Order Neurons Research Articles

Vitamin D, Testosterone, Epigenetics and Pain an Evolving Concept of Neurosignaling, Neuroplasticity and Homeostasis

The thought of exploring a possible relationship between the broad systems of steroid hormone physiology (specifically vitamin D and testosterone) and nocioception was prompted by an unexpectedly frequent personal clinical observation. Patients with chronic pain syndromes or chronic musculoskeletal pain often have low serum levels of vitamin D and testos-terone. Mining for relevant information in Pub Med, Medline and Cochrane Systems Review, three concepts repeatedly emerge that provide a common context for understanding the mechanics of these diverse sys-tems—epigenetic, homeostasis and neuroplasticity. Viewing homeostasis within the framework of epigenetics allows reasoned speculation as to how various human systems interact to maintain integrity and function, while simultaneously responding in a plastic manner to external stimuli. Cell signaling supports normal function by regulating synaptic activity, but can also effect plastic change in the central and peripheral nervous system. This is most commonly achieved by post-translational remodeling of chromatin. There is thus persistent epigenetic change in protein synthesis with all the related downstream effects but without disruption of normal DNA se-quencing. In itself, this may be considered an example of genomic homeo-stasis. Epigenetic mechanisms in nociception and analgesia are active in the paleospinothalamic and neospinothalamic tracts at all levels. Physiologic response to a nociceptive insult, whether mechanical, inflammatory or ischemic, is provided by cell signaling that is significantly enhanced through epigenetic mechanisms at work in nociceptors, Gamma-Aminobutyric Acid (GABA) and glutamate receptors, voltage gated receptors, higher order neurons in the various dorsal horn laminae and proximal nociceptive pro-cessing centers in the brainstem and cortex. The mediators of these direct or epigenetic effects are various ligands also active in signaling, such as free radicals, substance P, a variety of cytokines, growth factors and G proteins, stress responsive proteins, matrix and structural proteins such as reelin and the Jmjd3 gene/enzyme. Calcitriol, the vitamin D receptor and vitamin D Responsive Elements collectively determine regulatory effects of this secosteroid hormone. Agents of homeostasis and plasticity include various D-system specific cytochrome enzymes (CYP 24, CYP 27 A1, B1), as well as more widely active enzymes and protein cell signalers (Jmjd3, Calbindin, BMP), many of which play a role in the nociceptive system. While the highlighted information represents an understanding of complex systems that is currently in its infancy, there are clear results from reliable research at a foundational level. These results are beginning to tell a compelling tale of the homeostasis and plasticity inherent in vitamin D and nociception systems.

Functional Reintegration of Sensory Neurons and Transitional Dendritic Reduction of Mitral/Tufted Cells during Injury-Induced Recovery of the Larval Xenopus Olfactory Circuit.

Understanding the mechanisms involved in maintaining lifelong neurogenesis has a clear biological and clinical interest. In the present study, we performed olfactory nerve transection on larval Xenopus to induce severe damage to the olfactory circuitry. We surveyed the timing of the degeneration, subsequent rewiring and functional regeneration of the olfactory system following injury. A range of structural labeling techniques and functional calcium imaging were performed on both tissue slices and whole brain preparations. Cell death of olfactory receptor neurons and proliferation of stem cells in the olfactory epithelium were immediately increased following lesion. New olfactory receptor neurons repopulated the olfactory epithelium and once again showed functional responses to natural odorants within 1 week after transection. Reinnervation of the olfactory bulb (OB) by newly formed olfactory receptor neuron axons also began at this time. Additionally, we observed a temporary increase in cell death in the OB and a subsequent loss in OB volume. Mitral/tufted cells, the second order neurons of the olfactory system, largely survived, but transiently lost dendritic tuft complexity. The first odorant-induced responses in the OB were observed 3 weeks after nerve transection and the olfactory network showed signs of major recovery, both structurally and functionally, after 7 weeks.

