Neuronal Components Research Articles

An Analysis of Methylome Evolution in Primates.

Although the investigation of the epigenome becomes increasingly important, still little is known about the long-term evolution of epigenetic marks and systematic investigation strategies are still lacking. Here, we systematically demonstrate the transfer of classic phylogenetic methods such as maximum likelihood based on substitution models, parsimony, and distance-based to interval-scaled epigenetic data. Using a great apes blood data set, we demonstrate that DNA methylation is evolutionarily conserved at the level of individual CpGs in promotors, enhancers, and genic regions. Our analysis also reveals that this epigenomic conservation is significantly correlated with its transcription factor binding density. Binding sites for transcription factors involved in neuron differentiation and components of AP-1 evolve at a significantly higher rate at methylation than at the nucleotide level. Moreover, our models suggest an accelerated epigenomic evolution at binding sites of BRCA1, chromobox homolog protein 2, and factors of the polycomb repressor 2 complex in humans. For most genomic regions, the methylation-based reconstruction of phylogenetic trees is at par with sequence-based reconstruction. Most strikingly, phylogenetic reconstruction using methylation rates in enhancer regions was ineffective independently of the chosen model. We identify a set of phylogenetically uninformative CpG sites enriched in enhancers controlling immune-related genes.

Morphological and Calcium Signaling Alterations of Neuroglial Cells in Cerebellar Cortical Dysplasia Induced by Carmustine.

Cortical dysplasias are alterations in the organization of the layers of the brain cortex due to problems in neuronal migration during development. The neuronal component has been widely studied in experimental models of cortical dysplasias. In contrast, little is known about how glia are affected. In the cerebellum, Bergmann glia (BG) are essential for neuronal migration during development, and in adult they mediate the control of fine movements through glutamatergic transmission. The aim of this study was to characterize the morphology and intracellular calcium dynamics of BG and astrocytes from mouse cerebellum and their modifications in a model of cortical dysplasia induced by carmustine (BCNU). Carmustine-treated mice were affected in their motor coordination and balance. Cerebellar dysplasias and heterotopias were more frequently found in lobule X. Morphology of BG cells and astrocytes was affected, as were their spontaneous [Ca2+]i transients in slice preparation and in vitro.

Sensory Neuron TLR4 mediates the development of nerve-injury induced mechanical hypersensitivity in female mice

Recent studies have brought to light the necessity to discern sex-specific differences in various pain states and different cell-types that mediate these differences. These studies have uncovered the role of neuroimmune interactions to mediate pain states in a sex-specific fashion. While investigating immune function in pain development, we discovered that females utilize immune components of sensory neurons to mediate neuropathic pain development. We utilized two novel transgenic mouse models that eitherrestore expression of toll-like receptor (TLR) 4 inNav1.8 nociceptors on a TLR4-null background (TLR4LoxTB) or remove TLR4 specifically from Nav1.8 nociceptors (TLR4fl/fl). After spared nerve injury (SNI), a model of neuropathic injury, we observed a robust female-specific onset of mechanical hypersensitivity in our transgenic animals. Female Nav1.8-TLR4fl/fl knockout animals were less mechanically sensitive than cre-negative TLR4fl/fl littermates. Conversely, female Nav1.8-TLR4LoxTB reactivated animals were as mechanically sensitive as their wild-type counterparts. These sex and cell-specific effects were not recapitulated in male animals of either strain. Additionally, we find the danger associated molecular pattern, high mobility group box-1 (HGMB1), a potent TLR4 agonist, localization and ATF3 expression in females is dependent on TLR4 expression in dorsal root ganglia (DRG) populations following SNI. These experiments provide novel evidence toward sensory neuron specific modulation of pain in a sex-dependent manner.

