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Nausea is an uncomfortable sensation that accompanies many therapeutics, especially diabetes treatments involving glucagon-like peptide-1 receptor (GLP1R) agonists. Recent studies in mice have revealed that GLP1R-expressing neurons in the area postrema play critical roles in nausea. Here, we characterized a ligand-conjugated saporin that can efficiently ablate GLP1R+ cells from humans, mice, and the Suncus murinus, a small animal model capable of emesis. This new tool provides a strategy to manipulate specific neural pathways in the area postrema in the Suncus murinus and may help elucidate roles of area postrema GLP1R+ neurons in emesis during therapeutics involving GLP1R agonists.

Among contributors to diffusible signaling are portal systems which join two capillary beds through connecting veins. Portal systems allow diffusible signals to be transported in high concentrations directly from one capillary bed to the other without dilution in the systemic circulation. Two portal systems have been identified in the brain. The first was discovered almost a century ago and connects the median eminence to the anterior pituitary gland. The second was discovered a few years ago and links the suprachiasmatic nucleus to the organum vasculosum of the lamina terminalis, a sensory circumventricular organ (CVO). Sensory CVOs bear neuronal receptors for sensing signals in the fluid milieu. They line the surface of brain ventricles and bear fenestrated capillaries thereby lacking blood–brain barriers. It is not known whether the other sensory CVOs, namely the subfornical organ (SFO), and area postrema (AP) form portal neurovascular connections with nearby parenchymal tissue. To preserve the integrity of the vasculature of CVOs and their adjacent neuropil, we combined iDISCO clearing and light‐sheet microscopy to acquire volumetric images of blood vessels and traced the vasculature in two experiments. In the first, the whole brain vasculature was registered to the Allen Brain Atlas in order to identify the nuclei to which the SFO and AP are attached. In the second study, regionally specified immunolabeling was used to identify the attachment sites and vascular connections between the AP, and the SFO to their respective parenchymal attachment sites. There are venous portal pathways linking the capillary vessels of the SFO and the posterior septal nuclei, namely the septofimbrial nucleus and the triangular nucleus of the septum. Unlike the arrangement of portal vessels, the AP and the nucleus of the solitary tract share a common capillary bed. Taken together, the results reveal that all three sensory CVOs bear direct capillary connections to adjacent neuropil, providing a direct route for diffusible signals to travel from their source to their targets. [ABSTRACT FROM AUTHOR]

The area postrema (AP) is a key circumventricular organ involved in the regulation of autonomic functions. Accurate identification of the AP via MRI is essential in neuroimaging but it is challenging. This study evaluated 3D FSE Cube T2WI, 3D FSE Cube FLAIR, and 3D DIR sequences to improve AP detection in patients with and without multiple sclerosis (MS). A case–control study included 35 patients with MS and 35 with other non-demyelinating central nervous system diseases (ND-CNSD). MRI images were acquired employing 3D DIR, 3D FSE Cube FLAIR, and 3D FSE Cube T2WI sequences. The evaluation of AP was conducted using a 3-point scale. Statistical analysis was performed with the chi-square test used to assess group homogeneity and differences between sequences. No significant differences were found in the visualization of the AP between the MS and ND-CNSD groups across the sequences or planes. The AP was not visible in 27.6% of the 3D FSE Cube T2WI sequences, while it was visualized in 99% of the 3D FSE Cube FLAIR sequences and 100% of the 3D DIR sequences. The 3D DIR sequence showed superior performance in identifying the AP. [ABSTRACT FROM AUTHOR]

[Display omitted] • A high-fat diet influences neural stem and progenitor cell in the medulla of adult mice. • Short-term high-fat diet promoted proliferation of neural progenitor cells. • Short-term high-fat diet promoted proliferation of glial cells. • Long-term high-fat diet induced microglia iNOS in the medulla. It has been widely established that neural stem cells (NSCs) exist in the adult mammalian brain. The area postrema (AP) and the ependymal cell layer of the central canal (CC) in the medulla were recently identified as NSC niches. There are two types of NSCs: astrocyte-like cells in the AP and tanycyte-like cells in the CC. However, limited information is currently available on the characteristics and functional significance of these NSCs and their progeny in the AP and CC. The AP is a part of the dorsal vagal complex (DVC), together with the nucleus of the solitary tract (Sol) and the dorsal motor nucleus of the vagus (10 N). DVC is the primary site for the integration of visceral neuronal and hormonal cues that act to inhibit food intake. Therefore, we examined the effects of high-fat diet (HFD) on NSCs and progenitor cells in the AP and CC. Eight-week-old male mice were fed HFD for short (1 week) and long periods (4 weeks). To detect proliferating cells, mice consecutively received intraperitoneal injections of BrdU for 7 days. Brain sections were processed with immunohistochemistry using various cell markers and BrdU antibodies. Our data demonstrated that adult NSCs and neural progenitor cells (NPCs) in the medulla responded more strongly to short-term HFD than to long-term HFD. HFD increased astrocyte density in the Sol and 10 N, and increased microglial/macrophage density in the AP and Sol. Furthermore, long-term HFD induced mild inflammation in the medulla, suggesting that it affected the proliferation of NSCs and NPCs. [ABSTRACT FROM AUTHOR]

Introduction: The area postrema, located on the floor of the fourth ventricle, regulates vomiting, fluid balance, osmoregulation, and immunomodulation. First documented in 1896, it has been a subject of scientific interest ever since. Area postrema syndrome (APS) is characterised by intractable nausea, vomiting, or hiccups, typically associated with neuromyelitis optica spectrum disorder (NMOSD). This paper presents a case of APS related with autoimmunity due to systemic lupus erythematosus (SLE) and not related to NMOSD. Additionally, a comprehensive review of the literature is conducted. Case report: A 27-year-old Colombian female with a five-year history of systemic lupus erythematosus (SLE) presented with vomiting, epigastric pain, dysphagia, and seizures. Initial tests suggested acute pancreatitis and a lupus flare, but imaging of the gastrointestinal tract showed no abnormalities. Brain MRI revealed a lesion in the area postrema, indicating area postrema syndrome (APS). Treatment with hydrocortisone and later high-dose methylprednisolone and cyclophosphamide led to improvement. Negative anti-aquaporin 4 antibodies ruled out neuromyelitis optica spectrum disorder (NMOSD), leading to a probable diagnosis of APS associated with SLE. Conclusion: Given the patient's negative AQP4-IgG results, clinical profile, and medical history, we propose APS associated with SLE, marking the first reported case in Latin America.

The central nervous system regulates feeding, weight and glucose homeostasis in rodents and humans, but the site-specific mechanisms remain unclear. The dorsal vagal complex in the brainstem that contains the nucleus of the solitary tract (NTS) and area postrema (AP) emerges as a regulatory center that impacts energy and glucose balance by monitoring hormonal and nutrient changes. However, the specific mechanistic metabolic roles of the NTS and AP remain elusive. This mini-review highlights methods to study their distinct roles and recent findings on their metabolic differences and similarities of growth differentiation factor 15 (GDF15) action and glucose sensing in the NTS and AP. In summary, future research aims to characterize hormonal and glucose sensing mechanisms in the AP and/or NTS carries potential to unveil novel targets that lower weight and glucose levels in obesity and diabetes.

