A closed-loop negative feedback model for the pancreas: A new paradigm and pathway to a cure.

BACKGROUND AND AIMS: To develop a model that describes how the pancreas functions, how the rate of synthesis of digestive enzymes is regulated, and finally what puts the pancreas to rest between meals. METHODS: We applied the principals of control theory to previously published canine data to develop a model for how the canine pancreas functions. Using this model, we then describe the steps needed to apply this model to the human pancreas. RESULTS: This new closed-loop negative feedback model describes what regulates digestive enzyme synthesis. This model is based on basolateral exocytosis of butyrylcholinesterase (BCHE) into the interstitial space. It is this level of BCHE * BCHE activity that controls the rate of canine pancreas digestive enzyme synthesis, and in the absence of stimulation from the vagus nerve, puts the pancreas to rest between meals. CONCLUSIONS: Finding secretagogue-specific inhibitory enzymes in the human pancreas that are analogous to BCHE in the canine, and blocking its associated receptors, may lead to a cure for human pancreatitis.

What is the Vagal-Adrenal Axis?

Some recent publications have used the term "vagal-adrenal axis" to account for mechanisms involved in the regulation of inflammation by electroacupuncture. This concept proposes that efferent parasympathetic nerve fibers in the vagus directly innervate the adrenal glands to influence catecholamine secretion. Here, we discuss evidence for anatomical and functional links between the vagi and adrenal glands that may be relevant in the context of inflammation and its neural control by factors, including acupuncture. First, we find that evidence for any direct vagal parasympathetic efferent innervation of the adrenal glands is weak and likely artifactual. Second, we find good evidence that vagal afferent fibers directly innervate the adrenal gland, although their function is uncertain. Third, we highlight a wealth of evidence for indirect pathways, whereby vagal afferent signals act via the central nervous system to modify adrenal-dependent anti-inflammatory responses. Vagal afferents, not efferents, are thus the likely key to these phenomena.

Vagal predominance correlates with mood state changes of winter-over expeditioners during prolonged Antarctic residence.

OBJECTIVE: Winter-over expeditioners in Antarctica are challenged by various environmental and psycho-social stress factors, which may induce psychophysiological changes. The autonomic nervous system (ANS) plays a crucial role in the adaptation process under stress. However, the relationship between ANS activity and the mood states of expeditioners remains largely unexplored. This study aims to uncover the pattern of ANS adjustment under extreme Antarctic environments and provide new insights into the correlations between ANS activity and mood state changes, which may provide scientific data for medical interventions. METHODS: Fourteen expeditioners at Zhongshan Station participated in this study. The study was conducted during four representative periods: pre-Antarctica, Antarctica-1 (pre-winter), Antarctica-2 (winter), and Antarctica-3 (summer). The heart rate variability (HRV) of the expeditioners was continuously measured for 24 hours to evaluate ANS activity. Plasma levels of catecholamines were tested by ELISA. Mood states were assessed by the Profile of Mood States (POMS) scale. RESULTS: HRV analysis showed a disturbance of ANS during winter and summer periods. For frequency domain parameters, very low frequency (VLF), low frequency (LF), high frequency (HF), and total power (TP) significantly increased during the second half of the mission. Especially, LF/HF ratio decreased during summer, indicating the predominance of vagal tone. Results of the time domain analysis showed increased heart rate variability during the austral winter and summer. Plasma epinephrine (E) significantly increased during residence in Antarctica. Compared with pre-Antarctica, the vigor, depression, and anger scores of the expeditioners decreased significantly during the austral summer. Notably, the depression score showed a moderate positive correlation with LF/HF, while weak negative correlations with other HRV indicators, including TP, VLF, and LF. Anger score showed a moderate positive correlation with LF/HF and weak negative correlations with the average normal-to-normal (NN) interval, and the root mean square of differences between adjacent RR intervals (RMSSD). Plasma E level weakly correlated with the average NN interval. CONCLUSION: Prolonged residence in Antarctica increased the ANS activities and shifted the cardiac autonomic modulation towards vagal predominance. The alteration of HRV correlated with mood states and plasma epinephrine levels.

