No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Internal senses of the vagus nerve
Abstract
The vagus nerve is an indispensable body-brain connection that controls vital aspects of autonomic physiology like breathing, heart rate, blood pressure, and gut motility, reflexes like coughing and swallowing, and survival behaviors like feeding, drinking, and sickness responses. Classical physiological studies and recent molecular/genetic approaches have revealed a tremendous diversity of vagal sensory neuron types that innervate different internal organs, with many cell types remaining poorly understood. Here, we review the state of knowledge related to vagal sensory neurons that innervate the respiratory, cardiovascular, and digestive systems. We focus on cell types and their response properties, physiological/behavioral roles, engaged neural circuits and, when possible, sensory receptors. We are only beginning to understand the signal transduction mechanisms used by vagal sensory neurons and upstream sentinel cells, and future studies are needed to advance the field of interoception to the level of mechanistic understanding previously achieved for our external senses.
... The vagus nerve supports bidirectional communication between peripheral organs and the central nervous system. Consequently, the vagal afferent pathway connecting the viscera to the brain is associated with a wide range of functions that require brain-body interactions [1,2]. Classical theories describe the 'wandering' nerve (the Latin translation of vagus) as an integral part of the parasympathetic system, and mainly point to an inhibitory role in processes that govern the internal stability of bodily function (homeostasis). ...
... Instead of a narrow role in promoting relaxation, vagal signals not only converge on cholinergic neurons (i.e., the main pathway of the parasympathetic system) but also modulate multiple neurotransmission systems [9]. Rigorous anatomical work supports such a plurality of modulatory effects by showing multifaceted downstream signaling cascades that affect diverse organ systems [10], sensory neuron types [1], and brain regions [11] that are connected to vagal function. Further evidence for the regulation of reward responses in the motivational circuit has been provided by studies using invasive [6,12] or non-invasive [13] vagus nerve stimulation (VNS) that reveal stimulation-induced changes in dopamine release and brain responses in the midbrain and striatum. ...
... Interoceptive signals can be evoked by changes in bodily states (e.g., lack of nutrients) or emulated by vagus nerve stimulation (VNS). The resulting viscerosensory input (red) reaches the nucleus of the solitary tract (NST) via vagal afferents (1). Neuromodulatory pathways support the amplification of interoceptive inputs (2) which are integrated and weighted against sensory signals originating from the external world (exteroception) in the insula (3). ...
... Thus, neural brain circuits are large neuronal networks composed of highly dynamic and flexible afferents, integration centers, and efferent output projections. The overall functional implications for disease pathogeneses of neural brain circuits are countless, ranging to respond to immediate survival needs such as danger avoidance, heat, blood pressure, response to hunger and thirst, but also to processing long-term brain traits such as many types of memory, chronic pain adjustments, organ injury, and even strategic thinking and planning [12,13]. While this article cannot comprehensively cover the enormous recent progress to understand integration centers, several basic principles require attention. ...
... The ABC consists of all components of the peripheral nervous system that differentially innervate different segments of the arterial tree, and other components of the vascular system such as lymph vessels, high endothelial venules in secondary lymphoid tissues, veins, and others, in territory-specific ways [30,35,[43][44][45]. The ABC emerges as heterogeneous networks of peripheral nervous system connections with its major component, i.e., the dorsal root ganglia, and nodose ganglia as sensors, and the cranial nerves and sympathetic ganglia as effectors [12,30,35]. New features of the peripheral nervous system innervation of the ABC including the direct innervation of medium-and large-sized arteries were discovered following the anatomical and cellular characterization of neuroimmune cardiovascular interfaces in the aorta adventitia in atherosclerotic mice and human cardiovascular tissues [35,46,47]. ...
... Defining and delineating the CBC with its major circuit components, i.e., the ABC and the HBC, became possible through the recent identification of a neuroimmune cardiovascular interface-triggered structural ABC [35,63]. It is well established that there are multiple bidirectional interactions between the arteries and the heart in physiology and pathophysiology, forming a multilayered and large CBC network [12,43,64]. These interactions are particularly apparent when risk factors of atherosclerosis are considered: hypertension is sensed by various neurons of the HBC including those sensing atrial filling, aorta distension, and left ventricular failure leading to tachycardia, possibly supraventricular arrhythmias, and these neuronal activities may lead to a reduced blood supply and the perfusion of vital organs including the heart, the kidney, and the brain [12,30,35,36,38,43]. ...
Three systemic biological systems, i.e., the nervous, the immune, and the cardiovascular systems, form a mutually responsive and forward-acting tissue network to regulate acute and chronic cardiovascular function in health and disease. Two sub-circuits within the cardiovascular system have been described, the artery brain circuit (ABC) and the heart brain circuit (HBC), forming a large cardiovascular brain circuit (CBC). Likewise, the nervous system consists of the peripheral nervous system and the central nervous system with their functional distinct sensory and effector arms. Moreover, the immune system with its constituents, i.e., the innate and the adaptive immune systems, interact with the CBC and the nervous system at multiple levels. As understanding the structure and inner workings of the CBC gains momentum, it becomes evident that further research into the CBC may lead to unprecedented classes of therapies to treat cardiovascular diseases as multiple new biologically active molecules are being discovered that likely affect cardiovascular disease progression. Here, we weigh the merits of integrating these recent observations in cardiovascular neurobiology into previous views of cardiovascular disease pathogeneses. These considerations lead us to propose the Neuroimmune Cardiovascular Circuit Hypothesis.
... The integrity of vital organs requires simultaneously operating tissue-specific physiological responses while maintaining a high level of adaptability to potential perturbations of their steady state. Viscero-sensory afferents play a key role monitoring organ integrity by sensing the tissue environment and conveying the status of visceral organs to second order neurons located in the brainstem, a process that has been coined "interoception" (1)(2)(3). There is increasing evidence that interoceptive sensory afferents are highly heterogeneous, including dozens of intermingled sensory neuron subtypes organized in at least 37 clusters (4)(5)(6). ...
... As one of the largest barrier tissues in the human body, the lungs have respiratory performance under neuronal control with a higher complexity of vagal afferent innervation compared to other visceral organs (1)(2)(3)(4)(5)(6). Vagal sensory afferents detect insults to airway integrity, resulting in engagement of various neuronal circuits that trigger protective reflexes like cough, swallow, vocal cord adduction, and laryngeal closure (5). ...
... Murine VG are composed of jugular and nodose ganglion fused together into a single complex, while these ganglia are anatomically separated in humans (1,4,52). The human nodose ganglion alone is considerably larger than the mouse vagal ganglion including a proportionally higher number of neuronal cell bodies (2,53,54). However, we see a similar distinct TMC3 mRNA expression pattern in sections generated from human donor VG (which was not certified by peer review) is the author/funder. ...
Sensory neurons of the vagal ganglia (VG) innervate lungs and play a critical role in maintaining airway homeostasis. However, the specific VG neurons that innervate lungs, and the mechanisms by which these neurons sense and respond to airway insults, are not well understood. Here, we identify a subpopulation of lung-innervating VG neurons defined by their expression of Tmc3 . Single cell transcriptomics illuminated several subpopulations of Tmc3+ sensory neurons, revealing distinct Piezo2 - and Trpv1 -expressing subclusters. Furthermore, Tmc3 deficiency in VG neurons leads to global and subcluster specific transcriptional changes related to metabolic and ion channel function. Importantly, we show that broncho-constriction and dilation can be modulated through inhibition or activation of Tmc3+ VG neurons resulting in a decrease or increase of end-expiratory lung volume, respectively. Together, our data show that Tmc3 is a marker of lung-innervating neurons and may play a pivotal role in maintaining fundamental inspiratory and expiratory processes.
Significance
Harnessing the neuronal mechanisms that regulate lung function offers potential alternatives to existing corticosteroid treatment regimens for respiratory illness associated with acute bronchoconstriction including asthma, COPD, and emphysema. Our findings define Transmembrane channel-like 3 , Tmc3 , as a marker of lung-innervating sensory neurons, identify distinct subpopulations of Tmc3 + neurons with unique transcriptional profiles, and show that activation or inhibition of these neurons has a significant impact on airway function. Our work highlights potential avenues of novel targeted intervention in respiratory conditions driven by dysfunctional neuronal reflexes.
... Sensory neurons that constitute the interoceptive nervous system relay information to the brain from vital organs in the body 5 . Within the airways, sensory neurons provide essential feedback to control breathing, promote gas exchange, protect the airways through cough and laryngeal guarding reflexes, detect pathogens to induce sickness, and elicit perceptions of breathlessness, also known as dyspnoea or air hunger 1,2,6-8 . ...
... The vagus nerve provides the major sensory innervation of the airways, and classical studies have described airway neurons as rapidly adapting mechanoreceptors, slowly adapting mechanoreceptors or chemosensitive C fibres 1,2,5 . Recent single-cell expression profiling and genetic approaches have revealed a richer diversity of vagal neurons in the larynx, trachea and lungs 6,[14][15][16][17] . ...
Airway integrity must be continuously maintained throughout life. Sensory neurons guard against airway obstruction and, on a moment-by-moment basis, enact vital reflexes to maintain respiratory function1,2. Decreased lung capacity is common and life-threatening across many respiratory diseases, and lung collapse can be acutely evoked by chest wall trauma, pneumothorax or airway compression. Here we characterize a neuronal reflex of the vagus nerve evoked by airway closure that leads to gasping. In vivo vagal ganglion imaging revealed dedicated sensory neurons that detect airway compression but not airway stretch. Vagal neurons expressing PVALB mediate airway closure responses and innervate clusters of lung epithelial cells called neuroepithelial bodies (NEBs). Stimulating NEBs or vagal PVALB neurons evoked gasping in the absence of airway threats, whereas ablating NEBs or vagal PVALB neurons eliminated gasping in response to airway closure. Single-cell RNA sequencing revealed that NEBs uniformly express the mechanoreceptor PIEZO2, and targeted knockout of Piezo2 in NEBs eliminated responses to airway closure. NEBs were dispensable for the Hering–Breuer inspiratory reflex, which indicated that discrete terminal structures detect airway closure and inflation. Similar to the involvement of Merkel cells in touch sensation3,4, NEBs are PIEZO2-expressing epithelial cells and, moreover, are crucial for an aspect of lung mechanosensation. These findings expand our understanding of neuronal diversity in the airways and reveal a dedicated vagal pathway that detects airway closure to help preserve respiratory function.
... The transcriptomic identities, anatomical organization and functional role of cardiac VSNs remain mostly unknown. In particular, the cardiac ventricles are innervated by VSNs with mainly unmyelinated c-fibres 12,13 . Medical textbooks postulate that activation of these VSNs gives rise to the cardioinhibitory BJR that causes bradycardia and systemic hypotension, which in turn leads to syncope 14,15 . ...
... This result suggests that NPY2R VSNs are not involved in the continuous maintenance of resting baseline physiology. Next, we induced the baroreflex or the BJR through injection of the widely accepted substrates phenylephrine (PE; baroreflex), sodium nitroprusside (SNP; baroreflex) 8 or phenyl biguanide (PBG; BJR) 12 . ...
Visceral sensory pathways mediate homeostatic reflexes, the dysfunction of which leads to many neurological disorders¹. The Bezold–Jarisch reflex (BJR), first described2,3 in 1867, is a cardioinhibitory reflex that is speculated to be mediated by vagal sensory neurons (VSNs) that also triggers syncope. However, the molecular identity, anatomical organization, physiological characteristics and behavioural influence of cardiac VSNs remain mostly unknown. Here we leveraged single-cell RNA-sequencing data and HYBRiD tissue clearing⁴ to show that VSNs that express neuropeptide Y receptor Y2 (NPY2R) predominately connect the heart ventricular wall to the area postrema. Optogenetic activation of NPY2R VSNs elicits the classic triad of BJR responses—hypotension, bradycardia and suppressed respiration—and causes an animal to faint. Photostimulation during high-resolution echocardiography and laser Doppler flowmetry with behavioural observation revealed a range of phenotypes reflected in clinical syncope, including reduced cardiac output, cerebral hypoperfusion, pupil dilation and eye-roll. Large-scale Neuropixels brain recordings and machine-learning-based modelling showed that this manipulation causes the suppression of activity across a large distributed neuronal population that is not explained by changes in spontaneous behavioural movements. Additionally, bidirectional manipulation of the periventricular zone had a push–pull effect, with inhibition leading to longer syncope periods and activation inducing arousal. Finally, ablating NPY2R VSNs specifically abolished the BJR. Combined, these results demonstrate a genetically defined cardiac reflex that recapitulates characteristics of human syncope at physiological, behavioural and neural network levels.
... These descending axons comprise the vagal efferent system and are the focus of this review. Most vagal axons transmit sensory information from viscera to the brain and are the subject of other recent reviewse.g., [5,6]. Also, since vagal efferent anatomy and function have been extensively reviewed elsewhere, e.g., [6][7][8][9][10][11][12][13][14][15], this review focuses instead on recent insights into the molecular organization of the efferent vagus gained from single-cell genomics and genetic technology. ...
... In the heart and lungs, other general visceral efferents maintain homeostasis through reflexive changes in cardiorespiratory function. For instance, in the baroreflex, stretch-sensing vagal sensory fibers in the aortic arches detect increases in blood pressure and signal to cardiovagal neurons in the nAmb to decrease blood pressure by slowing heart rate [5,46]. Another reflex, respiratory sinus arrythmia, involves signaling from inhibitory respiratory neurons in the brainstem to cardiovagal neurons, which decreases heart rate with each breath out [47]. ...
