Central Neural System Research Articles

Intraoperative Germinoma Staining: A Technical Note.

As the main treatment modality of central neural system germinomas is radiotherapy and/or chemotherapy, the exact initial diagnosis of the disease is crucial. Depending on the different national protocols, histologic verification can be obligatory in some instances. This is a serious challenge, taking into account the usual location and nonspecific macroscopic appearance of these lesions. Here, we propose a safe and effective method of intraoperative tumor enhancement that can increase the confidence of the surgeon during the intervention.

PC12 differentiation to neuron cells activated by a low-level laser at 660 nm on UV pre-treated CR-39 scaffolds with parallel microchannels.

The lack of regeneration of injured neurons in the central and peripheral neural system leads to the failure of damaged tissue repair in patients. While there is no definitive cure for most neurodegenerative diseases, new therapeutic methods that cause the proliferation and differentiation of neurons are of interest. Challenges such as the inability of neuronal cells to proliferate after injury, the lack of a stimulus for initial stimulation, and the presence of the microenvironment around CNS neurons contain several inhibitory factors that prevent neuron regeneration, thus, creating a structure similar to the extracellular matrix helps the cell proliferation in current treatment. A rapid method of neuron-like cell differentiation of PC12 cells is introduced here based on a novel synthetic scaffold. Initially, poly allyldiglycol carbonate (CR-39) substrate is textured under a high dose of ArF UV excimer laser (1000 shot, 300 mJ/pulse equivalent to 300 J/cm2 at 193 nm) to create superficial periodic parallel microchannels with the micrometer spacing and sub-micron width. Ultraviolet treated CR-39 (UT CR-39) provides a suitable scaffold to speed up the transformation/differentiation of PC12 cells. The latter is pheochromocytoma of the rat adrenal medulla as an embryonic origin from the neural crest usually exposed to the nerve growth factor (NGF). In fact, PC12 cells are seeded on the microchannels and simultaneously are stimulated by coherent red photons at 660 nm within the therapeutic window. The UT CR-39 scaffold undergoes extra improvement of ∼ 30% after 12 minutes of laser activation regarding the photo-biomodulation (PBM) mechanism. The cell activation due to the coherent photons also gives rise to enhanced proliferation/differentiation. Here, PC12 cells are efficiently differentiated into neurons according to immunocytochemistry (ICC) and Western Blot verification tests based on MAP2 and synapsin-1 protein expression. In general, UT CR-39 acts as a superior bed to elevate the population of neuron-like cells up to threefold against those of untreated (control)ones. We conclude that the surface cross-linking due to UV exposure and subsequent induced hydrophilicity notably contribute to the neuron-like cell differentiation of PC12 without adding NGF.

Altered N-linked glycosylation in depression: A pre-clinical study

BackgroundNeuroimmune plays an important role in major depressive disorders (MDD). N-linked protein glycosylation (NLG) might contribute to depression by regulating the neuroinflammatory response. As microglia is the main executor of neuroimmune function in the central neural system (CNS), targeting the process of N-linked protein glycosylation of microglia in the mice used for studying depression might potentially offer new avenues for the strategy for MDD. MethodsThe chronic unpredictable mild stress (CUMS) mouse model was established for the whole brain microglia isolating. Then, RNA samples of microglia were extracted for transcriptome sequencing and mRNA analysis. Immunofluorescence (IF) was used to identify the expression level of NLG-related enzyme, B4galt1, in microglia. ResultsThe data showed that NLG was positively related to depression. Moreover, the NLG-related gene, B4galt1 increased expression in the microglia of CUMS mice. Then, the inhibition of NLG reversed the depressive behavior in CUMS mice. The expression level of B4galt1 in CUMS mice was upregulating following the NLG-inhibitor treatment. Similar results haven't been observed in neurons. Information obtained from these experiments showed increasing expression of B4galt1 in microglia following depressive-like behaviors. ConclusionsThese findings indicate that NLG in microglia is associated with MDD, and suggest that therapeutically targeting NLG might be an effective strategy for depression. LimitationsHow to modulate the B4galt1 or NLG pathways in microglia efficiently and economically request new technologies.

PIWI-Interacting RNAs: A Pivotal Regulator in Neurological Development and Disease.