Vagal-α7 nicotinic acetylcholine receptor signaling exacerbates influenza severity by promoting lung epithelial cell infection.

The vagus nerve circuit, operating through the alpha-7 nicotinic acetylcholine receptor (α7 nAChR), regulates the inflammatory response by influencing immune cells. However, the role of vagal-α7 nAChR signaling in influenza virus infection is unclear. In particular, does vagal-α7 nAChR signaling impact the infection of alveolar epithelial cells (AECs), the primary target cells of influenza virus? Here, we demonstrated a distinct role of α7 nAChR in type II AECs compared to its role in immune cells during influenza infection. We found that deletion of Chrna7 (encoding gene of α7 nAChR) in type II AECs or disruption of vagal circuits reduced lung influenza infection and protected mice from influenza-induced lung injury. We further unveiled that activation of α7 nAChR enhanced influenza infection through PTP1B-NEDD4L-ASK1-p38MAPK pathway. Mechanistically, activation of α7 nAChR signaling decreased p38MAPK phosphorylation during infection, facilitating the nuclear export of influenza viral ribonucleoproteins and thereby promoting infection. Taken together, our findings reveal a mechanism mediated by vagal-α7 nAChR signaling that promotes influenza viral infection and exacerbates disease severity. Targeting vagal-α7 nAChR signaling may offer novel strategies for combating influenza virus infections.

Electrical stimulation of the vagus nerve ameliorates inflammation and disease activity in a rat EAE model of multiple sclerosis.

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).

Brainstem Dbh+ neurons control allergen-induced airway hyperreactivity.

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.

Transcutaneous auricular vagus nerve stimulation to acutely reduce emotional vulnerability and improve emotional regulation in borderline personality disorder (tVNS-BPD): study protocol for a randomized, single-blind, sham-controlled trial.

BACKGROUND: Borderline personality disorder (BPD) is considered a disorder of emotion regulation resulting from the expression of a biologically determined emotional vulnerability (that is, heightened sensitivity to emotion, increased emotional intensity/reactivity, and a slow return to emotional baseline) combined with exposure to invalidating environments. Vagal tone has been associated with activity in cortical regions involved in emotion regulation and a lower resting state of vagal tone has been observed in BPD patients relative to healthy controls. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has been shown to reduce temper outbursts in adults with Prader-Willi Syndrome, to enhance recognition of emotions in healthy students, and to improve depressive and anxiety symptoms. Furthermore, a single session of taVNS has been shown to acutely alter the recognition of facial expressions of negative valence in adolescents with MDD and increase emotion recognition in controls. However, the effect of taVNS on emotional vulnerability and regulation in individuals diagnosed with BPD has not been investigated. Our aims are to determine if taVNS is effective in acutely reducing emotional vulnerability and improve emotional regulation in BPD patients. METHODS: Forty-two patients will be randomized to a single session of taVNS or sham-taVNS while going through an affect induction procedure. It will consist of the presentation of one neutral and three negative affect-evoking 4-min-long videos in sequence, each of which is followed by a 4-min post-induction period during which participants will rate the quality and intensity of their current self-reported emotions (post-induction ratings) and the perceived effectiveness in managing their emotions during the video presentation. The rating of the current self-reported emotions will be repeated after every post-induction period (recovery ratings). Mixed models with individuals as random effect will be used to investigate the ratings at each stage of the study, taking into account the repeated measures of the same individuals at baseline, pre-induction, post-induction, and recovery. DISCUSSION: The study has potential to yield new insights into the role of vagal tone in emotion dysregulation in BPD and offer preliminary data on the effectiveness of taVNS as a possible non-invasive brain stimulation to treat a core symptom of BPD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05892900. Retrospectively registered on Jun 07, 2023.

Sinus Node Dysfunction Triggered by Tonsillar Abscess: Effects of Vagal Nerve Compression.

