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Vasoactive intestinal polypeptide (VIP) is known to be present in a subclass of cortical interneurons. Here, using three different antibodies, we demonstrate that VIP is also present in the giant layer 5 pyramidal (Betz) neurons which are characteristic of the limb and axial representations of the marmoset primary motor cortex (cytoarchitectural area 4ab). No VIP staining was observed in smaller layer 5 pyramidal cells present in the primary motor facial representation (cytoarchitectural area 4c), or in the premotor cortex (e.g. the caudal subdivision of the dorsal premotor cortex, A6DC), indicating the selective expression of VIP in Betz cells. VIP in Betz cells was colocalized with neuronal specific marker (NeuN) and a calcium-binding protein parvalbumin (PV). PV also intensely labelled axon terminals surrounding Betz cell somata. VIP-positive interneurons were more abundant in the superficial cortical layers and constituted about 5–7% of total cortical neurons, with the highest density observed in area 4c. Our results demonstrate the expression of VIP in the largest excitatory neurons of the primate cortex, which may offer new functional insights into the role of VIP in the brain, and provide opportunities for genetic manipulation of Betz cells. [ABSTRACT FROM AUTHOR]

Abstract Vasoactive intestinal polypeptide (VIP) is known to be present in a subclass of cortical interneurons. Here, using three different antibodies, we demonstrate that VIP is also present in the giant layer 5 pyramidal (Betz) neurons which are characteristic of the limb and axial representations of the marmoset primary motor cortex (cytoarchitectural area 4ab). No VIP staining was observed in smaller layer 5 pyramidal cells present in the primary motor facial representation (cytoarchitectural area 4c), or in the premotor cortex (e.g. the caudal subdivision of the dorsal premotor cortex, A6DC), indicating the selective expression of VIP in Betz cells. VIP in Betz cells was colocalized with neuronal specific marker (NeuN) and a calcium-binding protein parvalbumin (PV). PV also intensely labelled axon terminals surrounding Betz cell somata. VIP-positive interneurons were more abundant in the superficial cortical layers and constituted about 5–7% of total cortical neurons, with the highest density observed in area 4c. Our results demonstrate the expression of VIP in the largest excitatory neurons of the primate cortex, which may offer new functional insights into the role of VIP in the brain, and provide opportunities for genetic manipulation of Betz cells.

Pregnancy outcome relies on the maintenance of immune and metabolic homeostasis at the maternal fetal interface. Maternal and perinatal morbidity and mortality is associated with impaired placental development. Multiple regulatory effects of the endogenous-produced vasoactive intestinal peptide (VIP) on vascular, metabolic and immune functions at the maternal-fetal interface have been reported. Here we studied the involvement of the two primary high affinity receptors for VIP (VPAC1 and VPAC2) on maternal immune response, placental homeostasis and pregnancy outcome. Targeted disruption of each receptor gene led to altered placental structure, vascular and trophoblast functional markers and shaped the functional profiles of macrophages and neutrophils towards a proinflammatory state. Several changes in pregnant mice were receptor specific: ROS production elicited by VIP on neutrophils was selectively dependent on the presence of VPAC1 whereas apoptosis rate was associated with the VPAC2 deletion. In peritoneal macrophages from pregnant mice, levels of MHC-II, TLR2, and IL-10 were selectively altered in VPAC2 receptor-deficient mice, whereas IL-6 gene expression was reduced only in mice lacking VPAC1 receptors. Additionally, MMP9 mRNA in isolated TGCs was reduced in VPAC2 receptor deleted mice, while the percentage of IL-12 cells in post-phagocytosis macrophage cultures was selectively reduced in VPAC2 receptor deficient mice. The results indicate that manipulation of VPAC1 and VPAC2 receptor affects immune, vascular and metabolic environment at the maternal fetal interface. These mouse models offer new approaches to study pregnancy complications adding new perspectives to the development of VPAC receptor-selective drugs.

Background & Aims: Although chronic diarrhea and constipation are common, the treatment is symptomatic because their pathophysiology is poorly understood. Accumulating evidence suggests that the microbiota modulates gut function, but the underlying mechanisms are unknown. We therefore investigated the pathways by which microbiota modulates gastrointestinal motility in different sections of the alimentary tract. Methods: Gastric emptying, intestinal transit, muscle contractility, acetylcholine release, gene expression, and vasoactive intestinal polypeptide (VIP) immunoreactivity were assessed in wild-type and Myd88-/-Trif-/- mice in germ-free, gnotobiotic, and specific pathogen-free conditions. Effects of transient colonization and antimicrobials as well as immune cell blockade were investigated. VIP levels were assessed in human full-thickness biopsies by Western blot. Results: Germ-free mice had similar gastric emptying but slower intestinal transit compared with specific pathogen-free mice or mice monocolonized with Lactobacillus rhamnosus or Escherichia coli, the latter having stronger effects. Although muscle contractility was unaffected, its neural control was modulated by microbiota by up-regulating jejunal VIP, which co-localized with and controlled cholinergic nerve function. This process was responsive to changes in the microbial composition and load and mediated through toll-like receptor signaling, with enteric glia cells playing a key role. Jejunal VIP was lower in patients with chronic intestinal pseudo-obstruction compared with control subjects. Conclusions: Microbial control of gastrointestinal motility is both region- and bacteria-specific; it reacts to environmental changes and is mediated by innate immunity-neural system interactions. By regulating cholinergic nerves, small intestinal VIP plays a key role in this process, thus providing a new therapeutic target for patients with motility disorders.

