestrate our behavior and physiology accordingly. Wound healing has been shown to vary with time perception rather than actual time, suggesting that clock manipulation can affect physiological responses. ^(87){ }^{87} Similarly, in patients with type 2 diabetes, blood glucose levels seem more responsive to perceived time than actual time. ^(88){ }^{88} This indicates that the brain’s internal clock, the suprachiasmatic nucleus (SCN) of the hypothalamus, can synchronize bodily functions with environmental cues or circadian rhythms scale to avoid internal conflicts. Interestingly, there are also peripheral circadian clocks that can maintain circadian oscillations in isolation from the SCN but nonetheless rely on central inputs for synchronization across the organism. ^(89){ }^{89} 大脑不仅能预测需求和生理状态，还能在多个系统和整个时间内实现同步。大脑监测时间的独特能力使其成为一种非常有效的同步机制。例如，我们的昼夜节律使免疫细胞在一天中同步调动。此外，骨骼的生长以及造血干细胞在血液和骨髓中的移动也是定时在夜间进行的，这与生长激素 (GH)(\mathrm{GH}) 的释放同步，并由交感神经对骨髓的支配进行管理。 ^(86){ }^{86} 除了昼夜节律协调一天中的生理过程外，时间感知也是我们感知过程的一部分，因为我们会预测某个过程需要多长时间，并据此协调我们的行为和生理。有研究表明，伤口愈合会随着时间感知的变化而变化，而不是随着实际时间的变化而变化，这表明操纵时钟会影响生理反应。 ^(87){ }^{87} 同样，在 2 型糖尿病患者中，血糖水平似乎对感知时间的反应比对实际时间的反应更大。 ^(88){ }^{88} 这表明，大脑的内部时钟，即下丘脑的簇上核（SCN），可以使身体机能与环境线索或昼夜节律尺度同步，以避免内部冲突。有趣的是，还有一些外周昼夜节律钟，它们可以在脱离SCN的情况下保持昼夜节律振荡，但仍然依赖中枢输入来实现整个机体的同步。 ^(89){ }^{89}
The anticipatory capacity of the brain in the context of immune regulation is manifested by motivated behaviors, such as mating and feeding, which can potentially increase pathogen exposure. These behaviors involve the ventral tegmental area’s (VTA) dopaminergic neurons, an area implicated in motivated behaviors. Indeed, a study has shown that anticipation of mating is sufficient to prime the immune system, specifically an increase in interleukin (IL)-2 levels, but inhibition of VTA activity eliminates this typical response. ^(90){ }^{90} Direct activation of the VTA with DREADDs was shown to enhance immune activity against bacteria and cancer. ^(91,92){ }^{91,92} It is important to note that the artificial manipulations of the VTA or other reward system components with chemogenetics or optogenetics are isolated from the physiological context, and more detailed analysis of the specific projections is required. Interestingly, positive expectations like hope that involve reward system activation have been associated with the placebo response and improved physiological responses. Nevertheless, the placebo is a more complex phenomenon that also involves conditioning processes. 大脑在免疫调节方面的预测能力表现为交配和进食等动机行为，这些行为可能会增加病原体的接触机会。这些行为涉及腹侧被盖区（VTA）的多巴胺能神经元，该区域与动机行为有关。事实上，一项研究表明，交配的预期足以激发免疫系统，特别是白细胞介素（IL）-2水平的增加，但抑制VTA的活动则会消除这种典型的反应。 ^(90){ }^{90} 研究表明，用DREADDs直接激活VTA可增强针对细菌和癌症的免疫活性。 ^(91,92){ }^{91,92} 需要注意的是，利用化学遗传学或光遗传学对VTA或其他奖赏系统成分进行的人工操作是脱离生理环境的，需要对具体的投射进行更详细的分析。有趣的是，希望等涉及奖赏系统激活的积极期望与安慰剂反应和生理反应改善有关。然而，安慰剂是一种更复杂的现象，还涉及调节过程。