The vagus nerve vitally connects the brain and body to coordinate digestive, cardiorespiratory, and immune functions. Its efferent neurons, which project their axons from the brainstem to the viscera, are thought to comprise "functional units" - neuron populations dedicated to the control of specific vagal reflexes or organ functions. Previous research indicates that these functional units differ from one another anatomically, neurochemically, and physiologically but have yet to define their identity in an experimentally tractable way. However, recent work with genetic technology and single-cell genomics suggests that genetically distinct subtypes of neurons may be the functional units of the efferent vagus. Here we review how these approaches are revealing the organizational principles of the efferent vagus in unprecedented detail.
... A full treatise of the vagus nerve family is out of the scope of this short review; however, interested readers may consult a multi-part comprehensive monograph by Yan and Silberstein, of which the first two parts have been cited here [17,18]. Collectively, the vagus nerves control a multitude of physiological functions, including heart rate, digestion, and breathing [10,19,20]. The particular vagus nerve involved in syncope is often referred to as vagal sensory neuron (VSN). ...
Observed and recorded in various forms since ancient times, ‘syncope’ is often popularly called ‘fainting’, such that the two terms are used synonymously. Syncope/fainting can be caused by a variety of conditions, including but not limited to head injuries, vertigo, and oxygen deficiency. Here, we draw on a large body of literature on syncope, including the role of a recently discovered set of specialized mammalian neurons. Although the etiology of syncope still remains a mystery, we have attempted to provide a comprehensive account of what is known and what still needs to be performed. Much of our understanding of syncope is owing to studies in the laboratory mouse, whereas evidence from human patients remains scarce. Interestingly, the cardioinhibitory Bezold–Jarisch reflex, recognized in the early 1900s, has an intriguing similarity to—and forms the basis of—syncope. In this review, we have integrated this minimal model into the modern view of the brain–neuron–heart signaling loop of syncope, to which several signaling events contribute. Molecular signaling is our major focus here, presented in terms of a normal heart, and thus, syncope due to abnormal or weak heart activity is not discussed in detail. In addition, we have offered possible directions for clinical intervention based on this model. Overall, this article is expected to generate interest in chronic vertigo and syncope/fainting, an enigmatic condition that affects most humans at some point in life; it is also hoped that this may lead to a mechanism-based clinical intervention in the future.
... The vagus nerve connects visceral tissues with the CNS, mediates internal sensory and physiological regulation in the body and responds to external stimuli [36]. The vagus nerve is the most extensive nerve that projects into the respiratory tract, from the pharynx to the alveoli. ...
... The main structural components of the reward system [76] An fMRI study shows that decisions that reveal risk avoidance in the context of reward and a tendency to take risk in the context of losses (i.e. typical behavior surrounding risk according to probability theory) are accompanied by activation of parts of the amygdala that are not activated when making atypical decisions, such as propensity To risk in the context of reward and to avoid risk in case of losses [78] [82]. Functional magnetic resonance imaging (fMRI) experiments showed how the nucleus accumbens interacts with dopamine in various situations involving an expected reward [76] [81]: ...
... The enhanced functional connectivity from the AIC to the SN and node of the vagal nerve represented the enhanced bottom-up process of interoception due to the training. The AIC and the dorsal ACC are vital nodes of the SN [2,15,23], and NTS is a crucial node of the vagal nerve [51,52], which is a gateway of interoceptive inputs from the body. All of them are the main "bottom-up" pathway of interoception [30], enhanced by psychotherapies related to interoceptive training like yoga and mindfulness. ...
Interoception is the perception of afferent information that arises from anywhere and everywhere within the body. Recently, interoceptive accuracy could be enhanced by cognitive training. Given that the anterior insula cortex (AIC) is a key node of interoception, we hypothesized that resting functional connectivity (RSFC) from AIC was involved in an effect of interoceptive training. To address this issue, we conducted a longitudinal intervention study using interoceptive training and obtained RSFC using fMRI before and after the intervention. A heartbeat perception task evaluated interoceptive accuracy. Twenty-two healthy volunteers (15 females, age 19.9 ± 2.0 years) participated. After the intervention, interoceptive accuracy was enhanced, and anxiety levels and somatic symptoms were reduced. Also, RSFC from AIC to the dorsolateral prefrontal cortex (DLPFC), superior marginal gyrus (SMG), anterior cingulate cortex (ACC), and brain stem, including nucleus tractus solitarius (NTS) were enhanced, and those from AIC to the visual cortex (VC) were decreased according to enhanced interoceptive accuracy. The neural circuit of AIC, ACC, and NTS is involved in the bottom-up process of interoception. The neural circuit of AIC, DLPFC, and SMG is involved in the top-down process of interoception, which was thought to represent the cognitive control of emotion. The findings provided a better understanding of neural underpinnings of the effect of interoceptive training on somatic symptoms and anxiety levels by enhancing both bottom-up and top-down processes of interoception, which has a potential contribution to the structure of psychotherapies based on the neural mechanism of psychosomatics.
... Gastrointestinal (GI) infusion of fats 23 or sugars 24 activate the vagus nerve and cause DS dopamine efflux, 25,26 , yet previous attempts to address the role of the vagus nerve in appetition have yielded mixed results. 25,[27][28][29][30] Because vagal sensory neurons are molecularly heterogeneous [31][32][33] and play a role in diverse physiological functions, 34,35 we reasoned that previously used chemical or surgical lesioning approaches that interrupt global vagal activity lack the specificity required to test the role of distinct vagal sensory populations in nutrient reinforcement. To overcome this problem, we applied virally delivered molecular tools to the nodose ganglia (NG) of Fos TRAP mice to manipulate neuronal populations of the vagus nerve that are activated in response to gastric infusions of sugar or fat. ...
... Как только расширяется знании в области неврологии все больше становиться очевидным доминирующее влияние нервной системы в патогенезе многих соматических заболеваний, особенно при патологии желудочно-кишечного тракта (ЖКТ) [1]. Лэнгли впервые ввел термин "автономная нервная система" в 1897 году для описания нервных волокон, которые иннервируют ткани, кроме скелетных мышц. ...
The vagus nerve is an essential connection between the body and the brain that controls vital aspects of autonomic physiology such as respiration, heart rate, blood pressure and intestinal motility, reflexes such as coughing and swallowing, and survival behaviors such as eating, drinking and response to nausea. The stomach has a complex nervous apparatus. The innervation of the stomach is provided by both the somatic and the autonomic nervous system. The stomach receives innervation from the vagus nerve and derivatives of the celiac plexus (superior mesenteric, gastric, splenic, hepatic). The vagus nerve has the greatest influence on the work of the stomach and intestines. The vagus nerve is the longest splanchnic nerve, literally wandering throughout the body. The vagus nerves play a dominant role in stimulating gastric secretion. The basal or continuous secretion of gastric juice in normal humans is entirely due to tonic impulses in the vagus nerves. The purpose of our review was to identify the pathogenetic role of the vagus nerve in gastric and duodenal ulcers.
... These results suggest that by increasing the precision of cardiac afferents, taVNS enables the impact of cardiac prediction error signals on allostatic adjustments. It is well-known that the vagus nerve conveys afferent cardiovascular information (Hainsworth, 1995;Prescott & Liberles, 2022;Rajendran et al., 2023) to the brain via the NST (Ran et al., 2022). From the NST, afferent interoceptive information flows continuously and hierarchically between higher-level networks involved in the multimodal representation of the organism and lowerlevel networks that send efferent signals to regulate energy expenditure (Rajendran et al., 2023). ...
It has recently been suggested that predictive processing principles may apply to interoception, defined as the processing of hormonal, autonomic, visceral, and immunological signals. In the current study, we aimed at providing empirical evidence for the role of cardiac interoceptive prediction errors signals on allostatic adjustments, using transcutaneous auricular vagus nerve stimulation (taVNS) as a tool to modulate the processing of interoceptive afferents. In a within‐subject design, participants performed a cardiac‐related interoceptive task (heartbeat counting task) under taVNS and sham stimulation, spaced 1‐week apart. We observed that taVNS, in contrast to sham stimulation, facilitated the maintenance of interoceptive accuracy levels over time (from the initial, stimulation‐free, baseline block to subsequent stimulation blocks), suggesting that vagus nerve stimulation may have helped to maintain engagement to cardiac afferent signals. During the interoceptive task, taVNS compared to sham, produced higher heart‐evoked potentials (HEP) amplitudes, a potential readout measure of cardiac‐related prediction error processing. Further analyses revealed that the positive relation between interoceptive accuracy and allostatic adjustments—as measured by heart rate variability (HRV)—was mediated by HEP amplitudes. Providing initial support for predictive processing accounts of interoception, our results suggest that the stimulation of the vagus nerve may increase the precision with which interoceptive signals are processed, favoring their influence on allostatic adjustments.
... Vagal afferents, with their soma in the nodose ganglia, mostly innervate many internal organs. Traditionally, the role of interoception, that is, the sense of internal organs, is thought to be mediated largely by the vagal afferents (1)(2)(3)(4)(5)(6)(7). However, the involvement of DRG and somatosensory pathways in interoception is being increasingly recognized across many internal organs (8)(9)(10). ...
Adipose tissue innervation is critical for regulating metabolic and energy homeostasis. While the sympathetic efferent innervation of fat is well characterized, the role of sensory or afferent innervation remains less explored. This article reviews previous work on adipose innervation and recent advances in the study of sensory innervation of adipose tissues. We discuss key open questions, including the physiological implications of adipose afferents in homeostasis as well as potential cross talk with sympathetic neurons, the immune system, and hormonal pathways. We also outline the general technical challenges of studying dorsal root ganglia innervating fat, along with emerging technologies that may overcome these barriers. Finally, we highlight areas for further research to deepen our understanding of the afferent function of adipose innervation.
... The major role is played by the vagus nerve, which comprises 80% of afferent fibers and 20% of efferent fibers [104]. Microbiota metabolites, gut hormones, and nutrients interact with the afferent branch of the vagus nerve and conduct signals to the CNS. ...
Autism spectrum disorder (ASD) is a neuropsychiatric condition characterized by impaired social interactions and repetitive stereotyped behaviors. Growing evidence highlights an important role of the gut–brain–microbiome axis in the pathogenesis of ASD. Research indicates an abnormal composition of the gut microbiome and the potential involvement of bacterial molecules in neuroinflammation and brain development disruptions. Concurrently, attention is directed towards the role of short-chain fatty acids (SCFAs) and impaired intestinal tightness. This comprehensive review emphasizes the potential impact of maternal gut microbiota changes on the development of autism in children, especially considering maternal immune activation (MIA). The following paper evaluates the impact of the birth route on the colonization of the child with bacteria in the first weeks of life. Furthermore, it explores the role of pro-inflammatory cytokines, such as IL-6 and IL-17a and mother’s obesity as potentially environmental factors of ASD. The purpose of this review is to advance our understanding of ASD pathogenesis, while also searching for the positive implications of the latest therapies, such as probiotics, prebiotics or fecal microbiota transplantation, targeting the gut microbiota and reducing inflammation. This review aims to provide valuable insights that could instruct future studies and treatments for individuals affected by ASD.
... Vagal sensory nerves, derived from vagal sensory neurons situated in the jugular and nodose ganglia, innervate visceral organs in the respiratory, cardiovascular, digestive and endocrine systems, sensing and transmitting the sensory information about body's internal environment to the central nervous system (Prescott and Liberles, 2022;Zhao et al., 2022). The normal function of vagal sensory nerves is essential for maintaining the optimal physiological activities of the viscera, and for initiating the host defense in response to inhaled or ingested harmful chemicals and pathogens. ...
Heightened excitability of vagal sensory neurons in inflammatory visceral diseases contributes to unproductive and difficult-to-treat neuronally based symptoms such as visceral pain and dysfunction. Identification of targets and modulators capable of regulating the excitability of vagal sensory neurons may lead to novel therapeutic options. KCNQ1-5 genes encode KV7.1-7.5 potassium channel α-subunits. Homotetrameric or heterotetrameric KV7.2-7.5 channels can generate the so-called M-current (IM) known to decrease the excitability of neurons including visceral sensory neurons. This study aimed to address the hypothesis that KV7.2/7.3 channels are key regulators of vagal sensory neuron excitability by evaluating the effects of KCNQ2/3-selective activator, ICA-069673, on IM in mouse nodose neurons and determining its effects on excitability and action potential firings using patch clamp technique. The results showed that ICA-069673 enhanced IM density, accelerated the activation and delayed the deactivation of M-channels in a concentration-dependent manner. ICA-069673 negatively shifted the voltage-dependent activation of IM and increased the maximal conductance. Consistent with its effects on IM, ICA-069673 induced a marked hyperpolarization of resting potential and reduced the input resistance. The hyperpolarizing effect was more pronounced in partially depolarized neurons. Moreover, ICA-069673 caused a 3-fold increase in the minimal amount of depolarizing current needed to evoke an action potential, and significantly limited the action potential firings in response to sustained suprathreshold stimulations. ICA-069673 had no effect on membrane currents when Kcnq2 and Kcnq3 were deleted. These results indicate that opening KCNQ2/3-mediated M-channels is sufficient to suppress the excitability and enhance spike accommodation in vagal visceral sensory neurons. Significance Statement This study supports the hypothesis that selectively activating KCNQ2/3-mediated M-channels is sufficient to suppress the excitability and action potential firings in vagal sensory neurons. These results provide evidence in support of further investigations into the treatment of various visceral disorders that involve nociceptor hyperexcitability with selective KCNQ2/3 M-channel openers.