Simple Summary: The basolateral amygdala (BLA) contains neurons that produce neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP). These neuropeptides are involved in the regulation of several brain functions and behaviors, and there is evidence that, in some brain regions, the acetylcholine might modulate its expression. Thus, we study if aging alters the BLA densities of NPY- and VIP-positive neurons and cholinergic varicosities. We also investigate if any potential change in these parameters might be related to insufficient trophic support provided by the neurotrophin nerve growth factor (NGF). We found that the density of NPY-positive neurons was reduced in aged rats, whereas the density of VIP-immunoreactive neurons was unchanged. The decreased expression of NPY was fully reversed by intracerebroventricular administration of NGF. The density of cholinergic varicosities was similar in adult and old rats, and the infusion of NGF to aged rats increased their density to greater than the values of adult and old rats. These results indicate that the NPY expression in the BLA is affected by aging, and also show that this age-related change can be associated with alterations in the NGF trophic support. Furthermore, the results also show that the BLA cholinergic innervation is particularly resistant to age effects. The basolateral amygdala (BLA) contains interneurons that express neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP), both of which are involved in the regulation of functions and behaviors that undergo deterioration with aging. There is considerable evidence that, in some brain areas, the expression of NPY and VIP might be modulated by acetylcholine. Importantly, the BLA is one of the brain regions that has one of the densest cholinergic innervations, which arise mainly from the basal forebrain cholinergic neurons. These cholinergic neurons depend on nerve growth factor (NGF) for their survival, connectivity, and function. Thus, in this study, we sought to determine if aging alters the densities of NPY- and VIP-positive neurons and cholinergic varicosities in the BLA and, in the affirmative, if those changes might rely on insufficient trophic support provided by NGF. The number of NPY-positive neurons was significantly reduced in aged rats, whereas the number of VIP-immunoreactive neurons was unaltered. The decreased NPY expression was fully reversed by the infusion of NGF in the lateral ventricle. The density of cholinergic varicosities was similar in adult and old rats. On the other hand, the density of cholinergic varicosities is significantly higher in old rats treated with NGF than in adult and old rats. Our results indicate a dissimilar resistance of different populations of BLA interneurons to aging. Furthermore, the present data also show that the BLA cholinergic innervation is particularly resistant to aging effects. Finally, our results also show that the reduced NPY expression in the BLA of aged rats can be related to changes in the NGF neurotrophic support. [ABSTRACT FROM AUTHOR]

VIPomas are a type of neuroendocrine tumor that independently produces vasoactive intestinal peptide (VIP). VIPomas causing watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome are not frequently observed in adult patients without pancreatic ailments. However, in children, the occurrence of a VIPoma originating in the pancreas is exceedingly uncommon. Instead, WDHA syndrome is more commonly associated with neurogenic tumors that secrete VIP, often located in the retroperitoneum or mediastinum. Among infants, chronic diarrhea is a prevalent issue that often necessitates the attention of pediatric gastroenterologists. The underlying causes are diverse, and delays in arriving at a definitive diagnosis can give rise to complications affecting the overall well-being of the child. The authors present the case of an infant with chronic watery diarrhea, subocclusion manifestations, mild hypokalemia, and metabolic hyperchloremic acidosis secondary to a VIPoma in the retroperitoneum that was diagnosed via abdominal ultrasound and tomography. The laboratory results revealed lowered potassium levels and an excessive secretion of VIP. Following the surgical removal of the tumor, the diarrhea resolved, and both electrolyte levels and the imbalanced hormone levels returned to normal. Immunohistochemical examination confirmed the diagnosis of ganglioneuroblastoma, with N-MYC negative on molecular biology tests. We present the clinical and histo-genetic aspects of this rare clinical entity, with a literature review. [ABSTRACT FROM AUTHOR]

Abstract Background Migraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal role in the pathogenesis of migraine. This knowledge has led to the development of CGRP(-receptor) therapies. Yet, a substantial proportion of patients do not respond to these treatments. Therefore, alternative targets for future therapies are warranted. The current narrative review provides a comprehensive overview of the pathophysiological role of these possible non-CGRP targets in migraine. Findings We covered targets of the metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, and adrenomedullin), intracellular targets (nitric oxide (NO), phosphodiesterase-3 (PDE3) and -5 (PDE5)), and ion channels (potassium, calcium, transient receptor potential (TRP), and acid-sensing ion channels (ASIC)). The majority of non-CGRP targets were able to induce migraine-like attacks, except for (i) calcium channels, as it is not yet possible to directly target channels to elucidate their precise involvement in migraine; (ii) TRP channels, activation of which can induce non-migraine headache; and (iii) ASICs, as their potential in inducing migraine attacks has not been investigated thus far. Drugs that target its receptors exist for PACAP, NO, and the potassium, TRP, and ASIC channels. No selective drugs exist for the other targets, however, some existing (migraine) treatments appear to indirectly antagonize responses to amylin, adrenomedullin, and calcium channels. Drugs against PACAP, NO, potassium channels, TRP channels, and only a PAC1 antibody have been tested for migraine treatment, albeit with ambiguous results. Conclusion While current research on these non-CGRP drug targets has not yet led to the development of efficacious therapies, human provocation studies using these targets have provided valuable insight into underlying mechanisms of migraine headaches and auras. Further studies are needed on these alternative therapies in non-responders of CGRP(-receptor) targeted therapies with the ultimate aim to pave the way towards a headache-free future for all migraine patients.

The basolateral amygdala (BLA) contains interneurons that express neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP), both of which are involved in the regulation of functions and behaviors that undergo deterioration with aging. There is considerable evidence that, in some brain areas, the expression of NPY and VIP might be modulated by acetylcholine. Importantly, the BLA is one of the brain regions that has one of the densest cholinergic innervations, which arise mainly from the basal forebrain cholinergic neurons. These cholinergic neurons depend on nerve growth factor (NGF) for their survival, connectivity, and function. Thus, in this study, we sought to determine if aging alters the densities of NPY- and VIP-positive neurons and cholinergic varicosities in the BLA and, in the affirmative, if those changes might rely on insufficient trophic support provided by NGF. The number of NPY-positive neurons was significantly reduced in aged rats, whereas the number of VIP-immunoreactive neurons was unaltered. The decreased NPY expression was fully reversed by the infusion of NGF in the lateral ventricle. The density of cholinergic varicosities was similar in adult and old rats. On the other hand, the density of cholinergic varicosities is significantly higher in old rats treated with NGF than in adult and old rats. Our results indicate a dissimilar resistance of different populations of BLA interneurons to aging. Furthermore, the present data also show that the BLA cholinergic innervation is particularly resistant to aging effects. Finally, our results also show that the reduced NPY expression in the BLA of aged rats can be related to changes in the NGF neurotrophic support.

Background: Migraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal role in the pathogenesis of migraine. This knowledge has led to the development of CGRP(-receptor) therapies. Yet, a substantial proportion of patients do not respond to these treatments. Therefore, alternative targets for future therapies are warranted. The current narrative review provides a comprehensive overview of the pathophysiological role of these possible non-CGRP targets in migraine. Findings: We covered targets of the metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, and adrenomedullin), intracellular targets (nitric oxide (NO), phosphodiesterase-3 (PDE3) and -5 (PDE5)), and ion channels (potassium, calcium, transient receptor potential (TRP), and acid-sensing ion channels (ASIC)). The majority of non-CGRP targets were able to induce migraine-like attacks, except for (i) calcium channels, as it is not yet possible to directly target channels to elucidate their precise involvement in migraine; (ii) TRP channels, activation of which can induce non-migraine headache; and (iii) ASICs, as their potential in inducing migraine attacks has not been investigated thus far. Drugs that target its receptors exist for PACAP, NO, and the potassium, TRP, and ASIC channels. No selective drugs exist for the other targets, however, some existing (migraine) treatments appear to indirectly antagonize responses to amylin, adrenomedullin, and calcium channels. Drugs against PACAP, NO, potassium channels, TRP channels, and only a PAC1 antibody have been tested for migraine treatment, albeit with ambiguous results. Conclusion: While current research on these non-CGRP drug targets has not yet led to the development of efficacious therapies, human provocation studies using these targets have provided valuable insight into underlying mechanisms of migraine headaches and auras. Further studies are needed on these alternative therapies in non-responders of CGRP(-receptor) targeted therapies with the ultimate aim to pave the way towards a headache-free future for all migraine patients. [ABSTRACT FROM AUTHOR]