The central nervous system regulates feeding, weight and glucose homeostasis in rodents and humans, but the site-specific mechanisms remain unclear. The dorsal vagal complex in the brainstem that contains the nucleus of the solitary tract (NTS) and area postrema (AP) emerges as a regulatory center that impacts energy and glucose balance by monitoring hormonal and nutrient changes. However, the specific mechanistic metabolic roles of the NTS and AP remain elusive. This mini-review highlights methods to study their distinct roles and recent findings on their metabolic differences and similarities of growth differentiation factor 15 (GDF15) action and glucose sensing in the NTS and AP. In summary, future research aims to characterize hormonal and glucose sensing mechanisms in the AP and/or NTS carries potential to unveil novel targets that lower weight and glucose levels in obesity and diabetes. [ABSTRACT FROM AUTHOR]

Motilin (MLN) is a peptide hormone originally isolated from the mucosa of the porcine intestine. Its orthologs have been identified in various vertebrates. Although MLN regulates gastrointestinal motility in tetrapods from amphibians to mammals, recent studies indicate that MLN is not involved in the regulation of isolated intestinal motility in zebrafish, at least in vitro. To determine the unknown function of MLN in teleosts, we examined the expression of MLN and the MLN receptor (MLNR) at the cellular level in Japanese medaka (Oryzias latipes). Quantitative PCR revealed that mln mRNA was limitedly expressed in the gut, whereas mlnr mRNA was not detected in the gut but was expressed in the brain and kidney. By in situ hybridization and immunohistochemistry, mlnr mRNA was detected in the dopaminergic neurons of the area postrema in the brain and the noradrenaline-producing cells in the interrenal gland of the kidney. Furthermore, we observed efferent projections of mlnr-expressing dopaminergic neurons in the lobus vagi (XL) and nucleus motorius nervi vagi (NXm) of the medulla oblongata by establishing a transgenic medaka expressing the enhanced green fluorescence protein driven by the mlnr promoter. The expression of dopamine receptor mRNAs in the XL and cholinergic neurons in NXm was confirmed by in situ hybridization. These results indicate novel sites of MLN activity other than the gastrointestinal tract. MLN may exert central and peripheral actions through the regulation of catecholamine release in medaka. [ABSTRACT FROM AUTHOR]

Abstract Background Neuromyelitis Optica Spectrum Disorder (NMOSD) is an inflammatory autoimmune disease with high risk of recurrence and disability, the treatment goal is a recurrence free state. Area postrema (AP) is one of the most common involved area of NMOSD, which may have a particular significance in the pathogenesis of NMOSD and clinical heterogeneity. Our study is to investigate the clinical and recurrent characteristics AP onset NMOSD patients. Methods A retrospective study was done in a cohort of 166 AQP4-IgG seropositive NMOSD patients which were identified by the 2015 IPND criteria. The patients were divided into AP onset (APO-NMOSD) group and non-AP onset (NAPO-NMOSD) group based on the initial episode location. Clinical features and recurrence differences of two groups were compared. Results The APO-NMOSD group and NAPO-NMOSD group had a population ratio of 24:142. APO-NMOSD patients were younger (34.6y VS 42.3y, P = 0.013), had lower EDSS at first episode (0.7 VS 4.2, p = 0.028) and last follow up (1.9 VS 3.3, p = 0.001), more likely to have multi-core lesions at the first attack (33.3% VS 9.2%, P = 0.001). Also, they had a higher annual recurrence rate (0.4 ± 0.28 VS 0.19 ± 0.25, P = 0.012). In natural course NMOSD patients without immunotherapy, APO-NMSOD had a shorter time of first relapse (P

The area postrema (AP) is a key circumventricular organ involved in the regulation of autonomic functions. Accurate identification of the AP via MRI is essential in neuroimaging but it is challenging. This study evaluated 3D FSE Cube T2WI, 3D FSE Cube FLAIR, and 3D DIR sequences to improve AP detection in patients with and without multiple sclerosis (MS). A case–control study included 35 patients with MS and 35 with other non-demyelinating central nervous system diseases (ND-CNSD). MRI images were acquired employing 3D DIR, 3D FSE Cube FLAIR, and 3D FSE Cube T2WI sequences. The evaluation of AP was conducted using a 3-point scale. Statistical analysis was performed with the chi-square test used to assess group homogeneity and differences between sequences. No significant differences were found in the visualization of the AP between the MS and ND-CNSD groups across the sequences or planes. The AP was not visible in 27.6% of the 3D FSE Cube T2WI sequences, while it was visualized in 99% of the 3D FSE Cube FLAIR sequences and 100% of the 3D DIR sequences. The 3D DIR sequence showed superior performance in identifying the AP.

Background: Neuromyelitis Optica Spectrum Disorder (NMOSD) is an inflammatory autoimmune disease with high risk of recurrence and disability, the treatment goal is a recurrence free state. Area postrema (AP) is one of the most common involved area of NMOSD, which may have a particular significance in the pathogenesis of NMOSD and clinical heterogeneity. Our study is to investigate the clinical and recurrent characteristics AP onset NMOSD patients. Methods: A retrospective study was done in a cohort of 166 AQP4-IgG seropositive NMOSD patients which were identified by the 2015 IPND criteria. The patients were divided into AP onset (APO-NMOSD) group and non-AP onset (NAPO-NMOSD) group based on the initial episode location. Clinical features and recurrence differences of two groups were compared. Results: The APO-NMOSD group and NAPO-NMOSD group had a population ratio of 24:142. APO-NMOSD patients were younger (34.6y VS 42.3y, P = 0.013), had lower EDSS at first episode (0.7 VS 4.2, p = 0.028) and last follow up (1.9 VS 3.3, p = 0.001), more likely to have multi-core lesions at the first attack (33.3% VS 9.2%, P = 0.001). Also, they had a higher annual recurrence rate (0.4 ± 0.28 VS 0.19 ± 0.25, P = 0.012). In natural course NMOSD patients without immunotherapy, APO-NMSOD had a shorter time of first relapse (P < 0.001) and higher annual recurrence rate (0.31 ± 0.22 VS 0.16 ± 0.26, P = 0.038) than NAPO-NMOSD. APO-NMOSD group also have a higher risk of having the first relapsing compared to optic neuritis onset-NMOSD (HR 2.641, 95% CI 1.427–4.887, p = 0.002) and myelitis onset-NMOSD group (HR 3.593, 95% CI 1.736–7.438, p = 0.001). Compared to NAPO-NMOSD, APO-NMOSD has a higher likelihood of brainstem recurrence (28.6% vs. 4.7%, p<0.001) during the first recurrence, while NAPO-NMOSD is more susceptible to optic nerve involvement (10.7% vs. 41.1%, p = 0.01). Conclusion: AQP4-IgG seropositive NMOSD patients with AP onset are youngers and have higher risk of recurrence. Clinicians should pay attention to AP damage in NMOSD, as it indicates a potential risk of recurrence. Trial registration: Retrospectively registered. [ABSTRACT FROM AUTHOR]