Nerve Excitability and Neuropathic Pain is Reduced by BET Protein Inhibition After Spared Nerve Injury

Neuropathic pain is a common disability produced by enhanced neuronal excitability after nervous system injury. The pathophysiological changes that underlie the generation and maintenance of neuropathic pain require modifications of transcriptional programs. In particular, there is an induction of pro-inflammatory neuromodulators levels, and changes in the expression of ion channels and other factors intervening in the determination of the membrane potential in neuronal cells. We have previously found that inhibition of the BET proteins epigenetic readers reduced neuroinflammation after spinal cord injury. Within the present study we aimed to determine if BET protein inhibition may also affect neuroinflammation after a peripheral nerve injury, and if this would beneficially alter neuronal excitability and neuropathic pain. For this purpose, C57BL/6 female mice underwent spared nerve injury (SNI), and were treated with the BET inhibitor JQ1, or vehicle. Electrophysiological and algesimetry tests were performed on these mice. We also determined the effects of JQ1 treatment after injury on neuroinflammation, and the expression of neuronal components important for the maintenance of axon membrane potential. We found that treatment with JQ1 affected neuronal excitability and mechanical hyperalgesia after SNI in mice. BET protein inhibition regulated cytokine expression and reduced microglial reactivity after injury. In addition, JQ1 treatment altered the expression of SCN3A, SCN9A, KCNA1, KCNQ2, KCNQ3, HCN1 and HCN2 ion channels, as well as the expression of the Na+/K+ ATPase pump subunits. In conclusion, both, alteration of inflammation, and neuronal transcription, could be the responsible epigenetic mechanisms for the reduction of excitability and hyperalgesia observed after BET inhibition. Inhibition of BET proteins is a promising therapy for reducing neuropathic pain after neural injury. PerspectiveNeuropathic pain is a common disability produced by enhanced neuronal excitability after nervous system injury. The underlying pathophysiological changes require modifications of transcriptional programs. This study notes that inhibition of BET proteins is a promising therapy for reducing neuropathic pain after neural injury.

A Rare Case of a Congenital Nasopharyngeal Ganglioglioma With Dyspnea in a 1-Month-Old Male Infant: A Case Report

Background: A ganglioglioma (GG), a tumor with both neuronal and astrocytic components, rarely occurs outside the central nervous system.Case Summary: We present the first reported case of a 1-month-old male with a congenital nasopharyngeal GG, nasal congestion, and dyspnea; we include the operative video. Magnetic resonance imaging was used to explore whether the tumor communicated with the intracranial space. We used an endoscopic plasma technique to ensure complete tumor resection. This afforded a good visual field, endoscopic magnification, and good hemostasis.Conclusions: We report a rare case of a nasopharyngeal GG triggering nasal congestion and dyspnea in a 1-month-old male, and report our experience with the treatment of nasopharyngeal GG and similar diseases.

Developmental Exposure to Domoic Acid Disrupts Startle Response Behavior and Circuitry in Zebrafish.

Harmful algal blooms produce potent neurotoxins that accumulate in seafood and are hazardous to human health. Developmental exposure to the harmful algal bloom toxin, domoic acid (DomA), has behavioral consequences well into adulthood, but the cellular and molecular mechanisms of DomA developmental neurotoxicity are largely unknown. To assess these, we exposed zebrafish embryos to DomA during the previously identified window of susceptibility and used the well-known startle response circuit as a tool to identify specific neuronal components that are targeted by exposure to DomA. Exposure to DomA reduced startle responsiveness to both auditory/vibrational and electrical stimuli, and even at the highest stimulus intensities tested, led to a dramatic reduction of one type of startle (short-latency c-starts). Furthermore, DomA-exposed larvae had altered kinematics for both types of startle responses tested, exhibiting shallower bend angles and slower maximal angular velocities. Using vital dye staining, immunolabeling, and live imaging of transgenic lines, we determined that although the sensory inputs were intact, the reticulospinal neurons required for short-latency c-starts were absent in most DomA-exposed larvae. Furthermore, axon tracing revealed that DomA-treated larvae also showed significantly reduced primary motor neuron axon collaterals. Overall, these results show that developmental exposure to DomA targets large reticulospinal neurons and motor neuron axon collaterals, resulting in measurable deficits in startle behavior. They further provide a framework for using the startle response circuit to identify specific neural populations disrupted by toxins or toxicants and to link these disruptions to functional consequences for neural circuit function and behavior.