Difference of onset of increase of PRL content in the anterior pituitary gland and plasma PRL concentration during the late stage of chicken embryogenesis is well known. To investigate the disagreement, changes in PRL content and PRL mRNA levels, and the effects of vasoactive intestinal polypeptides (VIP) on PRL release and PRL mRNA expression were examined using western blot analysis and real-time PCR quantification. Changes in SPRL content were strongly correlated with PRL mRNA levels. The increase in PRL content on day 17 of incubation may be caused by the increase in PRL mRNA levels on day 16 of incubation. Additionally, the effects of VIP on PRL release from the embryonic anterior pituitary gland were not observed until day 18 of embryogenesis. These results suggest that increased levels of PRL mRNA and PRL content in the anterior pituitary gland are closely correlated. However, the increased expression of PRL mRNA observed on day 17 and the initiation of PRL release from the anterior pituitary gland on day 19 were differentially regulated. According to the results of western blot analysis, the proportion of glycosylated PRL (G-PRL) and non-glycosylated PRL (NG-PRL) in the anterior pituitary gland at the end stage of development differed from the proportion of PRL released from the anterior pituitary gland. According to the results of two-dimensional western blot analysis, no isoforms with different isoelectric points were detected in the culture medium on days 19 and 20. These data suggest that the peptide chains of G-PRL and NG-PRL were not modified. In conclusion, the differentiation of PRL-producing cells and the maturation of the hypothalamus and anterior pituitary gland were completed at the end stage of incubation, and that different factors regulated the initiation of PRL mRNA expression before day 18 of incubation.

Vasoactive intestinal peptide (VIP), a gut peptide hormone originally reported as a vasodilator in 1970, has multiple physiological and pathological effects on development, growth, and the control of neuronal, epithelial, and endocrine cell functions that in turn regulate ion secretion, nutrient absorption, gut motility, glycemic control, carcinogenesis, immune responses, and circadian rhythms. Genetic ablation of this peptide and its receptors in mice also provides new insights into the contribution of VIP towards physiological signaling and the pathogenesis of related diseases. Here, we discuss the impact of VIP on gastrointestinal function and diseases based on recent findings, also providing insight into its possible therapeutic application to diabetes, autoimmune diseases and cancer.

Simple Summary: The enteric nervous system (ENS) is responsible for regulating the main functions of the intestines, i.e., absorption, secretion, peristalsis and sensation. The ENS is composed of nerve cells that form clusters in the form of ganglia arranged in nerve plexuses. Individual ganglia communicate through a system of nerve fibres. Each nerve cell or nerve fibre contains biologically active substances exerting a specific effect on the ENS. One such substance is extracellular adenosine 5′-triphosphate (ATP), which by activating purinoreceptors (including P2X2 receptors) may affect the functioning of the ENS. Previous research on the P2X2 receptor has focused mainly on laboratory animals, while little is known about this receptor in large mammals. Therefore, our research concerned the presence of the P2X2 receptor in the ENS of the small intestine of the pig and whether it coexists with the biologically active substances included in standard analyses in the ENS. The research showed that the P2X2 receptor is present in the neurons of the small intestine and coexists with some of the biologically active substances tested. These findings may suggest that the P2X2 receptor, activated by ATP, may exert an influence on the function of the small intestinal ENS of the pig. Extracellular adenosine 5′-triphosphate (ATP) is one of the best-known and frequently studied neurotransmitters. Its broad spectrum of biological activity is conditioned by the activation of purinergic receptors, including the P2X2 receptor. The P2X2 receptor is present in the central and peripheral nervous system of many species, including laboratory animals, domestic animals, and primates. However, the distribution of the P2X2 receptor in the nervous system of the domestic pig, a species increasingly used as an experimental model, is as yet unknown. Therefore, this study aimed to determine the presence of the P2X2 receptor in the neurons of the enteric nervous system (ENS) of the pig small intestine (duodenum, jejunum, and ileum) by the immunofluorescence method. In addition, the chemical code of P2X2-immunoreactive (IR) ENS neurons of the porcine small intestine was analysed by determining the coexistence of selected neuropeptides, i.e., vasoactive intestinal polypeptide (VIP), substance P (sP), and galanin. P2X2-IR neurons were present in the myenteric plexus (MP), outer submucosal plexus (OSP), and inner submucosal plexus (ISP) of all sections of the small intestine (duodenum, jejunum, and ileum). From 44.78 ± 2.24% (duodenum) to 63.74 ± 2.67% (ileum) of MP neurons were P2X2-IR. The corresponding ranges in the OSP ranged from 44.84 ± 1.43% (in the duodenum) to 53.53 ± 1.21% (in the jejunum), and in the ISP, from 53.10 ± 0.97% (duodenum) to 60.57 ± 2.24% (ileum). Immunofluorescence staining revealed the presence of P2X2-IR/galanin-IR and P2X2-IR/VIP-IR neurons in the MP, OSP, and ISP of the sections of the small intestine. The presence of sP was not detected in the P2X2-IR neurons of any ganglia tested in the ENS. Our results indicate for the first time that the P2X2 receptor is present in the MP, ISP, and OSP neurons of all small intestinal segments in pigs, which may suggest that its activation influences the action of the small intestine. Moreover, there is a likely functional interaction between P2X2 receptors and galanin or VIP, but not sP, in the ENS of the porcine small intestine. [ABSTRACT FROM AUTHOR]

VIPomas are a type of neuroendocrine tumor that independently produces vasoactive intestinal peptide (VIP). VIPomas causing watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome are not frequently observed in adult patients without pancreatic ailments. However, in children, the occurrence of a VIPoma originating in the pancreas is exceedingly uncommon. Instead, WDHA syndrome is more commonly associated with neurogenic tumors that secrete VIP, often located in the retroperitoneum or mediastinum. Among infants, chronic diarrhea is a prevalent issue that often necessitates the attention of pediatric gastroenterologists. The underlying causes are diverse, and delays in arriving at a definitive diagnosis can give rise to complications affecting the overall well-being of the child. The authors present the case of an infant with chronic watery diarrhea, subocclusion manifestations, mild hypokalemia, and metabolic hyperchloremic acidosis secondary to a VIPoma in the retroperitoneum that was diagnosed via abdominal ultrasound and tomography. The laboratory results revealed lowered potassium levels and an excessive secretion of VIP. Following the surgical removal of the tumor, the diarrhea resolved, and both electrolyte levels and the imbalanced hormone levels returned to normal. Immunohistochemical examination confirmed the diagnosis of ganglioneuroblastoma, with N-MYC negative on molecular biology tests. We present the clinical and histo-genetic aspects of this rare clinical entity, with a literature review.