BACKGROUND Compression of the vagus nerve by a pharyngeal mass is a well-documented condition that can result in sinus node dysfunction (SND). However, there is scarce literature on extrinsic vagal nerve compression from a tonsillar abscess. CASE REPORT A 59-year-old woman with a history of asthma and chronic throat discomfort presented to the Emergency Department with bradycardia, palpitations, and voice changes. Following a shellfish allergy hospitalization, an otolaryngology evaluation revealed an enlarged right tonsil, recommending tonsillectomy, but scheduling challenges persisted. The patient reported mild throat pain, dysphagia, hoarseness, rhinorrhea, and exertional dyspnea and was admitted for the evaluation of peritonsillar mass. She was found to be bradycardic with a heart rate of 47, with an electrocardiogram revealing SND. Albuterol and ipratropium nebulizers, as well as dexamethasone and pantoprazole, were initiated. With this treatment, the patient symptomatically improved with a new heart rate of 68. She was discharged with outpatient appointments, but was unfortunately lost to follow-up. CONCLUSIONS This case reveals sinus node dysfunction resulting from extrinsic vagal nerve compression by a tonsillar abscess. Pressure on the vagus nerve can trigger bradycardia and low blood pressure, possibly due to compensatory overfiring of afferent vagal nerve signals from local mass effect. Early recognition and antibiotic treatment are essential to prevent cardiac complications. Clinicians must remain vigilant for such extrinsic causes, particularly in patients with chronic sore throat and cardiac symptoms. Further research and case reports are needed to deepen our understanding of this rare yet significant association.

NerveTracker: a Python-based software toolkit for visualizing and tracking groups of nerve fibers in serial block-face microscopy with ultraviolet surface excitation images.

Significance: Information about the spatial organization of fibers within a nerve is crucial to our understanding of nerve anatomy and its response to neuromodulation therapies. A serial block-face microscopy method [three-dimensional microscopy with ultraviolet surface excitation (3D-MUSE)] has been developed to image nerves over extended depths ex vivo. To routinely visualize and track nerve fibers in these datasets, a dedicated and customizable software tool is required. Aim: Our objective was to develop custom software that includes image processing and visualization methods to perform microscopic tractography along the length of a peripheral nerve sample. Approach: We modified common computer vision algorithms (optic flow and structure tensor) to track groups of peripheral nerve fibers along the length of the nerve. Interactive streamline visualization and manual editing tools are provided. Optionally, deep learning segmentation of fascicles (fiber bundles) can be applied to constrain the tracts from inadvertently crossing into the epineurium. As an example, we performed tractography on vagus and tibial nerve datasets and assessed accuracy by comparing the resulting nerve tracts with segmentations of fascicles as they split and merge with each other in the nerve sample stack. Results: We found that a normalized Dice overlap ( Dice norm ) metric had a mean value above 0.75 across several millimeters along the nerve. We also found that the tractograms were robust to changes in certain image properties (e.g., downsampling in-plane and out-of-plane), which resulted in only a 2% to 9% change to the mean Dice norm values. In a vagus nerve sample, tractography allowed us to readily identify that subsets of fibers from four distinct fascicles merge into a single fascicle as we move ∼ 5 mm along the nerve's length. Conclusions: Overall, we demonstrated the feasibility of performing automated microscopic tractography on 3D-MUSE datasets of peripheral nerves. The software should be applicable to other imaging approaches. The code is available at https://github.com/ckolluru/NerveTracker.

Effects of Acute Guarana (Paullinia cupana) Ingestion on Mental Performance and Vagal Modulation Compared to a Low Dose of Caffeine.