Medico-legal application of ubiquitin C-terminal hydrolase L1 in mild and moderate head injured patients

Abstract: Introduction: Head trauma is considered a frequent cause of death and disability in Egypt and worldwide. Evaluation of head injured patient is required in different forensic settings. Recently, biomarkers have been introduced to predict outcomes of traumatic head injury. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is one of the novel biomarkers with neuronal specific components. Thus, the current study aimed to evaluate the medico-legal application of UCH-L1 as a prognostic marker in mild and moderate head injured patients. The current study was conducted on forty-five adult subjects during the period from June 2018 to December 2018. They were divided into: 15 mild head injured patients (group I), 15 moderate head injured patients (group II) and 15 healthy subjects served as controls (group III). All participants were subjected to history taking, clinical examination, head computed tomography scan, and estimation of UCH-L1 concentration. Results: UCH-L1 concentration was significantly higher in group I and II compared to group III, moreover it was significantly higher in group II compared to group I. Significant positive correlations were observed between UCH-L1 concentration and each of hospitalization period and duration of post-traumatic amnesia in all head injured patients. The median concentration of UCH-L1 in patients who developed complications (11.90 ng/ml) was significantly higher than in patients who didn’t have complications (0.04 ng/ml). UCH-L1 could predict complications at cut off value > 0.2 ng/ml. Conclusions: Serum UCH-L1 could be useful for forensic experts to establish cause-effect relationship between poor outcome and trauma in head injured patients.

Segregation of neuronal-vascular components in a retinal nerve fiber layer for thickness measurement using OCT and OCT angiography.

Assessment of the circumpapillary retinal nerve fiber layer (RNFL) provides crucial knowledge on the status of the optic nerve. Current circumpapillary RNFL measurements consider only thickness, but an accurate evaluation should also consider blood vessel contribution. Previous studies considered the presence of major vessels in RNFL thickness measurements from optical coherence tomography (OCT). However, such quantitative measurements do not account for smaller vessels, which could also affect circumpapillary RNFL measurements. We present an approach to automatically segregate the neuronal and vascular components in circumpapillary RNFL by combining vascular information from OCT angiography (OCTA) and structural data from OCT. Automated segmentation of the circumpapillary RNFL using a state-of-the-art deep learning network is first performed and followed by the lateral and depth-resolved localization of the vascular component by vertically projecting the vessels along the circular scan from OCTA vessels map onto the segmented RNFL. Using this proposed approach, we compare the correlations of circumpapillary RNFL thicknesses with age at different levels of vessel exclusion (exclusion of major vessels only vs both major- and micro-vessels) and also evaluate the thickness variability in 75 healthy eyes. Our results show that the ratio of major- and micro-vessels to circumpapillary RNFL achieved a stronger correlation with aging (r = 0.478, P < .001) than the ratio with only major vessels to circumpapillary RNFL (r = 0.027, P = .820). Exclusion of blood vessels from circumpapillary RNFL thickness using OCTA imaging provides a better measure of the neuronal components and could potentially improve the diagnostic performance for disease detection.

Glioblastomas with primitive neuronal component harbor a distinct methylation and copy-number profile with inactivation of TP53, PTEN, and RB1

Glioblastoma IDH-wildtype presents with a wide histological spectrum. Some features are so distinctive that they are considered as separate histological variants or patterns for the purpose of classification. However, these usually lack defined (epi-)genetic alterations or profiles correlating with this histology. Here, we describe a molecular subtype with overlap to the unique histological pattern of glioblastoma with primitive neuronal component. Our cohort consists of 63 IDH-wildtype glioblastomas that harbor a characteristic DNA methylation profile. Median age at diagnosis was 59.5 years. Copy-number variations and genetic sequencing revealed frequent alterations in TP53, RB1 and PTEN, with fewer gains of chromosome 7 and homozygous CDKN2A/B deletions than usually described for IDH-wildtype glioblastoma. Gains of chromosome 1 were detected in more than half of the cases. A poorly differentiated phenotype with frequent absence of GFAP expression, high proliferation index and strong staining for p53 and TTF1 often caused misleading histological classification as carcinoma metastasis or primitive neuroectodermal tumor. Clinically, many patients presented with leptomeningeal dissemination and spinal metastasis. Outcome was poor with a median overall survival of only 12 months. Overall, we describe a new molecular subtype of IDH-wildtype glioblastoma with a distinct histological appearance and genetic signature.

