RESUMO
After ingestion of toxin-contaminated food, the brain initiates a series of defensive responses (e.g., nausea, retching, and vomiting). How the brain detects ingested toxin and coordinates diverse defensive responses remains poorly understood. Here, we developed a mouse-based paradigm to study defensive responses induced by bacterial toxins. Using this paradigm, we identified a set of molecularly defined gut-to-brain and brain circuits that jointly mediate toxin-induced defensive responses. The gut-to-brain circuit consists of a subset of Htr3a+ vagal sensory neurons that transmit toxin-related signals from intestinal enterochromaffin cells to Tac1+ neurons in the dorsal vagal complex (DVC). Tac1+ DVC neurons drive retching-like behavior and conditioned flavor avoidance via divergent projections to the rostral ventral respiratory group and lateral parabrachial nucleus, respectively. Manipulating these circuits also interferes with defensive responses induced by the chemotherapeutic drug doxorubicin. These results suggest that food poisoning and chemotherapy recruit similar circuit modules to initiate defensive responses.
Assuntos
Eixo Encéfalo-Intestino , Núcleos Parabraquiais , Nervo Vago , Animais , Camundongos , Neurônios/fisiologia , Neurônios Aferentes/fisiologia , Nervo Vago/fisiologiaRESUMO
Recent events bring the importance of respiratory health to the forefront of our collective attention. In this issue of Cell, a new study by Prescott and Umans et al. reveals how a dedicated laryngeal sensory motor reflex circuit protects our airways from aspirated foods or liquids.
Assuntos
Laringe , Nervo Vago , ReflexoRESUMO
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 (â¼100 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.
Assuntos
Nervo Glossofaríngeo/fisiologia , Faringe/inervação , Nervo Vago/fisiologia , Vias Aferentes , Animais , Feminino , Regulação da Expressão Gênica/genética , Nervo Glossofaríngeo/metabolismo , Laringe/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Purinérgicos P2Y1/genética , Receptores Purinérgicos P2Y1/metabolismo , Células Receptoras Sensoriais/metabolismo , Nervo Vago/metabolismoRESUMO
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.
Assuntos
Comportamento Alimentar/fisiologia , Fenômenos Genéticos , Células Receptoras Sensoriais/fisiologia , Nervo Vago/fisiologia , Proteína Relacionada com Agouti/metabolismo , Animais , Encéfalo/fisiologia , Trato Gastrointestinal/inervação , Marcadores Genéticos , Mecanorreceptores/metabolismo , Camundongos , Nervo Vago/anatomia & histologia , Vísceras/inervaçãoRESUMO
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.
Assuntos
Intestinos/fisiologia , Recompensa , Substância Negra/fisiologia , Nervo Vago/fisiologia , Vias Aferentes/metabolismo , Vias Aferentes/fisiologia , Animais , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Ácido Glutâmico/metabolismo , Intestinos/inervação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , OptogenéticaRESUMO
Neural inputs from internal organs are essential for normal autonomic function. The vagus nerve is a key body-brain connection that monitors the digestive, cardiovascular, and respiratory systems. Within the gastrointestinal tract, vagal sensory neurons detect gut hormones and organ distension. Here, we investigate the molecular diversity of vagal sensory neurons and their roles in sensing gastrointestinal inputs. Genetic approaches allowed targeted investigation of gut-to-brain afferents involved in homeostatic responses to ingested nutrients (GPR65 neurons) and mechanical distension of the stomach and intestine (GLP1R neurons). Optogenetics, in vivo ganglion imaging, and genetically guided anatomical mapping provide direct links between neuron identity, peripheral anatomy, central anatomy, conduction velocity, response properties in vitro and in vivo, and physiological function. These studies clarify the roles of vagal afferents in mediating particular gut hormone responses. Moreover, genetic control over gut-to-brain neurons provides a molecular framework for understanding neural control of gastrointestinal physiology.