... Gastrointestinal (GI) infusion of fats 23 or sugars 24 activate the vagus nerve and cause DS dopamine efflux, 25,26 , yet previous attempts to address the role of the vagus nerve in appetition have yielded mixed results. 25,[27][28][29][30] Because vagal sensory neurons are molecularly heterogeneous [31][32][33] and play a role in diverse physiological functions, 34,35 we reasoned that previously used chemical or surgical lesioning approaches that interrupt global vagal activity lack the specificity required to test the role of distinct vagal sensory populations in nutrient reinforcement. To overcome this problem, we applied virally delivered molecular tools to the nodose ganglia (NG) of Fos TRAP mice to manipulate neuronal populations of the vagus nerve that are activated in response to gastric infusions of sugar or fat. ...
Food is a powerful natural reinforcer that guides feeding decisions. The vagus nerve conveys internal sensory information from the gut to the brain about nutritional value; however, the cellular and molecular basis of macronutrient-specific reward circuits is poorly understood. Here, we monitor in vivo calcium dynamics to provide direct evidence of independent vagal sensing pathways for the detection of dietary fats and sugars. Using activity-dependent genetic capture of vagal neurons activated in response to gut infusions of nutrients, we demonstrate the existence of separate gut-brain circuits for fat and sugar sensing that are necessary and sufficient for nutrient-specific reinforcement. Even when controlling for calories, combined activation of fat and sugar circuits increases nigrostriatal dopamine release and overeating compared with fat or sugar alone. This work provides new insights into the complex sensory circuitry that mediates motivated behavior and suggests that a subconscious internal drive to consume obesogenic diets (e.g., those high in both fat and sugar) may impede conscious dieting efforts.
... Particularly in the cervical vagus nerve, which is the current targeted location for electrode array implantation, large, myelinated A-fibers and B-fibers convey information from primary motor neurons in the brain that control muscles or sensory neurons, convey information from muscles and joints back to the brain, and convey information regarding pain sensation [4]. Small unmyelinated C-fibers constitute the peripheral axons of sensory vagal neurons, and transmit mechanical, chemical, thermal and inflammatory signals from visceral organs to the brainstem [5]. Current VNS approaches at the cervical level indiscriminately stimulate the entire nerve bundle, resulting in considerable adverse side effects when providing therapeutic treatments [4]. ...
... The metabolites of the microbiota could transmit information from the intestines to the CNS via afferent neurons. This process leads to the generation of adaptive or maladaptive responses following integration within the CNS [115]. Direct interaction between the gut microbiota and the afferent fibers of the VN was not established. ...
As the global population ages, the prevalence of neurodegenerative diseases is surging. These disorders have a multifaceted pathogenesis, entwined with genetic and environmental factors. Emerging research underscores the profound influence of diet on the development and progression of health conditions. Intermittent fasting (IF), a dietary pattern that is increasingly embraced and recommended, has demonstrated potential in improving neurophysiological functions and mitigating pathological injuries with few adverse effects. Although the precise mechanisms of IF’s beneficial impact are not yet completely understood, gut microbiota and their metabolites are believed to be pivotal in mediating these effects. This review endeavors to thoroughly examine current studies on the shifts in gut microbiota and metabolite profiles prompted by IF, and their possible consequences for neural health. It also highlights the significance of dietary strategies as a clinical consideration for those with neurological conditions.
... The enhanced functional connectivity from the AIC to the SN and node of the vagal nerve represented the enhanced bottom-up process of interoception due to the training. The AIC and the dorsal ACC are vital nodes of the SN 2, 12, 19 , and NTS is a crucial node of vagal nerve 44,45 which is a gateway of interoceptive inputs from the body. All of them are the main "bottom-up" pathway of interoception 26 , enhanced by psychotherapies related to interoceptive training like yoga and mindfulness. ...
Interoception is the perception of afferent information that arises from anywhere and everywhere within the body. Recently, interoceptive accuracy could be enhanced by cognitive training. Given that the anterior insula cortex (AIC) is a key node of interoception, we hypothesized that resting functional connectivity (RSFC) from AIC was involved in an effect of interoceptive training. To address this issue, we conducted a longitudinal intervention study using interoceptive training and obtained RSFC using fMRI before and after the intervention. A heartbeat perception task evaluated interoceptive accuracy. Twenty-two healthy volunteers (15 females, age 19.9 ± 2.0 years) participated. After the intervention, interoceptive accuracy was enhanced, and anxiety levels and somatic symptoms were reduced. Also, RSFC from AIC to the dorsolateral prefrontal cortex (DLPFC), superior marginal gyrus (SMG), anterior cingulate cortex (ACC), and brain stem, including nucleus tractus solitarius (NTS) were enhanced, and those from AIC to the visual cortex (VC) were decreased according to enhanced interoceptive accuracy. The neural circuit of AIC, ACC, and NTS is involved in the bottom-up process of interoception. The neural circuit of AIC, DLPFC, and SMG is involved in the top-down process of interoception, which was thought to represent the cognitive control of emotion. The findings provided a better understanding of neural underpinnings of the effect of interoceptive training on somatic symptoms and anxiety levels by enhancing both bottom-up and top-down processes of interoception, which has a potential contribution to the structure of psychotherapies based on the neural mechanism of psychosomatics. Trial registration number: UMIN000037548.
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000042812
... The internal structure of the vagus nerve is complex, encompassing nerve fibers with diverse morphological features, fascicular organizations, and functional associations (Stakenborg et al., 2020;Havton et al., 2021). Approximately 80% of vagal nerve fibers are afferent (Berthoud and Neuhuber, 2000;Powley et al., 2019), enabling sensory neurons in the nodose ganglia (NG) to relay a variety of bodily signals to the nucleus tractus solitarius (NTS) in the brainstem (Prescott and Liberles, 2022;Ran et al., 2022). These signals, once in the NTS, can further ascend to various brain regions (Craig, 2002;Browning and Travagli, 2014;Berntson and Khalsa, 2021). ...
Introduction
The vagus nerve, the primary neural pathway mediating brain-body interactions, plays an essential role in transmitting bodily signals to the brain. Despite its significance, our understanding of the detailed organization and functionality of vagal afferent projections remains incomplete.
Methods
In this study, we utilized manganese-enhanced magnetic resonance imaging (MEMRI) as a non-invasive and in vivo method for tracing vagal nerve projections to the brainstem and assessing their functional dependence on cervical vagus nerve stimulation (VNS). Manganese chloride solution was injected into the nodose ganglion of rats, and T1-weighted MRI scans were performed at both 12 and 24 h after the injection.
Results
Our findings reveal that vagal afferent neurons can uptake and transport manganese ions, serving as a surrogate for calcium ions, to the nucleus tractus solitarius (NTS) in the brainstem. In the absence of VNS, we observed significant contrast enhancements of around 19–24% in the NTS ipsilateral to the injection side. Application of VNS for 4 h further promoted nerve activity, leading to greater contrast enhancements of 40–43% in the NTS.
Discussion
These results demonstrate the potential of MEMRI for high-resolution, activity-dependent tracing of vagal afferents, providing a valuable tool for the structural and functional assessment of the vagus nerve and its influence on brain activity.
... A major mediator of brainbody communication is the 10 th cranial nerve, the vagus 1,2 , which innervates a wide array of body parts including the pharynx, larynx and most visceral organs in vertebrates. Vagus sensory afferents send information about diverse aspects of internal state to the brain, and in turn, vagus motor efferents transmit appropriate reflexive motor responses including coughing, gagging, swallowing, esophagus and gut peristalsis, stomach emptying, heart rate and pancreatic and gall bladder secretion [1][2][3][4] . ...
Motor neurons in the central nervous system often lie in a continuous topographic map, where neurons that innervate different body parts are spatially intermingled. This is the case for the efferent neurons of the vagus nerve, which innervate diverse muscle and organ targets in the head and viscera for brain-body communication. It remains elusive how neighboring motor neurons with different fixed peripheral axon targets develop the separate somatodendritic (input) connectivity they need to generate spatially precise body control. Here we show that vagus motor neurons in the zebrafish indeed generate spatially appropriate peripheral responses to focal sensory stimulation even when they are transplanted into ectopic positions within the topographic map, indicating that circuit refinement occurs after the establishment of coarse topography. Refinement depends on motor neuron synaptic transmission, suggesting that an experience-dependent periphery-to-brain feedback mechanism establishes specific input connectivity amongst intermingled motor populations.
Krause corpuscles, which were discovered in the 1850s, are specialized sensory structures found within the genitalia and other mucocutaneous tissues1–4. The physiological properties and functions of Krause corpuscles have remained unclear since their discovery. Here we report the anatomical and physiological properties of Krause corpuscles of the mouse clitoris and penis and their roles in sexual behaviour. We observed a high density of Krause corpuscles in the clitoris compared with the penis. Using mouse genetic tools, we identified two distinct somatosensory neuron subtypes that innervate Krause corpuscles of both the clitoris and penis and project to a unique sensory terminal region of the spinal cord. In vivo electrophysiology and calcium imaging experiments showed that both Krause corpuscle afferent types are A-fibre rapid-adapting low-threshold mechanoreceptors, optimally tuned to dynamic, light-touch and mechanical vibrations (40–80 Hz) applied to the clitoris or penis. Functionally, selective optogenetic activation of Krause corpuscle afferent terminals evoked penile erection in male mice and vaginal contraction in female mice, while genetic ablation of Krause corpuscles impaired intromission and ejaculation of males and reduced sexual receptivity of females. Thus, Krause corpuscles of the clitoris and penis are highly sensitive mechanical vibration detectors that mediate sexually dimorphic mating behaviours.
CITATION Dallal-York J and Troche MS (2024) Hypotussic cough in persons with dysphagia: biobehavioral interventions and pathways to clinical implementation. Front. Rehabil. Sci. 5:1394110. Cough is a powerful, protective expulsive behavior that assists in maintaining respiratory health by clearing foreign material, pathogens, and mucus from the airways. Therefore, cough is critical to survival in both health and disease. Importantly, cough protects the airways and lungs from both antegrade (e.g., food, liquid, saliva) and retrograde (e.g., bile, gastric acid) aspirate contents. Aspiration is often the result of impaired swallowing (dysphagia), which allows oral and/or gastric contents to enter the lung, especially in individuals who also have cough dysfunction (dystussia). Cough hyposensitivity, downregulation, or desensitization-collectively referred to as hypotussia-is common in individuals with dysphagia, and increases the likelihood that aspirated material will reach the lung. The consequence of hypotussia with reduced airway clearance can include respiratory tract infection, chronic inflammation, and long-term damage to the lung parenchyma. Despite the clear implications for health, the problem of managing hypotussia in individuals with dysphagia is frequently overlooked. Here, we provide an overview of the current interventions and treatment approaches for hypotussic cough. We synthesize the available literature to summarize research findings that advance our understanding of these interventions, as well as current gaps in knowledge. Further, we highlight pragmatic resources to increase awareness of hypotussic cough interventions and provide support for the clinical implementation of evidence-based treatments. In culmination, we discuss potential innovations and future directions for hypotussic cough research.
The body–brain axis is emerging as a principal conductor of organismal physiology. It senses and controls organ function1,2, metabolism³ and nutritional state4–6. Here we show that a peripheral immune insult strongly activates the body–brain axis to regulate immune responses. We demonstrate that pro-inflammatory and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body–brain circuit produced unregulated and out-of-control inflammatory responses. By contrast, activating, rather than silencing, this circuit affords neural control of immune responses. We used single-cell RNA sequencing, combined with functional imaging, to identify the circuit components of this neuroimmune axis, and showed that its selective manipulation can effectively suppress the pro-inflammatory response while enhancing an anti-inflammatory state. The brain-evoked transformation of the course of an immune response offers new possibilities in the modulation of a wide range of immune disorders, from autoimmune diseases to cytokine storm and shock.
Airway neuroendocrine (NE) cells have been proposed to serve as specialized sensory epithelial cells that modulate respiratory behavior by communicating with nearby nerve endings. However, their functional properties and physiological roles in the healthy lung, trachea, and larynx remain largely unknown. In this work, we show that murine NE cells in these compartments have distinct biophysical properties but share sensitivity to two commonly aspirated noxious stimuli, water and acid. Moreover, we found that tracheal and laryngeal NE cells protect the airways by releasing adenosine 5′-triphosphate (ATP) to activate purinoreceptive sensory neurons that initiate swallowing and expiratory reflexes. Our work uncovers the broad molecular and biophysical diversity of NE cells across the airways and reveals mechanisms by which these specialized excitable cells serve as sentinels for activating protective responses.
Physiological dysfunction confers negative valence to coincidental sensory cues to induce the formation of aversive associative memory. How peripheral tissue stress engages neuromodulatory mechanisms to form aversive memory is poorly understood. Here, we show that in the nematode C. elegans, mitochondrial disruption induces aversive memory through peroxisomal β-oxidation genes in non-neural tissues, including pmp-4/very-long-chain fatty acid transporter, dhs-28/3-hydroxylacyl-CoA dehydrogenase, and daf-22/3-ketoacyl-CoA thiolase. Upregulation of peroxisomal β-oxidation genes under mitochondrial stress requires the nuclear hormone receptor NHR-49. Importantly, the memory-promoting function of peroxisomal β-oxidation is independent of its canonical role in pheromone production. Peripheral signals derived from the peroxisomes target NSM, a critical neuron for memory formation under stress, to upregulate serotonin synthesis and remodel evoked responses to sensory cues. Our genetic, transcriptomic, and metabolomic approaches establish peroxisomal lipid signaling as a crucial mechanism that connects peripheral mitochondrial stress to central serotonin neuromodulation in aversive memory formation.