Evaluation of the neuronal and microvascular components of the macula in patients with diabetic retinopathy.

To investigate whether abnormal retinal microcirculation correlates with retinal neuronal changes in untreated diabetic eyes without macular edema. This study enrolled 29 diabetic patients without diabetic retinopathy (DR), 18 patients with mild non-proliferative diabetic retinopathy (NPDR), 15 patients with moderate NPDR, 14 patients with severe NPDR, 27 patients with proliferative diabetic retinopathy (PDR), and 25 healthy control subjects. Pattern electroretinography (PERG) and optical coherence tomography angiography (OCT-A) tests were performed. Differences in the mean values for the area, acircularity index, and perimeter of foveal avascular zone were statistically significant between the healthy control group and the diabetic patients (P < 0.05 for all). P50 and N95 amplitudes were statistically significantly lower in the PDR group compared to diabetic patients without DR, control, and moderate NPDR groups (P < 0.05 for all). The whole retina vessel densities in superficial and deep capillary plexus were lower in the PDR group compared to the diabetic patients without DR and control group (P < 0.05 for all). There were statistically significant positive correlations between the amplitudes of the P50 and N95 waves with the vessel densities. The existence of significant correlations between PERG and OCT-A parameters in diabetic patients has shown that vascular and neuronal changes in the macula affect each other in diabetic patients.

Effects of Extracorporeal Shockwave Therapy on Clinical and Neurophysiological Indices of Spasticity Inpatients With Upper Motor Neuron Lesions: A Systematic Review and Meta-analysis

Objective: Spasticity is one of the components of an Upper Motor Neuron (UMN) lesion that occurs usually after a period of flaccidity in the form of velocity-dependent resistance to passive stretch. Spasticity is a significant cause of limited mobility and disability in neurological diseases. There are several clinical approaches to control spasticity. Recently, Shock Wave Therapy (SWT) has been reported to be a new, safe, and effective method for reducing spasticity for people with upper motor neuron lesions. We conducted a meta-analysis of relevant clinical trials to assess the effect of applying SWT on spasticity in UMN lesions. Materials &amp; Methods: An electronic search was performed in PubMed, ISI Web of Science, Scopus, Science Direct, MEDLINE, and Google scholar from January 2005 to January 2020. Studies were included if they measured spasticity with the Modified Ashworth Scale (MAS) or/and neurophysiological indices in patients with stroke, multiple sclerosis, and cerebral palsy. The keywords of muscle hypertonia or spasticity, extracorporeal shock wave therapy, stroke, multiple sclerosis, and cerebral palsy were used. Two independent researchers searched articles, screened eligible studies against the inclusion criteria, and assessed the methodological quality of included studies. The methodological quality of studies was evaluated using the Downs and Black tool. The difference between the means was considered as the effect size in the MAS and Hoffman reflex/motor response (H/M) ratio before and after the intervention with 95% CI in random-effects models. Analyzes were performed using STATA software version 11. Results: The initial search led to the retrieval of 98 studies based on the inclusion and exclusion criteria, of which 24 full-text articles were reviewed and 14 articles were included in the meta-analysis process. All 14 articles had examined the effects of shockwave on the MAS. Four studies with 120 patients had examined the effects of shockwave therapy on the H/M ratio. Significant reduction in MAS grade was observed immediately [I2 = 100%, P&lt;0.001, SMD=1.38 with 95%CI: (0.80, 1.87)] and three months after SWT [I2 = 100%, P&lt;0.001, SMD=1.13 with 95%CI: (0.50, 1.76)] in comparison with the baseline values. ESWT had no significant effects on the H/M ratio [I2 = 97.5%, P&lt;0.001, SMD=1.09 with 95%CI: (-0.54, 2.73)]. Conclusion: SWT can improve spasticity based on the MAS. The lack of SWT effects on the neurophysiological parameter of spasticity supports this opinion that SWT acts on the non-neural component of spasticity. Differences observed in studies in terms of treatment sessions, intervals of treatment sessions, energy density, number of shocks, and follow-up duration need to be examined more closely. More randomized clinical trials are needed in the future to analyze the impact of these factors on the efficacy of SWT for spastic patients.

