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Bile acids (BAs) are cholesterol derivatives synthesized in the liver and released into the digestive tract to facilitate lipid uptake during the digestion process. Most of these BAs are reabsorbed and recycled back to the liver. Some of these BAs progress to other tissues through the bloodstream. The presence of BAs in the central nervous system (CNS) has been related to their capacity to cross the blood–brain barrier (BBB) from the systemic circulation. However, the expression of enzymes and receptors involved in their synthesis and signaling, respectively, support the hypothesis that there is an endogenous source of BAs with a specific function in the CNS. Over the last decades, BAs have been tested as treatments for many CNS pathologies, with beneficial effects. Although they were initially reported as neuroprotective substances, they are also known to reduce inflammatory processes. Most of these effects have been related to the activation of the Takeda G protein-coupled receptor 5 (TGR5). This review addresses the new challenges that face BA research for neuroscience, focusing on their molecular functions. We discuss their endogenous and exogenous sources in the CNS, their signaling through the TGR5 receptor, and their mechanisms of action as potential therapeutics for neuropathologies. [ABSTRACT FROM AUTHOR]

Early life stress (ELS), characterized as abuse, neglect, and abandonment, can cause several adverse consequences in the lives of affected individuals. ELS experiences can affect an individual's development in variable ways, persisting in the long term and promoting lasting impacts, considering that early exposure to stressors can be biologically incorporated, as prolonged stimulation of stress response systems affects the development of the brain structure and other body systems, increasing the risk of diseases associated with stress and cognitive impairment. This type of stress increases the risk of developing major depressive disorder (MDD) in a severe form that does not respond adequately to traditional antidepressant treatments. Several alterations are studied as mechanisms that relate ELS with MDD, such as epigenetic alterations, neurotransmitters, and neuronal signaling. This review discusses research that brings evidence about the ELS mechanisms involved in synaptic impairments and MDD. The processes involved in epigenetic changes and the HPA axis are highlighted, as well as changes in neurotransmitters and neuronal signaling mechanisms. [ABSTRACT FROM AUTHOR]

ABSTRACT Schistosomes are parasitic flatworms that cause schistosomiasis, a neglected tropical disease of worldwide importance. Since standard treatment of schistosomiasis relies on a single drug, praziquantel, alternative drugs are needed. G protein-coupled receptors (GPCRs) represent promising targets for new anthelmintics. Although GPCRs represent a prominent receptor class in schistosomes, functional studies are limited just as knowledge about their ligands. Candidate ligands are neuropeptides acting as neurotransmitters, neuromodulators, or hormones in the nervous system. Transcriptomics studies in Schistosoma mansoni indicated that nearly all neuropeptide genes (Sm_npps) and a subgroup of GPCRs exhibited a sex- and pairing-dependent expression profile. Among these was the rhodopsin orphan GPCR20 (SmGPCR20), which we characterized in our study. Using a yeast two-hybrid-based approach, we identified specific interactions between SmGPCR20 and two neuropeptides SmNPP26 and SmNPP40. As analyzed by qRT-PCR, Smgpcr20, Smnpp26, and Smnpp40 showed sex- and/or pairing-influenced expression. Whole-mount in situ hybridization exhibited transcripts of these genes in neuronal cells, subtegumental area, and parenchyma of both sexes. Furthermore, we received indication for co-localization of transcripts of these genes in the anterior “head” region of single-sex females and in particular patterns along the worm body indicating neuronal expression. RNA interference (RNAi) with combinations of double-stranded RNAs against the three genes resulted in reduced egg production. Confocal microscopy revealed morphologic changes in the female gonads. Furthermore, RNAi in first-time paired females caused a reduced length of females after double knockdown of SmGPCR20 and SmNPP26 and changes in the ovary. In addition, we found reduced transcript levels of egg formation-associated and gonad-specifically transcribed genes and the stem-cell marker nanos-1. The obtained results suggest that SmNPP26 and SmNPP40 are potential ligands of SmGPCR20 and that this GPCR in combination with both neuropeptides affects egg production, oogenesis, and growth of S. mansoni females. IMPORTANCE Schistosomes cause schistosomiasis, one of the neglected tropical diseases as defined by the WHO. For decades, the treatment of schistosomiasis relies on a single drug, praziquantel. Due to its wide use, there is justified fear of resistance against this drug, and a vaccine is not available. Besides its biological relevance in signal transduction processes, the class of G protein-coupled receptors (GPCRs) is also well suited for drug design. Against this background, we characterized one GPCR of Schistosoma mansoni, SmGPCR20, at the molecular and functional level. We identified two potential neuropeptides (NPPs) as ligands, SmNPP26 and SmNPP40, and unraveled their roles, in combination with SmGPCR20, in neuronal processes controlling egg production, oogenesis, and growth of S. mansoni females. Since eggs are closely associated with the pathogenesis of schistosomiasis, our results contribute to the understanding of processes leading to egg production in schistosomes, which is under the control of pairing in this exceptional parasite.