Nausea is a discomforting sensation of gut malaise that remains a major clinical challenge. Several visceral poisons induce nausea through the area postrema, a sensory circumventricular organ that detects bloodborne factors. Here, we use genetic approaches based on an area postrema cell atlas to reveal inhibitory neurons that counteract nausea-associated poison responses. The gut hormone glucose insulinotropic peptide (GIP) activates area postrema inhibitory neurons that project locally and elicit inhibitory currents in nausea-promoting excitatory neurons through γ-aminobutyric acid (GABA) receptors. Moreover, GIP blocks behavioral responses to poisons in wild-type mice, with protection eliminated by targeted area postrema neuron ablation. These findings provide insights into the basic organization of nausea-associated brainstem circuits and reveal that area postrema inhibitory neurons are an effective pharmacological target for nausea intervention.

Background and objectives: Both myelin oligodendrocyte glycoprotein-IgG associated disorders (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD) are demyelinating diseases of the central nervous system. They present similar clinical manifestations such as optica neuritis, myelitis and area postrema syndrome (APS). The distinctions of optica neuritis (ON) and myelitis between them have been elaborated to great length while their differences in APS remain to be elucidated. We aim to report the frequency of APS in patients with MOGAD as well as NNOSD patients, and to compare the characteristics of APS between patients with MOGAD and those with NMOSD. Methods: Seven MOG-IgG positive APS patients were retrospectively identified between 2017 and 2022. APS phenotypes have been previously described. The similarities and differences between MOGAD and NMOSD patients with APS was compared, including the frequency and duration of APS between the two diseases, and their incidences of accompanied subtentorial lesions have also been described and compared. Results: We reviewed a cohort of 218 MOG-IgG-positive patients, and 396 patients with NMOSD. 200 MOGAD patients and 332 NMOSD patients were included in this study. In the cohort, seven patients with MOG-IgG-positive antibody presented with APS were analyzed, four of whom had disease onset with APS. Of the 332 patients with NMOSD, 47 had APS attacks while 31 had APS at disease onset. In patients with MOGAD, 2 had nausea, 3 had vomiting, 5 had hiccups, and 1 patient presented with all three symptoms above. In patients with NMOSD, 70.2 % had nausea, vomiting and hiccups at the same time during APS attacks. Apart from the medulla oblongata, other subtentorial regions were also affected in 6/7 MOGAD patients while 14/47 NMOSD patients had other subtentorial regions involved. During an APS attack, the incidence of concomitant lesions in the brainstem and other regions was significantly greater in MOGAD than in the NMOSD cohort (P = 0.008*). Conclusion: APS is a rare, but not isolated clinical manifestation of MOGAD. APS happened more frequently with other supratentorial and subtentorial lesions in MOGAD. The symptoms of NVH (nausea, vomiting, hiccups) tended to happen respectively in MOGAD compared with NMOSD. The phenotype or mechanism of APS in MOGAD may differ from that in NMOSD.

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.

Objective: Rare coexistence of disease or pathology Background: Neuromyelitis optica spectrum disorder (NMOSD) is a demyelinating disease of the central nervous system that includes the triad of transverse myelitis, optic neuritis, and area postrema syndrome (APS), characterized by intractable nausea and vomiting. NMOSD can be part of a paraneoplastic syndrome and is associated with sero-positivity to aquaporin-4 (AQP-4). We present a patient with uncontrollable nausea and vomiting who developed herpes zoster and acute myelitis and was finally diagnosed with paraneoplastic NMOSD due to breast cancer. Case Report: A 51-year-old woman was hospitalized due to 2 weeks of intractable nausea and vomiting. Although contrast- enhanced thoracoabdominal computed tomography (CT) on day 4 suggested breast cancer in her left breast, the etiology of her symptoms remained unknown. On day 13, she developed herpes zoster, followed by acute myelitis on day 25. Magnetic resonance imaging (MRI) showing longitudinal extensive transverse myelitis and an elevated serum AQP-4 antibody level led to the diagnosis of NMOSD. Brain MRI detected a small lesion in the dorsal medulla oblongata, which explained the preceding APS. After starting intravenous methylprednisolone pulse therapy, her nausea and vomiting rapidly subsided. Breast cancer was resected on day 63, and immunohistochemical staining revealed overexpression of AQP-4 in the tumor cells, suggesting paraneoplastic NMOSD. Conclusions: This report has highlighted the presentation and diagnosis of NMOSD and supports the possibility that this can present as part of a paraneoplastic syndrome. In addition, diagnosis of NMOSD preceded by APS requires meticulous history taking and careful interpretation of MRI in the dorsal medulla oblongata. [ABSTRACT FROM AUTHOR]

Area postrema syndrome (APS) develops in patients with lesions found in the floor of the fourth ventricle and manifests with nausea, intractable vomiting, and hiccup. APS is most commonly associated with neuromyelitis optica spectrum disorders although it may develop in some other conditions as well. We have presented a case study of APS with positional vertigo developed in a 41-year-old woman caused by acute disseminated encephalomyelitis after COVID-19 vaccination. Quasi benign paroxysmal positional vertigo acutely manifested with nausea, vomiting, and vertigo that dramatically worsened with head movement. Physical examination revealed patchy hypesthesia on the left side of the face and decreased convergence of the left eye. MRI scan showed a lesion adjacent to the floor of the fourth ventricle (area postrema). The manifestations totally regressed on glucocorticoids without any relapse during 1-year follow-up.