This is a review of proton devices for neuromorphic information processing. While solid-state devices utilizing various ions have been widely studied for non-volatile memory, the proton, which is the smallest ion, has been relatively overlooked despite its advantage of being able to move through various solids at room temperature. With this advantage, it should be possible to control proton kinetics not only for fast analog memory function, but also for real-time neuromorphic information processing in the same time scale as humans. Here, after briefing the neuromorphic concept and the basic proton behavior in solid-state devices, we review the proton devices that have been reported so far, classifying them according to their device structures. The benchmark clearly shows the time scales of proton relaxation ranges from several milliseconds to hundreds of seconds, and completely match the time scales for expected neuromorphic functions. The incorporation of proton degrees of freedom in electronic devices will also facilitate access to electrochemical phenomena and subsequent phase transitions, showing great promise for neuromorphic information processing in the real-time and highly interactive edge devices.
Syok hemoragi didefinisikan sebagai kondisi jaringan perifer dan organ tidak mampu melakukan perfusi akibat kehilangan darah dalam volume tertentu. Prediksi tingkat keparahan syok hewan pada fase prehospital masih belum banyak dilaporkan. Kendala keterbatasan alat untuk deteksi tekanan darah, membuat nilai syok indeks (SI) sulit untuk dilakukan. Penelitian ini dilakukan untuk menduga nilai SI berdasarkan volume darah yang dikeluarkan, dengan kondisi syok yang dikonfirmasi dengan gambaran klinis. Penelitian ini menggunakan lima ekor kelinci jenis New Zealand White yang diinduksi syok hemoragi sebanyak 10% dengan cara evakuasi darah melalui arteri carotis. Parameter fisiologi yang teramati yaitu; heart rate (HR), respiration rate(RR), mean arterial pressure (MAP), tekanan sistol dan diastol, dan saturasi oksigen (SPO2). Nilai syok indeks (SI) pada penelitian ini yaitu 1,6 ± 0,4 atau dalam level sedang-berat. Level SI berbeda dengan parameter fisiologis, yang menunjukkan perbaikan menuju nilai baseline hampir pada seluruh parameter (HR, RR, MAP, sistol, SPO2) pada menit ke-15 pascasyok. Gambaran klinis dan SI, tidak menunjukkan relevansi, sehingga nilai SI belum dapat digunakan sebagai penduga tingkat keparahan syok, karena membutuhkan cut-off point syok atau mempertimbangkan penggunaan modified shock index (MSI) atau simple Shock Index (sSI) sebagai metode untuk penduga/prediksi syok. Dibutuhkan penelitian lebih lanjut untuk membuat klasifikasi syok khusus hewan kelinci.
Vagus nerve stimulation (VNS) has been approved as a treatment for various conditions, including drug‐resistant epilepsy, migraines, chronic cluster headaches and treatment‐resistant depression. It is known to have anti‐inflammatory, anti‐nociceptive and anti‐adrenergic effects, and its therapeutic potential for diverse pathologies is being investigated. VNS can be achieved through invasive (iVNS) or non‐invasive (niVNS) means, targeting different branches of the vagus nerve. iVNS devices require surgical implantation and have associated risks, while niVNS devices are generally better tolerated and have a better safety profile. Studies have shown that both iVNS and niVNS can reduce inflammation and pain perception in patients with acute and chronic conditions. VNS devices, such as the VNS Therapy System and MicroTransponder Vivistim, have received Food and Drug Administration approval for specific indications. Other niVNS devices, like NEMOS and gammaCore, have shown effectiveness in managing epilepsy, pain and migraines. VNS has also demonstrated potential in autoimmune disorders, such as rheumatoid arthritis and Crohn's disease, as well as neurological disorders like epilepsy and migraines. In addition, VNS has been explored in cardiovascular disorders, including post‐operative atrial fibrillation and myocardial ischemia–reperfusion injury, and has shown positive outcomes. The mechanisms behind VNS's effects include the cholinergic anti‐inflammatory pathway, modulation of cytokines and activation of specialised pro‐resolving mediators. The modulation of inflammation by VNS presents a promising avenue for investigating its potential to improve the healing of chronic wounds. However, more research is needed to understand the specific mechanisms and optimise the use of VNS in wound healing. Ongoing clinical trials may support the use of this modality as an adjunct to improve healing.
SARS-CoV-2, the virus responsible for COVID-19, triggers symptoms such as sneezing, aches and pain. These symptoms are mediated by a subset of sensory neurons, known as nociceptors, that detect noxious stimuli, densely innervate the airway epithelium, and interact with airway resident epithelial and immune cells. However, the mechanisms by which viral infection activates these neurons to trigger pain and airway reflexes are unknown. Here, we show that the coronavirus papain-like protease (PLpro) directly activates airway-innervating trigeminal and vagal nociceptors in mice and human iPSC-derived nociceptors. PLpro elicits sneezing and acute pain in mice and triggers the release of neuropeptide calcitonin gene-related peptide (CGRP) from airway afferents. We find that PLpro-induced sneeze and pain requires the host TRPA1 ion channel that has been previously demonstrated to mediate pain, cough, and airway inflammation. Our findings are the first demonstration of a viral product that directly activates sensory neurons to trigger pain and airway reflexes and highlight a new role for PLpro and nociceptors in COVID-19.
Increasing evidence links the gut microbiome and the nervous system in health and disease. This narrative review discusses current views on the interaction between the gut microbiota, the intestinal epithelium, and the brain, and provides an overview of the communication routes and signals of the bidirectional interactions between gut microbiota and the brain, including circulatory, immunological, neuroanatomical, and neuroendocrine pathways. Similarities and differences in healthy gut microbiota in humans and mice exist that are relevant for the translational gap between non-human model systems and patients. There is an increasing spectrum of metabolites and neurotransmitters that are released and/or modulated by the gut microbiota in both homeostatic and pathological conditions. Dysbiotic disruptions occur as consequences of critical illnesses such as cancer, cardiovascular and chronic kidney disease but also neurological, mental, and pain disorders, as well as ischemic and traumatic brain injury. Changes in the gut microbiota (dysbiosis) and a concomitant imbalance in the release of mediators may be cause or consequence of diseases of the central nervous system and are increasingly emerging as critical links to the disruption of healthy physiological function, alterations in nutrition intake, exposure to hypoxic conditions and others, observed in brain disorders. Despite the generally accepted importance of the gut microbiome, the bidirectional communication routes between brain and gut are not fully understood. Elucidating these routes and signaling pathways in more detail offers novel mechanistic insight into the pathophysiology and multifaceted aspects of brain disorders.
Cardiac dysfunction is a severe complication that is as-sociated with an increased risk of mortality in multiple diseases. One potential solution that has been researched is the electrical stimulation of the vagus nerve to exert cardioprotection. This method has been shown to reduce the systemic inflammatory response and maintain im-mune homeostasis of the heart. However, the invasive procedure of electrode implantation poses a risk of nerve or fiber damage. Here, we propose transthoracic ultrasound stimulation of vagus nerve to allevi-ate cardiac dysfunction caused by lipopolysaccharide. We developed a noninvasive transthoracic ultrasound stimulation system and exposed anesthetized mice to ultrasound protocol or sham stimulation 24 hours after lipopolysaccharide treatment. Results showed that daily heart tar-geting ultrasound stimulation for 4 days significantly increased left ventricular systolic function (
p
= 0.01) and improved ejection fraction (
p
= 0.03) and shortening fraction (
p
= 0.04). Furthermore, ultrasound stimulation significantly reduced inflammation cytokines, including IL-6 (p = 0.03) and IL-1β (
p
= 0.04). In addition, cervical vagotomy abrogated the effect of ultrasound stimulation, suggesting the involve-ment of the vagus nerve anti-inflammatory effect. Finally, the same ultrasound treatment but for a longer period (14 days) also significantly increased cardiac function in naturally aged mice. Collectively, these findings suggest that the potential of transthoracic ultrasound stimula-tion as a possible novel noninvasive approach in the context of cardiac dysfunction with reduced systolic function, and provide new targets for rehabilitation of peripheral organ function.
Interoception, the ability to precisely and timely sense internal body signals, is critical for life. The interoceptive system monitors a large variety of mechanical, chemical, hormonal, and pathological cues using specialized organ cells, organ innervating neurons, and brain sensory neurons. It is important for maintaining body homeostasis, providing motivational drives, and regulating autonomic, cognitive, and behavioral functions. However, compared to external sensory systems, our knowledge about how diverse body signals are coded at a system level is quite limited. In this review, we focus on the unique features of interoceptive signals and the organization of the interoceptive system, with the goal of better understanding the coding logic of interoception.
Expected final online publication date for the Annual Review of Physiology, Volume 86 is February 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Gut-liver-brain axis is a three-way highway of information interaction system among the gastrointestinal tract, liver, and nervous systems. In the past few decades, breakthrough progress has been made in the gut liver brain axis, mainly through understanding its formation mechanism and increasing treatment strategies. In this review, we discuss various complex networks including barrier permeability, gut hormones, gut microbial metabolites, vagus nerve, neurotransmitters, immunity, brain toxic metabolites, β-amyloid (Aβ) metabolism, and epigenetic regulation in the gut-liver-brain axis. Some therapies containing antibiotics, probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), polyphenols, low FODMAP diet and nanotechnology application regulate the gut liver brain axis. Besides, some special treatments targeting gut-liver axis include farnesoid X receptor (FXR) agonists, takeda G protein-coupled receptor 5 (TGR5) agonists, glucagon-like peptide-1 (GLP-1) receptor antagonists and fibroblast growth factor 19 (FGF19) analogs. Targeting gut-brain axis embraces cognitive behavioral therapy (CBT), antidepressants and tryptophan metabolism-related therapies. Targeting liver-brain axis contains epigenetic regulation and Aβ metabolism-related therapies. In the future, a better understanding of gut-liver-brain axis interactions will promote the development of novel preventative strategies and the discovery of precise therapeutic targets in multiple diseases.
On exposure to cosmetic pollutants, gastrointestinal dysbiosis, which is characterised by a disturbance in the gut microbiota, has come into focus as a possible contributor to the occurrence of neurotoxic consequences. It is normal practice to use personal care products that include parabens, phthalates, sulphates, triclosans/triclocarbans and micro/nano plastics. These substances have been found in a variety of bodily fluids and tissues, demonstrating their systemic dispersion. Being exposed to these cosmetic pollutants has been linked in recent research to neurotoxicity, including cognitive decline and neurodevelopmental problems. A vital part of sustaining gut health and general well-being is the gut flora. Increased intestinal permeability, persistent inflammation, and impaired metabolism may result from disruption of the gut microbial environment, which may in turn contribute to neurotoxicity. The link between gastrointestinal dysbiosis and the neurotoxic effects brought on by cosmetic pollutants may be explained by a number of processes, primarily the gut-brain axis. For the purpose of creating preventative and therapeutic measures, it is crucial to comprehend the intricate interactions involving cosmetic pollutants, gastrointestinal dysbiosis, and neurotoxicity. This review provides an in-depth understanding of the various hazardous cosmetic pollutants and its potential role in the occurrence of neurological disorders via gastrointestinal dysbiosis, providing insights into various described and hypothetical mechanisms regarding the complex toxic effects of these industrial pollutants.
Ferumoxytol, approved by the U.S. Food and Drug Administration in 2009, is one of the intravenous iron oxide nanoparticles authorized for the treatment of iron deficiency in chronic kidney disease and end‐stage renal disease. With its exceptional magnetic properties, catalytic activity, and immune activity, as well as good biocompatibility and safety, ferumoxytol has gained significant recognition in various biomedical diagnoses and treatments. Unlike most existing reviews on this topic, this review primarily focuses on the recent clinical and preclinical advances of ferumoxytol in disease treatment, spanning anemia, cancer, infectious inflammatory diseases, regenerative medicine application, magnetic stimulation for neural modulation, etc. Additionally, the newly discovered mechanisms associated with the biological effects of ferumoxytol are discussed, including its magnetic, catalytic, and immunomodulatory properties. Finally, the summary and future prospects concerning the treatment and application of ferumoxytol‐based nanotherapeutics are presented.
The brainstem serves as an intermediary processor of haemodynamic sensations via nucleus tractus solitaries (NTS) in regulating circulatory system. After sensing visceral inputs, the NTS relays information to efferent pathways to modulate peripheral viscera. However, the neural computation mechanism underlying how the NTS processes viscerosensory input remains unknown. Here, we show the computational principles embedded inside the NTS of rats, producing haemodynamic modulation in concert. Our findings demonstrate that the collective dynamics leveraging from neuronal population within the NTS neural circuit encode input-driven haemodynamics. The NTS exhibits the neural trajectory, the dynamical trace of neural states, which is confined to low-dimensional latent space and may represent haemodynamic perturbations. Surprisingly, by normalizing neural trajectory of rats, we found the across-rat common rules for the viscerosensory-information processing by the NTS. Furthermore, the common rules allowed to identify inter-subject variable haemodynamics by quantifying the computational mechanisms in neuro-haemodynamic axis. Our findings provide pioneering insights into understanding the neural computation involved in regulation of visceral functions by the autonomic nervous system.