Background/Aims: Circadian rhythms in behavior and physiology are programmed by the suprachiasmatic nucleus (SCN) of the hypothalamus. A subset of SCN neurons produce the neuropeptide arginine vasopressin (AVP), but it remains unclear whether AVP signaling influences the SCN clock directly. Methods: Here, we test that AVP signaling acting through V1A and V1B receptors influences molecular rhythms in SCN neurons. V1 receptor agonists were applied ex vivo to PERIOD2::LUCIFERASE SCN slices, allowing for real-time monitoring of changes in molecular clock function. Results: V1A/B agonists reset the phase of the SCN molecular clock in a time-dependent manner, with larger magnitude responses by the female SCN. Further, we found evidence that both Gαq and Gαs signaling pathways interact with V1A/B-induced SCN resetting, and that this response requires vasoactive intestinal polypeptide (VIP) signaling. Conclusions: Collectively, this work indicates that AVP signaling resets SCN molecular rhythms in conjunction with VIP signaling and in a manner influenced by sex. This highlights the utility of studying clock function in both sexes and suggests that signal integration in central clock circuits regulates emergent properties important for the control of daily rhythms in behavior and physiology. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with a strong neuroinflammatory component. Current treatments principally target the immune system but fail to preserve long-term myelin health and do not prevent neurological decline. Studies over the past two decades have shown that the structurally related neuropeptides VIP and PACAP (vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide, respectively) exhibit pronounced anti-inflammatory activities and reduce clinical symptoms in MS disease models, largely via actions on their bivalent VIP receptor type 1 and 2. Here, using the cuprizone demyelination model, we demonstrate that PACAP and VIP, and strikingly the PACAP-selective receptor PAC1 agonist maxadilan, prevented locomotor deficits in the horizontal ladder and open field tests. Moreover, only PACAP and maxadilan were able to prevent myelin deterioration, as assessed by a reduction in the expression of the myelin markers proteolipid protein 1, oligodendrocyte transcription factor 2, quaking-7 (APC) and Luxol Fast Blue staining. Furthermore, PACAP and maxadilan (but not VIP), prevented striatal synaptic loss and diminished astrocyte and microglial activation in the corpus callosum of cuprizone-fed mice. In vitro, PACAP or maxadilan prevented lipopolysaccharide (LPS)-induced polarisation of primary astrocytes at 12-24 h, an effect that was not seen with maxadilan in LPS-stimulated microglia. Taken together, our data demonstrates for the first time that PAC1 agonists provide distinctive protective effects against white matter deterioration, neuroinflammation and consequent locomotor dysfunctions in the cuprizone model. The results indicate that targeting the PAC1 receptor may provide a path to treat myelin-related diseases in humans., (© 2024 The Author(s). Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

VIPoma is an extremely rare neuroendocrine tumour. Majority of the lesions occur in the pancreas. There is usually a long and recurrent history of secretory diarrhoea. Current diagnostic methods help in diagnosing a VIPoma once it is suspected. We herein report a case of VIPoma which had the delay in diagnosis and presented at an extremely unusual location (pyloroduodenal) who underwent laparoscopic resection for the same.

Sex differences in behaviour partly arise from the sexual dimorphism of brain anatomy between males and females. However, the sexual dimorphism of the tree shrew brain is unclear. In the present study, we examined the detailed distribution of vasoactive intestinal polypeptide‐immunoreactive (VIP‐ir) neurons and fibres in the suprachiasmatic nucleus (SCN) and VIP‐ir fibres in the bed nucleus of the stria terminalis (BST) of male and female tree shrews. The overall volume of the SCN in male tree shrews was comparable with that in females. However, males showed a significantly higher density of VIP‐ir cells and fibres in the SCN than females. The shape of the VIP‐stained area in coronal sections was arched, elongated or oval in the lateral division (STL) and the anterior part of the medial division (STMA) of the BST and oval or round in the posterior part of the medial division of the BST (STMP). The volume of the VIP‐stained BST in male tree shrews was similar to that in females. The overall distribution of VIP‐ir fibres was similar between the sexes throughout the BST except within the STMA, where darkly stained fibres were observed in males, whereas lightly stained fibres were observed in females. Furthermore, male tree shrews showed a significantly higher intensity of Nissl staining in the medial preoptic area (MPA) and the ventral part of the medial division of the BST than females. These findings are the first to reveal sexual dimorphism in the SCN, BST and MPA of the tree shrew brain, providing neuroanatomical evidence of sexual dimorphism in these regions related to their roles in sex differences in physiology and behaviour. [ABSTRACT FROM AUTHOR]

Vasoactive intestinal peptide (VIP) is a neuropeptide that is produced by the lymphoid cells and plays a major role in immunological functions for controlling the homeostasis of the immune system. VIP has been identified as a potent anti-inflammatory factor, in boosting both innate and adaptive immunity. Since December 2019, SARS‐Cov‐2 was found responsible for the disease COVID‐19 which has spread worldwide. No specific therapies or 100% effective vaccines are yet available for the treatment of COVID‐19. Drug repositioning may offer a strategy and several drugs have been repurposed, including lopinavir/ritonavir, remdesivir, favipiravir, and tocilizumab. This paper describes the main pharmacological properties of synthetic VIP drug (Aviptadil) which is now under clinical trials. A patented formulation of vasoactive intestinal polypeptide (VIP), named RLF-100 (Aviptadil), was developed and finally got approved for human trials by FDA in 2001 and in European medicines agency in 2005. It was awarded Orphan Drug Designation in 2001 by the US FDA for the treatment of acute respiratory distress syndrome and for the treatment of pulmonary arterial hypertension in 2005. Investigational new drug (IND) licenses for human trials of Aviptadil was guaranteed by both the US FDA and EMEA. Preliminary clinical trials seem to support Aviptadil's benefit. However, such drugs like Aviptadil in COVID‐19 patients have peculiar safety profiles. Thus, adequate clinical trials are necessary for these compounds. [ABSTRACT FROM AUTHOR]