Indeed, early 20th-century studies demonstrated that the immune system could undergo conditioning. Exposure to an im-mune-stimulating or suppressive agent coupled with a neutral stimulus (saccharine) can induce conditioned immune responses to the neutral stimulus alone. ^(93){ }^{93} Several brain areas, including the IC, were implicated in this conditioning. ^(94){ }^{94} Recently, it was shown that the IC stores an immunological representation in the brain. ^(95){ }^{95} Reactivation of neuronal ensembles in the IC that were active during inflammatory conditions resulted in a recall of the inflammatory state, even in the absence of a new immune 事实上，20 世纪早期的研究就证明，免疫系统可以进行条件反射。接触一种刺激或抑制免疫系统的物质，再加上一种中性刺激（糖精），就能诱发对中性刺激的条件性免疫反应。 ^(93){ }^{93} 包括集成电路在内的几个脑区与这种条件反射有关。 ^(94){ }^{94} 最近，有研究表明，IC在大脑中储存着免疫表征。 ^(95){ }^{95} 重新激活集成电路中在炎症状态下活跃的神经元组合，会使人回忆起炎症状态，即使在没有新的免疫反应的情况下也是如此。
challenge. These effects were suggested to be mediated by IC neurons connected to peripheral organs such as the colon and peritoneum through the DMV and rostral VLM, supporting the role of the autonomic nervous system in mediating these effects. ^(95){ }^{95} 挑战。这些效应被认为是由通过 DMV 和喙侧 VLM 连接到结肠和腹膜等外周器官的 IC 神经元介导的，支持自主神经系统在介导这些效应中的作用。 ^(95){ }^{95}
These findings suggest that the brain can induce specific immunological reactions, which may have evolved as a mechanism for efficiently addressing environmental challenges that are likely to recur. This phenomenon could be likened to the body’s anticipatory measure against future assaults similar to the original encounter. This “immunological memory” within the brain, specifically in the IC, can create a rapid and efficient defense mechanism before the body is challenged. For example, it can prime gut immune cells when preparing to drink from a water source that previously caused an infection. However, such “memory responses” can become maladaptive in autoimmune patients by triggering inflammatory episodes in response to specific stimuli. Recent studies on allergies revealed that avoidance behaviors induced when encountering an established allergen are a result of neuroimmune interactions. ^(96,97){ }^{96,97} These studies show that mast cells connected to allergen-specific IgE antibodies secrete mediators that activate the NTS, PBN, and CeA.^(97)\mathrm{CeA} .{ }^{97} Also, in cases of IBD, imaging studies show altered activity in key brain areas involved in interoception, potentially inducing inflammatory flares in response to stressful triggers. Indeed, manipulation of key brain areas by deep brain stimulation (DBS) or reactivation of cytokine-activated NTS neurons has potent immunomodulatory and endocrine effects. ^(98){ }^{98} By understanding these underlying mechanisms, we can develop more effective and targeted therapeutic strategies that leverage the neuroimmune interface. Furthermore, these findings emphasize the brain’s role as a synchronizer and regulator of bodily physiology, as these specific stimulations had local effects on the immune response. 这些研究结果表明，大脑可以诱发特定的免疫反应，这可能是一种进化机制，可以有效地应对可能再次出现的环境挑战。这种现象可以被比作人体对未来类似于最初遭遇的攻击的预测措施。大脑中的这种 "免疫记忆"，特别是在集成电路中，可以在身体受到挑战之前建立一种快速高效的防御机制。例如，当准备饮用曾导致感染的水源时，它可以激发肠道免疫细胞。然而，这种 "记忆反应 "在自身免疫性疾病患者中会变得不适应，因为它会在特定刺激下引发炎症发作。最近对过敏症的研究表明，遇到过敏原时诱发的回避行为是神经免疫相互作用的结果。 ^(96,97){ }^{96,97} 这些研究表明，与过敏原特异性IgE抗体相连的肥大细胞会分泌介质，激活NTS、PBN和 CeA.^(97)\mathrm{CeA} .{ }^{97} 此外，在IBD病例中，成像研究显示，参与互感的关键脑区的活动发生了改变，可能会诱发炎症发作，以应对应激性诱因。事实上，通过脑深部刺激（DBS）或重新激活细胞因子激活的NTS神经元来操纵关键脑区，具有强大的免疫调节和内分泌作用。 ^(98){ }^{98} 通过了解这些潜在机制，我们可以开发出更有效、更有针对性的治疗策略，充分利用神经免疫界面。此外，这些发现还强调了大脑作为人体生理同步器和调节器的作用，因为这些特定的刺激会对免疫反应产生局部影响。