The communication between the gut and brain is crucial for regulating various essential physiological functions, such as energy balance, fluid homeostasis, immune response, and emotion. The vagal sensory pathway plays an indispensable role in connecting the gut to the brain. Recently, our knowledge of the vagal gut-brain axis has significantly advanced through molecular genetic studies, revealing a diverse range of vagal sensory cell types with distinct peripheral innervations, response profiles, and physiological functions. Here, we review the current understanding of how vagal sensory neurons contribute to gut-brain communication. First, we highlight recent transcriptomic and genetic approaches that have characterized different vagal sensory cell types. Then, we focus on discussing how different subtypes encode numerous gut-derived signals and how their activities are translated into physiological and behavioral regulations. The emerging insights into the diverse cell types and functional properties of vagal sensory neurons have paved the way for exciting future directions, which may provide valuable insights into potential therapeutic targets for disorders involving gut-brain communication.
The enteric nervous system is largely autonomous, and the central nervous system is compartmentalized behind the blood-brain barrier. Yet the intestinal microbiota shapes gut function, local and systemic immune responses, and central nervous system functions including cognition and mood. In this review, we address how the gut microbiota can profoundly influence neural and immune networks. Although many of the interactions between these three systems originate in the intestinal mucosa, intestinal function and immunity are modulated by neural pathways that connect the gut and brain. Furthermore, a subset of microbe-derived penetrant molecules enters the brain and regulates central nervous system function. Understanding how these seemingly isolated entities communicate has the potential to open up new avenues for therapies and interventions.
The gastrointestinal tract is in a state of constant motion. These movements are tightly regulated by the presence of food and help digestion by mechanically breaking down and propelling gut content. Mechanical sensing in the gut is thought to be essential for regulating motility; however, the identity of the neuronal populations, the molecules involved, and the functional consequences of this sensation are unknown. Here, we show that humans lacking PIEZO2 exhibit impaired bowel sensation and motility. Piezo2 in mouse dorsal root, but not nodose ganglia is required to sense gut content, and this activity slows down food transit rates in the stomach, small intestine, and colon. Indeed, Piezo2 is directly required to detect colon distension in vivo. Our study unveils the mechanosensory mechanisms that regulate the transit of luminal contents throughout the gut, which is a critical process to ensure proper digestion, nutrient absorption, and waste removal.
The vagus nerve, with its myriad constituent axon branches and innervation targets, has long been a model of anatomical complexity in the nervous system. The branched architecture of the vagus nerve is now appreciated to be highly organized around the topographic and/or molecular identities of the neurons that innervate each target tissue. However, we are only just beginning to understand the developmental mechanisms by which heterogeneous vagus neuron identity is specified, patterned, and used to guide the axons of particular neurons to particular targets. Here, we summarize our current understanding of the complex topographic and molecular organization of the vagus nerve, the developmental basis of neuron specification and patterned axon guidance that supports this organization, and the regenerative mechanisms that promote, or inhibit, the restoration of vagus nerve organization after nerve damage. Finally, we highlight key unanswered questions in these areas and discuss potential strategies to address these questions.
The vagal ganglia, comprised of the superior (jugular) and inferior (nodose) ganglia of the vagus nerve, receive somatosensory information from the head and neck, or viscerosensory information from the inner organs, respectively. Developmentally, the cranial neural crest gives rise to all vagal glial cells and to neurons of the jugular ganglia, while the epibranchial placode gives rise to neurons of the nodose ganglia. Crest-derived nodose glial progenitors can additionally generate autonomic neurons in the peripheral nervous system, but how these progenitors generate neurons is unknown. Here, we found that some Sox10+ neural crest-derived cells in, and surrounding, the nodose ganglion transiently expressed Phox2b, a master regulator of autonomic nervous system development, during early embryonic life. Our genetic lineage tracing analysis revealed that despite their common developmental origin and extreme spatial proximity a substantial proportion of glial cells in the nodose, but not in the neighboring jugular ganglia, have a history of Phox2b expression. Lastly, we used single cell RNA-sequencing (scRNA-seq) to demonstrate that these progenitors give rise to all major glial subtypes in the nodose ganglia, including Schwann cells, satellite glia and glial precursors, and mapped their spatial distribution by in situ hybridization. Our work demonstrates that these crest- derived nodose glial progenitors transiently express Phox2b, give rise to the entire complement of nodose glial cells and display a transcriptional program that may underlie their bipotent nature.
Significance statement
The nodose ganglia contain sensory neurons that innervate many inner organs and play key roles in homeostatic behaviors such as digestion, regulation of blood pressure and heart rate, and breathing. Nodose sensory neurons are supported by nodose glial cells, which are understudied compared to their neuronal neighbors. Specifically, the genetic program governing their development is not fully understood. Here, we uncover a transcriptional program unique to nodose glial cells (transient expression of Phox2b) that resolves the 40-year-old finding that nodose glial progenitors can also give rise to autonomic neurons (whose development depends on Phox2b expression). Lastly, we leveraged single cell RNA-sequencing to identify the four major subtypes of nodose glial cells and used subtype specific marker genes to map their spatial distribution.
Mechanosensation is the ability to detect dynamic mechanical stimuli (e.g., pressure, stretch, and shear stress) and is essential for a wide variety of processes, including our sense of touch on the skin. How touch is detected and transduced at the molecular level has proved to be one of the great mysteries of sensory biology. A major breakthrough occurred in 2010 with the discovery of a family of mechanically gated ion channels that were coined PIEZOs. The last 10 years of investigation have provided a wealth of information about the functional roles and mechanisms of these molecules. Here we focus on PIEZO2, one of the two PIEZO proteins found in humans and other mammals. We review how work at the molecular, cellular, and systems levels over the past decade has transformed our understanding of touch and led to unexpected insights into other types of mechanosensation beyond the skin.
Sensory neurons relay gut-derived signals to the brain, yet the molecular and functional organization of distinct populations remains unclear. Here, we employed intersectional genetic manipulations to probe the feeding and glucoregulatory function of distinct sensory neurons. We reconstruct the gut innervation patterns of numerous molecularly defined vagal and spinal afferents and identify their downstream brain targets. Bidirectional chemogenetic manipulations, coupled with behavioral and circuit mapping analysis, demonstrated that gut-innervating, glucagon-like peptide 1 receptor (GLP1R)-expressing vagal afferents relay anorexigenic signals to parabrachial nucleus neurons that control meal termination. Moreover, GLP1R vagal afferent activation improves glucose tolerance, and their inhibition elevates blood glucose levels independent of food intake. In contrast, gut-innervating, GPR65-expressing vagal afferent stimulation increases hepatic glucose production and activates parabrachial neurons that control normoglycemia, but they are dispensable for feeding regulation. Thus, distinct gut-innervating sensory neurons differentially control feeding and glucoregulatory neurocircuits and may provide specific targets for metabolic control.
Across animal species, meals are terminated after ingestion of large food volumes, yet underlying mechanosensory receptors have so far remained elusive. Here, we identify an essential role for Drosophila Piezo in volume-based control of meal size. We discover a rare population of fly neurons that express Piezo, innervate the anterior gut and crop (a food reservoir organ), and respond to tissue distension in a Piezo-dependent manner. Activating Piezo neurons decreases appetite, while Piezo knockout and Piezo neuron silencing cause gut bloating and increase both food consumption and body weight. These studies reveal that disrupting gut distension receptors changes feeding patterns, and identify a key role for Drosophila Piezo in internal organ mechanosensation.
The TGFβ cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted expression pattern of its receptor, GDNF Family Receptor α-like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake; we generated Gfral
Cre
and conditional Gfral
CreERT
mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating Gfral
Cre
-expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRPPBN) neurons. Silencing CGRPPBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated pathophysiologic signals to suppress nutrient uptake and absorption.
The carotid body (CB) is the main peripheral chemoreceptor for arterial respiratory gases O 2 and CO 2, and pH, eliciting reflex ventilatory, cardiovascular and humoral responses to maintain homeostasis. This review examines the fundamental biology underlying CB chemoreceptor function, its contribution to integrated physiologic responses, and its role in maintaining health and potentiating disease. Emphasis will be placed on: i) Transduction mechanisms in chemoreceptor (type I) cells, highlighting the role played by the hypoxic inhibition of O 2 -dependent K ⁺ channels and mitochondrial oxidative metabolism, and their modification by intracellular molecules and other ionic channels; ii) Synaptic mechanisms linking type I cells and petrosal nerve terminals, focusing on the role played by the main proposed transmitters and modulatory gases, and the participation of glial cells in regulation of the chemosensory process; iii) Integrated reflex responses to CB activation, emphasizing that the responses differ dramatically depending on the nature of the physiological, pathological or environmental challenges, and the interactions of the chemoreceptor reflex with other reflexes in optimizing oxygen delivery to the tissues; and iv) The contribution of enhanced CB chemosensory discharge to autonomic and cardiorespiratory pathophysiology in obstructive sleep apnea, congestive heart failure, resistant hypertension and metabolic diseases, and how modulation of enhanced CB reactivity in disease conditions may attenuate pathophysiology.
Background
The gut-brain axis, which mediates the bi-directional communication between the gastrointestinal system and the central nervous system (CNS), plays a fundamental role in multiple areas of physiology including regulation of appetite, metabolism, and gastrointestinal function. The biology of the gut-brain axis is central to the efficacy of glucagon-like peptide-1 (GLP-1) - based therapies, which are now leading treatments for type 2 diabetes (T2DM) and obesity. This success, and research to suggest a much broader role for gut-brain circuits in physiology and disease, has led to increasing interest in targeting such circuits for the discovery of new therapeutics. However, our current knowledge of this biology is limited, largely because the scientific tools have not been available to enable a detailed mechanistic understanding of gut-brain communication.
Scope of Review
In this review we will provide an overview of the current understanding of how sensory information from the gastrointestinal system is communicated to the central nervous system, with an emphasis on circuits involved in the regulation of feeding and metabolism. We will then describe how recent technologies are enabling a better understanding of this system at a molecular level, and how this information is leading to novel insights into gut-brain communication. Finally, we will discuss current therapeutic approaches which leverage the gut-brain axis for the treatment of diabetes, obesity, and related disorders, and describe potential novel approaches which have been enabled by recent advances in the field.
Major Conclusions
The gut-brain axis is intimately involved in the regulation of glucose homeostasis and appetite, and this system plays a key role in mediating the efficacy of therapeutics which have had a major impact on the treatment of T2DM and obesity. Research of the gut-brain axis has historically largely focused on the study of individual components of this system, but new technologies are now enabling a better understanding of how signals from these components are orchestrated to regulate metabolism. While this work reveals a complexity of signaling even greater than previously appreciated, new insights are already being leveraged to explore fundamentally new approaches to the treatment of metabolic diseases.
Connections between the gut and brain monitor the intestinal tissue and its microbial and dietary content¹, regulating both physiological intestinal functions such as nutrient absorption and motility2,3, and brain-wired feeding behaviour². It is therefore plausible that circuits exist to detect gut microorganisms and relay this information to areas of the central nervous system that, in turn, regulate gut physiology⁴. Here we characterize the influence of the microbiota on enteric-associated neurons by combining gnotobiotic mouse models with transcriptomics, circuit-tracing methods and functional manipulations. We find that the gut microbiome modulates gut-extrinsic sympathetic neurons: microbiota depletion leads to increased expression of the neuronal transcription factor cFos, and colonization of germ-free mice with bacteria that produce short-chain fatty acids suppresses cFos expression in the gut sympathetic ganglia. Chemogenetic manipulations, translational profiling and anterograde tracing identify a subset of distal intestine-projecting vagal neurons that are positioned to have an afferent role in microbiota-mediated modulation of gut sympathetic neurons. Retrograde polysynaptic neuronal tracing from the intestinal wall identifies brainstem sensory nuclei that are activated during microbial depletion, as well as efferent sympathetic premotor glutamatergic neurons that regulate gastrointestinal transit. These results reveal microbiota-dependent control of gut-extrinsic sympathetic activation through a gut–brain circuit.
Aims/hypothesisInsulin-like peptide-5 (INSL5) is found only in distal colonic L cells, which co-express glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). GLP-1 is a well-known insulin secretagogue, and GLP-1 and PYY are anorexigenic, whereas INSL5 is considered orexigenic. We aimed to clarify the metabolic impact of selective stimulation of distal colonic L cells in mice.Methods
Insl5 promoter-driven expression of Gq-coupled Designer Receptor Exclusively Activated by Designer Drugs (DREADD) was employed to activate distal colonic L cells (LdistalDq). IPGTT and food intake were assessed with and without DREADD activation.ResultsLdistalDq cell stimulation with clozapine N-oxide (CNO; 0.3 mg/kg i.p.) increased plasma GLP-1 and PYY (2.67- and 3.31-fold, respectively); INSL5 was not measurable in plasma but was co-secreted with GLP-1 and PYY in vitro. IPGTT (2 g/kg body weight) revealed significantly improved glucose tolerance following CNO injection. CNO-treated mice also exhibited reduced food intake and body weight after 24 h, and increased defecation, the latter being sensitive to 5-hydroxytryptamine (5-HT) receptor 3 inhibition. Pre-treatment with a GLP1 receptor-blocking antibody neutralised the CNO-dependent improvement in glucose tolerance but did not affect the reduction in food intake, and an independent group of animals pair-fed to the CNO-treatment group demonstrated attenuated weight loss. Pre-treatment with JNJ-31020028, a neuropeptide Y receptor type 2 antagonist, abolished the CNO-dependent effect on food intake. Assessment of whole body physiology in metabolic cages revealed LdistalDq cell stimulation increased energy expenditure and increased activity. Acute CNO-induced food intake and glucose homeostasis outcomes were maintained after 2 weeks on a high-fat diet.Conclusions/interpretationThis proof-of-concept study demonstrates that selective distal colonic L cell stimulation has beneficial metabolic outcomes.