Background: Dietary restriction (DR) is a well-established universal anti-aging intervention, and is neuroprotective in multiple models of nervous system disease, including models with cerebellar pathology. The beneficial effects of DR are associated with a rearrangement of gene expression that modulate metabolic and cytoprotective pathways. However, the effect of DR on the cerebellar transcriptome remained to be fully defined. Results: Here we analyzed the effect of a classical 30% DR protocol on the transcriptome of cerebellar cortex of young-adult male mice using RNAseq. We found that about 5% of expressed genes were differentially expressed in DR cerebellum, the far majority of whom showing subtle expression changes. A large proportion of down-regulated genes are implicated in signaling pathways, in particular pathways associated with neuronal signaling. DR up regulated pathways in large part were associated with cytoprotection and DNA repair. Analysis of the expression of cell-specific gene sets, indicated a strong enrichment of DR down genes in Purkinje cells, while genes specifically associated with granule cells did not show such a preferential down-regulation. Conclusion: Our data show that DR may have a clear effect on the cerebellar transcriptome inducing a mild shift from physiology towards maintenance and repair, and having cell-type specific effects. [ABSTRACT FROM AUTHOR]

BackgroundDietary restriction (DR) is a well-established universal anti-aging intervention, and is neuroprotective in multiple models of nervous system disease, including models with cerebellar pathology. The beneficial effects of DR are associated with a rearrangement of gene expression that modulate metabolic and cytoprotective pathways. However, the effect of DR on the cerebellar transcriptome remained to be fully defined.ResultsHere we analyzed the effect of a classical 30% DR protocol on the transcriptome of cerebellar cortex of young-adult male mice using RNAseq. We found that about 5% of expressed genes were differentially expressed in DR cerebellum, the far majority of whom showing subtle expression changes. A large proportion of down-regulated genes are implicated in signaling pathways, in particular pathways associated with neuronal signaling. DR up regulated pathways in large part were associated with cytoprotection and DNA repair. Analysis of the expression of cell-specific gene sets, indicated a strong enrichment of DR down genes in Purkinje cells, while genes specifically associated with granule cells did not show such a preferential down-regulation.ConclusionOur data show that DR may have a clear effect on the cerebellar transcriptome inducing a mild shift from physiology towards maintenance and repair, and having cell-type specific effects.

Transcription factor EB (TFEB) is a conserved master transcriptional activator of autophagy and lysosomal genes that modulates organismal lifespan regulation and stress resistance. As neurons can coordinate organism‐wide processes, we investigated the role of neuronal TFEB in stress resistance and longevity. To this end, the Caenorhabditis elegans TFEB ortholog, hlh‐30, was rescued panneuronally in hlh‐30 loss of function mutants. While important in the long lifespan of daf‐2 animals, neuronal HLH‐30/TFEB was not sufficient to restore normal lifespan in short‐lived hlh‐30 mutants. However, neuronal HLH‐30/TFEB rescue mediated robust improvements in the heat stress resistance of wildtype but not daf‐2 animals. Notably, these mechanisms can be uncoupled, as neuronal HLH‐30/TFEB requires DAF‐16/FOXO to regulate longevity but not thermoresistance. Through further transcriptomics profiling and functional analysis, we discovered that neuronal HLH‐30/TFEB modulates neurotransmission through the hitherto uncharacterized protein W06A11.1 by inducing peripheral mitochondrial fragmentation and organismal heat stress resistance in a non‐cell autonomous manner. Taken together, this study uncovers a novel mechanism of heat stress protection mediated by neuronal HLH‐30/TFEB. [ABSTRACT FROM AUTHOR]

