The biliary system consisting of bile ducts and the gall bladder plays a crucial role in digestion and its function is controlled by both humoral and neural mechanisms. Despite the intense pain associated with gall bladder and bile duct pathologies, little is known about the sensory innervation, particularly sensory innervation by the vagus nerve. Here using anterograde viral tracing from either the left or right nodose ganglion, we demonstrate the presence of a dense sensory innervation of the murine gall bladder by vagal afferents. Entering via the cystic duct, bundles of vagal sensory axons travel along blood vessels from the neck towards the fundus of the gall bladder, where individual axons divide copiously to innervate large territories of the gall bladder wall. Reminiscent of the stomach wall, some vagal afferent axons end in intramuscular array-like endings or in laminar endings within gall bladder ganglia or in the tunica fibromuscularis. However, most axons form a variety of nondistinct endings mostly in the muscle layer. The innervation pattern is consistent with the detection of both mechanical and chemical stimuli. This calls for functional studies determining specific sensory modalities, and translational studies exploring their possible involvement in immune regulation, pain sensation, and interoceptive capacity.

The stomach is one of the major targets of the vagus nerve. Vagal cholinergic parasympathetic (efferent) neurons are located in the dorsal motor nucleus of the vagus (DMV) in the caudal brainstem. They do not directly innervate gastric effector cells, but instead a large portion of enteric neurons located in the myenteric plexus, which act as muscle motor neurons and function-specific pattern generators that can regulate specific motility and secretion programs in coordination with physiological needs and environmental conditions. Vagal sensory (afferent) neurons located in the nodose ganglia (NG) innervate all layers of the stomach wall, where they pick up mechanical and chemical signals to inform the brain and effectuate vago-vagal reflexes. The most abundant terminal structures, intraganglionic laminar endings (IGLEs), are in intimate contact with myenteric plexus neurons. Besides sensing gastric tension, they are likely also chemosensors and provide a link between the enteric nervous system and the brain. Transcriptomic analyses of vagal efferent and afferent neurons allowed making great progress on deciphering their respective coding logic, with a predominantly labeled line organization emerging as the general principle. Because of their distinct molecular fingerprints, separate populations of vagal efferents and afferents with unique morphologies and functions have become experimentally and therapeutically accessible. However, the full coding logic also depends on the organization of the peripheral interface with the enteric nervous system, as well as the central interface represented by 2nd and higher order sensory neurons and pre-autonomic neurons upstream of the DMV, which are only starting to be understood.

Canonical parasympathetic innervation of tissues/organs is accomplished by two in-series neurons, often called pre- and postganglionic neurons. Such two-neuron in-series organization has recently been challenged by claiming direct vagal preganglionic innervation of Brunner's glands (BGs) in the duodenal bulb, as well as the spleen, and the liver. To resolve this controversial issue, we labeled vagal preganglionic neurons in the dorsal motor nucleus of the vagus (DMV) by injecting a Cre-dependent AAV construct to express tdTomato in ChAT-IRES-Cre transgenic mice and analyzed the distribution of labeled fibers in the duodenal bulb. We found that labeled vagal preganglionic fibers terminate exclusively in myenteric ganglia but not in or between BGs. This lack of direct BG innervation is unlikely to result from incomplete labeling of vagal preganglionic neurons, as the entire extent of the DMV was well covered by bilateral injections, and there were abundant vagal axons and terminals in the gastric myenteric plexus and other vagal targets. BGs were innervated by a consistent supply of cholinergic (VAChT-positive) and sparsely by adrenergic (TH-positive) nerve fibers. There was also a moderate supply of vagal afferents anterogradely traced from the nodose ganglia and CGRP-positive fibers. We conclude that BGs in the mouse are not directly innervated by vagal preganglionic neurons of DMV origin but receive cholinergic innervation from myenteric plexus neurons serving as postganglionic neurons. Further experiments will be necessary to clarify the issue for other vagal targets.

There is increasing interest in interoceptive mechanisms as a key player in mental health. The vagus nerve is an important pathway of communication between the body and the brain, and recent advances in neurobiological techniques have enabled the identification of function-specific populations of vagal sensory neurons. Here we briefly review this progress, focusing on vagal innervation of the gut and its involvement in ingestive behavior, metabolic regulation, and immune defense. While we have learned much about the organization of the peripheral interface of the sensory vagal system, dissemination of information within the brain is still poorly understood. Yet, a deeper understanding of the brain's integration of vagal input will be necessary for the informed development of neuromodulation therapies for various diseases linked to interoception.

The canonical autonomic nervous system pathway to peripheral targets consists of two neurons in series, i.e., preganglionic and postganglionic. However, several recent reports claim a direct innervation of some sub-diaphragmatic organs by neurons of the vagal dorsal motor nucleus without intercalated postganglionic neurons. The aim of this minireview is to summarize these studies e.g. on direct vagal preganglionic innervation of Brunner's glands, liver and spleen and to critically discuss their unorthodox findings and discrepancies with previous literature. We conclude that rigorous re-evaluation by complementary state-of-the-art strategies is obligatory.