Objectives In patients with RA, baricitinib not only improves arthritis symptom severity, but also patients' neuropsychological symptoms, such as depression and fatigue. However, the cellular mechanisms through which baricitinib can affect neural activity is unexplored. While the blood–brain barrier (BBB) permeability of this drug remains unclear, Janus kinase inhibitors (JAKi) might reach the area postrema, which is a unique brain region with a weak BBB function. Our recent study demonstrated microglial activation during experimental arthritis in the area postrema. Therefore, we sought to assess the effect of baricitinib on microglia in the area postrema using the CIA mouse model. Methods Microglia number and morphology in the area postrema were assessed by immunostaining for ionized calcium-binding adaptor molecule-1 (Iba-1). Data were collected on post-immunization day 35 (early phase) and 84 (late phase), and compared between baricitinib- and vehicle-treated mice. The effect on signal transducers and activators of transcription (STAT3) in the area postrema was also immunohistochemically examined. Behavioural outcomes were assessed by examining feeding behaviours and sucrose preference tests. Results In the early phase, activated microglial levels in the area postrema were decreased by baricitinib, accompanied by the inhibition of phosphorylated-STAT3 and recovery of food intake and sucrose preference. On the other hand, baricitinib did not affect microglial morphology in the late phase. Conclusion Our results demonstrate that baricitinib can affect brain cells, specifically microglia, in the brain region with a weak BBB and mitigate aberrant behaviours during autoimmune arthritis, pointing to the potential therapeutic effect of JAKi on brain pathologies underpinning RA. [ABSTRACT FROM AUTHOR]

ObjectiveTo define the frequency, duration, and severity of intractable nausea, vomiting, or hiccups in aquaporin-4-immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and propose diagnostic criteria and a severity scale for area postrema syndrome (APS).MethodsAn International NMOSD database was interrogated for frequency of APS. Patients with AQP4-IgG-positive NMOSD completed an APS symptom questionnaire. Nausea and vomiting severity was derived from the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) score. The diagnostic criteria, severity scale, and immunotherapy response was applied to a prospective validation cohort of patients from multiple centers.ResultsAnalysis of an international database for AQP4-IgG-seropositive NMOSD (n = 430) revealed a high prevalence of isolated APS attacks (onset 7.1%-10.3%; subsequent 9.4%-14.5%) across continents. For 100 patients with 157 episodes of APS, nausea (n = 127, 81%) lasted for a median of 14 days (range 2-365), vomiting (113, 72%) with a median of 5 episodes/d (2-40) lasted 1-20 minutes, and hiccups (102, 65%) lasted a median of 14 days (2-365). Symptoms consistently and completely resolved following immunotherapy. Data were used to propose APS diagnostic criteria and repurpose PUQE score (hiccups severity grade based on symptom duration). The clinical utility was demonstrated in a prospective validation cohort.ConclusionIsolated APS attacks are frequently encountered both at onset and during the NMOSD course. The diagnostic criteria proposed here will assist clinicians in recognizing APS. Diagnosis of an APS attack earlier than 48 hours is possible if a dorsal medulla lesion is detected. Accurate diagnosis and evaluation of APS attack severity will assist in outcome measurement in NMOSD clinical trials.

Emesis is composed of 3 independent digestive tract correlates that are individually organized by a brainstem neural network and all 3 hierarchically organized by a central pattern generator. The central pattern generator may be in the Bötzinger nucleus of the brain stem. The digestive tract sensory mechanisms that activate vomiting are the digestive tract mucosa or chemoreceptive trigger zone of the area postrema. Regardless of the initial stimulus, the area postrema may be activated in order to inhibit orthograde digestive tract motility and reflux blocking reflexes that would interfere with anterograde movement, which is the basic purpose of vomiting. The digestive tract correlates are (1) relaxation of the upper stomach and contraction of the lower pharynx, (2) retrograde giant contraction, and (3) the pharyngo-esophageal responses during retching and vomitus expulsion. The proximal gastric response allows gastroesophageal reflux, the lower pharyngeal response prevents supra-esophageal reflux, and both last the duration of the vomit process. The retrograde giant contraction empties the proximal digestive tract of noxious agents and supplies the stomach with fluids to neutralize the gastric acid which protect the esophagus from damage during expulsion. The retch mixes the gastric contents with acid neutralizer and gives momentum to the expelled bolus. During vomitus expulsion the esophagus is maximally stretched longitudinally which stiffens its wall to allow rapid transport as the suprahyoid muscles and diaphragmatic dome contract, and the hiatal fibers relax. [ABSTRACT FROM AUTHOR]

Anatomical tracing studies examining the vagal system can conflate details of sensory afferent and motor efferent neurons. Here, we used a serotype of adeno‐associated virus that transports retrogradely and exhibits selective tropism for vagal afferents, to map their soma location and central termination sites within the nucleus of the solitary tract (NTS). We examined the vagal sensory afferents innervating the trachea, duodenum, stomach, or heart, and in some animals, from two organs concurrently. We observed no obvious somatotopy in the somata distribution within the nodose ganglion. The central termination patterns of afferents from different organs within the NTS overlap substantially. Convergence of vagal afferent inputs from different organs onto single NTS neurons is observed. Abdominal and thoracic afferents terminate throughout the NTS, including in the rostral NTS, where the 7th cranial nerve inputs are known to synapse. To address whether the axonal labeling produced by viral transduction is so widespread because it fills axons traveling to their targets, and not just terminal fields, we labeled pre and postsynaptic elements of vagal afferents in the NTS. Vagal afferents form multiple putative synapses as they course through the NTS, with each vagal afferent neuron distributing sensory signals to multiple second‐order NTS neurons. We observe little selectivity between vagal afferents from different visceral targets and NTS neurons with common neurochemical phenotypes, with afferents from different organs making close appositions with the same NTS neuron. We conclude that specific viscerosensory information is distributed widely within the NTS and that the coding of this input is probably determined by the intrinsic properties and projections of the second‐order neuron. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 virus gains entry to cells by binding to angiotensin-converting enzyme 2 (ACE2). Since circumventricular organs and parts of the hypothalamus lack a blood–brain barrier, and immunohistochemical studies demonstrate that ACE2 is highly expressed in circumventricular organs which are intimately connected to the hypothalamus, and the hypothalamus itself, these might be easy entry points for SARS-CoV-2 into the brain via the circulation. High ACE2 protein expression is found in the subfornical organ, area postrema, and the paraventricular nucleus of the hypothalamus (PVH). The subfornical organ and PVH are parts of a circuit to regulate osmolarity in the blood, through the secretion of anti-diuretic hormone into the posterior pituitary. The PVH is also the stress response centre in the brain. It controls not only pre-ganglionic sympathetic neurons, but is also a source of corticotropin-releasing hormone, that induces the secretion of adrenocorticotropic hormone from the anterior pituitary. It is proposed that the function of ACE2 in the circumventricular organs and the PVH could be diminished by binding with SARS-CoV-2, thus leading to a reduction in the ACE2/Ang (1–7)/Mas receptor (MasR) signalling axis, that modulates ACE/Ang II/AT1R signalling. This could result in increased presympathetic activity/neuroendocrine secretion from the PVH, and effects on the hypothalamic–pituitary–adrenal axis activity. Besides the bloodstream, the hypothalamus might also be affected by SARS-CoV-2 via transneuronal spread along the olfactory/limbic pathways. Exploring potential therapeutic pathways to prevent or attenuate neurological symptoms of COVID-19, including drugs which modulate ACE signalling, remains an important area of unmet medical need. [ABSTRACT FROM AUTHOR]