Epilepsy is a common symptom of many neurological disorders and can lead to neuronal damage that plays a major role in seizure-related disability. The peptidyl-prolyl isomerase Pin1 has wide-ranging influences on the occurrence and development of neurological diseases. It has also been suggested that Pin1 acts on epileptic inhibition, and the molecular mechanism has recently been reported. In this review, we primarily focus on research concerning the mechanisms and functions of Pin1 in neurons. In addition, we highlight the significance and potential applications of Pin1 in neuronal diseases, especially epilepsy. We also discuss the molecular mechanisms by which Pin1 controls synapses, ion channels and neuronal signaling pathways to modulate epileptic susceptibility. Since neurotransmitters and some neuronal signaling pathways, such as Notch1 and PI3K/Akt, are vital to the nervous system, the role of Pin1 in epilepsy is discussed in the context of the CaMKII-AMPA receptor axis, PSD-95-NMDA receptor axis, NL2/gephyrin-GABA receptor signaling, and Notch1 and PI3K/Akt pathways. The effect of Pin1 on the progression of epilepsy in animal models is discussed as well. This information will lead to a better understanding of Pin1 signaling pathways in epilepsy and may facilitate development of new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Stearic acid represents one of the most abundant fatty acids in the Western diet and profoundly regulates health and diseases of animals and human beings. We previously showed that stearic acid supplementation promoted development of the terrestrial model nematode Caenorhabditis elegans in chemically defined CeMM food environment. However, whether stearic acid regulates development of other nematodes remains unknown. Here, we found that dietary supplementation with stearic acid could promote the development of the marine nematode Litoditis marina, belonging to the same family as C. elegans, indicating the conserved roles of stearic acid in developmental regulation. We further employed transcriptome analysis to analyze genome-wide transcriptional signatures of L. marina with dietary stearic acid supplementation. We found that stearic acid might promote development of L. marina via upregulation of the expression of genes involved in aminoacyl-tRNA biosynthesis, translation initiation and elongation, ribosome biogenesis, and transmembrane transport. In addition, we observed that the expression of neuronal signaling-related genes was decreased. This study provided important insights into how a single fatty acid stearic acid regulates development of marine nematode, and further studies with CRISPR genome editing will facilitate demonstrating the molecular mechanisms underlying how a single metabolite regulates animal development and health. [ABSTRACT FROM AUTHOR]

Acid-sensing ion channels (ASICs) are activated by extracellular acidification. Because ASIC currents are transient, these channels appear to be ideal sensors for detecting the onset of rapid pH changes. ASICs are involved in neuronal death after ischemic stroke, and in the sensation of inflammatory pain. Ischemia and inflammation are associated with a slowly developing, long-lasting acidification. Recent studies indicate however that ASICs are unable to induce an electrical signaling activity under standard experimental conditions if pH changes are slow. In situations associated with slow and sustained pH drops such as high neuronal signaling activity and ischemia, the extracellular K+ concentration increases, and the Ca2+ concentration decreases. We hypothesized that the concomitant changes in H+, K+, and Ca2+ concentrations may allow a long-lasting ASIC-dependent induction of action potential (AP) signaling. We show that for acidification from pH7.4 to pH7.0 or 6.8 on cultured cortical neurons, the number of action potentials and the firing time increased strongly if the acidification was accompanied by a change to higher K+ and lower Ca2+ concentrations. Under these conditions, APs were also induced in neurons from ASIC1a–/– mice, in which a pH of ≤ 5.0 would be required to activate ASICs, indicating that ASIC activation was not required for the AP induction. Comparison between neurons of different ASIC genotypes indicated that the ASICs modulate the AP induction under such changed ionic conditions. Voltage-clamp measurements of the Na+ and K+ currents in cultured cortical neurons showed that the lowering of the pH inhibited Na+ and K+ currents. In contrast, the lowering of the Ca2+ together with the increase in the K+ concentration led to a hyperpolarizing shift of the activation voltage dependence of voltage-gated Na+ channels. We conclude that the ionic changes observed during high neuronal activity mediate a sustained AP induction caused by the potentiation of Na+ currents, a membrane depolarization due to the changed K+ reversal potential, the activation of ASICs, and possibly effects on other ion channels. Our study describes therefore conditions under which slow pH changes induce neuronal signaling by a mechanism involving ASICs. [ABSTRACT FROM AUTHOR]