GABAergic neurons play a crucial role in shaping cortical activity. Even though GABAergic neurons constitute a small fraction of cortical neurons, their peculiar morphology and functional properties make them an intriguing and challenging task to study. Here, we review the basic anatomical features, the circuit properties, and the possible role in the relevant behavioral task of a subclass of GABAergic neurons that express vasoactive intestinal polypeptide (VIP). These studies were performed using transgenic mice in which the VIP-expressing neurons can be recognized using fluorescent proteins and optogenetic manipulation to control (or regulate) their electrical activity. Cortical VIP-expressing neurons are more abundant in superficial cortical layers than other cortical layers, where they are mainly studied. Optogenetic and paired recordings performed in ex vivo cortical preparations show that VIP-expressing neurons mainly exert their inhibitory effect onto somatostatin-expressing (SOM) inhibitory neurons, leading to a disinhibitory effect onto excitatory pyramidal neurons. However, this subclass of GABAergic neurons also releases neurotransmitters onto other GABAergic and non-GABAergic neurons, suggesting other possible circuit roles than a disinhibitory effect. The heterogeneity of VIP-expressing neurons also suggests their involvement and recruitment during different functions via the inhibition/disinhibition of GABAergic and non-GABAergic neurons locally and distally, depending on the specific local circuit in which they are embedded, with potential effects on the behavioral states of the animal. Although VIP-expressing neurons represent only a tiny fraction of GABAergic inhibitory neurons in the cortex, these neurons' selective activation/inactivation could produce a relevant behavioral effect in the animal. Regardless of the increasing finding and discoveries on this subclass of GABAergic neurons, there is still a lot of missing information, and more studies should be done to unveil their role at the circuit and behavior level in different cortical layers and across different neocortical areas. [ABSTRACT FROM AUTHOR]

GABAergic neurons play a crucial role in shaping cortical activity. Even though GABAergic neurons constitute a small fraction of cortical neurons, their peculiar morphology and functional properties make them an intriguing and challenging task to study. Here, we review the basic anatomical features, the circuit properties, and the possible role in the relevant behavioral task of a subclass of GABAergic neurons that express vasoactive intestinal polypeptide (VIP). These studies were performed using transgenic mice in which the VIP-expressing neurons can be recognized using fluorescent proteins and optogenetic manipulation to control (or regulate) their electrical activity. Cortical VIP-expressing neurons are more abundant in superficial cortical layers than other cortical layers, where they are mainly studied. Optogenetic and paired recordings performed in ex vivo cortical preparations show that VIP-expressing neurons mainly exert their inhibitory effect onto somatostatin-expressing (SOM) inhibitory neurons, leading to a disinhibitory effect onto excitatory pyramidal neurons. However, this subclass of GABAergic neurons also releases neurotransmitters onto other GABAergic and non-GABAergic neurons, suggesting other possible circuit roles than a disinhibitory effect. The heterogeneity of VIP-expressing neurons also suggests their involvement and recruitment during different functions via the inhibition/disinhibition of GABAergic and non-GABAergic neurons locally and distally, depending on the specific local circuit in which they are embedded, with potential effects on the behavioral states of the animal. Although VIP-expressing neurons represent only a tiny fraction of GABAergic inhibitory neurons in the cortex, these neurons’ selective activation/inactivation could produce a relevant behavioral effect in the animal. Regardless of the increasing finding and discoveries on this subclass of GABAergic neurons, there is still a lot of missing information, and more studies should be done to unveil their role at the circuit and behavior level in different cortical layers and across different neocortical areas.

Inflammatory bowel disease (IBD) constitutes an important clinically significant condition that results in morbidity and mortality. IBD can be generally classified into either ulcerative colitis (UC) or Crohn's disease (CD) that differs in the clinical and histopathology. The role of neuropeptides in the pathogenesis of these conditions is becoming increasingly recognized for their importance in modulating the inflammatory state. Animal models provide the greatest insight to better understand the pathophysiology of both disorders which will hopefully allow for improved treatment strategies. This review will provide a better understanding of the role of murine models for studying colitis.

OPINION STATEMENT:Hypersecretory conditions affecting the stomach account for significant morbidity and mortality manifested in some cases with peptic ulcer, gastrointestinal hemorrhage, and/or gastroesophageal reflux disease (GERD). The diagnosis of gastric acid hypersecretory states can be challenging and relies on the use of quantitative assays to measure gastric acid secretion and serum gastrin. The most common etiology for hypergastrinemia is the use of potent gastric acid inhibitors such as the proton pump inhibitors. The differential diagnosis of this condition is of critical importance, and will dictate management decisions. Conditions such as atrophic gastritis are relatively benign and can lead to hypergastrinemia without the presence of gastric acid hypersecretion. Zollinger-Ellison syndrome, on the other hand, causes hypergastrinemia with profound gastric acid hypersecretion [1]. More common causes of hypergastrinemia include gastric outlet obstruction, ileus, and chronic renal failure [2]. In most cases, proton pump inhibitors will be used to manage these conditions. In some instances, surgical therapy may be required. This chapter will review the important clinical causes of gastric acid hypersecretion and provide insights to the best medical management options to better care for patients with these disorders.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two neuropeptides that contribute to the regulation of intestinal motility and secretion, exocrine and endocrine secretions, and homeostasis of the immune system. Their biological effects are mediated by three receptors named VPAC1, VPAC2 and PAC1 that belong to class B GPCRs. VIP and PACAP receptors have been identified as potential therapeutic targets for the treatment of chronic inflammation, neurodegenerative diseases and cancer. However, pharmacological use of endogenous ligands for these receptors is limited by their lack of specificity (PACAP binds with high affinity to VPAC1, VPAC2 and PAC1 receptors while VIP recognizes both VPAC1 and VPAC2 receptors), their poor oral bioavailability (VIP and PACAP are 27- to 38-amino acid peptides) and their short half-life. Therefore, the development of non-peptidic small molecules or specific stabilized peptidic ligands is of high interest. Structural similarities between VIP and PACAP receptors are major causes of difficulties in the design of efficient and selective compounds that could be used as therapeutics. In this study we performed structure-based virtual screening against the subset of the ZINC15 drug library. This drug repositioning screen provided new applications for a known drug: ticagrelor, a P2Y12 purinergic receptor antagonist. Ticagrelor inhibits both VPAC1 and VPAC2 receptors which was confirmed in VIP-binding and calcium mobilization assays. A following analysis of detailed ticagrelor binding modes to all three VIP and PACAP receptors with molecular dynamics revealed its allosteric mechanism of action. Using a validated homology model of inactive VPAC1 and a recently released cryo-EM structure of active VPAC1 we described how ticagrelor could block conformational changes in the region of 'tyrosine toggle switch' required for the receptor activation. We also discuss possible modifications of ticagrelor comparing other P2Y12 antagonist – cangrelor, closely related to ticagrelor but not active for VPAC1/VPAC2. This comparison with inactive cangrelor could lead to further improvement of the ticagrelor activity and selectivity for VIP and PACAP receptor sub-types. [ABSTRACT FROM AUTHOR]