Abstract Background Sick sinus syndrome (SSS) is known to occur due to lesions in the medulla oblongata. Although medullary lesions have occurred in patients with neuromyelitis optica spectrum disorder (NMOSD), there are few reports of SSS associated with NMOSD. We report a patient with NMOSD who developed refractory nausea, vomiting and SSS as the initial manifestation. Case presentation A 77-year-old female developed refractory nausea and frequent episodes of syncope. The patient was diagnosed with SSS because sinus pauses lasting five to six seconds were observed, and pacemaker implantation was performed. Two months later, she was referred to our hospital because of limb weakness and sensory impairment that progressed over a month. The patient was confirmed to have muscle weakness; manual muscle testing revealed grade 4 in the upper extremities and grade 3 in the lower extremities. Tendon reflexes were diminished, while no pathological reflexes were present. Thermal and pain sensations were impaired in the upper and lower extremities, and vibration sensation was impaired in both lower extremities. Bladder and rectal disturbances were also noted. Optic neuritis was not detected. T2-weighted magnetic resonance imaging (MRI) showed high-intensity lesions in the dorsal part of the medulla oblongata and C3–6 cervical cord. Her serum was positive for antibodies against aquaporin 4, and a diagnosis of NMOSD was made. She was treated with two courses of an intravenous methylprednisolone pulse and one course of plasma exchange. Then, she was transferred to another hospital for rehabilitation. Conclusions Because SSS is a life-threatening complication, clinicians should be aware of the possibility that medullary lesions in NMOSD can cause SSS as the initial manifestation.

Background and Purpose: The timely and accurate diagnosis of neuromyelitis optica spectrum disorder (NMOSD) is essential and exposure to multiple sclerosis (MS) disease‐modifying therapies may result in permanent neurological disability. Methods: Standardized 3‐Tesla 3‐dimensional brain MRI studies were retrospectively studied from people with NMOSD, MS, other CNS neurological diseases, and healthy control subjects. Comparisons of surface texture characteristics at the area postrema involving absolute introverted planar triangle counts, representing more complex and concave tissue topography, along with the spatial dissemination pattern of these triangles were performed cross‐sectionally and longitudinally. An ideal introverted planar triangle threshold separating groups with NMOSD and MS was accomplished using the highest Youden's J statistic. For the classification of NMOSD, out‐of‐sample and in‐sample measurements of the following were acquired: sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: The study cohort included 60 people with NMOSD, 100 people with MS, 12 with other neurological diseases, and five healthy controls. Significantly higher cross‐sectional median introverted triangle counts were observed when the NMOSD (median [interquartile range]: 100 [23.5]) group was compared to MS (65 [20.25]; p <.0001) and other neurological diseases (66 [13.75]; p <.0001). Distinct spatial dissemination patterns of triangles extending craniocaudally at the region of interest within the dorsal medulla was also seen between groups with NMOSD and MS (p <.0001). For the identification of NMOSD, out‐of‐sample sensitivity (83%), specificity (100%), PPV (100%), and NPV (60%) were achieved. Conclusions: Cross‐sectional and longitudinal dorsal medulla surface texture differences within selective regions of vulnerability differentiate NMOSD from MS. [ABSTRACT FROM AUTHOR]

Cushing's syndrome is due to increased glucocorticoid levels in the body, and it is characterized by several clinical alterations which concern both vegetative and behavioral functions. The anatomical correlates of these effects remain largely unknown. Apart from peripheral effects induced by corticosteroids as counter-insular hormones, only a few reports are available concerning the neurobiology of glucocorticoid-induced vegetative and behavioral alterations. In the present study, C57 Black mice were administered daily a chronic treatment with corticosterone in drinking water. This treatment produces a significant and selective increase of TH-positive neurons within two nuclei placed in the lateral column of the brainstem reticular formation. These alterations significantly correlate with selective domains of Cushing's syndrome. Specifically, the increase of TH neurons within area postrema significantly correlates with the development of glucose intolerance, which is in line with the selective control by area postrema of vagal neurons innervating the pancreas. The other nucleus corresponds to the retrorubral field, which is involved in the behavioral activity. In detail, the retrorubral field is likely to modulate anxiety and mood disorders, which frequently occur following chronic exposure to glucocorticoids. To our knowledge, this is the first study that provides the neuroanatomical basis underlying specific symptoms occurring in Cushing's syndrome. [ABSTRACT FROM AUTHOR]

Abstract Background Although area postrema syndrome (APS) is one of the core clinical features of neuromyelitis optic spectrum disorder (NMOSD), it is frequently misdiagnosed as gastrointestinal or systemic disorders. In this study, we describe the diagnostic challenges in NMOSD patients with APS and their characteristic clinical and radiological features. All patients who attended our university hospitals during the period from March 2019 to August 2020 with a diagnosis of NMOSD according to the latest diagnostic criteria were admitted and evaluated clinically, radiologically with gadolinium-enhanced brain and spinal MRI, measures of serum Anti-Aquaporin 4 (Anti-AQP4) and clinical status using the Expanded Disability Status Scale (EDSS) scores. APS was diagnosed if there was a history of intractable nausea, vomiting, or hiccups (INVH) that had lasted longer than 1 week with the exclusion of other etiologies, or less than 48 h if associated with a lesion in the dorsal medulla on MRI scan. Results Twenty out of 90 (22.2%) identified patients with a diagnosis of NMOSD had a history of unexplained intractable nausea, vomiting or hiccoughs lasting an average of 20 days. Seventeen patients were anti-Aquaporin 4 seropositive. Seven patients (35%) presented initially with isolated clinical features of APS and were diagnosed only after subsequent relapse. Patients with APS preceding other core clinical presentations (13 cases, 65%) were diagnosed after development of motor manifestations. All patients developed acute myelitis during the course of illness. Brain and spinal MRI scans showed that 13 had a linear lesion in the dorsal tegmentum of the medulla oblongata adjacent to the fourth ventricle. Otherwise, longitudinally extensive transverse myelitis was found in 80%, while 35% showed extension of the cord lesion to the AP. Conclusions APS as a core clinical characteristic of NMOSD is not a rare presentation as was previously thought and can occur in both AQP4-seropositive and seronegative NMOSD.

This article presents a clinical review of a patient with an extremely rare assotiation of opticoneuromyelitis and skin melanoma. The paper noted the typical clinical and neuroimaging signs of opticoneuromyelitis and the rare manifestations of myelitic syndrome such as segmental muscle hypertonicity and hand hyperkinesis. The question remains open as to whether these two processes in a patient are linked by a single pathogenesis in the form of a paraneoplastic neurological syndrome or whether two independent diseases are represent there. Two observations of a combination of melanoma and opticoneuromyelitis as a manifestation of the paraneoplastic syndrome have been analysed in the literature. The article highlights the difficulties in the treatment of this patient, as the immunomodulatory therapy used for both diseases has a different vectorial focus. Immunosuppression is recommended for the treatment of opticoneuromyelitis, while immune activation is recommended for melanoma.