Acid-sensing ion channels (ASICs) are activated by extracellular acidification. Because ASIC currents are transient, these channels appear to be ideal sensors for detecting the onset of rapid pH changes. ASICs are involved in neuronal death after ischemic stroke, and in the sensation of inflammatory pain. Ischemia and inflammation are associated with a slowly developing, long-lasting acidification. Recent studies indicate however that ASICs are unable to induce an electrical signaling activity under standard experimental conditions if pH changes are slow. In situations associated with slow and sustained pH drops such as high neuronal signaling activity and ischemia, the extracellular K+ concentration increases, and the Ca2+ concentration decreases. We hypothesized that the concomitant changes in H+, K+, and Ca2+ concentrations may allow a long-lasting ASIC-dependent induction of action potential (AP) signaling. We show that for acidification from pH7.4 to pH7.0 or 6.8 on cultured cortical neurons, the number of action potentials and the firing time increased strongly if the acidification was accompanied by a change to higher K+ and lower Ca2+ concentrations. Under these conditions, APs were also induced in neurons from ASIC1a–/– mice, in which a pH of ≤ 5.0 would be required to activate ASICs, indicating that ASIC activation was not required for the AP induction. Comparison between neurons of different ASIC genotypes indicated that the ASICs modulate the AP induction under such changed ionic conditions. Voltage-clamp measurements of the Na+ and K+ currents in cultured cortical neurons showed that the lowering of the pH inhibited Na+ and K+ currents. In contrast, the lowering of the Ca2+ together with the increase in the K+ concentration led to a hyperpolarizing shift of the activation voltage dependence of voltage-gated Na+ channels. We conclude that the ionic changes observed during high neuronal activity mediate a sustained AP induction caused by the potentiation of Na+ currents, a membrane depolarization due to the changed K+ reversal potential, the activation of ASICs, and possibly effects on other ion channels. Our study describes therefore conditions under which slow pH changes induce neuronal signaling by a mechanism involving ASICs.

Proteasomes are critical for peripheral nervous system (PNS) function. Here, we investigate mammalian PNS proteasomes and reveal the presence of the neuronal membrane proteasome (NMP). We show that specific inhibition of the NMP on distal nerve fibers innervating the mouse hind paw leads to reduction in mechanical and pain sensitivity. Through investigating PNS NMPs, we demonstrate their presence on the somata and proximal and distal axons of a subset of dorsal root ganglion (DRG) neurons. Single-cell RNA sequencing experiments reveal that the NMP-expressing DRGs are primarily MrgprA3+ and Cysltr2+. NMP inhibition in DRG cultures leads to cell-autonomous and non-cell-autonomous changes in Ca2+ signaling induced by KCl depolarization, αβ-meATP, or the pruritogen histamine. Taken together, these data support a model whereby NMPs are expressed on a subset of somatosensory DRGs to modulate signaling between neurons of distinct sensory modalities and indicate the NMP as a potential target for controlling pain. [Display omitted] • The neuronal membrane proteasome (NMP) is found in peripheral somatosensory neurons • The NMP selectively localizes to specific types of somatosensory neurons • The NMP mediates crosstalk between sensory neurons to modulate sensitivity to stimulation • Inhibition of the NMP reduces sensitivity to mechanical and painful stimuli Proteasomes are critical for sensory neuron function. Villalón Landeros et al. uncover a specialized proteasome in somatosensory neurons called the neuronal membrane proteasome (NMP). The NMP mediates crosstalk between somatosensory neurons to modulate sensitivity to stimulation. Inhibition of the NMP reduces sensitivity to mechanical and painful stimuli in vivo. [ABSTRACT FROM AUTHOR]