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two neuropeptides that contribute to the regulation of intestinal motility and secretion, exocrine and endocrine secretions, and homeostasis of the immune system. Their biological effects are mediated by three receptors named VPAC1, VPAC2 and PAC1 that belong to class B GPCRs. VIP and PACAP receptors have been identified as potential therapeutic targets for the treatment of chronic inflammation, neurodegenerative diseases and cancer. However, pharmacological use of endogenous ligands for these receptors is limited by their lack of specificity (PACAP binds with high affinity to VPAC1, VPAC2 and PAC1 receptors while VIP recognizes both VPAC1 and VPAC2 receptors), their poor oral bioavailability (VIP and PACAP are 27- to 38-amino acid peptides) and their short half-life. Therefore, the development of non-peptidic small molecules or specific stabilized peptidic ligands is of high interest. Structural similarities between VIP and PACAP receptors are major causes of difficulties in the design of efficient and selective compounds that could be used as therapeutics. In this study we performed structure-based virtual screening against the subset of the ZINC15 drug library. This drug repositioning screen provided new applications for a known drug: ticagrelor, a P2Y12 purinergic receptor antagonist. Ticagrelor inhibits both VPAC1 and VPAC2 receptors which was confirmed in VIP-binding and calcium mobilization assays. A following analysis of detailed ticagrelor binding modes to all three VIP and PACAP receptors with molecular dynamics revealed its allosteric mechanism of action. Using a validated homology model of inactive VPAC1 and a recently released cryo-EM structure of active VPAC1 we described how ticagrelor could block conformational changes in the region of ‘tyrosine toggle switch’ required for the receptor activation. We also discuss possible modifications of ticagrelor comparing other P2Y12 antagonist – cangrelor, closely related to ticagrelor but not active for VPAC1/VPAC2. This comparison with inactive cangrelor could lead to further improvement of the ticagrelor activity and selectivity for VIP and PACAP receptor sub-types.

Extracellular adenosine 5′-triphosphate (ATP) is one of the best-known and frequently studied neurotransmitters. Its broad spectrum of biological activity is conditioned by the activation of purinergic receptors, including the P2X2 receptor. The P2X2 receptor is present in the central and peripheral nervous system of many species, including laboratory animals, domestic animals, and primates. However, the distribution of the P2X2 receptor in the nervous system of the domestic pig, a species increasingly used as an experimental model, is as yet unknown. Therefore, this study aimed to determine the presence of the P2X2 receptor in the neurons of the enteric nervous system (ENS) of the pig small intestine (duodenum, jejunum, and ileum) by the immunofluorescence method. In addition, the chemical code of P2X2-immunoreactive (IR) ENS neurons of the porcine small intestine was analysed by determining the coexistence of selected neuropeptides, i.e., vasoactive intestinal polypeptide (VIP), substance P (sP), and galanin. P2X2-IR neurons were present in the myenteric plexus (MP), outer submucosal plexus (OSP), and inner submucosal plexus (ISP) of all sections of the small intestine (duodenum, jejunum, and ileum). From 44.78 ± 2.24% (duodenum) to 63.74 ± 2.67% (ileum) of MP neurons were P2X2-IR. The corresponding ranges in the OSP ranged from 44.84 ± 1.43% (in the duodenum) to 53.53 ± 1.21% (in the jejunum), and in the ISP, from 53.10 ± 0.97% (duodenum) to 60.57 ± 2.24% (ileum). Immunofluorescence staining revealed the presence of P2X2-IR/galanin-IR and P2X2-IR/VIP-IR neurons in the MP, OSP, and ISP of the sections of the small intestine. The presence of sP was not detected in the P2X2-IR neurons of any ganglia tested in the ENS. Our results indicate for the first time that the P2X2 receptor is present in the MP, ISP, and OSP neurons of all small intestinal segments in pigs, which may suggest that its activation influences the action of the small intestine. Moreover, there is a likely functional interaction between P2X2 receptors and galanin or VIP, but not sP, in the ENS of the porcine small intestine.

VIPoma is an extremely rare neuroendocrine tumour. Majority of the lesions occur in the pancreas. There is usually a long and recurrent history of secretory diarrhoea. Current diagnostic methods help in diagnosing a VIPoma once it is suspected. We herein report a case of VIPoma which had the delay in diagnosis and presented at an extremely unusual location (pyloroduodenal) who underwent laparoscopic resection for the same. [ABSTRACT FROM AUTHOR]

Exposure to a high‐fat diet (HFD) has been reported to impair central autonomic and enteric neurocircuitries, however, the relevant mechanisms and their time course are inadequately clarified. This study aimed to investigate the effects of HFD consumption through the period of adolescence on gastric motor functions in adulthood. Male Sprague‐Dawley rats consumed a regular diet or HFD (60% kcal by fat) from 4 to 12 weeks of age. Body weight and food intake were monitored weekly. In adult rats, gastric emptying (GE) was measured. Additionally, using in‐vitro organ bath, contractile and relaxant responses of antral and fundic strips were assessed with bethanechol and sodium nitroprusside (SNP), respectively. The expressions of choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP) were detected by immunofluorescence, whereas, the number of myenteric neurons were evaluated by staining with cuprolinic blue and enteric neuronal marker PGP 9.5. In adulthood, the HFD did not alter food intake, while significantly increasing the body weight. In HFD‐fed adult rats, increased visceral fat mass was accompanied by delayed GE. Moreover, bethanechol‐ and SNP‐induced responses were attenuated in antral and fundic tissues. HFD remarkably decreased the number of myenteric neurons and NOS immunoreactivity both in fundus and antrum. HFD remarkably decreased ChAT expression, while increasing the immunoreactivity for VIP in antrum. In conclusion, consumption of HFD between early adolescence and adulthood results in obesity and impairment of gastric motor functions. Particularly, HFD‐induced gastric dysmotility appears to be predominantly dependent on the modifications in the non‐adrenergic non‐cholinergic inhibitory neurotransmission. [ABSTRACT FROM AUTHOR]