Abstract Background Central nervous system (CNS)-mediated symptoms, such as fatigue, depression, and hyperalgesia, are common complications among patients with rheumatoid arthritis (RA). However, it remains unclear how the peripheral pathology of RA spreads to the brain. Accumulated evidence showing an association between serum cytokine levels and aberrant CNS function suggests that humoral factors participate in this mechanism. In contrast to the well-known early responses of microglia (CNS-resident immune cells) in the area postrema [AP; a brain region lacking a blood–brain barrier (BBB)] to experimental inflammation, microglial alterations in the AP during chronic inflammation like RA remain unclear. Therefore, to determine whether microglia in the AP can react to persistent autoimmune-arthritis conditions, we analyzed these cells in a mouse model of collagen-induced arthritis (CIA). Methods Microglial number and morphology were analyzed in the AP of CIA and control mice (administered Freund’s adjuvant or saline). Immunostaining for ionized calcium-binding adaptor molecule-1 was performed at various disease phases: “pre-onset” [post-immunization day (PID) 21], “establishment” (PID 35), and “chronic” (PID 56 and 84). Quantitative analyses of microglial number and morphology were performed, with principal component analysis used to classify microglia. Interleukin-1β (IL-1β) mRNA expression was analyzed by multiple fluorescent in situ hybridization and real-time polymerase chain reaction. Behavioral changes were assessed by sucrose preference test. Results Microglia in the AP significantly increased in density and exhibited changes in morphology during the establishment and chronic phases, but not the pre-onset phase. Non-subjective clustering classification of cell morphology (CIA, 1,256 cells; saline, 852 cells) showed that the proportion of highly activated microglia increased in the CIA group during establishment and chronic phases. Moreover, the density of IL-1β-positive microglia, a hallmark of functional activation, was increased in the AP. Sucrose preferences in CIA mice negatively correlated with IL-1β expression in brain regions containing the AP. Conclusions Our findings demonstrate that microglia in the AP can sustain their activated state during persistent autoimmune arthritis, which suggests that chronic inflammation, such as RA, may affect microglia in brain regions lacking a BBB and have various neural consequences.

Cushing's syndrome is due to increased glucocorticoid levels in the body, and it is characterized by several clinical alterations which concern both vegetative and behavioral functions. The anatomical correlates of these effects remain largely unknown. Apart from peripheral effects induced by corticosteroids as counter-insular hormones, only a few reports are available concerning the neurobiology of glucocorticoid-induced vegetative and behavioral alterations. In the present study, C57 Black mice were administered daily a chronic treatment with corticosterone in drinking water. This treatment produces a significant and selective increase of TH-positive neurons within two nuclei placed in the lateral column of the brainstem reticular formation. These alterations significantly correlate with selective domains of Cushing's syndrome. Specifically, the increase of TH neurons within area postrema significantly correlates with the development of glucose intolerance, which is in line with the selective control by area postrema of vagal neurons innervating the pancreas. The other nucleus corresponds to the retrorubral field, which is involved in the behavioral activity. In detail, the retrorubral field is likely to modulate anxiety and mood disorders, which frequently occur following chronic exposure to glucocorticoids. To our knowledge, this is the first study that provides the neuroanatomical basis underlying specific symptoms occurring in Cushing's syndrome.

A fundamental requirement for all animals is to sense and respond to changes in environmental O 2 availability. Low O 2 (hypoxia) typically stimulates breathing, a universal and critical response termed the hypoxic ventilatory response (HVR). In this study, we test the hypothesis that taste-signaling pathways are used for O 2 sensing and activation of the HVR. We show that Merkel-like cells (MLCs), which are part of the taste-bud complex, function as O 2 chemoreceptor cells in larval zebrafish and that transduction of the O 2 signal uses taste-signaling pathways. Specifically, MLCs responded to hypoxia in vivo with an increase in Ca2+ activity that can drive the HVR. In addition, MLCs transmit O 2 signals to afferent cranial nerves IX and X (nIX/X), which project into the area postrema within the hindbrain and synapse with interneurons that are in contact with vagal motor neurons. Hypoxia or chemo-activation of nIX/X caused Ca2+ activity to increase within the area postrema and elicited hyperventilation. The results provide the first demonstration of an O 2 signaling pathway that commences with the activation of taste receptors (MLCs) to yield a critical physiological reflex, the HVR. • Merkel-like cells (MLCs) function as zebrafish O 2 chemoreceptor cells • MLCs directly transmit O 2 signals to afferent cranial nerves • Activation of afferent cranial nerves drives hyperventilation during hypoxia Pan and Perry show that Merkel-like cells (MLCs), which are part of the taste-bud complex in developing zebrafish, are responsive to oxygen in vivo and can transmit oxygen signals to the central nervous system via peripheral sensory neurons to drive increased breathing during hypoxia, the classic hypoxic ventilatory response. [ABSTRACT FROM AUTHOR]

Abstract Background Early stage neuromyelitis optica spectrum disorders (NMOSD) with non-opticospinal manifestations as initial symptoms are easily misdiagnosed; however, data on the full symptom profile are limited. Moreover, the clinical characteristics and long-term outcomes of these patients remain unknown. We sought to analyze the clinical characteristics, imaging features, and long-term outcomes of NMOSD with non-opticospinal manifestations as initial symptoms. Methods We retrospectively included relevant patients from our center. Clinical, demographic, magnetic resonance imaging, treatment, and outcome data were compared according to the non-opticospinal vs. opticospinal initial symptoms. Results We identified 43 (9.13 %) patients with non-opticospinal initial symptoms among 471 patients with NMOSD. Of these, 88.37 % developed optic neuritis/myelitis during an average follow-up period of 6.33 years. All the non-opticospinal symptoms were brain/brainstem symptoms. Most of the symptoms and associated brain lesions were reversible. These patients had a younger onset age (P

Objective: Growth differentiation factor 15 (GDF15) is known to play a role in feeding, nausea, and body weight, with action through the GFRAL-RET receptor complex in the area postrema (AP) and nucleus tractus solitarius (NTS). To further elucidate the underlying cell type-specific molecular mechanisms downstream of GDF15 signaling, we used a single nuclei RNA sequencing (snRNAseq) approach to profile AP and NTS cellular subtype-specific transcriptomes after systemic GDF15 treatment. Methods: AP and NTS micropunches were used for snRNAseq from Sprague Dawley rats 6 h following GDF15 or saline injection, and Seurat was used to identify cellular subtypes and cell type-specific alterations in gene expression that were due to the direct and secondary effects of systemic GDF15 treatment. Results: Using the transcriptome profile of ∼35,000 individual AP/NTS nuclei, we identified 19 transcriptomically distinct cellular subtypes, including a single population Gfral and Ret positive excitatory neurons, representing the primary site of action for GDF15. A total of ∼600 cell type-specific differential expression events were identified in neurons and glia, including the identification of transcriptome alterations specific to the direct effects of GDF15 in the Gfral-Ret positive excitatory neurons and shared transcriptome alterations across neuronal and glial cell types. Downstream analyses identified shared and cell type-specific alterations in signaling pathways and upstream regulatory mechanisms of the observed transcriptome alterations. Conclusions: These data provide a considerable advance in our understanding of AP and NTS cell type-specific molecular mechanisms associated with GDF15 signaling. The identified cellular subtype-specific regulatory mechanism and signaling pathways likely represent important targets for future pharmacotherapies.