Graphical abstract
The taste of sugar is one of the most basic sensory percepts for humans and other animals. Animals can develop a strong preference for sugar even if they lack sweet taste receptors, indicating a mechanism independent of taste1–3. Here we examined the neural basis for sugar preference and demonstrate that a population of neurons in the vagal ganglia and brainstem are activated via the gut–brain axis to create preference for sugar. These neurons are stimulated in response to sugar but not artificial sweeteners, and are activated by direct delivery of sugar to the gut. Using functional imaging we monitored activity of the gut–brain axis, and identified the vagal neurons activated by intestinal delivery of glucose. Next, we engineered mice in which synaptic activity in this gut-to-brain circuit was genetically silenced, and prevented the development of behavioural preference for sugar. Moreover, we show that co-opting this circuit by chemogenetic activation can create preferences to otherwise less-preferred stimuli. Together, these findings reveal a gut-to-brain post-ingestive sugar-sensing pathway critical for the development of sugar preference. In addition, they explain the neural basis for differences in the behavioural effects of sweeteners versus sugar, and uncover an essential circuit underlying the highly appetitive effects of sugar.
Mechanosensory feedback from the digestive tract to the brain is critical for limiting excessive food and water intake, but the underlying gut–brain communication pathways and mechanisms remain poorly understood1–12. Here we show that, in mice, neurons in the parabrachial nucleus that express the prodynorphin gene (hereafter, PBPdyn neurons) monitor the intake of both fluids and solids, using mechanosensory signals that arise from the upper digestive tract. Most individual PBPdyn neurons are activated by ingestion as well as the stimulation of the mouth and stomach, which indicates the representation of integrated sensory signals across distinct parts of the digestive tract. PBPdyn neurons are anatomically connected to the digestive periphery via cranial and spinal pathways; we show that, among these pathways, the vagus nerve conveys stomach-distension signals to PBPdyn neurons. Upon receipt of these signals, these neurons produce aversive and sustained appetite-suppressing signals, which discourages the initiation of feeding and drinking (fully recapitulating the symptoms of gastric distension) in part via signalling to the paraventricular hypothalamus. By contrast, inhibiting the same population of PBPdyn neurons induces overconsumption only if a drive for ingestion exists, which confirms that these neurons mediate negative feedback signalling. Our findings reveal a neural mechanism that underlies the mechanosensory monitoring of ingestion and negative feedback control of intake behaviours upon distension of the digestive tract. A population of neurons in the parabrachial nucleus that expresses prodynorphin monitors ingestion using mechanosensory signals from the upper digestive tract, and mediates negative feedback control of intake when the digestive tract is distended.
Postingestive nutrient sensing can induce food preferences. However, much less is known about the ability of postingestive signals to modulate food-seeking behaviors. Here we report a causal connection between postingestive sucrose sensing and vagus-mediated dopamine neuron activity in the ventral tegmental area (VTA), supporting food seeking. The activity of VTA dopamine neurons increases significantly after administration of intragastric sucrose, and deletion of the NMDA receptor in these neurons, which affects bursting and plasticity, abolishes lever pressing for postingestive sucrose delivery. Furthermore, lesions of the hepatic branch of the vagus nerve significantly impair postingestive-dependent VTA dopamine neuron activity and food seeking, whereas optogenetic stimulation of left vagus nerve neurons significantly increases VTA dopamine neuron activity. These data establish a necessary role of vagus-mediated dopamine neuron activity in postingestive-dependent food seeking, which is independent of taste signaling.
Mechanosensory neurons across physiological systems sense force using diverse terminal morphologies. Arterial baroreceptors are sensory neurons that monitor blood pressure for real-time stabilization of cardiovascular output. Various aortic sensory terminals have been described, but those that sense blood pressure are unclear because of a lack of selective genetic tools. Here, we find that all baroreceptor neurons are marked in Piezo2-ires-Cre mice and then use genetic approaches to visualize the architecture of mechanosensory endings. Cre-guided ablation of vagal and glossopharyngeal PIEZO2 neurons eliminates the baroreceptor reflex and aortic depressor nerve effects on blood pressure and heart rate. Genetic mapping reveals that PIEZO2 neurons form a distinctive mechanosensory structure: macroscopic claws that surround the aortic arch and exude fine end-net endings. Other arterial sensory neurons that form flower-spray terminals are dispensable for baroreception. Together, these findings provide structural insights into how blood pressure is sensed in the aortic vessel wall. : Min et al. use genetic approaches to reveal how neurons sense blood pressure. Elevated blood pressure evokes a classic neuronal reflex (the baroreceptor reflex), found here to require PIEZO2 neurons. To sense blood pressure, PIEZO2 neurons form large claws that surround the aorta and are decorated with mechanosensory endings. Keywords: vagus nerve, mechanosensation, petrosal ganglia, nodose ganglion, interoception, autonomic nervous system
Bronchopulmonary sensory neurons are derived from the vagal sensory ganglia and are essential for monitoring the physical and chemical environment of the airways and lungs. Subtypes are heterogenous in their responsiveness to stimuli, phenotype, and developmental origin, but they collectively serve to regulate normal respiratory and pulmonary processes and elicit a diverse range of defensive physiological responses that protect against noxious stimuli. In this study, we aimed to investigate the transcriptional features of vagal bronchopulmonary sensory neurons using single-cell RNA sequencing (scRNA-seq) to provide a deeper insight into their molecular profiles. Retrogradely labeled vagal sensory neurons projecting to the airways and lungs were hierarchically clustered into five types reflecting their developmental lineage (neural crest versus placodal) and putative function (nociceptors versus mechanoreceptors). The purinergic receptor subunit P2rx2 is known to display restricted expression in placodal-derived nodose neurons, and we demonstrate that the gene profiles defining cells high and low in expression of P2rx2 include G protein coupled receptors and ion channels, indicative of preferential expression in nodose or jugular neurons. Our results provide valuable insight into the transcriptional characteristics of bronchopulmonary sensory neurons and provide rational targets for future physiological investigations.
Sensory functions of the vagus nerve are critical for conscious perceptions and for monitoring visceral functions in the cardio-pulmonary and gastrointestinal systems. Here, we present a comprehensive identification, classification, and validation of the neuron types in the neural crest (jugular) and placode (nodose) derived vagal ganglia by single-cell RNA sequencing (scRNA-seq) transcriptomic analysis. Our results reveal major differences between neurons derived from different embryonic origins. Jugular neurons exhibit fundamental similarities to the somatosensory spinal neurons, including major types, such as C-low threshold mechanoreceptors (C-LTMRs), A-LTMRs, Aδ-nociceptors, and cold-, and mechano-heat C-nociceptors. In contrast, the nodose ganglion contains 18 distinct types dedicated to surveying the physiological state of the internal body. Our results reveal a vast diversity of vagal neuron types, including many previously unanticipated types, as well as proposed types that are consistent with chemoreceptors, nutrient detectors, baroreceptors, and stretch and volume mechanoreceptors of the respiratory, gastrointestinal, and cardiovascular systems.
Satiation is the process by which eating and drinking reduce appetite. For thirst, oropharyngeal cues have a critical role in driving satiation by reporting to the brain the volume of fluid that has been ingested1–12. By contrast, the mechanisms that relay the osmolarity of ingested fluids remain poorly understood. Here we show that the water and salt content of the gastrointestinal tract are precisely measured and then rapidly communicated to the brain to control drinking behaviour in mice. We demonstrate that this osmosensory signal is necessary and sufficient for satiation during normal drinking, involves the vagus nerve and is transmitted to key forebrain neurons that control thirst and vasopressin secretion. Using microendoscopic imaging, we show that individual neurons compute homeostatic need by integrating this gastrointestinal osmosensory information with oropharyngeal and blood-borne signals. These findings reveal how the fluid homeostasis system monitors the osmolarity of ingested fluids to dynamically control drinking behaviour. Drinking behaviour in mice is regulated by a signal derived from the water and salt content of the gastrointestinal tract that is transmitted to forebrain neurons that control thirst via the vagus nerve.
Significance
Intestinal tuft cells are sentinels monitoring the luminal contents and play a critical role in type 2 immunity. In this work, Trichinella spiralis excretion–secretion and extract were shown to directly induce interleukin 25 (IL-25) release from the intestinal villi, evoke calcium responses in tuft cells, and activate Tas2r bitter-taste receptors, whereas the bitter compound salicin was shown to activate and induce tuft cells to release IL-25. Gα-gustducin/Gβ1γ13 and/or Gαo/Gβ1γ13, Plcβ2, Ip 3 r2, and Trpm5 comprise the signal transduction pathways that tuft cells utilize to initiate type 2 immune responses. Potentiation of Trpm5 by a natural sweet compound, stevioside, can enhance the tuft cell–ILC2 circuit’s activity, indicating that modulating these signaling components can help devise new means of combating parasites.
Hypoxia resulting from reduced oxygen (O 2 ) levels in the arterial blood is sensed by the carotid body (CB) and triggers reflex stimulation of breathing and blood pressure to maintain homeostasis. Studies in the past five years provided novel insights into the roles of heme oxygenase-2 (HO-2), a carbon monoxide (CO)-producing enzyme, and NADH dehydrogenase Fe-S protein 2, a subunit of the mitochondrial complex I, in hypoxic sensing by the CB. HO-2 is expressed in type I cells, the primary O2-sensing cells of the CB, and binds to O 2 with low affinity. O 2 -dependent CO production from HO-2 mediates hypoxic response of the CB by regulating H 2 S generation. Mice lacking NDUFS2 show that complex I-generated reactive oxygen species acting on K ⁺ channels confer type I cell response to hypoxia. Whether these signaling pathways operate synergistically or independently remains to be studied.
Dissecting the gut-brain axis
It is generally believed that cells in the gut transduce sensory information through the paracrine action of hormones. Kaelberer et al. found that, in addition to the well-described classical paracrine transduction, enteroendocrine cells also form fast, excitatory synapses with vagal afferents (see the Perspective by Hoffman and Lumpkin). This more direct circuit for gut-brain signaling uses glutamate as a neurotransmitter. Thus, sensory cues that stimulate the gut could potentially be manipulated to influence specific brain functions and behavior, including those linked to food choices.
Science , this issue p. eaat5236 ; see also p. 1203
Significance
Mechanical forces are important for normal gastrointestinal tract function. The enterochromaffin cells in the gastrointestinal epithelium have been proposed, but not previously shown, to be specialized sensors that convert forces into serotonin release, and serotonin released from these cells is important for normal gastrointestinal secretion and motility. The findings in this study show that some enterochromaffin cells are indeed mechanosensitive, and that they use mechanosensitive Piezo2 channels to generate an ionic current that is critical for the intracellular Ca ²⁺ increase, serotonin release, and epithelial fluid secretion.
Mammalian adaptation to oxygen flux occurs at many levels, from shifts in cellular metabolism to physiological adaptations facilitated by the sympathetic nervous system and carotid body (CB). Interactions between differing forms of adaptive response to hypoxia, including transcriptional responses orchestrated by the Hypoxia Inducible transcription Factors (HIFs), are complex and clearly synergistic. We show here that there is an absolute developmental requirement for HIF-2α, one of the HIF isoforms, for growth and survival of oxygen sensitive glomus cells of the carotid body. The loss of these cells renders mice incapable of ventilatory responses to hypoxia, and this has striking effects on processes as diverse as arterial pressure regulation, exercise performance, and glucose homeostasis. We show that the expansion of the glomus cells is correlated with mTORC1 activation, and is functionally inhibited by rapamycin treatment. These findings demonstrate the central role played by HIF-2α in carotid body development, growth and function.
Lung-innervating nociceptor sensory neurons detect noxious or harmful stimuli and consequently protect organisms by mediating coughing, pain, and bronchoconstriction. However, the role of sensory neurons in pulmonary host defense is unclear. Here, we found that TRPV1⁺ nociceptors suppressed protective immunity against lethal Staphylococcus aureus pneumonia. Targeted TRPV1⁺-neuron ablation increased survival, cytokine induction, and lung bacterial clearance. Nociceptors suppressed the recruitment and surveillance of neutrophils, and altered lung γδ T cell numbers, which are necessary for immunity. Vagal ganglia TRPV1⁺ afferents mediated immunosuppression through release of the neuropeptide calcitonin gene–related peptide (CGRP). Targeting neuroimmunological signaling may be an effective approach to treat lung infections and bacterial pneumonia.
Objective
Integration of nutritional, microbial and inflammatory events along the gut-brain axis can alter bowel physiology and organism behaviour. Colonic sensory neurons activate reflex pathways and give rise to conscious sensation, but the diversity and division of function within these neurons is poorly understood. The identification of signalling pathways contributing to visceral sensation is constrained by a paucity of molecular markers. Here we address this by comprehensive transcriptomic profiling and unsupervised clustering of individual mouse colonic sensory neurons.