Abstract Background Administration of endogenous mediators or exogenous chemicals in migraine patients provoke early headaches and delayed migraine-like attacks. Although migraine provoking substances are normally vasodilators, dilation of arterial vessels does not seem to be the sole contributing factor, and the underlying mechanisms of the delayed migraine pain are mostly unknown. Sustained mechanical allodynia is a common response associated with the local administration of various proalgesic substances in experimental animals and humans. Here, we investigated the ability of a series of endogenous mediators which provoke or do not provoke migraine in patients, to cause or not cause mechanical allodynia upon their injection in the mouse periorbital area. Methods Mechanical allodynia was assessed with the von Frey filament assay. Stimuli were given by subcutaneous injection in the periorbital area of C57BL/6J mice; antagonists were administered by local and systemic injections. Results Calcitonin gene related peptide (CGRP), but not adrenomedullin and amylin, pituitary adenylyl cyclase activating peptide (PACAP), but not vasoactive intestinal polypeptide (VIP), histamine, prostaglandin E2 (PGE2) and prostacyclin (PGI2), but not PGF2α, evoked a dose-dependent periorbital mechanical allodynia. The painful responses were attenuated by systemic or local (periorbital) administration of antagonists for CGRP (CLR/RAMP1), PACAP (PAC-1), histamine H1, PGE2 (EP4), and PGI2 (IP) receptors, respectively. Conclusions The correspondence between substances that provoke (CGRP; PACAP, histamine, PGE2, PGI2), or do not provoke (VIP and PGF2α), migraine-like attacks in patients and periorbital allodynia in mice suggests that the study of allodynia in mice may provide information on the proalgesic mechanisms of migraine-provoking agents in humans. Results underline the ability of migraine-provoking substances to initiate mechanical allodynia by acting on peripheral terminals of trigeminal afferents.

Homeostasis of the human immune system is regulated by many cellular components, including two neuropeptides, VIP and PACAP, primary stimuli for three class B G protein-coupled receptors, VPAC1, VPAC2, and PAC1. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) regulate intestinal motility and secretion and influence the functioning of the endocrine and immune systems. Inhibition of VIP and PACAP receptors is an emerging concept for new pharmacotherapies for chronic inflammation and cancer, while activation of their receptors provides neuroprotection. A small number of known active compounds for these receptors still impose limitations on their use in therapeutics. Recent cryo-EM structures of VPAC1 and PAC1 receptors in their agonist-bound active state have provided insights regarding their mechanism of activation. Here, we describe major molecular switches of VPAC1, VPAC2, and PAC1 that may act as triggers for receptor activation and compare them with similar non-covalent interactions changing upon activation that were observed for other GPCRs. Interhelical interactions in VIP and PACAP receptors that are important for agonist binding and/or activation provide a molecular basis for the design of novel selective drugs demonstrating anti-inflammatory, anti-cancer, and neuroprotective effects. The impact of genetic variants of VIP, PACAP, and their receptors on signalling mediated by endogenous agonists is also described. This sequence diversity resulting from gene splicing has a significant impact on agonist selectivity and potency as well as on the signalling properties of VIP and PACAP receptors.

Background & Aims: Although chronic diarrhea and constipation are common, the treatment is symptomatic because their pathophysiology is poorly understood. Accumulating evidence suggests that the microbiota modulates gut function, but the underlying mechanisms are unknown. We therefore investigated the pathways by which microbiota modulates gastrointestinal motility in different sections of the alimentary tract., Methods: Gastric emptying, intestinal transit, muscle contractility, acetylcholine release, gene expression, and vasoactive intestinal polypeptide (VIP) immunoreactivity were assessed in wild-type and Myd88 -/- Trif -/- mice in germ-free, gnotobiotic, and specific pathogen-free conditions. Effects of transient colonization and antimicrobials as well as immune cell blockade were investigated. VIP levels were assessed in human full-thickness biopsies by Western blot., Results: Germ-free mice had similar gastric emptying but slower intestinal transit compared with specific pathogen-free mice or mice monocolonized with Lactobacillus rhamnosus or Escherichia coli, the latter having stronger effects. Although muscle contractility was unaffected, its neural control was modulated by microbiota by up-regulating jejunal VIP, which co-localized with and controlled cholinergic nerve function. This process was responsive to changes in the microbial composition and load and mediated through toll-like receptor signaling, with enteric glia cells playing a key role. Jejunal VIP was lower in patients with chronic intestinal pseudo-obstruction compared with control subjects., Conclusions: Microbial control of gastrointestinal motility is both region- and bacteria-specific; it reacts to environmental changes and is mediated by innate immunity-neural system interactions. By regulating cholinergic nerves, small intestinal VIP plays a key role in this process, thus providing a new therapeutic target for patients with motility disorders., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In the brain, there is a vast diversity of different structures, circuitries, cell types, and cellular genetic expression profiles. While this large diversity can often occlude a clear understanding of how the brain works, careful analyses of analogous studies performed across different brain areas can hint at commonalities in neuronal organization. This in turn can yield a fundamental understanding of necessary circuitry components that are crucial for how information is processed across the brain. In this review, we outline recent in vivo and in vitro studies that have been performed in different cortical areas to characterize the vasoactive intestinal polypeptide (VIP)- and/or calretinin (CR)-expressing cells that specialize in inhibiting GABAergic interneurons. In doing so, we make the case that, across cortical structures, interneuron-specific cells commonly specialize in the synaptic disinhibition of excitatory neurons, which can ungate the integration and plasticity of external inputs onto excitatory neurons. In line with this, activation of interneuron- specific cells enhances animal performance across a variety of behavioral tasks that involve learning, memory formation, and sensory discrimination, and may represent a key target for therapeutic interventions under different pathological conditions. As such, interneuron-specific cells across different cortical structures are an essential network component for information processing and normal brain function.

Abstract Background Although the pelvic autonomic plexus branches are considered to be a mixture of sympathetic and parasympathetic nerves, little is known regarding the composite fibers of the pelvic plexus branches. This study aimed to investigate the immunohistochemical features of sympathetic and parasympathetic nerves in the pelvic autonomic plexus branches. Methods Using 10 donated elderly male cadavers, the detailed topohistology of nerve fibers at and around the bladder, seminal vesicle, prostate, and rectum was examined. Neuronal nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP) were used as parasympathetic nerve markers; tyrosine hydroxylase (TH) was used as a sympathetic nerve marker. The myenteric plexus of the colon was utilized as a positive control. Results Most nerve fibers in the bladder, seminal vesicle, prostate, and rectum were both nNOS- and TH-positive. Thus, pelvic plexus branches were classified into two types: 1) triple-positive mixed nerves (nNOS+, VIP+, TH+, thick myelinated fibers + or -) and 2) double-positive mixed nerves (nNOS+, VIP-, TH+, thick myelinated fibers + or -). Notably, triple-positive nerves were localized within the posterosuperior part of the plexus (near the rectum) and travelled anteroinferiorly toward the posterolateral corner of the prostate. The posteriorly and inferiorly located nerves were predominantly composed of parasympathetic, rather than sympathetic, fibers. In contrast, nerve fibers within and along the bladder and seminal vesicle contained either no or few VIP-positive nerves. These superiorly located nerves were characterized by clear sympathetic nerve dominance. Conclusions The nerves of the pelvic plexus branches were clearly classified into nerves around the bladder and seminal vesicle (VIP-negative) and nerves around the prostate (VIP-positive). Although nNOS- and VIP-positive nerve fibers are candidate cavernous nerves, cavernous nerve identity cannot be definitively concluded for these nerves in the periprostatic region.