Assuntos
Vias Neurais , Neurônios/metabolismo , Células Receptoras Sensoriais/metabolismo , Nervo Vago/metabolismo , Animais , Gânglios/metabolismo , Motilidade Gastrointestinal , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Camundongos , Optogenética , Receptores Acoplados a Proteínas G/metabolismo , Serotonina/metabolismo , Estômago/inervaçãoRESUMO
Breathing is essential for survival and under precise neural control. The vagus nerve is a major conduit between lung and brain required for normal respiration. Here, we identify two populations of mouse vagus nerve afferents (P2ry1, Npy2r), each a few hundred neurons, that exert powerful and opposing effects on breathing. Genetically guided anatomical mapping revealed that these neurons densely innervate the lung and send long-range projections to different brainstem targets. Npy2r neurons are largely slow-conducting C fibers, while P2ry1 neurons are largely fast-conducting A fibers that contact pulmonary endocrine cells (neuroepithelial bodies). Optogenetic stimulation of P2ry1 neurons acutely silences respiration, trapping animals in exhalation, while stimulating Npy2r neurons causes rapid, shallow breathing. Activating P2ry1 neurons did not impact heart rate or gastric pressure, other autonomic functions under vagal control. Thus, the vagus nerve contains intermingled sensory neurons constituting genetically definable labeled lines with different anatomical connections and physiological roles.
Assuntos
Respiração , Células Receptoras Sensoriais/fisiologia , Nervo Vago/citologia , Animais , Tronco Encefálico/fisiologia , Pulmão/inervação , Camundongos , Receptores Acoplados a Proteínas G/metabolismo , Células Receptoras Sensoriais/citologia , Nervo Vago/fisiologiaRESUMO
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.
Assuntos
Encéfalo , Citocinas , Inflamação , Neuroimunomodulação , Animais , Feminino , Masculino , Camundongos , Encéfalo/citologia , Encéfalo/imunologia , Encéfalo/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Neuroimunomodulação/imunologia , Neuroimunomodulação/fisiologia , Neurônios/fisiologia , Nervo Vago/citologia , Nervo Vago/fisiologia , Análise da Expressão Gênica de Célula ÚnicaRESUMO
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.
Assuntos
Pulmão , Reflexo , Respiração , Mecânica Respiratória , Nervo Vago , Animais , Feminino , Masculino , Camundongos , Células Epiteliais/metabolismo , Pulmão/citologia , Pulmão/inervação , Pulmão/fisiologia , Mecanorreceptores/metabolismo , Parvalbuminas/metabolismo , Reflexo/fisiologia , Células Receptoras Sensoriais/metabolismo , Nervo Vago/fisiologia , Complacência Pulmonar/fisiologia , Mecânica Respiratória/fisiologiaRESUMO
Exaggerated airway constriction triggered by repeated exposure to allergen, also called hyperreactivity, is a hallmark of asthma. Whereas vagal sensory neurons are known to function in allergen-induced hyperreactivity1-3, the identity of downstream nodes remains poorly understood. Here we mapped a full allergen circuit from the lung to the brainstem and back to the lung. Repeated exposure of mice to inhaled allergen activated the nuclei of solitary tract (nTS) neurons in a mast cell-, interleukin-4 (IL-4)- and vagal nerve-dependent manner. Single-nucleus RNA sequencing, followed by RNAscope assay at baseline and allergen challenges, showed that a Dbh+ nTS population is preferentially activated. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted hyperreactivity whereas chemogenetic activation promoted it. Viral tracing indicated that Dbh+ nTS neurons project to the nucleus ambiguus (NA) and that NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that directly drive airway constriction. Delivery of noradrenaline antagonists to the NA blunted hyperreactivity, suggesting noradrenaline as the transmitter between Dbh+ nTS and NA. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. This knowledge informs how neural modulation could be used to control allergen-induced airway hyperreactivity.
Assuntos
Alérgenos , Tronco Encefálico , Hiper-Reatividade Brônquica , Dopamina beta-Hidroxilase , Pulmão , Neurônios , Animais , Feminino , Masculino , Camundongos , Alérgenos/imunologia , Asma/imunologia , Asma/fisiopatologia , Tronco Encefálico/citologia , Tronco Encefálico/fisiologia , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Interleucina-4/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/inervação , Pulmão/fisiopatologia , Mastócitos/imunologia , Neurônios/enzimologia , Neurônios/fisiologia , Norepinefrina/antagonistas & inibidores , Norepinefrina/metabolismo , Núcleo Solitário/citologia , Núcleo Solitário/fisiologia , Nervo Vago/citologia , Nervo Vago/fisiologia , Bulbo/citologia , Bulbo/efeitos dos fármacos , Gânglios Autônomos/citologia , Dopamina beta-Hidroxilase/metabolismoRESUMO
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.