Another aspect that highlights the anticipatory component of the neuroimmune connection is stress. The stress response predicts potential damage to the organism and influences the distribution and activity of leukocytes. Immune cells can be rapidly mobilized to the blood in response to acute stress, positioning the immune system for any potential challenge. Interestingly, different acute stressors involve distinct brain areas, which induce various effects on the immune system. For instance, motor circuits can prompt rapid neutrophil mobilization from bone marrow to tissues, mediated by neutrophil-attracting chemokines from skeletal muscle. ^(99){ }^{99} By contrast, the PVN governs the movement of monocytes and lymphocytes from secondary lymphoid organs back to the bone marrow through glucocorticoid signaling. ^(99){ }^{99} Similarly, neurons in the CeA and PVN that express corticotropin-releasing hormone (CRH) are connected to the splenic nerve and autonomically enhance humoral responses. ^(100){ }^{100} These stress-induced leukocyte shifts are also associated with altered disease susceptibilities. Yet, they represent an essential brain-immune connection to prepare the immune system for an upcoming challenge and are part of the ongoing process of immunoception. 另一个凸显神经-免疫联系中预测成分的方面是压力。应激反应会预测机体可能受到的损害，并影响白细胞的分布和活性。免疫细胞可在急性应激反应时迅速被调动到血液中，使免疫系统能够应对任何潜在的挑战。有趣的是，不同的急性应激源会涉及不同的大脑区域，从而对免疫系统产生不同的影响。例如，在骨骼肌中性粒细胞吸引趋化因子的介导下，运动回路可促使中性粒细胞从骨髓迅速迁移到组织中。 ^(99){ }^{99} 与此相反，PVN通过糖皮质激素信号传导，控制单核细胞和淋巴细胞从次级淋巴器官返回骨髓。 ^(99){ }^{99} 同样，CeA和PVN中表达促肾上腺皮质激素释放激素（CRH）的神经元与脾神经相连，可自主增强体液反应。 ^(100){ }^{100} 这些应激诱导的白细胞变化也与疾病易感性的改变有关。然而，它们代表了大脑与免疫系统之间的重要联系，使免疫系统为即将到来的挑战做好准备，也是正在进行的免疫感知过程的一部分。
Immunoception, the brain’s representation of the immunological state of the organism, like other aspects of interoception, is bidirectional and dynamic. It is composed of local, reflex, and 免疫感知是大脑对机体免疫状态的表征，与互感的其他方面一样，具有双向性和动态性。它由局部、反射和
central components that feed into each other. The immune system, highly diverse and deeply embedded, constantly monitors the local environment. When detecting damage, it requires mobilization of the immune cells to target sites, facilitated by changes in behavior, metabolism, and local blood flow. These changes are orchestrated by cytokines and immune mediators required for communication between immune cells, but also with the sensory neurons embedded in these tissues. The nervous system can then alter the blood flow to the target site. For example, sympathetic fibers surrounding blood vessels can regulate vessel permeability, influencing