Vascular Dysfunction in the Brain; Implications for Heavy Metal Exposures.

Normal or diseased conditions that alter the brain's requirement for oxygen and nutrients via alterations to neurovascular coupling have an impact on the level of the neurovascular unit; comprising neuronal, glial and vascular components. The communications between the components of the neurovascular unit are precise and accurate for its functions; hence a minute disturbance can result in neurovascular dysfunction. Heavy metals such as cadmium, mercury, and lead have been identified to increase the vulnerability of the neurovascular unit to damage. This review examines the role of heavy metals in neurovascular dysfunctions and the possible mechanisms by which these metals act. Risk factors ranging from lifestyle, environment, genetics, infections, and physiologic ageing involved in neurological dysfunctions were highlighted, while stroke was discussed as the prevalent consequence of neurovascular dysfunctions. Furthermore, the role of these heavy metals in the pathogenesis of stroke consequently pinpoints the importance of understanding the mechanisms of neurovascular damage in a bid to curb the occurrence of neurovascular dysfunctions.

Microscopic changes in the neurocytes of the cerebellar cortex in dynamics under conditions of experimental thermal injuryc

Summary. Thermal injury as a stress factor of exogenous origin, in which the development of multiple organ failure and dysfunction of organs and systems of the body occur. The nervous system is one of the first to perceive and respond to pain impulses. It is important to reorganize all the structural components of the microcirculatory tract and neurons as a result of endogenous intoxication, which develops during thermal trauma. The target of lesions is the cerebellum, as a multifunctional organ of the central nervous system. The aim of the study – to establish the microscopic reorganization of neurocytes of the cerebellar cortex in the dynamics under conditions of experimental thermal trauma to the skin. Materials and Methods. The experimental study was performed on 24 adult white male rats weighing 180–200 g. Simulation of third-degree burns was performed with copper plates heated in boiled water to a temperature of 97–100º on the epilated surface of the skin of animal bodies under thiopental sodium. The size of the affected areas was 18–20 % of the body of rats. Collection of material for microscopic examination was performed in accordance with generally accepted methods. Histological sections obtained on a sled microtome 5–6 μm thick were stained with hematoxylin and eosin, toluidine blue by the method of Nissl. Semi-thin sections made on an ultramicrotome LKB-3 were stained with methylene blue. The micropreparations were studied using a MICROmed SEO SCAN light microscope and photo-documented using a Vision CCD Camera with a histological image output system. Results. Microscopic studies have shown an interdependence between the duration of the experiment and abnormalities in the structural components of neurons in all layers of the cerebellar cortex. In the early stages of the experiment there are reactive changes, which are adaptive-compensatory in nature with initial destructive damage. On day 14, and especially after 21 days, polymorphism is observed, significant cell degeneration, manifested by pycnosis of the nuclei, the development of intra- and pericellular edema in neurons of the granular, ganglionic and granular layers of the cerebellar cortex

On P2X receptors in the brain: microvessels. Dedicated to the memory of the late Professor Geoffrey Burnstock (1929-2020).

This tribute article presents selected immunocytochemical and transmission electron microscope data on the location of ATP-gated P2X receptor in the rat brain, as studied in the 1990s in Prof G. Burnstock's laboratory at University College London. There are examples of immuno-ultrastructural findings and introductory information about pre- and post-synaptic location of P2X receptors in the rat cerebellum and endocrine hypothalamus to support the concept of purinergic transmission in the central nervous system. Then findings of diverse immunoreactivity for P2X1, P2X2, P2X4, and P2X6 receptors associated with brain microvessels are shown, including vascular endothelium and pericytes as well as perivascular astrocytes and neuronal components. These findings imply the involvement of P2X receptors and hence purinergic signalling in the neurovascular unit, at least in microvessels in the rat cerebellum and hypothalamic paraventricular and supraoptic nuclei examined here. Various aspects of P2X receptors in brain microvessels are discussed.

Subcellular Dissection of a Simple Neural Circuit: Functional Domains of the Mauthner-Cell During Habituation.