Oxytocin inhibits the rat medullary dorsal horn Sp5c/C1 nociceptive transmission through OT but not V1A receptors

The medullary dorsal horn (MDH or Sp5c/C1 region) plays a key role modulating the nociceptive input arriving from craniofacial structures. Some reports suggest that oxytocin could play a role modulating the nociceptive input at the MDH level, but no study has properly tested this hypothesis. Using an electrophysiological and pharmacological approach, the present study aimed to determine the effect of oxytocin on the nociceptive signaling in the MDH and the receptor involved. In sevoflurane, anesthetized rats, we performed electrophysiological unitary recordings of second order neurons at the MDH region responding to peripheral nociceptive-evoked responses of the first branch (V1; ophthalmic) of the trigeminal nerve. Under this condition, we constructed dose-response curves analyzing the effect of local spinal oxytocin (0.2–20 nmol) on MDH nociceptive neuronal firing. Furthermore, we tested the role of oxytocin receptors (OTR) or vasopressin V1A receptors (V1AR) involved in the oxytocin effects. Oxytocin dose-dependently inhibits the peripheral-evoked activity in nociceptive MDH neurotransmission. This inhibition is associated with a blockade of neuronal activity of Aδ- and C-fibers. Since this antinociception was abolished by pretreatment (in the MDH) with the potent and selective OTR antagonist (L-368,899; 20 nmol) and remained unaffected after the V1AR antagonist (SR49059; 20 nmol or 200 nmol), the role of OTR is implied. This electrophysiological study demonstrates that oxytocin inhibits the peripheral-evoked neuronal activity at MDH, through OTR activation. Thus, OTR may represent a new potential drug target to treat craniofacial nociceptive dysfunction in the MDH.

Winnerless competition in clustered balanced networks: inhibitory assemblies do the trick

Balanced networks are a frequently employed basic model for neuronal networks in the mammalian neocortex. Large numbers of excitatory and inhibitory neurons are recurrently connected so that the numerous positive and negative inputs that each neuron receives cancel out on average. Neuronal firing is therefore driven by fluctuations in the input and resembles the irregular and asynchronous activity observed in cortical in vivo data. Recently, the balanced network model has been extended to accommodate clusters of strongly interconnected excitatory neurons in order to explain persistent activity in working memory-related tasks. This clustered topology introduces multistability and winnerless competition between attractors and can capture the high trial-to-trial variability and its reduction during stimulation that has been found experimentally. In this prospect article, we review the mean field description of balanced networks of binary neurons and apply the theory to clustered networks. We show that the stable fixed points of networks with clustered excitatory connectivity tend quickly towards firing rate saturation, which is generally inconsistent with experimental data. To remedy this shortcoming, we then present a novel perspective on networks with locally balanced clusters of both excitatory and inhibitory neuron populations. This approach allows for true multistability and moderate firing rates in activated clusters over a wide range of parameters. Our findings are supported by mean field theory and numerical network simulations. Finally, we discuss possible applications of the concept of joint excitatory and inhibitory clustering in future cortical network modelling studies.

A Physicochemically Optimized and Neuroconductive Biphasic Nerve Guidance Conduit for Peripheral Nerve Repair.

Clinically available hollow nerve guidance conduits (NGCs) have had limited success in treating large peripheral nerve injuries. This study aims to develop a biphasic NGC combining a physicochemically optimized collagen outer conduit to bridge the transected nerve, and a neuroconductive hyaluronic acid-based luminal filler to support regeneration. The outer conduit is mechanically optimized by manipulating crosslinking and collagen density, allowing the engineering of a high wall permeability to mitigate the risk of neuroma formation, while also maintaining physiologically relevant stiffness and enzymatic degradation tuned to coincide with regeneration rates. Freeze-drying is used to seamlessly integrate the luminal filler into the conduit, creating a longitudinally aligned pore microarchitecture. The luminal stiffness is modulated to support Schwann cells, with laminin incorporation further enhancing bioactivity by improving cell attachment and metabolic activity. Additionally, this biphasic NGC is shown to support neurogenesis and gliogenesis of neural progenitor cells and axonal outgrowth from dorsal root ganglia. These findings highlight the paradigm that a successful NGC requires the concerted optimization of both a mechanical support phase capable of bridging a nerve defect and a neuroconductive phase with an architecture capable of supporting both Schwann cells and neurons in order to achieve functional regenerative outcome.