Interozeptive Afferenzen vermitteln dem Gehirn den Zustand des „inneren Milieus“, das geeignete Reaktionen einleitet, um die Homöostase zu sichern bzw. ihre Störung allostatisch zu korrigieren. In diesem Artikel wird u. a. die Möglichkeit diskutiert, dass Interozeptoren auch die zwischen den Brust- und Bauchorganen wirkenden Adhäsionskräfte detektieren und deren zentralnervöse Integration wesentlich zum Bewusstsein unseres „materiellen Selbst“ beiträgt. Osteopathische viszerale Techniken greifen in dieses Kräftespiel ein und beeinflussen so die Interozeption des Patienten.

The liver is a large organ with crucial functions in metabolism and immune defense, as well as blood homeostasis and detoxification, and it is clearly in bidirectional communication with the brain and rest of the body via both neural and humoral pathways. A host of neural sensory mechanisms have been proposed, but in contrast to the gut-brain axis, details for both the exact site and molecular signaling steps of their peripheral transduction mechanisms are generally lacking. Similarly, knowledge about function-specific sensory and motor components of both vagal and spinal access pathways to the hepatic parenchyma is missing. Lack of progress largely owes to controversies regarding selectivity of vagal access pathways and extent of hepatocyte innervation. In contrast, there is considerable evidence for glucose sensors in the wall of the hepatic portal vein and their importance for glucose handling by the liver and the brain and the systemic response to hypoglycemia. As liver diseases are on the rise globally, and there are intriguing associations between liver diseases and mental illnesses, it will be important to further dissect and identify both neural and humoral pathways that mediate hepatocyte-specific signals to relevant brain areas. The question of whether and how sensations from the liver contribute to interoceptive self-awareness has not yet been explored.

Purpose An overexpression of nerve growth factor (NGF) in the urothelium is discussed to lead to neuronal hyperinnervation of the bladder detrusor. The aim was to assess the sensory and sympathetic innervation of the detrusor in unclosed exstrophic bladders patients with known overexpression of NGF in the urothelium. Methods Full-thickness bladder biopsies were prospectively obtained from 34 infants at delayed primary bladder closure between 01/2015 and 04/2020. The bladder biopsies were immunohistochemically stained with antibodies against S100, calcitonin gene-related peptide (anti-CGRP), Neurofilament 200 (anti-NF200), and tyrosine-hydroxylase (anti-TH). Specimens from 6 children with congenital vesicoureterorenal reflux (VUR) served as controls. Results There was no statistically significant difference in nerve fiber density in any of the immunohistochemical assessments (anti-S100 [ p = 0.210], anti-CGRP [ p = 0.897], anti-NF200 [ p = 0.897]), and anti-TH [ p = 0.956]) between patients with BE and patients with VUR. However, we observed a trend toward lower nerve fiber densities in exstrophic detrusor. Conclusion Overall our results showed an unharmed innervation pattern in this cohort but a lower density of nerve fibers in the detrusor compared to controls. Further studies in patients after successful primary closure are needed to clarify the potential impact of the urothelial overexpression of NGF modulating the innervation pattern in exstrophic bladders.

This manuscript is a thoughtful and philosophically inspired comprehensive account of mystical, religious, and scientific ideas on the heart.It covers about 5000 years, from ancient Egypt to the present, quoting some references that are usually not found in the neurocardiological literature.It is well suited to enrich the scope of contemporary (neuro-)cardiologists' ideas.I have but one major and a few minor points to comment on.

Interoception plays an important role in homeostatic regulation of energy intake and metabolism. Major interoceptive pathways include gut-to-brain and adipose tissue-to brain signaling via vagal sensory nerves and hormones, such as leptin. However, signaling via spinal sensory neurons is rapidly emerging as an additional important signaling pathway. Here we provide an in-depth review of the known anatomy and functions of spinal sensory pathways and discuss potential mechanisms relevant for energy balance homeostasis in health and disease. Because sensory innervation by dorsal root ganglia (DRG) neurons goes far beyond vagally innervated viscera and includes adipose tissue, skeletal muscle, and skin, it is in a position to provide much more complete metabolic information to the brain. Molecular and anatomical identification of function specific DRG neurons will be important steps in designing pharmacological and neuromodulation approaches to affect energy balance regulation in disease states such as obesity, diabetes, and cancer.

This chapter briefly reviews available morphological and functional data on spinovestibular connections. The proposed proprioceptive and vestibular interactions in posture and oculomotor control have been supported by early anatomical studies. Using degeneration methods, spinovestibular afferents, in particular from caudal levels of the cord, and primary afferents from upper cervical nerves to vestibular nuclei have been described. Second-order spinal afferents to the vestibular nuclear complex arise mainly from rostral cervical levels, in particular, the contralateral central cervical nucleus, and distribute to cell group x, the medial and descending vestibular nuclei, and cell group f. Primary spinal afferents to vestibular nuclei originate almost exclusively from rostral cervical spinal ganglia, while fibers from caudal cervical levels are significantly sparser, and are even absent from thoracic and lumbosacral segments. The issue of neurochemical phenotypes remains to be studied in more detail using retrograde labeling from vestibular nuclei combined with immunocytochemistry.