Sensorimotor integration is a pivotal feature of the nervous system for ensuring a coordinated motor response to external stimuli. In essence, such neural circuits can optimize behavioral performance based on the saliency of environmental cues. In zebrafish, habituation of the acoustic startle response (ASR) is a simple behavior integrated into the startle command neurons, called the Mauthner cells. Whereas the essential neuronal components that regulate the startle response have been identified, the principles of how this regulation is integrated at the subcellular regions of the Mauthner cell, which in turn modulate the performance of the behavior, is still not well understood. Here, we reveal mechanistically distinct dynamics of excitatory inputs converging onto the lateral dendrite (LD) and axon initial segment (AIS) of the Mauthner cell by in vivo imaging glutamate release using iGluSnFR, an ultrafast glutamate sensing fluorescent reporter. We find that modulation of glutamate release is dependent on NMDA receptor activity exclusively at the AIS, which is responsible for setting the sensitivity of the startle reflex and inducing a depression of synaptic activity during habituation. In contrast, glutamate-release at the LD is not regulated by NMDA receptors and serves as a baseline component of Mauthner cell activation. Finally, using in vivo calcium imaging at the feed-forward interneuron population component of the startle circuit, we reveal that these cells indeed play pivotal roles in both setting the startle threshold and habituation by modulating the AIS of the Mauthner cell. These results indicate that a command neuron may have several functionally distinct regions to regulate complex aspects of behavior.

Le diagnostic histo-moléculaire des tumeurs gliales et glioneuronales

While rare compared to extra-cranial neoplasms, glial and glioneuronal tumors are responsible of high morbidity and mortality. In 2016, the World Health Organization introduced histo-molecular ("integrated") diagnostics for central nervous system tumors based on morphology, immunohistochemistry and the presence of key genetic alterations. This combined phenotypic-genotypic classification allows for a more objective diagnostic of brain tumors. The implementation of such a classification in daily practice requires immunohistochemical surrogates to detect common genetic alterations and sometimes expensive and not widely available molecular biology techniques. The first step in brain tumor diagnostics is to inquire about the clinical picture and the imaging findings. When dealing with a glial tumor, the pathologist needs to assess its nature, infiltrative or circumscribed. If the tumor is infiltrative, IDH1/2 genes (prognostic marker) and chromosomes 1p/19q (diagnosis of oligodendroglioma) need to be assessed. If the tumor appears circumscribed, the pathologist should look for a neuronal component associated with the glial component (glioneuronal tumor). A limited immunohistochemistry panel will help distinguish between diffuse glioma (IDH1-R132H, ATRX, p53) and circumscribed glial/glioneuronal tumor (CD34, neuronal markers, BRAF-V600E), and some antibodies may reliably detect genetic alterations (IDH1-R132H, BRAF-V600E and H3-K27M mutations). Chromosomal imbalances (1p/19q codeletion in oligodendroglioma; chromosome 7 gain/chromosome 10 loss and EGFR amplification in glioblastoma) and gene rearrangements (BRAF fusion, FGFR1 fusion) will be identified by molecular biology techniques. The up-coming edition of the WHO classification of the central nervous system tumors will rely more heavily on molecular alterations to accurately diagnose and treat brain tumors.

Outline of a Brain Model for Self-Observing Agents

Brain-inspired models for conscious robots should refer to the cellular double structure of the brain, consisting of the neuronal system and the glial system, embodying two ontological realms. Therefore, a purely neurobiological approach to machine consciousness is biased by an ontological fault in exclusively referring to the neuronal system. The brain model for self-observing agents outlined in this paper focuses on the glial-neuronal synaptic units (tripartite synapses). Whereas the neuronal component of the synapse embodies objective subjectivity processing sensory information, the glial component (astrocyte) embodies subjective subjectivity generating subjective behavior (intentions, consciousness) in its interactions with the neuronal part of the synapse. The elementary principle of the implementation of self-observing agents is this: a brain is capable of self-observation, if the concept of intention to observe something and the concept of the observed are located in different places. Based on a formalism of qualitative information processing, the architecture of self-observation is described in increasing complexity, building networks. It is suggested that if a robot brain is equipped with a network of modules for self-observation, the robot may generate subjective perspectives of self-observation indicating self-consciousness.