immune cell extravasation. ^(23){ }^{23} Then, at the reflex level, areas in the brainstem can become sensitive to these cytokines, initiating corrective responses that can dial up or tune down the immune response. ^(7,49,101){ }^{7,49,101} However, this reflexive response may not be sufficient to support every need of the organism, including changes in metabolic programs and behaviors relevant to support them. For example, various inflammatory states must align with specific metabolic programs to trigger tis-sue-protective mechanisms. ^(102){ }^{102} Indeed, surviving viral inflammation relies on functioning glucose utilization pathways, while bacterial inflammation survival depends on alternative fuels and ketogenic processes, which require changes in feeding behavior. ^(103){ }^{103} Therefore, the immune system necessitates integration with the nervous system to coordinate the complex physiological and behavioral changes needed for the organism’s survival. One intriguing example involves cachexia, which is evident in some forms of cancer. This severe wasting syndrome was shown to be mediated in part by the response to detection of circulating IL-6 by the AP. This leads to the activation of interconnected areas, including the NTS, PBN, PVN, CeA, BNST, and arcuate hypothalamic nucleus, ^(101){ }^{101} which collectively can induce the complex set of behavioral and metabolic changes evident in cachexia. Cachexia is functionally unclear because it is detrimental for survival, yet it may represent an adaptive process that goes awry of altering metabolic programs as a survival attempt. 免疫系统是一个相互促进的核心组成部分。免疫系统具有高度多样性和深度嵌入性，它不断监测当地环境。当检测到损害时，免疫系统需要调动免疫细胞到目标部位，并通过改变行为、新陈代谢和局部血流来实现。这些变化由细胞因子和免疫细胞间通信所需的免疫介质来协调，同时也与这些组织中的感觉神经元相联系。然后，神经系统可以改变流向目标部位的血流。例如，血管周围的交感神经纤维可以调节血管的通透性，从而影响免疫细胞的外渗。 ^(23){ }^{23} 然后，在反射水平上，脑干中的区域会对这些细胞因子变得敏感，启动纠正反应，从而提高或降低免疫反应。 ^(7,49,101){ }^{7,49,101} 然而，这种反射性反应可能不足以支持机体的每一种需求，包括新陈代谢程序的变化和支持这些变化的相关行为。例如，各种炎症状态必须与特定的新陈代谢程序保持一致，才能触发抗炎保护机制。 ^(102){ }^{102} 事实上，病毒性炎症的存活依赖于正常的葡萄糖利用途径，而细菌性炎症的存活则依赖于替代燃料和生酮过程，这需要改变进食行为。 ^(103){ }^{103} 因此，免疫系统必须与神经系统整合，以协调生物体生存所需的复杂生理和行为变化。一个有趣的例子涉及恶病质，这在某些形式的癌症中很明显。研究表明，这种严重的消瘦综合征部分是由 AP 对循环 IL-6 的检测反应介导的。 这导致相互关联的区域被激活，包括NTS、PBN、PVN、CeA、BNST和弓状下丘脑核， ^(101){ }^{101} 这些区域共同诱发了恶病质中明显的一系列复杂的行为和代谢变化。恶病质的功能尚不清楚，因为它不利于生存，但它可能代表了一种适应过程，而这种适应过程是为了生存而改变新陈代谢程序。
These examples highlight that the interplay between the nervous system and the immune system occurs through multiple levels of interaction. Each level processes different inputs and integrates other available information, infusing the immune system with additional capabilities and improving the overall physiological response. These capabilities include continuous monitoring, predictive functions, and the integration of complex data-faculties that greatly extend the autonomous capacity of the immune system. However, it is also clear that we are just in the early stages of understanding these interactions. We are only beginning to uncover how the brain forms immune representations and which information is gathered by the brain to form these representations (cytokines, immune activity, changes in affected tissues, metabolic information, etc.). Nevertheless, such understanding will allow us to better grasp the brain’s potential in modulating immune processes. Such understanding can lead to novel therapeutic strategies guided by the basic regulatory principles revealed by the nervous system. 