Guarana (GUA), a Brazilian seed extract, contains caffeine and other bioactive compounds that may have psychoactive effects. To assess the acute effects of GUA compared to a low dose of caffeine (CAF) on cognitive and mood parameters, twenty participants completed a double-blind, crossover experiment where they ingested capsules containing the following: (1) 100 mg CAF, (2) 500 mg GUA containing 130 mg caffeine, or (3) placebo (PLA). Cognitive tests (Simon and 2N-Back Task) were performed at the baseline (pre-ingestion) and 60 min after ingestion. The response time for the cognitive tests and heart rate variability were unaffected (p > 0.05) by treatment, although 2N-Back was overall faster (p = 0.001) across time. The accuracy in the 2N-Back Task showed a significant interaction effect (p = 0.029) due to higher post-ingestion versus pre-ingestion levels (p = 0.033), but only with the PLA. The supplements also had no effect on cognitive measures following physical fatigue (n = 11). There was an interaction effect on perceived mental energy, where the pre-ingestion of GUA had lower mental pep ratings compared to post-ingestion (p = 0.006) and post-exercise (p = 0.018) levels. Neither the acute ingestion of GUA nor low dose of CAF influenced cognitive performance or provided consistent benefit on mood or mental workload through vagal modulation. Additional investigations are beneficial to determining the lowest effective dose for CAF or GUA to influence mood and/or cognitive performance.

Humanity's evolved nest and its relation to cardiac vagal regulation in the first years of life.

BACKGROUND: The Evolved Developmental Niche (EDN) is a millions-year-old developmental system that matches the maturational schedule of the offspring, optimizing health. Every animal has a developmental niche. AIMS: Humanity has fallen away from providing its EDN. Does it matter? STUDY DESIGN: Several components of humanity's EDN were reviewed (breastfeeding, positive touch, allomothers, responsive care, free play) in relation to cardiac vagal nerve regulation, a signal of healthy development. Focal subjects were young children. OUTCOME MEASURES: A review of research on the selected EDN components in relation to vagal nerve function was performed. Data were available for all but the allomother component, which is typically not measured by western researchers, although allomothers provide EDN components alongside parents. RESULTS: Apart from the lack of research on allomother effects, all these EDN components have been shown to influence cardiac vagal regulation in young children. CONCLUSIONS: Converging evidence suggests that providing the EDN in early life may not only support aspects of a child's primal health system, but bolster capacities for social health and wellness, the cornerstone of a positive life trajectory.

Electroacupuncture treatment improves postoperative ileus by inhibiting the Th1 cell-mediated inflammatory response through the vagus nerve.

BACKGROUND: Electroacupuncture (EA) has been reported to improve intestinal motility in mice with postoperative ileus (POI). Previous studies, however, have yielded heterogeneous results regarding the effect of EA on POI. METHODS: Herein, a POI mouse model was constructed by intestinal manipulation. To evaluate the effect of EA treatment on colonic transit, the levels of inflammatory markers (macrophage inflammatory protein (MIP)-1α, interleukin (IL)-1ß, IL-6, monocyte chemotactic protein (MCP)-1 and intercellular adhesion molecule (ICAM)-1) were detected by enzyme-linked immunosorbent assay (ELISA); immune cell infiltration was detected by immunohistochemical staining of myeloperoxidase (MPO), ectodysplasin (ED)-1 and ED-2, and the percentage of CD4+ interferon (IFN)-γ+ Th1 cells and IFN-γ secretion levels were determined. Activated Th1 cells and pentoxifylline, a cell differentiation inhibitor, were used to assess the role of Th1 cells in EA treatment of POI. Neostigmine administration and unilateral vagotomy were performed to confirm whether the effects of EA treatment on Th1 cells were mediated by the vagus nerve (VN). RESULTS: The results revealed that EA treatment at ST36 improved POI, as indicated by a decreased level of inflammatory-related markers and immune cell infiltration and shortened colonic transit time. The activated Th1 cells abolished the effects of EA treatment on POI. The effects of EA treatment on POI were enhanced by stimulation of the VN along with a decreased level of Th1 cells, but these effects were abolished by vagotomy along with an increased percentage of Th1 cells; this result indicates that the VN mediates the role of Th1 cells in the effects of EA treatment of POI. CONCLUSION: Our findings showed that the effects of EA treatment of POI were mainly mediated by Th1 cells through the stimulation of the VN and inhibition of the inflammatory response.