PIWI-interacting RNAs (piRNAs), a class of small non-coding RNAs (sncRNAs) with 24-32 nucleotides (nt), were initially identified in the reproductive system. Unlike microRNAs (miRNAs) or small interfering RNAs (siRNAs), piRNAs normally guide P-element-induced wimpy testis protein (PIWI) families to slice extensively complementary transposon transcripts without the seed pairing. Numerous studies have shown that piRNAs are abundantly expressed in the brain, and many of them are aberrantly regulated in central neural system (CNS) disorders. However, the role of piRNAs in the related developmental and pathological processes is unclear. The elucidation of piRNAs/PIWI would greatly improve the understanding of CNS development and ultimately lead to novel strategies to treat neural diseases. In this review, we summarized the relevant structure, properties, and databases of piRNAs and their functional roles in neural development and degenerative disorders. We hope that future studies of these piRNAs will facilitate the development of RNA-based therapeutics for CNS disorders.

Peripheral cancer remodeling of central neural system.

Peripheral cancer remodeling of central neural system.

The Possibility of Improvement in Balance and Function Following Conjunct Effects of Transcranial Direct Current Stimulation and Whole-Body Vibration Therapy in Spastic Cerebral Palsy Patients: A Hypothesis Study

Cerebral palsy (CP) results from developmental brain injury, affecting posture and muscular coordination. Traditional treatments offer varying effectiveness, among them the most recent therapies are whole-body vibration therapy (WBVT) and transcranial direct current stimulation (tDCS). WBV enhances proprioceptive function, muscle mass, bone density, and joint stability by stimulating muscle spindle fibers and activating dormant motor units. It also modulates spastic reflexes through mechanoreceptors, proving more effective than traditional physiotherapy. tDCS, a non-invasive neuromodulation, reshapes cortical excitability and modulates synaptic plasticity by altering neuronal activity. It affects long-term potentiation and depression, crucial in learning and adaptive functions. tDCS's interaction with neurotransmitters, especially dopamine and GABA, and its effect on NMDA and dopaminergic receptors make it promising for CP rehabilitation. Both therapies offer novel insights into CP rehabilitation through their influence on central and peripheral neural system. This hypothesis study tends to explore the conjunct effects of transcranial direct current stimulation (tDCS) and whole-body vibration therapy (WBVT) on improving balance and function in children with spastic cerebral palsy. The hypothesis suggests that WBVT's vibratory input, alongside tDCS's central stimulation, enhances function by modulating neuronal excitability and sensory information. The tonic vibration reflex (TVR) from WBV is believed to amplify muscle strength and modulate spinal excitability. When integrated with tDCS, it might accelerate excitability in the motor cortex, essential for brain-injured patient rehabilitation. Despite evidence of individual benefits from both therapies, conjunct effects remain under-researched. Preliminary results show improvements in balance, gait velocity, and motor functions. Validating this combined approach could revolutionize treatment for children with spastic cerebral palsy.

Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice

Secretin, though originally discovered as a gut-derived hormone, is recently found to be abundantly expressed in the ventromedial hypothalamus, from which the central neural system controls satiety, energy metabolism, and bone homeostasis. However, the functional significance of secretin in the ventromedial hypothalamus remains unclear. Here we show that the loss of ventromedial hypothalamus-derived secretin leads to osteopenia in male and female mice, which is primarily induced by diminished cAMP response element-binding protein phosphorylation and upregulation in peripheral sympathetic activity. Moreover, the ventromedial hypothalamus-secretin inhibition also contributes to hyperphagia, dysregulated lipogenesis, and impaired thermogenesis, resulting in obesity in male and female mice. Conversely, overexpression of secretin in the ventromedial hypothalamus promotes bone mass accrual in mice of both sexes. Collectively, our findings identify an unappreciated secretin signaling in the central neural system for the regulation of energy and bone metabolism, which may serve as a new target for the clinical management of obesity and osteoporosis.

Association of Vitamin-D insufficiency and infertility: A Literature Review

Vitamin D receptors are present in both male and female central neural system and reproductive system hence Vitamin D sufficiency or insufficiency affects fertility. The present review aims to determine a correlation between Vitamin D insufficiency and infertility. Regarding female infertility, it was found that Vitamin D insufficiency is associated with increased issues during conception and higher miscarriage rate. Furthermore, Vitamin D insufficiency is associated with lower FSH levels affecting follicle formation, maturation and ovulation. Regarding male infertility, Vitamin D and its Receptor have been identified in the prostate, seminal vesicles, epididymis, germ cells, spermatogonia, spermatocytes and Sertoli cells. The prevalence of Vitamin D insufficiency is higher among men with lower sperm count and lower motility. However, the relation between Vitamin D and testosterone levels remain unclear. The present review stresses the effects of Vitamin D insufficiency in both male and female infertility.