Assuntos
Coração , Reflexo , Células Receptoras Sensoriais , Síncope , Nervo Vago , Humanos , Área Postrema , Bradicardia/complicações , Bradicardia/fisiopatologia , Baixo Débito Cardíaco/complicações , Baixo Débito Cardíaco/fisiopatologia , Ecocardiografia , Coração/fisiologia , Frequência Cardíaca , Hipotensão/complicações , Hipotensão/fisiopatologia , Fluxometria por Laser-Doppler , Rede Nervosa , Reflexo/fisiologia , Células Receptoras Sensoriais/fisiologia , Análise da Expressão Gênica de Célula Única , Síncope/complicações , Síncope/etiologia , Nervo Vago/citologia , Nervo Vago/fisiologiaRESUMO
Guided by sight, scent, texture, and taste, animals ingest food. Once ingested, it is up to the gut to make sense of the food's nutritional value. Classic sensory systems rely on neuroepithelial circuits to convert stimuli into signals that guide behavior. However, sensation of the gut milieu was thought to be mediated only by the passive release of hormones until the discovery of synapses in enteroendocrine cells. These are gut sensory epithelial cells, and those that form synapses are referred to as neuropod cells. Neuropod cells provide the foundation for the gut to transduce sensory signals from the intestinal milieu to the brain through fast neurotransmission onto neurons, including those of the vagus nerve. These findings have sparked a new field of exploration in sensory neurobiology-that of gut-brain sensory transduction.
Assuntos
Encéfalo/fisiologia , Células Enteroendócrinas/fisiologia , Sinapses/fisiologia , Nervo Vago/fisiologia , Animais , Humanos , Neurônios/fisiologia , Transdução de Sinais/fisiologiaRESUMO
The perception of fat evokes strong appetitive and consummatory responses1. Here we show that fat stimuli can induce behavioural attraction even in the absence of a functional taste system2,3. We demonstrate that fat acts after ingestion via the gut-brain axis to drive preference for fat. Using single-cell data, we identified the vagal neurons responding to intestinal delivery of fat, and showed that genetic silencing of this gut-to-brain circuit abolished the development of fat preference. Next, we compared the gut-to-brain pathways driving preference for fat versus sugar4, and uncovered two parallel systems, one functioning as a general sensor of essential nutrients, responding to intestinal stimulation with sugar, fat and amino acids, whereas the other is activated only by fat stimuli. Finally, we engineered mice lacking candidate receptors to detect the presence of intestinal fat, and validated their role as the mediators of gut-to-brain fat-evoked responses. Together, these findings reveal distinct cells and receptors that use the gut-brain axis as a fundamental conduit for the development of fat preference.
Assuntos
Eixo Encéfalo-Intestino , Encéfalo , Preferências Alimentares , Intestinos , Neurônios , Animais , Camundongos , Aminoácidos/metabolismo , Encéfalo/citologia , Encéfalo/fisiologia , Neurônios/metabolismo , Açúcares/metabolismo , Nervo Vago/citologia , Nervo Vago/fisiologia , Preferências Alimentares/fisiologia , Análise de Célula Única , Eixo Encéfalo-Intestino/genética , Eixo Encéfalo-Intestino/fisiologia , Intestinos/inervação , Intestinos/metabolismoRESUMO
Ingested food and water stimulate sensory systems in the oropharyngeal and gastrointestinal areas before absorption1,2. These sensory signals modulate brain appetite circuits in a feed-forward manner3-5. Emerging evidence suggests that osmolality sensing in the gut rapidly inhibits thirst neurons upon water intake. Nevertheless, it remains unclear how peripheral sensory neurons detect visceral osmolality changes, and how they modulate thirst. Here we use optical and electrical recording combined with genetic approaches to visualize osmolality responses from sensory ganglion neurons. Gut hypotonic stimuli activate a dedicated vagal population distinct from mechanical-, hypertonic- or nutrient-sensitive neurons. We demonstrate that hypotonic responses are mediated by vagal afferents innervating the hepatic portal area (HPA), through which most water and nutrients are absorbed. Eliminating sensory inputs from this area selectively abolished hypotonic but not mechanical responses in vagal neurons. Recording from forebrain thirst neurons and behavioural analyses show that HPA-derived osmolality signals are required for feed-forward thirst satiation and drinking termination. Notably, HPA-innervating vagal afferents do not sense osmolality itself. Instead, these responses are mediated partly by vasoactive intestinal peptide secreted after water ingestion. Together, our results reveal visceral hypoosmolality as an important vagal sensory modality, and that intestinal osmolality change is translated into hormonal signals to regulate thirst circuit activity through the HPA pathway.