Modeling and simulation of neuronal processes has evolved from the one-dimensional (1D), symmetry-exploiting cable equation to detailed 3D models that incorporate the ultrastructural architecture of neurons. While dimension-reduced models have the clear advantage of simplicity, which makes numerical simulation an easy task, they neglect structural details which may be relevant when studying the structure-function interplay in cells. The Poisson--Nernst--Planck equations represent the other end of the modeling spectrum, a continuum mechanics model that accounts for the 3D domain as well as the spatio-temporal ion concentrations involved in biochemical signaling. In the presented work, we show that three simpler models can be derived from the Poisson--Nernst--Planck equations: the broadly used 1D cable equation, a 3D version thereof, and a 1D electro-diffusion model. We identify the assumptions and approximations that are made for the simpler models and, using numerical simulation, assess the impact of violations of these assumptions on model accuracy in scenarios ranging from individual axon fibers and bundles to dendritic spine microdomains. It is shown that the coarsest model (1D cable equation) is able to accurately resolve the electric behavior in all scenarios, as long as the cellular geometry does not diverge significantly from symmetric local cylinders. In cases where the ionic spatio-temporal dynamics are relevant, more detailed models like the 3D Poisson--Nernst--Planck equations need to be employed. We conclude with guidelines as to which level of modeling detail is necessary to capture the underlying neurobiological features accurately. [ABSTRACT FROM AUTHOR]

Germ cells are vulnerable to stress. Therefore, how organisms protect their future progeny from damage in a fluctuating environment is a fundamental question in biology. We show that in Caenorhabditis elegans, serotonin released by maternal neurons during stress ensures the viability and stress resilience of future offspring. Serotonin acts through a signal transduction pathway conserved between C. elegans and mammalian cells to enable the transcription factor HSF1 to alter chromatin in soon-to-be fertilized germ cells by recruiting the histone chaperone FACT, displacing histones, and initiating protective gene expression. Without serotonin release by maternal neurons, FACT is not recruited by HSF1 in germ cells, transcription occurs but is delayed, and progeny of stressed C. elegans mothers fail to complete development. These studies uncover a novel mechanism by which stress sensing by neurons is coupled to transcription response times of germ cells to protect future offspring.

Acid-sensing ion channels (ASICs) are H+-activated neuronal Na+ channels. They are involved in fear behavior, learning, neurodegeneration after ischemic stroke and in pain sensation. ASIC activation has so far been studied only with fast pH changes, although the pH changes associated with many roles of ASICs are slow. It is currently not known whether slow pH changes can open ASICs at all. Here, we investigated to which extent slow pH changes can activate ASIC1a channels and induce action potential signaling. To this end, ASIC1a current amplitudes and charge transport in transfected Chinese hamster ovary cells, and ASIC-mediated action potential signaling in cultured cortical neurons were measured in response to defined pH ramps of 1–40 s duration from pH 7.4 to pH 6.6 or 6.0. A kinetic model of the ASIC1a current was developed and integrated into the Hodgkin-Huxley action potential model. Interestingly, whereas the ASIC1a current amplitude decreased with slower pH ramps, action potential firing was higher upon intermediate than fast acidification in cortical neurons. Indeed, fast pH changes (10 s) did in many experiments not generate action potentials. Computer simulations corroborated these observations. We provide here the first description of ASIC function in response to defined slow pH changes. Our study shows that ASIC1a currents, and neuronal activity induced by ASIC1a currents, strongly depend on the speed of pH changes. Importantly, with pH changes that take >10 s to complete, ASIC1a activation is inefficient. Therefore, it is likely that currently unknown modulatory mechanisms allow ASIC activity in situations such as ischemia and inflammation.