METTL3-Dependent N6-Methyladenosine Modification Programs Human Neural Progenitor Cell Proliferation.

METTL3, a methyltransferase responsible for N6-methyladenosine (m6A) modification, plays key regulatory roles in mammal central neural system (CNS) development. However, the specific epigenetic mechanisms governing human CNS development remain poorly elucidated. Here, we generated small-molecule-assisted shut-off (SMASh)-tagged hESC lines to reduce METTL3 protein levels, and found that METTL3 is not required for human neural progenitor cell (hNPC) formation and neuron differentiation. However, METTL3 deficiency inhibited hNPC proliferation by reducing SLIT2 expression. Mechanistic studies revealed that METTL3 degradation in hNPCs significantly decreased the enrichment of m6A in SLIT2 mRNA, consequently reducing its expression. Our findings reveal a novel functional target (SLIT2) for METTL3 in hNPCs and contribute to a better understanding of m6A-dependent mechanisms in hNPC proliferation.

GlioPredictor: A Deep Learning Model for Identification of High-Risk Low-Grade Glioma toward Adjuvant Treatment Planning

High-risk low-grade glioma (LGG) patients are recommended to undergo adjuvant radiotherapy whereas watchful waiting is recommended for low-risk LGG patients per the latest NCCN guidelines. Based on Radiation Therapy Oncology Group (RTOG) 9802, high-risk features include age >40 or subtotal resection (STR). However, in the era of molecular-based classification for tumors of central neural system, current risk classification criteria based on gross disease and patient demographics may be outdated. Here, we aim to develop a molecular-based glioma risk classification system (GlioPredictor) that could potentially facilitate identification of high-risk LGG patients. A total of 507 LGG cases from The Cancer Genome Atlas-low grade glioma (TCGA-LGG), and 1,309 cases from AACR GENIE v13.0 datasets were studied for genetic disparities between IDH1-wildtype and mutated cohorts, and varying age groups. Through a feature selection technique using genomic profiling and correlation analyses, features such as mutation status, copy number variations (CNVs), among other clinicopathologic features prognostic of IDH1 mutation status were selected as potential inputs to train an artificial neural networks (ANNs) that could predict IDH1 mutation status. Model performance was assessed using the area under the receiver operating characteristic curve (AUC). Memorial Sloan Kettering (MSK) dataset (n = 404) for LGG was used to cross-validate the trained ANN. The optimized ANN model has 6 layers with 6 input nodes, 20 hidden nodes, and a binary output layer. The weights and biases of the hidden layers of the best-performing model were retrieved and reconstructed to yield the GlioPredictor score-the predicted risk of progression for IDH1-wildtype LGG. Over 81% of glioma patients age less than 40 have IDH1 mutation, as compared with 31% in those age above 60. Using age > 40 as a cutoff failed to identify high-risk IDH1-mutant LGG with early progression. IDH1 mutation is associated with decreased CNVs of EGFR (21 % vs. 3%), CDKN2A (20% vs. 6%) and PTEN (14% vs. 1.7%), and increased percentage of mutations for TP53 (15% vs. 63%), and ATRX (10% vs. 54%) (p<0.001). Using these molecular features, along with the patient's age, an ANN model with 6 layers and 20 hidden nodes can predict IDH1 mutation status with over 90% accuracy and AUC score over 0.91. We have developed an ANN model that is capable of learning the prognostic features of LGG associated with an IDH1-mutated LGG cohort and using the features to predict high-risk patients from the IDH1-wildtype cohort. This ANN model facilitates the selection of LGG patients who could benefit from immediate adjuvant radiotherapy. Future work includes the integration of image features to improve the prediction performance of the GlioPredictor system.