Evaluation of mesenchymal stem cell modulation of trigeminal neuronal responses to cold

Tissue engineering protocols, such as regenerative endodontic procedures (REPs), comprise biologically based procedures designed to restore normal physiologic function. For REPs, the goal is reconstitution of the pulp-dentin complex by delivering mesenchymal stem cells (MSCs), including the stem cells of the apical papilla (SCAP) into a root canal system. Many patients regain cold sensitivity after REPs, but the mechanism is not understood. We hypothesized that SCAP modulate nociceptive function through a paracrine mechanism that activates cold-sensitive ion channels in neurons. We established a co-culture system with human SCAP and rat trigeminal (TG) sensory neurons in order to determine the effect of SCAP co-culture on neuronal responses using whole-cell patch-clamp electrophysiology. TG neurons co-cultured with SCAP demonstrated increased TRPA1-mediated (p<0.01) and TRPM8-mediated inward current densities (p<0.01) at 24h in co-culture. Cold stimulation to SCAP significantly increased ATP release (p<0.01), and supernatant collected after cold stimulation to SCAP was able to activate cultured TG neurons. Co-culture with SCAP significantly increased sustained ATP-evoked inward current density (p<0.05). These data suggest that SCAP release trophic factors that act on afferent neurons to enhance cold-sensitive ion channel activity.

Efficiency of rate and latency coding with respect to metabolic cost and time

Recent studies on the theoretical performance of latency and rate code in single neurons have revealed that the ultimate accuracy is affected in a nontrivial way by aspects such as the level of spontaneous activity of presynaptic neurons, amount of neuronal noise or the duration of the time window used to determine the firing rate. This study explores how the optimal decoding performance and the corresponding conditions change when the energy expenditure of a neuron in order to spike and maintain the resting membrane potential is accounted for. It is shown that a nonzero amount of spontaneous activity remains essential for both the latency and the rate coding. Moreover, the optimal level of spontaneous activity does not change so much with respect to the intensity of the applied stimulus. Furthermore, the efficiency of the temporal and the rate code converge to an identical finite value if the neuronal activity is observed for an unlimited period of time.

On the complex domain deep machine learning for face recognition

Biometric based verification and recognition has become the center of attention for many significant applications for security conscious societies, as it is believed that biometrics can provide accurate and reliable identification. The face biometrics are one that possesses the merits of both high accuracy and low intrusiveness. An efficient machine recognition of human faces in big dataset is both important and challenging tasks. This paper addresses an intelligent face recognition system that is pose invariant and can recognize multi-expression, occluded and blurred faces through efficient but compact deep learning. Superior functionality of neural network in a complex domain has been observed in recent researches. My work presents a new approach, which is the fusion of higher-order novel neuron models with multivariate statistical techniques in a complex domain with a sole goal of improving performance of biometric systems. This also aims at reducing the computational cost and providing a faster recognition system. This paper presents the formal algorithms for feature extraction with multivariate statistical techniques in complex domain and compare them their real domain counterpart. This paper also presents a classifier structure (OCON : One-Class-in-One-Neuron) which contains an ensemble of novel higher order neurons, which drastically reduces the complexity of proposed learning machine because only single neuron is sufficient to recognize a subject in the database. This novel fusion in the proposed deep learning machine has thoroughly presented its superiority over a wide spectrum of experiments. Advanced deep learning capabilities, and complex domain implementation in particular, are significantly advancing state-of-art in computer vision and pattern recognition.

Adiponectin at physiological level glucose-independently enhances inhibitory postsynaptic current onto NPY neurons in the hypothalamic arcuate nucleus

Adiponectin regulates glucose and lipid metabolism, acting against atherosclerosis and metabolic syndrome. Accumulating evidences suggest that adiponectin acts on the brain including the arcuate nucleus of hypothalamus (ARC). The ARC contains orexigenic neuropeptide Y (NPY)/agouti related peptide (AgRP) neurons and anorexigenic proopiomelanocortin (POMC) neurons, the first order neurons for feeding regulation. We recently reported that intracerebroventricular injection of adiponectin at low glucose level suppressed food intake, while at elevated glucose level it promoted food intake, exhibiting glucose-dependent reciprocal effects. As an underlying neuronal mechanism, physiological level of adiponectin at low glucose activated ARC POMC neurons and at high glucose inactivated them. Now, whether physiological level of adiponectin also affects NPY/AgRP neurons is essential for fully understanding the adiponectin action, but it remains to be clarified. We here report that a physiological dose of adiponectin, in both high and low glucose conditions, attenuated action potential firing without altering resting membrane potential in ARC NPY neurons. This adiponectin effect was abolished by GABAA receptor blockade. Adiponectin enhanced amplitude but not frequency of inhibitory postsynaptic current (IPSC) onto NPY neurons. These results demonstrate that adiponectin enhances IPSC onto NPY neurons to attenuate action potential firing in NPY neurons in a glucose-independent manner, being contrasted to its glucose-dependent effect on POMC neurons.