Moderate cardiac vagal tone is associated with more cooperation in children.

Childhood is a crucial period for prosocial development, including cooperative behaviors. Recent studies have shown a quadratic relation (inverted U-shape curve) between cardiac vagal tone (CVT) and various prosocial emotions and behaviors in children, but data are lacking on cooperative behaviors. In a sample of 111 school-aged children (M = 7.77; SD = 1.24, range: 6-11), we tested the association between the root mean square of successive differences in interbeat intervals (RMSSD) at rest, and cooperative behavior in a task designed to be comparable to a stag hunt game. We found evidence for an association between RMSSD and cooperation that follows an inverted U-shape. In addition, older children were more likely to cooperate than younger children. Lastly, we found an interaction between RMSSD and age such that the association between RMSSD and cooperation behavior was present for younger but not older children. In addition, we proposed an extension of the Johnson-Neyman test to assess the significant region of interaction between age and the linear and quadratic RMSSD. These results add to a growing literature suggesting that moderate RMSSD is associated with greater prosocial behavior and provide novel evidence that this association extends to children's cooperation.

Identifying vagal bronchopulmonary afferents mediating cough response to inhaled sulfur dioxide in mice.

Sulfur dioxide (SO2), a common environmental and industrial air pollutant, possesses a potent effect in eliciting cough reflex, but the primary type of airway sensory receptors involved in its tussive action has not been clearly identified. This study was carried out to determine the relative roles of three major types of vagal bronchopulmonary afferents [slowly adapting receptors (SARs), rapidly adapting receptors (RARs), and C-fibers] in regulating the cough response to inhaled SO2. Our results showed that inhalation of SO2 (300 or 600 ppm for 8 min) evoked an abrupt and intense stimulatory effect on bronchopulmonary C-fibers, which continued for the entire duration of inhalation challenge and returned toward the baseline in 1-2 min after resuming room air-breathing in anesthetized and mechanically ventilated mice. In stark contrast, the same SO2 inhalation challenge generated a distinct and consistent inhibitory effect on both SARs and phasic RARs; their phasic discharges synchronized with respiratory cycles during the baseline (breathing room air) began to decline progressively within 1-3 min after the onset of SO2 inhalation, ceased completely before termination of the 8-min inhalation challenge, and then slowly returned toward the baseline after >40 min. In a parallel study in awake mice, inhalation of SO2 at the same concentration and duration as that in the nerve recording experiments evoked cough responses in a pattern and time course similar to that observed in the C-fiber responses. Based on these results, we concluded that stimulation of vagal bronchopulmonary C-fibers is primarily responsible for triggering the cough response to inhaled SO2.NEW & NOTEWORTHY This study demonstrated that inhalation of a high concentration of sulfur dioxide, an irritant gas and common air pollutant, completely and reversibly inhibited the neural activities of both slowly adapting receptor and rapidly adapting receptor, two major types of mechanoreceptors in the lungs with their activities conducted by myelinated fibers. Furthermore, the results of this study suggested that stimulation of vagal bronchopulmonary C-fibers is primarily responsible for triggering the cough reflex responses to inhaled sulfur dioxide.

The Development of a New Vagus Nerve Simulation Electroceutical to Improve the Signal Attenuation in a Living Implant Environment.

An electroceutical is a medical device that uses electrical signals to control biological functions. It can be inserted into the human body as an implant and has several crucial advantages over conventional medicines for certain diseases. This research develops a new vagus nerve simulation (VNS) electroceutical through an innovative approach to overcome the communication limitations of existing devices. A phased array antenna with a better communication performance was developed and applied to the electroceutical prototype. In order to effectively respond to changes in communication signals, we developed the steering algorithm and firmware, and designed the smart communication protocol that operates at a low power that is safe for the patients. This protocol is intended to improve a communication sensitivity related to the transmission and reception distance. Based on this technical approach, the heightened effectiveness and safety of the prototype have been ascertained, with the actual clinical tests using live animals. We confirmed the signal attenuation performance to be excellent, and a smooth communication was achieved even at a distance of 7 m. The prototype showed a much wider communication range than any other existing products. Through this, it is conceivable that various problems due to space constraints can be resolved, hence presenting many benefits to the patients whose last resort to the disease is the VNS electroceutical.