Research progress of acupuncture mediated analgesia via regulating the function of endocannabinoid system

Endocannabinoid system (ECS), which composed of its ligands and receptors, widely distributes in peripheral tissues and nerve system. Through complex regulating mechanisms, ECS exerts a variety of biological functions including analgesia. Its utility in analgesic regulation has attracted extensive attention, and the related achievements have also been transformed into clinical practice. With the deepened understanding of the essence of pain, as well as the advances in research techniques, quantity of research evidences showed that ECS could be regulated by acupuncture treatment and exerted analgesic effect in inflammatory pain, neuropathic pain and other related diseases, and the mechanism had also been revealed gradually. By reviewing literatures related to acupuncture analgesia and ECS, we summarized the effect and mechanism of acupuncture analgesia involved with regulation of ECS, pointed out cannabinoid (CB) 1 receptor and CB2 receptor exerted analgesic effect in central and peripheral neural system through mechanisms of inhibiting neural activation and anti-inflammation, respectively. Therefore, we hope to provide reference and inspiration for relevant research and clinical practice in the future.

Retinal microvasculature is a potential biomarker for acute mountain sickness.

Increased cerebral blood flow resulting from altered capillary level autoregulation at high altitudes leads to capillary overperfusion and then vasogenic cerebral edema, which is the leading hypothesis of acute mountain sickness (AMS). However, studies on cerebral blood flow in AMS have been mostly restricted to gross cerebrovascular endpoints as opposed to the microvasculature. This study aimed to investigate ocular microcirculation alterations, the only visualized capillaries in the central neural system (CNS), during early-stage AMS using a hypobaric chamber. This study found that after high altitude simulation, the optic nerve showed retinal nerve fiber layer thickening (P=0.004-0.018) in some locations, and the area of the optic nerve subarachnoid space (P=0.004) enlarged. Optical coherence tomography angiography (OCTA) showed increased retinal radial peripapillary capillary (RPC) flow density (P=0.003-0.046), particularly on the nasal side of the nerve. The AMS-positive group had the largest increases in RPC flow density in the nasal sector (AMS-positive, Δ3.21±2.37; AMS-negative, Δ0.01±2.16, P=0.004). Among multiple ocular changes, OCTA increase in RPC flow density was associated with simulated early-stage AMS symptoms (beta=0.222, 95%CI, 0.009-0.435, P=0.042). The area under the receiver operating characteristics curve (AUC) for the changes in RPC flow density to predict early-stage AMS outcomes was 0.882 (95%CI, 0.746-0.998). The results further confirmed that overperfusion of microvascular beds is the key pathophysiologic change in early-stage AMS. RPC OCTA endpoints may serve as a rapid, noninvasive potential biomarker for CNS microvascular changes and AMS development during risk assessment of individuals at high altitudes.

DUSP2 deletion with CRISPR/Cas9 promotes Mauthner cell axonal regeneration at the early stage of zebrafish.

Axon regeneration of central neurons is a complex process that is tightly regulated by multiple extrinsic and intrinsic factors. The expression levels of distinct genes are changed after central neural system (CNS) injury and affect axon regeneration. A previous study identified dusp2 as an upregulated gene in zebrafish with spinal cord injury. Here, we found that dual specificity phosphatase 2 (DUSP2) is a negative regulator of axon regeneration of the Mauthner cell (M-cell). DUSP2 is a phosphatase that mediates the dephosphorylation of JNK. In this study, we knocked out dusp2 by CRISPR/Cas9 and found that M-cell axons of dusp2-/- zebrafish had a better regeneration at the early stage after birth (within 8 days after birth), while those of dusp2+/- zebrafish did not. Overexpression of DUSP2 in Tg (Tol 056) zebrafish by single-cell electroporation retarded the regeneration of M-cell axons. Western blotting results showed that DUSP2 knockout slightly increased the levels of phosphorylated JNK. These findings suggest that knocking out DUSP2 promoted the regeneration of zebrafish M-cell axons, possibly through enhancing JNK phosphorylation.