Spinophilin modulates pain through suppressing dendritic spine morphogenesis via negative control of Rac1-ERK signaling in rat spinal dorsal horn

Both spinophilin (SPN, also known as neurabin 2) and Rac1 (a member of Rho GTPase family) are believed to play key roles in dendritic spine (DS) remodeling and spinal nociception. However, how SPN interacts with Rac1 in the above process is unknown. Here, we first demonstrated natural existence of SPN-protein phosphatase 1-Rac1 complex in the spinal dorsal horn (DH) neurons by both double immunofluorescent labeling and co-immunoprecipitation, then the effects of SPN over-expression and down-regulation on mechanical and thermal pain sensitivity, GTP-bound Rac1-ERK signaling activity, and spinal DS density were studied. Over-expression of SPN in spinal neurons by intra-DH pAAV-CMV-SPN-3FLAG could block both mechanical and thermal pain hypersensitivity induced by intraplantar bee venom injection, however it had no effect on the basal pain sensitivity. Over-expression of SPN also resulted in a significant decrease in GTP-Rac1-ERK activities, relative to naive and irrelevant control (pAAV-MCS). In sharp contrast, knockdown of SPN in spinal neurons by intra-DH pAAV-CAG-eGFP-U6-shRNA[SPN] produced both pain hypersensitivity and dramatic elevation of GTP-Rac1-ERK activities, relative to naive and irrelevant control (pAAV-shRNA [NC]). Moreover, knockdown of SPN resulted in increase in DS density while over-expression of it had no such effect. Collectively, SPN is likely to serve as a regulator of Rac1 signaling to suppress DS morphogenesis via negative control of GTP-bound Rac1-ERK activities at postsynaptic component in rat DH neurons wherein both mechanical and thermal pain sensitivity are controlled.

Differential effects of the Piezo1 agonist Yoda1 in the trigeminovascular system: An electrophysiological and intravital microscopy study in rats

Migraine is associated with the activation and sensitisation of the trigeminovascular system and is often accompanied by mechanical hyperalgesia and allodynia. The mechanisms of mechanotransduction during a migraine attack are yet unknown. We have proposed that the ion channel Piezo1 may be involved, since it is expressed in endothelial cells as well as in trigeminal ganglion neurons, and thus, may contribute to the activation of both the vascular and neuronal component of the trigeminovascular system. We took advantage of extracellular recordings from the trigeminocervical complex – a key relay centre in the migraine pain pathway, to directly assess the impact of the differently applied Piezo1 agonist Yoda1 on the sensory processing at the spinal level. At a low dose, Yoda1 slightly facilitated the ongoing firing of central trigeminovascular neurons, however, at a high dose, this substance contributed to the suppression of their activity. Using intravital microscopy, we have revealed that Yoda1 at high dose can also induce the dilation of meningeal arteries innervated by trigeminal afferents. Collectively, here we have identified both neuronal and vascular modulation via selective activation of mechanosensitive Piezo1 channels, which provide new evidence in favour of the Piezo1 role in migraine pathogenesis. We propose several mechanisms that may underlie the revealed effects of Yoda1.

Integrated neuromorphic computing networks by artificial spin synapses and spin neurons

One long-standing goal in the emerging neuromorphic field is to create a reliable neural network hardware implementation that has low energy consumption, while providing massively parallel computation. Although diverse oxide-based devices have made significant progress as artificial synaptic and neuronal components, these devices still need further optimization regarding linearity, symmetry, and stability. Here, we present a proof-of-concept experiment for integrated neuromorphic computing networks by utilizing spintronics-based synapse (spin-S) and neuron (spin-N) devices, along with linear and symmetric weight responses for spin-S using a stripe domain and activation functions for spin-N. An integrated neural network of electrically connected spin-S and spin-N successfully proves the integration function for a simple pattern classification task. We simulate a spin-N network using the extracted device characteristics and demonstrate a high classification accuracy (over 93%) for the spin-S and spin-N optimization without the assistance of additional software or circuits required in previous reports. These experimental studies provide a new path toward establishing more compact and efficient neural network systems with optimized multifunctional spintronic devices.