Design
Unbiased single-cell RNA-sequencing was performed on retrogradely traced mouse colonic sensory neurons isolated from both thoracolumbar (TL) and lumbosacral (LS) dorsal root ganglia associated with lumbar splanchnic and pelvic spinal pathways, respectively. Identified neuronal subtypes were validated by single-cell qRT-PCR, immunohistochemistry (IHC) and Ca²⁺-imaging.
Results
Transcriptomic profiling and unsupervised clustering of 314 colonic sensory neurons revealed seven neuronal subtypes. Of these, five neuronal subtypes accounted for 99% of TL neurons, with LS neurons almost exclusively populating the remaining two subtypes. We identify and classify neurons based on novel subtype-specific marker genes using single-cell qRT-PCR and IHC to validate subtypes derived from RNA-sequencing. Lastly, functional Ca²⁺-imaging was conducted on colonic sensory neurons to demonstrate subtype-selective differential agonist activation.
Conclusions
We identify seven subtypes of colonic sensory neurons using unbiased single-cell RNA-sequencing and confirm translation of patterning to protein expression, describing sensory diversity encompassing all modalities of colonic neuronal sensitivity. These results provide a pathway to molecular interrogation of colonic sensory innervation in health and disease, together with identifying novel targets for drug development.
Asthma, accompanied by lung inflammation, bronchoconstriction and airway hyper-responsiveness, is a significant public health burden. Here we report that Mas-related G protein-coupled receptors (Mrgprs) are expressed in a subset of vagal sensory neurons innervating the airway and mediates cholinergic bronchoconstriction and airway hyper-responsiveness. These findings provide insights into the neural mechanisms underlying the pathogenesis of asthma.
Sneezing is a vital respiratory reflex frequently associated with allergic rhinitis and viral respiratory infections. However, its neural circuit remains largely unknown. A sneeze-evoking region was discovered in both cat and human brainstems, corresponding anatomically to the central recipient zone of nasal sensory neurons. Therefore, we hypothesized that a neuronal population postsynaptic to nasal sensory neurons mediates sneezing in this region. By screening major presynaptic neurotransmitters/neuropeptides released by nasal sensory neurons, we found that neuromedin B (NMB) peptide is essential for signaling sneezing. Ablation of NMB-sensitive postsynaptic neurons in the sneeze-evoking region or deficiency in NMB receptor abolished the sneezing reflex. Remarkably, NMB-sensitive neurons further project to the caudal ventral respiratory group (cVRG). Chemical activation of NMB-sensitive neurons elicits action potentials in cVRG neurons and leads to sneezing behavior. Our study delineates a peptidergic pathway mediating sneezing, providing molecular insights into the sneezing reflex arc.
The vagus nerve innervates many organs, and most, if not all, of its motor fibers are cholinergic. However, no one knows its organizing principles—whether or not there are dedicated neurons with restricted targets that act as “labeled lines” to perform certain functions, including two opposing ones (gastric contraction versus relaxation). By performing unbiased transcriptional profiling of DMV cholinergic neurons, we discovered seven molecularly distinct subtypes of motor neurons. Then, by using subtype-specific Cre driver mice, we show that two of these subtypes exclusively innervate the glandular domain of the stomach where, remarkably, they contact different enteric neurons releasing functionally opposing neurotransmitters (acetylcholine versus nitric oxide). Thus, the vagus motor nerve communicates via genetically defined labeled lines to control functionally unique enteric neurons within discrete subregions of the gastrointestinal tract. This discovery reveals that the parasympathetic nervous system utilizes a striking division of labor to control autonomic function.
Given the crucial role of the gastrointestinal tract and associated organs in handling nutrient assimilation and metabolism, it has long been known that its communication with the brain is important for the control of ingestive behavior and body weight regulation. It is also clear that gut-brain communication is bidirectional and utilizes both rapid neural and slower humoral mechanisms and pathways. However, progress in understanding these mechanisms and leveraging them for the treatment of obesity and metabolic disease has been hindered by the enormous dimension of the gut mucosa, the complexity of the signaling systems, and lack of specific tools. With the ascent of modern neurobiological technology, our understanding of the role of vagal afferents in gut-brain communication has begun to change. The first function-specific populations of vagal afferents providing nutritional feedback as well as feed-forward signals have been identified with genetics-guided methodology, and it is hoped that extension of the methodology to other neural communication pathways will follow soon. Currently, efficient clinical leveraging of gut-brain communication to treat obesity and metabolic disease is limited to a few gut hormones, but a more complete understanding of function-specific and projection-specific neuronal populations should make it possible to develop selective and more effective neuromodulation approaches.
Food intake is tightly regulated by complex and coordinated gut-brain interactions. Nutrients rapidly modulate activity in key populations of hypothalamic neurons that regulate food intake, including hunger-sensitive agouti-related protein (AgRP)-expressing neurons. Because individual macronutrients engage specific receptors in the gut to communicate with the brain, we reasoned that macronutrients may utilize different pathways to reduce activity in AgRP neurons. Here, we revealed that AgRP neuron activity in hungry mice is inhibited by site-specific intestinal detection of different macronutrients. We showed that vagal gut-brain signaling is required for AgRP neuron inhibition by fat. In contrast, spinal gut-brain signaling relays the presence of intestinal glucose. Further, we identified glucose sensors in the intestine and hepatic portal vein that mediate glucose-dependent AgRP neuron inhibition. Therefore, distinct pathways are activated by individual macronutrients to inhibit AgRP neuron activity.
Glucagon-like peptide-1 (GLP-1) is produced in gut endocrine cells and in the brain, and acts through hormonal and neural pathways to regulate islet function, satiety, and gut motility, supporting development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. Classic notions of GLP-1 acting as a meal-stimulated hormone from the distal gut are challenged by data supporting production of GLP-1 in the endocrine pancreas, and by the importance of brain-derived GLP-1 in the control of neural activity. Moreover, attribution of direct vs. indirect actions of GLP-1 is difficult, as many tissue and cellular targets of GLP-1 action do not exhibit robust or detectable GLP-1R expression. Furthermore, reliable detection of the GLP-1R is technically challenging, highly method-dependent, and subject to misinterpretation. Here we revisit the actions of GLP-1, scrutinizing key concepts supporting gut vs. extra-intestinal GLP-1 synthesis and secretion. We discuss new insights refining cellular localization of GLP-1R expression and integrate recent data to refine our understanding of how and where GLP-1 acts to control inflammation, cardiovascular function, islet hormone secretion, gastric emptying, appetite, and body weight. These findings update our knowledge of cell types and mechanisms linking endogenous vs. pharmacological GLP-1 action to activation of the canonical GLP-1R, and the control of metabolic activity in multiple organs.
Nausea, the unpleasant sensation of visceral malaise, remains a mysterious process. The area postrema is implicated in some nausea responses and is anatomically privileged to detect blood-borne signals. To investigate nausea mechanisms, we built an area postrema cell atlas through single-nucleus RNA sequencing, revealing a few neuron types. Using mouse genetic tools for cell-specific manipulation, we discovered excitatory neurons that induce nausea-related behaviors, with one neuron type mediating aversion imposed by multiple poisons. Nausea-associated responses to agonists of identified area postrema receptors were observed and suppressed by targeted cell ablation and/or gene knockout. Anatomical mapping revealed a distributed network of long-range excitatory but not inhibitory projections with subtype-specific patterning. These studies reveal the basic organization of area postrema nausea circuitry and provide a framework toward understanding and therapeutically controlling nausea.
Animal feeding is controlled by external sensory cues and internal metabolic states. Does it also depend on enteric neurons that sense mechanical cues to signal fullness of the digestive tract? Here, we identify a group of piezo-expressing neurons innervating the Drosophila crop (the fly equivalent of the stomach) that monitor crop volume to avoid food overconsumption. These neurons reside in the pars intercerebralis (PI), a neuro-secretory center in the brain involved in homeostatic control, and express insulin-like peptides with well-established roles in regulating food intake and metabolism. Piezo knockdown in these neurons of wild-type flies phenocopies the food overconsumption phenotype of piezo-null mutant flies. Conversely, expression of either fly Piezo or mammalian Piezo1 in these neurons of piezo-null mutants suppresses the overconsumption phenotype. Importantly, Piezo+ neurons at the PI are activated directly by crop distension, thus conveying a rapid satiety signal along the "brain-gut axis" to control feeding.
A fundamental question of physiology is how gut-brain signaling stimulates appetite. While many studies have emphasized the importance of vagal afferents to the brain in inducing satiation, little is known about whether and how the vagal-mediated gut-brain pathway senses orexigenic signals and stimulates feeding. Here, we identified a previously uncharacterized population of fasting-activated catecholaminergic neurons in the nucleus of the solitary tract (NTS). After characterizing the anatomical complexity among NTS catecholaminergic neurons, we surprisingly found that activation of NTS epinephrine (ENTS) neurons co-expressing neuropeptide Y (NPY) stimulated feeding, whereas activation of NTS norepinephrine (NENTS) neurons suppressed feeding. Monosynaptic tracing/activation experiments then showed that these NTS neurons receive direct vagal afferents from nodose neurons. Moreover, activation of the vagal→NPY/ENTS neural circuit stimulated feeding. Our study reveals an orexigenic role of the vagal→NTS pathway in controlling feeding, thereby providing important insights about how gut-brain signaling regulates feeding behavior.
While autonomic ganglia have been extensively studied in rats instead of mice, there is renewed interest in the anatomy of the mouse autonomic nervous system. This study examined the prevalence and anatomical features of a cell bridge linking two autonomic ganglia of the neck, namely, the nodose ganglion (NG) and the superior cervical ganglion (SCG) in a cohort of C57BL/6J mice. We identified a cell bridge between the NG and the cranial pole of the SCG. This cell bridge was tubular‐shaped with an average length and width of 700 and 240 μm, respectively. The cell bridge was frequently unilateral and significantly more prevalent in the ganglionic masses from males (38%) than females (21%). On each of its extremities, it contained a mixed of vagal afferents and postganglionic sympathetic neurons. The two populations of neurons abruptly replaced each other in the middle of the cell bridge. We examined the mRNA expression for selected autonomic markers in samples of the NG with or without cell bridge. Our results indicated that the cell bridge was enriched in both markers of postganglionic sympathetic and vagal afferents neurons. Lastly, using FluoroGold microinjection into the NG, we found that the existence of a cell bridge may occasionally lead to the inadvertent contamination of the SCG. In summary, this study describes the anatomy of a cell bridge variant consisting of the fusion of the mouse NG and SCG. The practical implications of our observations are discussed with respect to studies of the mouse vagal afferents, an area of research of increasing popularity.
This article is protected by copyright. All rights reserved.
Sensory neurons initiate defensive reflexes that ensure airway integrity. Dysfunction of laryngeal neurons is life-threatening, causing pulmonary aspiration, dysphagia, and choking, yet relevant sensory pathways remain poorly understood. Here, we discover rare throat-innervating neurons (∼100 neurons/mouse) that guard the airways against assault. We used genetic tools that broadly cover a vagal/glossopharyngeal sensory neuron atlas to map, ablate, and control specific afferent populations. Optogenetic activation of vagal P2RY1 neurons evokes a coordinated airway defense program—apnea, vocal fold adduction, swallowing, and expiratory reflexes. Ablation of vagal P2RY1 neurons eliminates protective responses to laryngeal water and acid challenge. Anatomical mapping revealed numerous laryngeal terminal types, with P2RY1 neurons forming corpuscular endings that appose laryngeal taste buds. Epithelial cells are primary airway sentinels that communicate with second-order P2RY1 neurons through ATP. These findings provide mechanistic insights into airway defense and a general molecular/genetic roadmap for internal organ sensation by the vagus nerve.
The ability of the nervous system to sense environmental stimuli and to relay these signals to immune cells via neurotransmitters and neuropeptides is indispensable for effective immunity and tissue homeostasis. Depending on the tissue microenvironment and distinct drivers of a certain immune response, the same neuronal populations and neuro-mediators can exert opposing effects, promoting or inhibiting tissue immunity. Here, we review the current understanding of the mechanisms that underlie the complex interactions between the immune and the nervous systems in different tissues and contexts. We outline current gaps in knowledge and argue for the importance of considering infectious and inflammatory disease within a conceptual framework that integrates neuro-immune circuits both local and systemic, so as to better understand effective immunity to develop improved approaches to treat inflammation and disease.
Pulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis (Mtb), manifests with a persistent cough as both a primary symptom and mechanism of transmission. The cough reflex can be triggered by nociceptive neurons innervating the lungs, and some bacteria produce neuron-targeting molecules. However, how pulmonary Mtb infection causes cough remains undefined, and whether Mtb produces a neuron-activating, cough-inducing molecule is unknown. Here, we show that an Mtb organic extract activates nociceptive neurons in vitro and identify the Mtb glycolipid sulfolipid-1 (SL-1) as the nociceptive molecule. Mtb organic extracts from mutants lacking SL-1 synthesis cannot activate neurons in vitro or induce cough in a guinea pig model. Finally, Mtb-infected guinea pigs cough in a manner dependent on SL-1 synthesis. Thus, we demonstrate a heretofore unknown molecular mechanism for cough induction by a virulent human pathogen via its production of a complex lipid.