The effectiveness of an osteopathic manual technique compared with a breathing exercise on vagal tone as indicated by heart rate variability, a crossover study.

INTRODUCTION: Parasympathetic nervous system (PSNS) function can be inferred by heart rate variability (HRV) providing indications about an individual's health. Manual therapy may influence PSNS function, however the research outcomes in this regard are equivocal. This study explored the PSNS effect of a measured breathing technique with suboccipital balanced ligamentous tension, an osteopathic manipulative therapy technique. METHODS: Healthy adult participants in this crossover study (n = 18) were randomly allocated into two groups with differing order of interventions. A 1:1 breathing rate of 6 breaths per minute maintained for 5 min was compared to the osteopathic intervention. HRV was measured for 5 min before and after each intervention and analysed using the root mean square of successive differences (RMSSD) between normal heartbeats and high frequency normalised units (HFnu). RESULTS: The RMSSD data demonstrated no significant difference between groups or within groups (p > 0.05) over time. HFnu results showed a significant between-group difference over the four time points (p = 0.004) with a medium effect size (ηp2 = 0.240), and no significant within-group difference (p > 0.05). DISCUSSION: The osteopathic intervention raised HRV to a small extent, however measured breathing lowered HRV. In the group that received the osteopathic technique first, HFnu values continued to rise post-osteopathic treatment possibly indicating an increasing parasympathetic effect over time. Recommendations for future studies include changing the breathing ratio to ensure parasympathetic response, take into account potential delayed effects of interventions, consider outcome measures less variable than HRV, and longer follow up times. CONCLUSION: This study suggests parasympathetic stimulation may occur with the application of suboccipital balanced ligamentous tension and sympathetic stimulation from measured breathing.

Electrophysiological Properties and Morphology of Cardiac and Pulmonary Motoneurons within the Dorsal Motor Nucleus of the Vagus of Rats.

The dorsal motor nucleus of the vagus (DMV) contains parasympathetic motoneurons that project to the heart and lungs. These motoneurons control ventricular excitability/contractility and airways secretions/blood flow, respectively. However, their electrophysiological properties, morphology and synaptic input activity remain unknown. One important ionic current described in DMV motoneurons controlling their electrophysiological behaviour is the A-type mediated by voltage-dependent K+ (Kv) channels. Thus, we compared the electrophysiological properties, synaptic activity, morphology, A-type current density, and single cell expression of Kv subunits, that contribute to macroscopic A-type currents, between DMV motoneurons projecting to either the heart or lungs of adult male rats. Using retrograde labelling, we visualized distinct DMV motoneurons projecting to the heart or lungs in acutely prepared medullary slices. Subsequently, whole cell recordings, morphological reconstruction and single motoneuron qRT-PCR studies were performed. DMV pulmonary motoneurons were more depolarized, electrically excitable, presented higher membrane resistance, broader action potentials and received greater excitatory synaptic inputs compared to cardiac DMV motoneurons. These differences were in part due to highly branched dendritic complexity and lower magnitude of A-type K+ currents. By evaluating expression of channels that mediate A-type currents from single motoneurons, we demonstrated a lower level of Kv4.2 in pulmonary versus cardiac motoneurons, whereas Kv4.3 and Kv1.4 levels were similar. Thus, with the distinct electrical, morphological, and molecular properties of DMV cardiac and pulmonary motoneurons, we surmise that these cells offer a new vista of opportunities for genetic manipulation providing improvement of parasympathetic function in cardiorespiratory diseases such heart failure and asthma.