Introduced less than two decades ago, glucagon‐like peptide‐1 receptor agonists rapidly reshaped the field of Type 2 diabetes mellitus (T2DM) care by providing glycaemic control in tandem with weight loss. However, FDA‐approved GLP‐1 receptor agonists are often accompanied by nausea and emesis and, in some lean T2DM patients, by undesired anorexia. Importantly, the hypophagic and emetic effects of GLP‐1 receptor agonists are caused by activation of central GLP‐1 receptors. This review summarizes two different approaches to mitigate the incidence and severity of nausea and emesis related to GLP‐1 receptor agonists: conjugation with vitamin B12, or related corrin ring‐containing compounds ('corrination'), and development of dual agonists of GLP‐1 receptors with glucose‐dependent insulinotropic polypeptide (GIP). Such approaches could lead to the generation of GLP‐1 receptor agonists with improved therapeutic efficacy, thus decreasing treatment attrition, increasing patient compliance and extending treatment to a broader population of T2DM patients. The data reviewed show that it is possible to pharmacologically separate the emetic effects of GLP‐1 receptor agonists from their glucoregulatory action. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc [ABSTRACT FROM AUTHOR]

Background: Sick sinus syndrome (SSS) is known to occur due to lesions in the medulla oblongata. Although medullary lesions have occurred in patients with neuromyelitis optica spectrum disorder (NMOSD), there are few reports of SSS associated with NMOSD. We report a patient with NMOSD who developed refractory nausea, vomiting and SSS as the initial manifestation.Case Presentation: A 77-year-old female developed refractory nausea and frequent episodes of syncope. The patient was diagnosed with SSS because sinus pauses lasting five to six seconds were observed, and pacemaker implantation was performed. Two months later, she was referred to our hospital because of limb weakness and sensory impairment that progressed over a month. The patient was confirmed to have muscle weakness; manual muscle testing revealed grade 4 in the upper extremities and grade 3 in the lower extremities. Tendon reflexes were diminished, while no pathological reflexes were present. Thermal and pain sensations were impaired in the upper and lower extremities, and vibration sensation was impaired in both lower extremities. Bladder and rectal disturbances were also noted. Optic neuritis was not detected. T2-weighted magnetic resonance imaging (MRI) showed high-intensity lesions in the dorsal part of the medulla oblongata and C3-6 cervical cord. Her serum was positive for antibodies against aquaporin 4, and a diagnosis of NMOSD was made. She was treated with two courses of an intravenous methylprednisolone pulse and one course of plasma exchange. Then, she was transferred to another hospital for rehabilitation.Conclusions: Because SSS is a life-threatening complication, clinicians should be aware of the possibility that medullary lesions in NMOSD can cause SSS as the initial manifestation. [ABSTRACT FROM AUTHOR]

Objective: Rare disease Background: Neuromyelitis optica spectrum disorder (NMOSD), which is also known as Devic disease, is a chronic disorder of the brain and spinal cord that includes inflammation of the optic nerve and spinal cord. Area postrema syndrome (APS) is due to involvement of the bulbar emetic reflex center, and has previously been described in NMOSD. Patients with APS may present with nausea, vomiting, or hiccups. This report is of a 33-year-old Asian American woman with history of APS who presented with NMOSD. Case Report: A 33-year-old Southeast Asian woman, 2 months postpartum, presented with fever, hypersomnolence, altered mental status, and difficulty ambulating. Neurological examination revealed a lethargic woman with poor attention span, broad-based gait ataxia, and positive Romberg's sign. Laboratory work-up showed sodium 123 milliequivalent/L (mEq/L). Brain magnetic resonance imaging (MRI) with contrast revealed bilateral, non-enhancing, patchy fluid-attenuated inversion recovery (FLAIR) hyperintensities in the anteroinferomedial thalamus extending to the mammillary bodies. Additional history revealed hospitalization for intractable nausea, vomiting, and hiccups 2 years ago. NMOSD was confirmed with positive AQP-4 antibody, prompting treatment with intravenous (i.v.) methylprednisolone, followed by plasmapheresis. Repeat brain MRI showed mild improvement of bilateral thalamic FLAIR hyperintensities and no clinical recurrence was reported with Rituximab treatment. Conclusions: This case highlights the importance of the diagnostic diligence required for NMOSD diagnosis. Multiple etiologies can mimic the clinical presentation of acute diencephalic syndrome; thus, a broad differential needs to be considered. This report presents the diagnostic work-up and management of a patient with a complex neurological condition that was diagnosed as NMOSD. [ABSTRACT FROM AUTHOR]

The occurrence of pure light exerts a variety of effects in the human body, which span from behavioral alterations, such as light-driven automatic motor activity, cognition and mood to more archaic vegetative functions, which encompass most organs of the body with remarkable effects on the cardiovascular system. Although empirical evidence clearly indicates occurrence of these widespread effects, the anatomical correlates and long-lasting changes within putatively specific neuronal circuitries remain largely unexplored. A specific role is supposed to take place for catecholamine containing neurons in the core of the brainstem reticular formation, which produces a widespread release of noradrenaline in the forebrain while controlling the vegetative nervous system. An indirect as well as a direct (mono-synaptic) retino-brainstem pathway is hypothesized to rise from a subtype of intrinsically photosensitive retinal ganglion cells (iPRGCs), subtype M1, which do stain for Brn3b, and project to the pre-tectal region (including the olivary pre-tectal nucleus). This pathway provides profuse axon collaterals, which spread to the periaqueductal gray and dorsal raphe nuclei. According to this evidence, a retino-reticular monosynaptic system occurs, which powerfully modulate the noradrenergic hub of reticular nuclei in the lateral column of the brainstem reticular formation. These nuclei, which are evidenced in the present study, provide the anatomical basis to induce behavioral and cardiovascular modulation. The occurrence of a highly interconnected network within these nuclei is responsible for light driven plastic effects, which may alter persistently behavior and vegetative functions as the consequence of long-lasting alterations in the environmental light stimulation of the retina. These changes, which occur within the core of an archaic circuitry such as the noradrenaline-containing neurons of the reticular formation, recapitulate, within the CNS, ancestral effects of light-driven changes, which can be detected already within the retina itself at the level of multipotent photic cells. [ABSTRACT FROM AUTHOR]