Recognizing tactile surface roughness with a biomimetic fingertip: A soft neuromorphic approach

Surface roughness is an important object property and can significantly affect the friction characteristics, wear resistance, and fatigue life of components. Although some work has been done on demonstrating the capability of specific tactile sensors for surface roughness discrimination, the soft neuromorphic approach by taking inspirations from neuroscience for tactile surface roughness discrimination is exceptionally rare. This paper aims to fill this gap, and presents a soft neuromorphic method for tactile surface roughness discrimination with a biomimetic fingertip. The analog tactile signals generated from polyvinylidene difluoride (PVDF) films are fed as input to the Izhikevich neurons in order to obtain spike trains. Two distinct decoding schemes based on k-nearest neighbors (kNN) in both spike feature space and spike train space are used for surface roughness discrimination. We thoroughly examined the different spike train distance based kNN (STD-kNN) algorithms for decoding spike trains. Eight standard rough surfaces with roughness values (Ra) of 50μm, 25μm, 12.5μm, 6.3μm 3.2μm, 1.6μm, 0.8μm, and 0.4μm are explored. The highest classification accuracy of (77.6±13.7) % can be achieved with kNN (k=11) classifier and the Victor−Purpura distance (q=0.024ms−1).

Modeling the network dynamics of pulse-coupled neurons.

We derive a mean-field approximation for the macroscopic dynamics of large networks of pulse-coupled theta neurons in order to study the effects of different network degree distributions and degree correlations (assortativity). Using the ansatz of Ott and Antonsen [Chaos 18, 037113 (2008)], we obtain a reduced system of ordinary differential equations describing the mean-field dynamics, with significantly lower dimensionality compared with the complete set of dynamical equations for the system. We find that, for sufficiently large networks and degrees, the dynamical behavior of the reduced system agrees well with that of the full network. This dimensional reduction allows for an efficient characterization of system phase transitions and attractors. For networks with tightly peaked degree distributions, the macroscopic behavior closely resembles that of fully connected networks previously studied by others. In contrast, networks with highly skewed degree distributions exhibit different macroscopic dynamics due to the emergence of degree dependent behavior of different oscillators. For nonassortative networks (i.e., networks without degree correlations), we observe the presence of a synchronously firing phase that can be suppressed by the presence of either assortativity or disassortativity in the network. We show that the results derived here can be used to analyze the effects of network topology on macroscopic behavior in neuronal networks in a computationally efficient fashion.

The Hunchback temporal transcription factor establishes, but is not required to maintain, early-born neuronal identity

BackgroundDrosophila and mammalian neural progenitors typically generate a diverse family of neurons in a stereotyped order. Neuronal diversity can be generated by the sequential expression of temporal transcription factors. In Drosophila, neural progenitors (neuroblasts) sequentially express the temporal transcription factors Hunchback (Hb), Kruppel, Pdm, and Castor. Hb is necessary and sufficient to specify early-born neuronal identity in multiple lineages, and is maintained in the post-mitotic neurons produced during each neuroblast expression window. Surprisingly, nothing is currently known about whether Hb acts in neuroblasts or post-mitotic neurons (or both) to specify first-born neuronal identity.MethodsHere we selectively remove Hb from post-mitotic neurons, and assay the well-characterized NB7-1 and NB1-1 lineages for defects in neuronal identity and function.ResultsWe find that loss of Hb from embryonic and larval post-mitotic neurons does not affect neuronal identity. Furthermore, removing Hb from post-mitotic neurons throughout the entire CNS has no effect on larval locomotor velocity, a sensitive assay for motor neuron and pre-motor neuron function.ConclusionsWe conclude that Hb functions in progenitors (neuroblasts/GMCs) to establish heritable neuronal identity that is maintained by a Hb-independent mechanism.We suggest that Hb acts in neuroblasts to establish an epigenetic state that is permanently maintained in early-born neurons.

Oxytocin Improves Social And Attentional Deficits In A Novel Genetically Modified Rat Model of Autism

This chapter introduces the concept of modeling. In the past chapters we discussed the analysis of data from various sources. Here, we build single neurons from scratch (in silico) to understand how they generate spiking behavior on the basis of biophysical properties. Specifically, we create them as objects in order to cover the subject of object-oriented programming (OOP) and discuss the virtues of OOP and simulations in general. We then simulate current injections into these model neurons in order to understand basic input–output relationships. Finally, we use curve-fitting techniques to model the spiking responses of these simulated neurons and discuss how to assess the goodness of fit between model and the data using standard metrics like root mean squared error or r squared.