Circadian rhythms are programmed by the suprachiasmatic nucleus (SCN), which relies on neuropeptide signaling to maintain daily timekeeping. Vasoactive intestinal polypeptide (VIP) is critical for SCN function, but the precise role of VIP neurons in SCN circuits is not fully established. To interrogate their contribution to SCN circuits, VIP neurons can be manipulated specifically using the DNA-editing enzyme Cre recombinase. Although the Cre transgene is assumed to be inert by itself, we find that VIP expression is reduced in both heterozygous and homozygous adult VIP-IRES-Cre mice (JAX 010908). Compared with wild-type mice, homozygous VIP-Cre mice display faster reentrainment and shorter free-running period but do not become arrhythmic in constant darkness. Consistent with this phenotype, homozygous VIP-Cre mice display intact SCN PER2::LUC rhythms, albeit with altered period and network organization. We present evidence that the ability to sustain molecular rhythms in the VIP-Cre SCN is not due to residual VIP signaling; rather, arginine vasopressin signaling helps to sustain SCN function at both intracellular and intercellular levels in this model. This work establishes that the VIP-IRES-Cre transgene interferes with VIP expression but that loss of VIP can be mitigated by other neuropeptide signals to help sustain SCN function. Our findings have implications for studies employing this transgenic model and provide novel insight into neuropeptide signals that sustain daily timekeeping in the master clock. [ABSTRACT FROM AUTHOR]

In the brain, there is a vast diversity of different structures, circuitries, cell types, and cellular genetic expression profiles. While this large diversity can often occlude a clear understanding of how the brain works, careful analyses of analogous studies performed across different brain areas can hint at commonalities in neuronal organization. This in turn can yield a fundamental understanding of necessary circuitry components that are crucial for how information is processed across the brain. In this review, we outline recent in vivo and in vitro studies that have been performed in different cortical areas to characterize the vasoactive intestinal polypeptide (VIP)- and/or calretinin (CR)-expressing cells that specialize in inhibiting GABAergic interneurons. In doing so, we make the case that, across cortical structures, interneuron-specific cells commonly specialize in the synaptic disinhibition of excitatory neurons, which can ungate the integration and plasticity of external inputs onto excitatory neurons. In line with this, activation of interneuron- specific cells enhances animal performance across a variety of behavioral tasks that involve learning, memory formation, and sensory discrimination, and may represent a key target for therapeutic interventions under different pathological conditions. As such, interneuron-specific cells across different cortical structures are an essential network component for information processing and normal brain function. [ABSTRACT FROM AUTHOR]

Introduction: Pituitary adenylate cyclase-activating polypeptide (PACAP) is found in two functional isoforms, namely PACAP38 and PACAP27. The migraine-inducing properties of PACAP38 are well studied. However, it is not known whether the lesser-known and under-studied protein isoform, PACAP27, can also induce migraine attacks. Here, we studied the effect of human PACAP27 infusion on induction of migraine in a provocation model.Methods: In a crossover study, 20 migraine without aura patients were randomly assigned to receive human PACAP27 (10 picomol/kg/min) or saline (placebo) infusion over 20 min. We recorded the migraine and associated symptoms.Results: All patients completed the study. PACAP27 provoked migraine-like attacks in 11 patients (55%) and two developed attacks after placebo (10%) (p = 0.022). The headache intensity and duration after PACAP27 was significantly greater compared to placebo (p = 0.003).Conclusion: PACAP27 triggers migraine attacks without aura. These novel data strengthen the role of PACAP and its receptors in migraine pathogenesis. [ABSTRACT FROM AUTHOR]

A 2-year-old male child presented with upper respiratory tract infection along with history of recurrent watery diarrhea for the last 9 months, which was being treated as lactose intolerance. Computed tomography revealed a 5 cm right adrenal mass; complete excision was performed. Histopathology revealed a mature adrenal ganglioneuroma. The patient is no longer suffering from frequent diarrhea and is doing fine on 1-year follow-up. In any pediatric patient with adrenal tumor presenting with watery diarrhea, vasoactive intestinal polypeptide-producing ganglioneuroma must be kept as differential diagnosis.

Purpose: The present study aimed to investigate whether cervical vagal nerve stimulation (VNS) could prevent retinal ganglion cell (RGC) loss and retinal dysfunction after ischemia/reperfusion (I/R) injury.Methods: First, rats were randomly divided into sham group (n = 4) and VNS group (n = 12). Activation of the nodose ganglia (NOG), nucleus of the solitary tract (NTS), superior salivatory nucleus (SSN), and pterygopalatine ganglion (PPG) neural circuit were evaluated by c-fos expression at 0 h after sham VNS and at 0 h (n = 4), 6 h (n = 4), 72 h (n = 4) after VNS. Secondly, rats were randomly assigned to I/R group (pressure-induced retinal ischemia for 1 h and reperfusion for 1 h in the right eye, n = 16) and I/R+VNS group (right cervical VNS for 2 h during the I/R period, n = 16). The left eye of each rat served as a control. Electroretinogram (ERG), RGC numbers, tumor necrosis factor-α (TNF-α) and vasoactive intestinal polypeptide (VIP) levels in retina were determined. Additionally, the level of VIP in PPG was evaluated.Results: In the first part of the study, compared with the sham group, the VNS group exhibited significantly increased expression of c-fos in NOG, NTS, SSN, and PPG tissues at 0, 6, and 72 h. In the second part of the study, compared with left eyes, retinal function in right eyes (as assessed by the a-wave, b-wave and the oscillatory potential amplitudes of ERG and RGC data) was significantly decreased by I/R. The decreased retinal function was attenuated by VNS. In addition, I/R induced an increase in inflammation, which was reflected by elevated TNF-α expression in the retina. VNS significantly attenuated the increase in I/R-induced inflammation. Moreover, VIP expression in the retina and PPG, which may contribute to the inhibition of the inflammatory response, was significantly increased after VNS.Conclusion: VNS could protect against retinal I/R injury by downregulating TNF-α. Upregulation of VIP expression due to activation of the NOG-NTS-SSN-PPG neural circuit may underlie to the protective effects of VNS.