Increased GABAergic projections in the paraventricular nucleus regulate colonic hypersensitivity via oxytocin in a rat model of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is characterized by gastrointestinal dysmotility and visceral hyperalgesia, and the impaired brain-gut axis is accepted as a crucial cause for the onset of IBS. The objective of this study is to investigate the effects of the adaptive changes in the central neural system induced by stress on IBS-like syndromes in rats. Long-term water avoidance stress (WAS) was used to prepare IBS animals. The changes in neuronal excitation and GABA expression were shown by immunohistochemistry. The mRNA and protein expressions of neurotransmitters were detected with Quantitative reverse-transcription PCR (qRT-PCR) and Enzyme-linked immunosorbent assay (ELISA). The intestinal transit time, fecal moisture content, and abdominal withdrawal reflex scores of rats were recorded to monitor intestinal motility and visceral hyperalgesia. In the WAS-treated rats with enhanced intestinal motility and visceral hypersensitivity, more GABAergic projections were found in the paraventricular nucleus (PVN) of the hypothalamus, which inhibited the firing rate of neurons and decreased the expression of oxytocin. Exogenous oxytocin improved gut motility and decreased AWR scores. The inhibition of oxytocin by the adaptive GABAergic projection in the PVN might be an important mediator of IBS, which indicates a potential novel therapeutic target.

Comprehensive characterization of TNFSF14/LIGHT with implications in prognosis and immunotherapy of human gliomas.

Glioblastoma multiforme (GBM) is a common central neural system malignant tumor among adults. Alongside its microscopic spread, immunosuppression in the tumor microenvironment also induces its refractoriness, which makes immunotherapy for GBM particularly important. Unfortunately, traditional immune checkpoint inhibitors (ICIs) often show limited therapeutic effects in GBM clinical trials, and new therapeutic strategies or targets are urgently needed. TNFSF14/LIGHT is a novel immune checkpoint molecule that plays essential roles in both innate and acquired immunity. Despite recent advances in our understanding of the function of TNFSF14/LIGHT in a variety of cancer types, the clinical and immunological importance of TNFSF14/LIGHT in human gliomas has not been fully explained. Here, we employed a comprehensive in silico analysis with publicly available data to analyze the molecular and immune characteristics of TNFSF14/LIGHT to explore its feasibility as an immunotherapy target. Totally, 2215 glioma cases were enrolled in the current study. Immunohistochemistry staining based on patient tissues (n = 34) was performed for the validation. TNFSF14/LIGHT was expressed higher in higher-WHO-grade gliomas and mesenchymal subtypes, and it was sensitive as a prognostic marker in GBM and low-grade glioma (LGG). A nomogram prognostic model was established based on TNFSF14/LIGHT expression together with other risk factors. Additionally, Gene Ontology and pathway analysis revealed that TNFSF14/LIGHT participated in T-cell activities and inflammatory processes. Moreover, analysis based on the structure and interactions of TNFSF14/LIGHT revealed its mutation sites in tumors as well as crucial interacting proteins. Analysis of IMvigor210 indicated the role of TNFSF14/LIGHT in immunotherapy. Altogether, our results reveal an underlying role of TNFSF14/LIGHT as an immunotherapy target in GBM.

Role of Demyelination in the Persistence of Neurological and Mental Impairments after COVID-19.

Long-term neurological and mental complications of COVID-19, the so-called post-COVID syndrome or long COVID, affect the quality of life. The most persistent manifestations of long COVID include fatigue, anosmia/hyposmia, insomnia, depression/anxiety, and memory/attention deficits. The physiological basis of neurological and psychiatric disorders is still poorly understood. This review summarizes the current knowledge of neurological sequelae in post-COVID patients and discusses brain demyelination as a possible mechanism of these complications with a focus on neuroimaging findings. Numerous reviews, experimental and theoretical studies consider brain demyelination as one of the mechanisms of the central neural system impairment. Several factors might cause demyelination, such as inflammation, direct effect of the virus on oligodendrocytes, and cerebrovascular disorders, inducing myelin damage. There is a contradiction between the solid fundamental basis underlying demyelination as the mechanism of the neurological injuries and relatively little published clinical evidence related to demyelination in COVID-19 patients. The reason for this probably lies in the fact that most clinical studies used conventional MRI techniques, which can detect only large, clearly visible demyelinating lesions. A very limited number of studies use specific methods for myelin quantification detected changes in the white matter tracts 3 and 10 months after the acute phase of COVID-19. Future research applying quantitative MRI assessment of myelin in combination with neurological and psychological studies will help in understanding the mechanisms of post-COVID complications associated with demyelination.

The Polycomb group gene rnf2 is essential for central and enteric neural system development in zebrafish.