Background: Coordinated calcium influx upon neuronal depolarization activates pathways that phosphorylate CaMKII, ERKs, and the transcription factor CREB and, therefore, expression of pro-survival and neuroprotective genes. Recent evidence indicates that amyloid-β protein precursor (AβPP) is trafficked to synapses and promotes their formation. At the synapse, AβPP interacts with synaptic proteins involved in vesicle exocytosis and affects calcium channel function.Objective: Herein, we examined the role of AβPP in depolarization-induced calcium-mediated signaling using acute cerebral slices from wild-type C57bl/6 mice and AβPP-/- C57bl/6 mice.Methods: Depolarization of acute cerebral slices from wild-type C57bl/6 and AβPP-/- C57bl/6 mice was used to induce synaptic signaling. Protein levels were examined by western blot and calcium dynamics were assessed using primary neuronal cultures.Results: In the absence of AβPP, decreased pCaMKII and pERKs levels were observed. This decrease was sensitive to the inhibition of N- and P/Q-type Voltage Gated Calcium Channels (N- and P/Q-VGCCs) by ω-conotoxin GVIA and ω-conotoxin MVIIC, respectively, but not to inhibition of L-type VGCCs by nifedipine. However, the absence of AβPP did not result in a statistically significant decrease of pCREB, which is a known substrate of pERKs. Finally, using calcium imaging, we found that down regulation of AβPP in cortical neurons results in a decreased response to depolarization and altered kinetics of calcium response.Conclusion: AβPP regulates synaptic activity-mediated neuronal signaling by affecting N- and P/Q-VGCCs. [ABSTRACT FROM AUTHOR]

Acid-sensing ion channels (ASICs) are H+-activated neuronal Na+ channels. They are involved in fear behavior, learning, neurodegeneration after ischemic stroke and in pain sensation. ASIC activation has so far been studied only with fast pH changes, although the pH changes associated with many roles of ASICs are slow. It is currently not known whether slow pH changes can open ASICs at all. Here, we investigated to which extent slow pH changes can activate ASIC1a channels and induce action potential signaling. To this end, ASIC1a current amplitudes and charge transport in transfected Chinese hamster ovary cells, and ASIC-mediated action potential signaling in cultured cortical neurons were measured in response to defined pH ramps of 1–40 s duration from pH 7.4 to pH 6.6 or 6.0. A kinetic model of the ASIC1a current was developed and integrated into the Hodgkin-Huxley action potential model. Interestingly, whereas the ASIC1a current amplitude decreased with slower pH ramps, action potential firing was higher upon intermediate than fast acidification in cortical neurons. Indeed, fast pH changes (<4 s) induced short action potential bursts, while pH changes of intermediate speed (4–10 s) induced longer bursts. Slower pH changes (>10 s) did in many experiments not generate action potentials. Computer simulations corroborated these observations. We provide here the first description of ASIC function in response to defined slow pH changes. Our study shows that ASIC1a currents, and neuronal activity induced by ASIC1a currents, strongly depend on the speed of pH changes. Importantly, with pH changes that take >10 s to complete, ASIC1a activation is inefficient. Therefore, it is likely that currently unknown modulatory mechanisms allow ASIC activity in situations such as ischemia and inflammation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mechanism of remote ischemic conditioning (RIC) remain not fully understood yet. Thus, a clinical trial was performed to assess the neuronal influence on its signal induction. METHODS: RIC was conducted on 45 patients who were randomized into 3 groups. Group A and B underwent brachial plexus anesthesia while RIC was performed on the blocked (A) and non-blocked side (B), respectively. In group C, RIC was conducted before regional anesthesia, thus serving as control group. All measurements were taken contralateral to RIC. The relative increase of microcirculatory parameters compared to baseline was evaluated and compared between the groups. RESULTS: Superficial blood flow (sBF) significantly increased in group A and C but values were higher among group C. Compared to group A, group C showed a significant increase of sBF during the initial 5 minutes of reperfusion (1.75; CI 1.139 – 2.361 vs. 0.97, CI 0.864 – 1.076, p < 0.05). Deep blood flow, tissue oxygen saturation and relative hemoglobin content were marginally influenced by RIC irrespectively of the presence of regional anesthesia. CONCLUSION: Despite regional anesthesia a significant RIC stimulus can be induced although its microcirculatory response is attenuated compared to control. Hence, RIC induction does not merely depend on neuronal signaling. [ABSTRACT FROM AUTHOR]

Synthesis of sugars from simple carbon sources is critical for survival of animals under limited nutrient availability. Thus, sugar-synthesizing enzymes should be present across the entire metazoan spectrum. Here, we explore the evolution of glucose and trehalose synthesis using a phylogenetic analysis of enzymes specific for the two pathways. Our analysis reveals that the production of trehalose is the more ancestral biochemical process, found in single cell organisms and primitive metazoans, but also in insects. The gluconeogenic-specific enzyme glucose-6-phosphatase (G6Pase) first appears in Cnidaria, but is also present in Echinodermata, Mollusca and Vertebrata. Intriguingly, some species of nematodes and arthropods possess the genes for both pathways. Moreover, expression data from Drosophila suggests that G6Pase and, hence, gluconeogenesis, initially had a neuronal function. We speculate that in insects—and possibly in some vertebrates—gluconeogenesis may be used as a means of neuronal signaling.