这些例子突出表明，神经系统和免疫系统之间的相互作用是通过多层次的互动实现的。每个层次都会处理不同的输入，并整合其他可用信息，为免疫系统注入更多能力，改善整体生理反应。这些能力包括持续监测、预测功能和复杂数据的整合--这些能力极大地扩展了免疫系统的自主能力。不过，我们显然还处于了解这些相互作用的早期阶段。我们才刚刚开始了解大脑如何形成免疫表征，以及大脑收集了哪些信息来形成这些表征（细胞因子、免疫活动、受影响组织的变化、新陈代谢信息等）。尽管如此，这种了解将使我们能够更好地掌握大脑在调节免疫过程方面的潜力。这种理解可以让我们在神经系统所揭示的基本调节原理的指导下，找到新的治疗策略。
CONCLUDING REMARKS 结束语
The nervous system pervades every organ and tissue in the body, providing an extraordinary capability for integrating infor- 神经系统遍布人体的每一个器官和组织，具有整合信息的非凡能力。
mation, eliciting rapid responses, and anticipating specific experiences. This intricate system enables the organism to operate cohesively. Despite our growing knowledge, we are still only at the threshold of understanding the complex mechanisms at play. Ongoing research promises to unveil new facets of physiology and may provide insights into conditions often regarded as psychosomatic. It is a common misconception to trivialize these conditions as being “all in your head,” yet it is increasingly clear that the brain’s activities resonate throughout the entire organism. What transpires within the neural confines has systemic repercussions, challenging us to broaden our perspective on health and disease. 它可以提供信息，引起快速反应，并预测特定的经历。这一错综复杂的系统使生物体能够协调一致地运作。尽管我们的知识在不断增长，但对其中复杂机制的了解仍处于起步阶段。正在进行的研究有望揭开生理学的新面貌，并为通常被视为心身疾病的病症提供启示。将这些病症轻描淡写地归结为 "全在你的脑袋里 "是一种常见的误解，但越来越清楚的是，大脑的活动会在整个机体中产生共鸣。在神经范围内发生的事情会产生系统性的影响，这就要求我们拓宽看待健康和疾病的视角。
ACKNOWLEDGMENTS 致谢
We would like to thank S. Schwarzbaum for editing the manuscript and her insightful comments. A.R. used GAI for partial text editing. A.R. and M.S. are supported by the ERC-COG (101088955). A.R. is a Howard Hughes Medical Institute (HHMI)-Wellcome Trust international scholar and Miriam and Sheldon G. Adelson Medical Research Foundation. J.C. is supported by the Helen Hay Whitney Foundation, and S.D.L. is an HHMI Investigator and is supported by P01 Al179273 and the Food Allergy Science Initiative. N.G. and M.C.P. are supported by the generous core funding from the Max Planck Society. 我们要感谢 S. Schwarzbaum 对稿件的编辑和她富有洞察力的评论。A.R. 使用 GAI 进行了部分文字编辑。A.R. 和 M.S. 得到了 ERC-COG (101088955) 的资助。A.R.是霍华德-休斯医学研究所（HHMI）-韦尔科姆基金会的国际学者，也是米丽娅姆-阿德尔森医学研究基金会（Miriam and Sheldon G. Adelson Medical Research Foundation）的成员。J.C.得到了海伦-海-惠特尼基金会（Helen Hay Whitney Foundation）的支持，S.D.L.是霍华德-休斯医学研究所（HHMI）的研究员，并得到了P01 Al179273和食物过敏科学计划的支持。N.G.和M.C.P.得到了马克斯-普朗克协会慷慨的核心资金支持。
DECLARATION OF INTERESTS 利益申报
S.D.L. is a co-founder and consultant for Nilo Therapeutics. S.D.L. 是 Nilo Therapeutics 的联合创始人和顾问。
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