Acute cardiorespiratory responses to O2 deficiency are essential for physiological homeostasis. The prototypical acute O2-sensing organ is the carotid body, which contains glomus cells expressing K+ channels whose inhibition by hypoxia leads to transmitter release and activation of nerve fibers terminating in the brainstem respiratory center. The mechanism by which changes in O2 tension modulate ion channels has remained elusive. Glomus cells express genes encoding HIF2α (Epas1) and atypical mitochondrial subunits at high levels, and mitochondrial NADH and reactive oxygen species (ROS) accumulation during hypoxia provides the signal that regulates ion channels. We report that inactivation of Epas1 in adult mice resulted in selective abolition of glomus cell responsiveness to acute hypoxia and the hypoxic ventilatory response. Epas1 deficiency led to the decreased expression of atypical mitochondrial subunits in the carotid body, and genetic deletion of Cox4i2 mimicked the defective hypoxic responses of Epas1-null mice. These findings provide a mechanistic explanation for the acute O2 regulation of breathing, reveal an unanticipated role of HIF2α, and link acute and chronic adaptive responses to hypoxia.
Glucose is the essential energy source for the brain, whose deficit, triggered by energy deprivation or therapeutic agents, can be fatal. Increased appetite is the key behavioral defense against hypoglycemia; however, the central pathways involved are not well understood. Here, we describe a glucoprivic feeding pathway by tyrosine hydroxylase (TH)-expressing neurons from nucleus of solitary tract (NTS), which project densely to the hypothalamus and elicit feeding through bidirectional adrenergic modulation of agouti-related peptide (AgRP)- and proopiomelanocortin (POMC)-expressing neurons. Acute chemogenetic inhibition of arcuate nucleus (ARC)-projecting NTS TH neurons or their target, AgRP neurons, impaired glucoprivic feeding induced by 2-Deoxy-D-glucose (2DG) injection. Neuroanatomical tracing results suggested that ARC-projecting orexigenic NTS TH neurons are largely distinct from neighboring catecholamine neurons projecting to parabrachial nucleus (PBN) that promotes satiety. Collectively, we describe a circuit organization in which an ascending pathway from brainstem stimulates appetite through key hunger neurons in the hypothalamus in response to hypoglycemia.
Gut-innervating nociceptor sensory neurons respond to noxious stimuli by initiating protective responses including pain and inflammation; however, their role in enteric infections is unclear. Here, we find that nociceptor neurons critically mediate host defense against the bacterial pathogen Salmonella enterica serovar Typhimurium (STm). Dorsal root ganglia nociceptors protect against STm colonization, invasion, and dissemination from the gut. Nociceptors regulate the density of microfold (M) cells in ileum Peyer's patch (PP) follicle-associated epithelia (FAE) to limit entry points for STm invasion. Downstream of M cells, nociceptors maintain levels of segmentous filamentous bacteria (SFB), a gut microbe residing on ileum villi and PP FAE that mediates resistance to STm infection. TRPV1+ nociceptors directly respond to STm by releasing calcitonin gene-related peptide (CGRP), a neuropeptide that modulates M cells and SFB levels to protect against Salmonella infection. These findings reveal a major role for nociceptor neurons in sensing and defending against enteric pathogens.
Energy homeostasis requires precise measurement of the quantity and quality of ingested food. The vagus nerve innervates the gut and can detect diverse interoceptive cues, but the identity of the key sensory neurons and corresponding signals that regulate food intake remains unknown. Here, we use an approach for target-specific, single-cell RNA sequencing to generate a map of the vagal cell types that innervate the gastrointestinal tract. We show that unique molecular markers identify vagal neurons with distinct innervation patterns, sensory endings, and function. Surprisingly, we find that food intake is most sensitive to stimulation of mechanoreceptors in the intestine, whereas nutrient-activated mucosal afferents have no effect. Peripheral manipulations combined with central recordings reveal that intestinal mechanoreceptors, but not other cell types, potently and durably inhibit hunger-promoting AgRP neurons in the hypothalamus. These findings identify a key role for intestinal mechanoreceptors in the regulation of feeding.
The carotid body (CB) is an arterial chemoreceptor organ located in the carotid bifurcation and has a well-recognized role in cardiorespiratory regulation. The CB contains neurosecretory sensory cells (glomus cells), which release transmitters in response to hypoxia, hypercapnia, and acidemia to activate afferent sensory fibers terminating in the respiratory and autonomic brainstem centers. Knowledge of the physiology of the CB has progressed enormously in recent years. Herein we review advances concerning the organization and function of the cellular elements of the CB, with emphasis on the molecular mechanisms of acute oxygen sensing by glomus cells. We introduce the modern view of the CB as a multimodal integrated metabolic sensor and describe the properties of the CB stem cell niche, which support CB growth during acclimatization to chronic hypoxia. Finally, we discuss the increasing medical relevance of CB dysfunction and its potential impact on the mechanisms of disease.
Expected final online publication date for the Annual Review of Physiology, Volume 82 is February 10, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Analysis of human pathology led Braak to postulate that α-synuclein (α-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing α-synucleinopathy in the brain in a novel gut-to-brain α-syn transmission mouse model, where pathological α-syn preformed fibrils were injected into the duodenal and pyloric muscularis layer. Spread of pathologic α-syn in brain, as assessed by phosphorylation of serine 129 of α-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain, including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons and motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and α-syn deficiency prevented the gut-to-brain spread of α-synucleinopathy and associated neurodegeneration and behavioral deficits. This study supports the Braak hypothesis in the etiology of idiopathic Parkinson's disease (PD).
Gut hormones have many key roles in the control of metabolism, as they target diverse tissues involved in the control of intestinal function, insulin secretion, nutrient assimilation and food intake. Produced by scattered cells found along the length of the intestinal epithelium, gut hormones generate signals related to the rate of nutrient absorption, the composition of the luminal milieu and the integrity of the epithelial barrier. Gut hormones already form the basis for existing and developing therapeutics for type 2 diabetes mellitus and obesity, exemplified by the licensed glucagon-like peptide 1 (GLP1) mimetics and dipeptidyl peptidase inhibitors that enhance GLP1 receptor activation. Modulating the release of the endogenous stores of GLP1 and other gut hormones is thought to be a promising strategy to mimic bariatric surgery with its multifaceted beneficial effects on food intake, body weight and blood glucose levels. This Review focuses on the molecular mechanisms underlying the modulation of gut hormone release by food ingestion, obesity and the gut microbiota. Depending on the nature of the stimulus, release of gut hormones involves recruitment of a variety of signalling pathways, including G protein-coupled receptors, nutrient transporters and ion channels, which are targets for future therapeutics for diabetes mellitus and obesity.
Homeostatic regulation of the intestinal enteroendocrine lineage hierarchy is a poorly understood process. We resolved transcriptional changes during enteroendocrine differentiation in real time at single-cell level using a novel knockin allele of Neurog3, the master regulator gene briefly expressed at the onset of enteroendocrine specification. A bi-fluorescent reporter, Neurog3Chrono, measures time from the onset of enteroendocrine differentiation and enables precise positioning of single-cell transcriptomes along an absolute time axis. This approach yielded a definitive description of the enteroendocrine hierarchy and its sub-lineages, uncovered differential kinetics between sub-lineages, and revealed time-dependent hormonal plasticity in enterochromaffin and L cells. The time-resolved map of transcriptional changes predicted multiple novel molecular regulators. Nine of these were validated by conditional knockout in mice or CRISPR modification in intestinal organoids. Six novel candidate regulators (Sox4, Rfx6, Tox3, Myt1, Runx1t1, and Zcchc12) yielded specific enteroendocrine phenotypes. Our time-resolved single-cell transcriptional map presents a rich resource to unravel enteroendocrine differentiation. The hierarchical lineage of intestinal enteroendocrine cells is defined at a spatiotemporal single-cell manner and validated using organoid and in vivo models.
Background
Although sensory feedback is a vital regulator of deglutition, it is not comprehensively considered in the standard dysphagia evaluation. Difficulty swallowing secondary to sensory loss may be termed “sensory dysphagia” and may account for cases receiving diagnoses of exclusion, like functional or idiopathic dysphagia.
Methods and Results
Three cases of idiopathic dysphagia were suspected to have sensory dysphagia. The patients had (1) effortful swallowing, (2) globus sensation, and (3) aspiration. Endoscopic sensory mapping revealed laryngopharyngeal sensory loss. Despite normal laryngeal motor function during voluntary maneuvers, laryngeal closure was incomplete during swallowing. The causes of sensory loss were identified: cranial neuropathy from Chiari malformation, immune‐mediated neuronopathy, and nerve damage from prior traumatic intubation.
Conclusions
Sensory loss may cause dysphagia without primary motor dysfunction. Sensory dysphagia should be classified as a distinct form of swallowing motility disorder to improve diagnosis. Increasing awareness and developing appropriate assessment tools may advance dysphagia care.
Heart rate and blood pressure control
PIEZO1 and PIEZO2 are two mechanically activated ion channels that are highly expressed in lungs, bladder, and skin. Zeng et al. found that both ion channels are expressed in sensory neurons of a ganglion complex that contribute to the baroreflex, a homeostatic mechanism that helps to keep blood pressure stable (see the Perspective by Ehmke). Conditional double knockout of PIEZO1 and PIEZO2 in these neurons abolished the baroreflex and disrupted blood pressure regulation and heart rates in mice. These changes were very similar to those seen in patients with baroreflex failure. In mice, selective activation of PIEZO2-expressing ganglion neurons triggered immediate increases in heart rate and blood pressure.
Science , this issue p. 464 ; see also p. 398
The gut is now recognized as a major regulator of motivational and emotional states. However, the relevant gut-brain neuronal circuitry remains unknown. We show that optical activation of gut-innervating vagal sensory neurons recapitulates the hallmark effects of stimulating brain reward neurons. Specifically, right, but not left, vagal sensory ganglion activation sustained self-stimulation behavior, conditioned both flavor and place preferences, and induced dopamine release from Substantia nigra. Cell-specific transneuronal tracing revealed asymmetric ascending pathways of vagal origin throughout the CNS. In particular, transneuronal labeling identified the glutamatergic neurons of the dorsolateral parabrachial region as the obligatory relay linking the right vagal sensory ganglion to dopamine cells in Substantia nigra. Consistently, optical activation of parabrachio-nigral projections replicated the rewarding effects of right vagus excitation. Our findings establish the vagal gut-to-brain axis as an integral component of the neuronal reward pathway. They also suggest novel vagal stimulation approaches to affective disorders.
The regulation of energy and glucose balance contributes to whole-body metabolic homeostasis, and such metabolic regulation is disrupted in obesity and diabetes. Metabolic homeostasis is orchestrated partly in response to nutrient and vagal-dependent gut-initiated functions. Specifically, the sensory and motor fibres of the vagus nerve transmit intestinal signals to the central nervous system and exert biological and physiological responses. In the past decade, the understanding of the regulation of vagal afferent signals and of the associated metabolic effect on whole-body energy and glucose balance has progressed. This Review highlights the contributions made to the understanding of the vagal afferent system and examines the integrative role of the vagal afferent in gastrointestinal regulation of appetite and glucose homeostasis. Investigating the integrative and metabolic role of vagal afferent signalling represents a potential strategy to discover novel therapeutic targets to restore energy and glucose balance in diabetes and obesity.
Many internal organs change volume periodically. For example, the stomach accommodates ingested food and drink, the bladder stores urine, the heart fills with blood, and the lungs expand with every breath. Specialized peripheral sensory neurons function as mechanoreceptors that detect tissue stretch to infer changes in organ volume and then relay this information to the brain. Central neural circuits process this information and evoke perceptions (satiety, nausea), control physiology (breathing, heart rate), and impact behavior (feeding, micturition). Yet, basic questions remain about how neurons sense organ distension and whether common sensory motifs are involved across organs. Here, we review candidate mechanosensory receptors, cell types, and neural circuits, focusing on the stomach, bladder, and airways. Understanding mechanisms of organ stretch sensation may provide new ways to treat autonomic dysfunction.
The small intestinal tuft cell-ILC2 circuit mediates epithelial responses to intestinal helminths and protists by tuft cell chemosensory-like sensing and IL-25-mediated activation of lamina propria ILC2s. Small intestine ILC2s constitutively express the IL-25 receptor, which is negatively regulated by A20 (Tnfaip3). A20 deficiency in ILC2s spontaneously triggers the circuit and, unexpectedly, promotes adaptive small-intestinal lengthening and remodeling. Circuit activation occurs upon weaning and is enabled by dietary polysaccharides that render mice permissive for Tritrichomonas colonization, resulting in luminal accumulation of acetate and succinate, metabolites of the protist hydrogenosome. Tuft cells express GPR91, the succinate receptor, and dietary succinate, but not acetate, activates ILC2s via a tuft-, TRPM5-, and IL-25-dependent pathway. Also induced by parasitic helminths, circuit activation and small intestinal remodeling impairs infestation by new helminths, consistent with the phenomenon of concomitant immunity. We describe a metabolic sensing circuit that may have evolved to facilitate mutualistic responses to luminal pathosymbionts.
Communication between the gut and brain is critical for homeostasis, but how this communication is represented in the dynamics of feeding circuits is unknown. Here we describe nutritional regulation of key neurons that control hunger in vivo. We show that intragastric nutrient infusion rapidly and durably inhibits hunger-promoting AgRP neurons in awake, behaving mice. This inhibition is proportional to the number of calories infused but surprisingly independent of macronutrient identity or nutritional state. We show that three gastrointestinal signals-serotonin, CCK, and PYY-are necessary or sufficient for these effects. In contrast, the hormone leptin has no acute effect on dynamics of these circuits or their sensory regulation but instead induces a slow modulation that develops over hours and is required for inhibition of feeding. These findings reveal how layers of visceral signals operating on distinct timescales converge on hypothalamic feeding circuits to generate a central representation of energy balance.