The development of central nervous system (CNS) and enteric nervous system (ENS) is under precise and strict control in vertebrates. Whether and how the Polycomb repressive complex 1 (PRC1) is involved in it remain unclear. To investigate the role of PRC1 in the nervous system development, using CRISPR/Cas9 technology, we have generated mutant zebrafish lines for the rnf2 gene which encodes Ring1b, the enzymatic component of the PRC1 complex. We show that rnf2 loss of function leads to abnormal migration and differentiation of neural crest and neural precursor cells. rnf2 mutant embryos exhibit aganglionosis, in which the hindgut is devoid of neurons. In particular, the formation of 5-HT serotonin neurons and myelinating glial cells is defective. Furthermore, ectopic expression of ENS marker genes is observed in forebrain of rnf2 mutant embryos. These findings suggest that the rnf2 gene plays an important role in the migration and differentiation of neural precursor cells, and its absence leads to abnormal development of ENS and CNS in zebrafish.

Solid Lipid Nanoparticles: A Nano Drug Carrying System in Treatment of Nervous Diseases

Solid lipid nanoparticle (SLN) is a unique colloidal system used to deliver drugs which is nontoxic, biodegradable, showing good biocompatibility, and have small particle size. The possibility of SLN to deliver the brain drugs without damaging the brain-blood barrier (BBB) makes SLN an advanced central nervous system (CNS) drug delivery system. SLNs delivering drugs to CNS are mostly prepared by applying high energy homogenization method to achieve a better surface modification. The central topic of this article is how the SLN can overcome the BBB and help treat the central neural system disease. Also, SLNs contain levodopa can go through the BBB to help treat Parkinson’s and SLNs coated with chitosan and loaded with ferric acid to treat Alzheimer’s Disease (AD) are highlighted in this article. The effectiveness of SLNs compared with traditional therapy is shown in the article. Additionally, further studies are needed to focus on higher encapsulation efficiency and drug load efficiency as well as the targeted intranasal drug delivery.

COVID-19 induced psychosis. Should we be concerned?

IntroductionCoronaviruses traditionally are considered to cause pulmonary diseases, often accompanied by gastrointestinal symptoms. Since the COVID-19 pandemic start in early 2020, there have been reports of a high prevalence of neuropsychiatric symptoms. Recent data show significant rates of neuropsychiatric diagnosis over the subsequent 6 months post-infection. Some of the data suggest the COVID-19 as a cause of new-onset psychotic symptoms in patients with no psychiatric history. Delusions, hallucinations, disorganized thoughts, and confusion were the most frequently reported psychotic features which low doses of antipsychotics seem to be helpful.ObjectivesBrief literature review about the relationship between COVID-19 and new-onset psychotic symptomatology.MethodsNon-systematic review through PubMed research using the terms “COVID-19”, “SARS-CoV-2”, “pandemics”, “psychotic symptoms” and “psychosis”.ResultsThe severity of the infection, especially in those with the need for hospitalization/intensive care, seems to have a clear effect on the gravity of subsequent neuropsychiatric symptoms, namely psychosis. Viral invasion of the central neural system, hypercoagulable states, and neuroinflammation are potential associated mechanisms. It’s important to consider the effect of therapies that may have the potential to cause psychosis (eg steroids). According to recent literature, around 0.9-4% of people exposed to the COVID-19 virus develop psychotic episodes, which is much higher than the incidence in the general population.ConclusionsPost-COVID-19 related psychosis has been reported in different nations. The pathophysiology is yet not clear, although the hyperinflammatory response has been suggested as the main mechanism for the neuropsychiatric manifestations. Given the high number of case reports with similar presentations, it’s important to proceed with more investigations.DisclosureNo significant relationships.

Potential Therapeutic Targeting Neurotransmitter Receptors in Diabetes.

Neurotransmitters are signaling molecules secreted by neurons to coordinate communication and proper function among different sections in the central neural system (CNS) by binding with different receptors. Some neurotransmitters as well as their receptors are found in pancreatic islets and are involved in the regulation of glucose homeostasis. Neurotransmitters can act with their receptors in pancreatic islets to stimulate or inhibit the secretion of insulin (β cell), glucagon (α cell) or somatostatin (δ cell). Neurotransmitter receptors are either G-protein coupled receptors or ligand-gated channels, their effects on blood glucose are mainly decided by the number and location of them in islets. Dysfunction of neurotransmitters receptors in islets is involved in the development of β cell dysfunction and type 2 diabetes (T2D).Therapies targeting different transmitter systems have great potential in the prevention and treatment of T2D and other metabolic diseases.