Thy-1 is a small membrane glycoprotein and member of the immunoglobulin superfamily of cell adhesion molecules. It is abundantly expressed in many cell types including neurons and is anchored to the outer membrane leaflet via a glycosyl phosphatidylinositol tail. Thy-1 displays a number of interesting properties such as fast lateral diffusion, which allows it to get in and out of membrane nanodomains with different lipid composition. Thy-1 displays a broad expression in different cell types and plays confirmed roles in cell development, adhesion and differentiation. Here, we explored the functions of Thy-1 in neuronal signaling, initiated by extracellular binding of αVβ3 integrin, may strongly dependent on the lipid content of the cell membrane. Also, we assort literature suggesting the association of Thy-1 with specific components of lipid rafts such as sialic acid containing glycosphingolipids, called gangliosides. Furthermore, we argue that Thy-1 positioning in nanodomains may be influenced by gangliosides. We propose that the traditional conception of Thy-1 localization in rafts should be reconsidered and evaluated in detail based on the potential diversity of neuronal nanodomains.

Importance: Schistosomes cause schistosomiasis, one of the neglected tropical diseases as defined by the WHO. For decades, the treatment of schistosomiasis relies on a single drug, praziquantel. Due to its wide use, there is justified fear of resistance against this drug, and a vaccine is not available. Besides its biological relevance in signal transduction processes, the class of G protein-coupled receptors (GPCRs) is also well suited for drug design. Against this background, we characterized one GPCR of Schistosoma mansoni , Sm GPCR20, at the molecular and functional level. We identified two potential neuropeptides (NPPs) as ligands, Sm NPP26 and Sm NPP40, and unraveled their roles, in combination with Sm GPCR20, in neuronal processes controlling egg production, oogenesis, and growth of S. mansoni females. Since eggs are closely associated with the pathogenesis of schistosomiasis, our results contribute to the understanding of processes leading to egg production in schistosomes, which is under the control of pairing in this exceptional parasite., Competing Interests: The authors declare no conflict of interest.

The functional complexity of the central nervous system (CNS) is unparalleled in living organisms. It arises from neural crest-derived cells that migrate by the exact route, leading to the formation of a complex network of neurons and glial cells. Recent studies have shown that novel crosstalk exists between the Notch1 and Nrf2 pathways and is associated with many neurological diseases. The Notch1–Nrf2 axis may act on nervous system development, and the molecular mechanism has recently been reported. In this review, we summarize the essential structure and function of the CNS. The significance of interactions between signaling pathways and between developmental processes like proliferation, apoptosis and migration in ensuring the correct development of the CNS is also presented. We primarily focus on research concerning possible mechanism of interaction between Notch1 and Nrf2 and the functions of Notch1-Nrf2 in neurons. There may be a direct interaction between Notch1 and NRF2, which is closely related to the crosstalk that occurs between them. The significance and potential applications of the Notch1–Nrf2 axis in abnormal development of the nervous system are been highlighten. We also discuss the molecular mechanisms by which the Notch1–Nrf2 axis controls the apoptosis, antioxidant pathway and differentiation of neurons to modulate the development of the nervous system. This information will lead to a better understanding of Notch1–Nrf2 axis signaling pathways in the nervous system and may facilitate the development of new therapeutic strategies. [Display omitted] • A direct interaction between Notch1 and NRF2 is closely related to the crosstalk that occurs between them. • There is a link between the Notch1–Nrf2 axis, the apoptosis of neuron and the development of the nervous system. • The crosstalk of Notch1 and Nrf2 pathways is the key regulator of the antioxidant function and the differentiation of CNS. • The key role of Notch1-Nrf2 in CNS may provide a promising therapeutic approach for CNS disorders. [ABSTRACT FROM AUTHOR]