Assuntos
Intestinos , Saciação , Células Receptoras Sensoriais , Sede , Gânglios Sensitivos/citologia , Intestinos/citologia , Intestinos/inervação , Concentração Osmolar , Pressão Osmótica , Saciação/fisiologia , Células Receptoras Sensoriais/citologia , Sede/fisiologia , Nervo Vago/citologia , Nervo Vago/fisiologia , Água/metabolismoRESUMO
Interoception, the ability to timely and precisely sense changes inside the body, is critical for survival1-4. Vagal sensory neurons (VSNs) form an important body-to-brain connection, navigating visceral organs along the rostral-caudal axis of the body and crossing the surface-lumen axis of organs into appropriate tissue layers5,6. The brain can discriminate numerous body signals through VSNs, but the underlying coding strategy remains poorly understood. Here we show that VSNs code visceral organ, tissue layer and stimulus modality-three key features of an interoceptive signal-in different dimensions. Large-scale single-cell profiling of VSNs from seven major organs in mice using multiplexed projection barcodes reveals a 'visceral organ' dimension composed of differentially expressed gene modules that code organs along the body's rostral-caudal axis. We discover another 'tissue layer' dimension with gene modules that code the locations of VSN endings along the surface-lumen axis of organs. Using calcium-imaging-guided spatial transcriptomics, we show that VSNs are organized into functional units to sense similar stimuli across organs and tissue layers; this constitutes a third 'stimulus modality' dimension. The three independent feature-coding dimensions together specify many parallel VSN pathways in a combinatorial manner and facilitate the complex projection of VSNs in the brainstem. Our study highlights a multidimensional coding architecture of the mammalian vagal interoceptive system for effective signal communication.
Assuntos
Percepção , Psicofisiologia , Nervo Vago , Órgão Vomeronasal , Animais , Encéfalo/metabolismo , Cálcio/metabolismo , Mamíferos/metabolismo , Camundongos , Células Receptoras Sensoriais/metabolismoRESUMO
The nervous system uses various coding strategies to process sensory inputs. For example, the olfactory system uses large receptor repertoires and is wired to recognize diverse odours, whereas the visual system provides high acuity of object position, form and movement1-5. Compared to external sensory systems, principles that underlie sensory processing by the interoceptive nervous system remain poorly defined. Here we developed a two-photon calcium imaging preparation to understand internal organ representations in the nucleus of the solitary tract (NTS), a sensory gateway in the brainstem that receives vagal and other inputs from the body. Focusing on gut and upper airway stimuli, we observed that individual NTS neurons are tuned to detect signals from particular organs and are topographically organized on the basis of body position. Moreover, some mechanosensory and chemosensory inputs from the same organ converge centrally. Sensory inputs engage specific NTS domains with defined locations, each containing heterogeneous cell types. Spatial representations of different organs are further sharpened in the NTS beyond what is achieved by vagal axon sorting alone, as blockade of brainstem inhibition broadens neural tuning and disorganizes visceral representations. These findings reveal basic organizational features used by the brain to process interoceptive inputs.