Objective: The area postrema (AP) and nucleus tractus solitarius (NTS) located in the hindbrain are key nuclei that sense and integrate peripheral nutritional signals and consequently regulate feeding behaviour. While single-cell transcriptomics have been used in mice to reveal the gene expression profile and heterogeneity of key hypothalamic populations, similar in-depth studies have not yet been performed in the hindbrain. Methods: Using single-nucleus RNA sequencing, we provide a detailed survey of 16,034 cells within the AP and NTS of mice in the fed and fasted states. Results: Of these, 8,910 were neurons that group into 30 clusters, with 4,289 from mice fed ad libitum and 4,621 from overnight fasted mice. A total of 7,124 nuclei were from non-neuronal cells, including oligodendrocytes, astrocytes, and microglia. Interestingly, we identified that the oligodendrocyte population was particularly transcriptionally sensitive to an overnight fast. The receptors GLP1R, GIPR, GFRAL, and CALCR, which bind GLP1, GIP, GDF15, and amylin, respectively, are all expressed in the hindbrain and are major targets for anti-obesity therapeutics. We characterise the transcriptomes of these four populations and show that their gene expression profiles are not dramatically altered by an overnight fast. Notably, we find that roughly half of cells that express GIPR are oligodendrocytes. Additionally, we profile POMC-expressing neurons within the hindbrain and demonstrate that 84% of POMC neurons express either PCSK1, PSCK2, or both, implying that melanocortin peptides are likely produced by these neurons. Conclusion: We provide a detailed single-cell level characterisation of AP and NTS cells expressing receptors for key anti-obesity drugs that are either already approved for human use or in clinical trials. This resource will help delineate the mechanisms underlying the effectiveness of these compounds and also prove useful in the continued search for other novel therapeutic targets.

Intracerebroventricular administration of the protein hormone fibroblast growth factor 19 (FGF19) to the hindbrain produces potent antidiabetic effects in hyperglycemic mice that are likely mediated through a vagal parasympathetic mechanism. FGF19 increases the synaptic excitability of parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV) from hyperglycemic, but not normoglycemic, mice but the source of this synaptic input is unknown. Neurons in the area postrema (AP) and nucleus tractus solitarius (NTS) express high levels of FGF receptors and exert glutamatergic control over the DMV. This study tested the hypothesis that FGF19 increases glutamate release in the DMV by increasing the activity of glutamatergic AP and NTS neurons in hyperglycemic mice. Glutamate photoactivation experiments confirmed that FGF19 increases synaptic glutamate release from AP and NTS neurons that connect to the DMV in hyperglycemic, but not normoglycemic mice. Contrary to expectations, FGF19 produced a mixed effect on intrinsic membrane properties in the NTS with a trend towards inhibition, suggesting that another mechanism was responsible for the observed effects on glutamate release in the DMV. Consistent with the hypothesis, FGF19 increased action potential-dependent glutamate release in the NTS in hyperglycemic mice only. Finally, glutamate photoactivation experiments confirmed that FGF19 increases the activity of glutamatergic AP neurons that project to the NTS in hyperglycemic mice. Together, these results support the hypothesis that FGF19 increases glutamate release from AP and NTS neurons that project to the DMV in hyperglycemic mice. FGF19 therefore modifies the local vago-vagal reflex circuitry at several points. Additionally, since the AP and NTS communicate with several other metabolic regulatory nuclei in the brain, FGF19 in the hindbrain may alter neuroendocrine and behavioral aspects of metabolism, in addition to changes in parasympathetic output.

Background: Although area postrema syndrome (APS) is one of the core clinical features of neuromyelitis optic spectrum disorder (NMOSD), it is frequently misdiagnosed as gastrointestinal or systemic disorders. In this study, we describe the diagnostic challenges in NMOSD patients with APS and their characteristic clinical and radiological features. All patients who attended our university hospitals during the period from March 2019 to August 2020 with a diagnosis of NMOSD according to the latest diagnostic criteria were admitted and evaluated clinically, radiologically with gadolinium-enhanced brain and spinal MRI, measures of serum Anti-Aquaporin 4 (Anti-AQP4) and clinical status using the Expanded Disability Status Scale (EDSS) scores. APS was diagnosed if there was a history of intractable nausea, vomiting, or hiccups (INVH) that had lasted longer than 1 week with the exclusion of other etiologies, or less than 48 h if associated with a lesion in the dorsal medulla on MRI scan. Results: Twenty out of 90 (22.2%) identified patients with a diagnosis of NMOSD had a history of unexplained intractable nausea, vomiting or hiccoughs lasting an average of 20 days. Seventeen patients were anti-Aquaporin 4 seropositive. Seven patients (35%) presented initially with isolated clinical features of APS and were diagnosed only after subsequent relapse. Patients with APS preceding other core clinical presentations (13 cases, 65%) were diagnosed after development of motor manifestations. All patients developed acute myelitis during the course of illness. Brain and spinal MRI scans showed that 13 had a linear lesion in the dorsal tegmentum of the medulla oblongata adjacent to the fourth ventricle. Otherwise, longitudinally extensive transverse myelitis was found in 80%, while 35% showed extension of the cord lesion to the AP. Conclusions: APS as a core clinical characteristic of NMOSD is not a rare presentation as was previously thought and can occur in both AQP4-seropositive and seronegative NMOSD. [ABSTRACT FROM AUTHOR]

Intracerebroventricular administration of the protein hormone fibroblast growth factor 19 (FGF19) to the hindbrain produces potent antidiabetic effects in hyperglycemic mice that are likely mediated through a vagal parasympathetic mechanism. FGF19 increases the synaptic excitability of parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV) from hyperglycemic, but not normoglycemic, mice but the source of this synaptic input is unknown. Neurons in the area postrema (AP) and nucleus tractus solitarius (NTS) express high levels of FGF receptors and exert glutamatergic control over the DMV. This study tested the hypothesis that FGF19 increases glutamate release in the DMV by increasing the activity of glutamatergic AP and NTS neurons in hyperglycemic mice. Glutamate photoactivation experiments confirmed that FGF19 increases synaptic glutamate release from AP and NTS neurons that connect to the DMV in hyperglycemic, but not normoglycemic mice. Contrary to expectations, FGF19 produced a mixed effect on intrinsic membrane properties in the NTS with a trend towards inhibition, suggesting that another mechanism was responsible for the observed effects on glutamate release in the DMV. Consistent with the hypothesis, FGF19 increased action potential-dependent glutamate release in the NTS in hyperglycemic mice only. Finally, glutamate photoactivation experiments confirmed that FGF19 increases the activity of glutamatergic AP neurons that project to the NTS in hyperglycemic mice. Together, these results support the hypothesis that FGF19 increases glutamate release from AP and NTS neurons that project to the DMV in hyperglycemic mice. FGF19 therefore modifies the local vago-vagal reflex circuitry at several points. Additionally, since the AP and NTS communicate with several other metabolic regulatory nuclei in the brain, FGF19 in the hindbrain may alter neuroendocrine and behavioral aspects of metabolism, in addition to changes in parasympathetic output. [ABSTRACT FROM AUTHOR]