Mesoporous and nonmesoporous SiO2@MnFe2O4 nanostructures were loaded with the hypoxia-inducible factor-1 inhibitor acriflavine for combined radiation and hypoxia therapies. The X-ray irradiation of the drug-loaded nanostructures not only triggered the release of the acriflavine inside the cells but also initiated an energy transfer from the nanostructures to surface-adsorbed oxygen to generate singlet oxygen. While the drug-loaded mesoporous nanostructures showed an initial drug release before the irradiation, the drug was primarily released upon X-ray radiation in the case of the nonmesoporous nanostructures. However, the drug loading capacity was less efficient for the nonmesoporous nanostructures. Both drug-loaded nanostructures proved to be very efficient in irradiated MCF-7 multicellular tumor spheroids. The damage of these nanostructures toward the nontumorigenic MCF-10A multicellular spheroids was very limited because of the small number of nanostructures that entered the MCF-10A spheroids, while similar concentrations of acriflavine without nanostructures were toxic for the MCF-10A spheroids.

Due to its pivotal role in autonomic networks and interoception, the vagus attracts continued interest from both basic scientists and therapists of various clinical disciplines. In particular, the widespread use of heart rate variability as an index of autonomic cardiac control and a proposed central role of the vagus in biopsychological concepts, e.g., the polyvagal theory, provide a good opportunity to recall basic features of vagal anatomy. In addition to the “classical” vagal brainstem nuclei, i.e., dorsal motor nucleus, nucleus ambiguus and nucleus tractus solitarii, the spinal trigeminal and paratrigeminal nuclei come into play as targets of vagal afferents. On the other hand, the nucleus of the solitary tract receives and integrates not only visceral but also somatic afferents.

To date, it has remained unclear whether gastrointestinal symptoms, which are frequently observed in patients with multiple sclerosis (MS), are accompanied by pathology of the enteric nervous system (ENS). Here, the neurotransmitter signature of ENS neurons and morphological alterations of interstitial cells of Cajal (ICCs) were studied in patients with MS and mice with experimental autoimmune encephalomyelitis (EAE), which is an animal model of MS. Immunohistochemical analysis was performed on colonic whole mounts from mice with EAE and on paraffin-embedded sections of intestinal tissue from patients with MS. Antibodies against neurotransmitters or their enzymes (including vasoactive intestinal peptide (VIP), neuronal nitric oxide synthase (nNOS), and choline acetyltransferase (ChAT)) were used in conjunction with pan-neuronal markers. In addition, the presence of anoctamin 1 (ANO1)-expressing ICCs was studied. ENS changes were observed in the myenteric plexus, but they were absent in the submucosal plexus of both EAE mice and patients with MS. There was a significant decrease in the percentage of ChAT-positive neurons in EAE mice as opposed to a trend toward an increase in patients with MS. Moreover, while ANO1 expression was decreased in EAE mice, patients with MS displayed a significant increase. Although additional studies are necessary to accomplish an in-depth characterization of ENS alterations in MS, our results imply that such alterations exist and may reveal novel insights into the pathophysiology of MS.

Clinical publications show consistently that headache is a common symptom in the coronavirus disease of 2019 (COVID-19). Several studies specifically investigated headache symptomatology and associated features in patients with COVID-19. The headache is frequently debilitating with manifold characters including migraine-like characteristics. Studies suggested that COVID-19 patients with headache vs. those without headache are more likely to have anosmia. We present a pathophysiological hypothesis which may explain this phenomenon, discuss current hypotheses about how the coronavirus SARS-CoV-2 enters the central nervous system and suggest that activation of the trigeminal nerve may contribute to both headache and anosmia in COVID-19.

Serotonin immunoreactivity was previously found in myenteric neurons co-innervating motor endplates in the mouse esophagus striated muscle and an involvement in motility control was suggested. However, it is not known if other neuroactive substances are present in these neurons and to what extent they co-localize. First, vasoactive intestinal peptide (VIP) was established as a bona fide marker for putative inhibitory myenteric neurons by evaluating co-localization with neuronal nitric oxide synthase (nNOS) and neuropeptide Y (NPY). Then, co-localization of serotonin and VIP was tested in co-innervating axons on motor endplates, which were visualized with α-bungarotoxin (α-BT) by multilabel immunofluorescence. Myenteric ganglia were also surveyed for co-localization in neuronal perikarya and varicosities. nNOS, NPY, and VIP were completely co-localized in enteric co-innervating nerve terminals on motor endplates. After co-staining with VIP, we found (a) serotonin (5-HT)-positive nerve endings without VIP (44% of 5-HT-positively innervated endplates), (b) 5-HT- and VIP-positive endings without co-localization (35%), and (c) 5-HT- and VIP-positive endings with co-localization (21%). About one-fifth of nerve terminals on motor endplates containing 5-HT originate from putative inhibitory peptidegic nitrergic neurons. However, the majority represents a different population presumably subserving different functions.