Assuntos
Tronco Encefálico , Sensação , Tronco Encefálico/anatomia & histologia , Tronco Encefálico/citologia , Tronco Encefálico/fisiologia , Cálcio/metabolismo , Postura/fisiologia , Sensação/fisiologia , Células Receptoras Sensoriais/fisiologia , Núcleo Solitário/anatomia & histologia , Núcleo Solitário/citologia , Núcleo Solitário/fisiologia , Nervo Vago/fisiologiaRESUMO
Somatosensory autonomic reflexes allow electroacupuncture stimulation (ES) to modulate body physiology at distant sites1-6 (for example, suppressing severe systemic inflammation6-9). Since the 1970s, an emerging organizational rule about these reflexes has been the presence of body-region specificity1-6. For example, ES at the hindlimb ST36 acupoint but not the abdominal ST25 acupoint can drive the vagal-adrenal anti-inflammatory axis in mice10,11. The neuroanatomical basis of this somatotopic organization is, however, unknown. Here we show that PROKR2Cre-marked sensory neurons, which innervate the deep hindlimb fascia (for example, the periosteum) but not abdominal fascia (for example, the peritoneum), are crucial for driving the vagal-adrenal axis. Low-intensity ES at the ST36 site in mice with ablated PROKR2Cre-marked sensory neurons failed to activate hindbrain vagal efferent neurons or to drive catecholamine release from adrenal glands. As a result, ES no longer suppressed systemic inflammation induced by bacterial endotoxins. By contrast, spinal sympathetic reflexes evoked by high-intensity ES at both ST25 and ST36 sites were unaffected. We also show that optogenetic stimulation of PROKR2Cre-marked nerve terminals through the ST36 site is sufficient to drive the vagal-adrenal axis but not sympathetic reflexes. Furthermore, the distribution patterns of PROKR2Cre nerve fibres can retrospectively predict body regions at which low-intensity ES will or will not effectively produce anti-inflammatory effects. Our studies provide a neuroanatomical basis for the selectivity and specificity of acupoints in driving specific autonomic pathways.
Assuntos
Glândulas Suprarrenais/fisiologia , Sistema Nervoso Autônomo , Eletroacupuntura , Nervo Vago/fisiologia , Pontos de Acupuntura , Animais , Membro Posterior/inervação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , ReflexoRESUMO
Multiple sclerosis (MS) is a demyelinating central nervous system (CNS) disorder that is associated with functional impairment and accruing disability. There are multiple U.S. Food and Drug Administration (FDA)-approved drugs that effectively dampen inflammation and slow disability progression. However, these agents do not work well for all patients and are associated with side effects that may limit their use. The vagus nerve (VN) provides a direct communication conduit between the CNS and the periphery, and modulation of the inflammatory reflex via electrical stimulation of the VN (VNS) shows efficacy in ameliorating pathology in several CNS and autoimmune disorders. We therefore investigated the impact of VNS in a rat experimental autoimmune encephalomyelitis (EAE) model of MS. In this study, VNS-mediated neuroimmune modulation is demonstrated to effectively decrease EAE disease severity and duration, infiltration of neutrophils and pathogenic lymphocytes, myelin damage, blood-brain barrier disruption, fibrinogen deposition, and proinflammatory microglial activation. VNS modulates expression of genes that are implicated in MS pathogenesis, as well as those encoding myelin proteins and transcription factors regulating new myelin synthesis. Together, these data indicate that neuroimmune modulation via VNS may be a promising approach to treat MS, that not only ameliorates symptoms but potentially also promotes myelin repair (remyelination).
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Estimulação do Nervo Vago , Nervo Vago , Animais , Encefalomielite Autoimune Experimental/terapia , Encefalomielite Autoimune Experimental/imunologia , Ratos , Esclerose Múltipla/terapia , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Estimulação do Nervo Vago/métodos , Inflamação/terapia , Inflamação/patologia , Modelos Animais de Doenças , Feminino , Bainha de Mielina/metabolismo , Barreira HematoencefálicaRESUMO
Coughing is a dynamic physiological process resulting from input of vagal sensory neurons innervating the airways and perceived airway irritation. Although cough serves to protect and clear the airways, it can also be exploited by respiratory pathogens to facilitate disease transmission. Microbial components or infection-induced inflammatory mediators can directly interact with sensory nerve receptors to induce a cough response. Analysis of cough-generated aerosols and transmission studies have further demonstrated how infectious disease is spread through coughing. This review summarizes the neurophysiology of cough, cough induction by respiratory pathogens and inflammation, and cough-mediated disease transmission.
Assuntos
Doenças Transmissíveis , Tosse , Humanos , Sistema Respiratório/inervação , Nervo Vago/fisiologia , Células Receptoras SensoriaisRESUMO
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.