Intracellular processes in neurons begins when the extracellular chemical signals such as neurotransmitters, attached at specific receptors which then activates a cascade of intracellular reactions included herein are proteins GTP, second messengers, protein kinases, ion channels, and other effector proteins that will change the instantaneous state of the physiology of the cell the target. The intracellular signal will also change the long-term performance by interfering with the transcription of genes that will change the protein composition of the target cell. Many components are involved in intracellular signal that will control the neurons, so that the necessary coordination of electrical and chemical signals in the nervous system. Also discussed here regarding the conducting various signals in neurons, including signaling pathways, type receptors, G proteins and molecular targets, second messengers, the target of second messengers, NGF/TrkA, long-term depression (LTD), and tyrosine phosphorylation hidrosilase.

ERK signaling is one of the important mitogen-activated protein kinases (MAPKs). However, the role of ERK signaling in the regulation of response to engineered nanomaterial exposure is still largely unclear. In this study, usingin vivoassay system ofCaenorhabditis elegans, we investigated the function of ERK signaling in response to graphene oxide (GO) exposure and the underlying molecular mechanism. GO exposure increased the expression of MEK-2/MEK and MPK-1/ERK in the ERK signaling pathway. Mutation ofmek-2ormpk-1resulted in a susceptibility to GO toxicity. Both the MEK-2 and the MPK-1 acted in neurons to regulate the response to GO exposure, and the neuronal expression of MEK-2 or MPK-1 caused a resistance to GO toxicity. In the neurons, SKN-1b/Nrf acted downstream of the MPK-1, and AEX-3, a guanine exchange factor for GTPase, further acted downstream of the SKN-1b to regulate the response to GO exposure. Therefore, a signaling cascade of MEK-2-MPK-1-SKN-1b/-AEX-3 was identified in the neurons required for the regulation of response to GO exposure. Moreover, genetic interaction assay demonstrated that the neuronal ERK signaling-mediated signaling pathway and the intestinal p38 MAPK-mediated signaling pathway functioned synergistically in the regulation of response to GO exposure. Our results highlight the crucial function of the neuronal ERK signaling in the regulation of response to nanomaterial exposure in organisms. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive deficits. Amyloidogenic processing of amyloid precursor protein (APP) produces amyloid β (Aβ), the major component of hallmark AD plaques. Synaptic activity stimulates APP cleavage, whereas APP promotes excitatory synaptic transmission, suggesting APP participates in neuronal homeostasis. However, mechanisms linking synaptic activity to APP processing are unclear. Here we show that Polo-like kinase 2 (Plk2), an activity-inducible regulator of homeostatic plasticity, directly binds and phosphorylates threonine-668 and serine-675 of APP in vitro and associates with APP in vivo . Plk2 accelerates APP amyloidogenic cleavage by β-secretase at synapses and is required for neuronal overactivity-stimulated Aβ secretion. These findings implicate Plk2 as a novel mediator of activity-dependent APP amyloidogenic processing. [ABSTRACT FROM AUTHOR]

Animal behavior is shaped through interplay among genes, the environment, and previous experience. As in mammals, satiety signals induce quiescence in Caenorhabditis elegans. Here we report that the C. elegans transcription factor ETS-5, an ortholog of mammalian FEV/Pet1, controls satiety-induced quiescence. Nutritional status has a major influence on C. elegans behavior. When foraging, food availability controls behavioral state switching between active (roaming) and sedentary (dwelling) states; however, when provided with high-quality food, C. elegans become sated and enter quiescence. We show that ETS-5 acts to promote roaming and inhibit quiescence by setting the internal “satiety quotient” through fat regulation. Acting from the ASG and BAG sensory neurons, we show that ETS-5 functions in a complex network with serotonergic and neuropeptide signaling pathways to control food-regulated behavioral state switching. Taken together, our results identify a neuronal mechanism for controlling intestinal fat stores and organismal behavioral states in C. elegans, and establish a paradigm for the elucidation of obesity-relevant mechanisms. [ABSTRACT FROM AUTHOR]