The Pharmacogenomics of Bipolar Disorder Study: A Combined Analysis Of Ips Neuronal Expression And Gwas Data Identifies Cbarp And Card19 As Associated With Lithium Response

Background Lithium was the first mood stabilizing medication and remains the most effective. A variety of data argue that lithium responsive bipolar disorder may be genetically distinct and hence lithium response may be a powerful probe distinguishing different forms of illness. The Pharmacogenomics of Bipolar Disorder study has recently completed a prospective trial of lithium in order to quantify lithium response in 585 subjects with bipolar I disorder and conducted a GWAS on this sample. We have also recently reported that iPS derived glutamatergic hippocampal neurons demonstrated a 4 fold higher spontaneous firing rate that was reversed by lithium, but only in cells from lithium responders. Realizing that it was very difficult to obtain GWAS-size samples from a prospective trial, the PGBD study was originally designed to use functional data from stem cell derived neurons in order to reduce the number of statistical tests. Methods 11 sites participated in a 2.5 year prospective trial of lithium in bipolar I subjects. After written informed consent and 4 months of stabilization, subjects were followed for 2 years on monotherapy. Response was quantified as time to relapse. 585 subjects were genotyped using the Illumina PsychArray. A pilot GWAS of 321 European American subjects was conducted using plink and principal components from ancestry markers. RNAseq was conducted on all the iPS experiments in which lithium or control was applied to hyperexcitable cells. Expression was analyzed and compared using EdgeR in the Bioconductor package. Results Genes were selected from the iPS RNAseq data that underwent a significant change in expression in response to lithium, but only in cells from lithium responders. This yielded a list of 469 genes which were then compared with brain eQTL databases. 143 of these genes had known variants affecting expression in brain. Of these 143 SNPs, 27 were directly genotyped. The GWAS p values for these 27 SNPs were examined and one SNP was identified (rs621071) on chromosome 1 that regulates a gene on chromosome 9 (CBARP) and a gene on chromosome 19 (CARD19). This SNP showed significant association to lithium response after Bonferroni correction for the much smaller number of tests (p=0.026). Discussion The combined analysis of GWAS and functional studies make possible genomewide analyses of smaller more difficult to phenotype samples. CBARP is a very interesting candidate that binds to CACNA1C and modulates current through L-type voltage gated calcium channels as have been implicated in bipolar disorder. The function of CARD19 is less clear but may involve inhibition of Bcl-10. Lastly, these results suggest that drug response may be a powerful phenotype with which to dissect different cellular mechanisms in bipolar disorder.

Secondary Hyperalgesia to Heat Stimuli Induced by Continuous Deep Pain: A Case Report

Central sensitization represents a functional change of second order neuron induced by continuous deep pain input and maintained by psychosocial factors. When afferent neurons are involved with central sensitization, secondary hyperalgesia can appear. Secondary hyperalgesia is an increased sensitivity to stimulation without a local cause. Reports on secondary hyperalgesia to heat stimuli are relatively rare compared to mechanical stimuli. And there were few reports of secondary hyperalgesia to heat stimuli in the oral cavity. We presented a case of secondary hyperalgesia to heat stimuli in the gingival area induced by continuous odontogenic pain with a review of the related literature.

Abstract B69: Tuft cell signaling can induce pancreatic inflammation and promote pancreatic ductal adenocarcinoma

Abstract The tuft cell is a chemosensory cell type that can interpret signals from luminal surfaces throughout the body in order to activate downstream effectors. One clear effector pathway of the tuft cell promotes a type-two immune response in the intestine after parasitic infection, suggesting that this cell population has the ability to communicate with the immune system. Furthermore, tuft cells have also been shown to activate sensory nerve fibers to lead to the production of a neuroinflammatory signal in the nasal epithelium. Therefore, tuft cells can promote effector inflammatory responses through direct immune cell signaling and through sensory nerve fibers. Pancreatic ductal adenocarcinoma (PDA) is characterized by a robust stromal reaction, a large component of which is composed of an immune response. It has been previously studied that this inflammatory response can function to promote both the initiation and progression of PDA. One mechanism by which inflammatory cells can be recruited to the pancreas is through neuroinflammatory pathways. Work with collaborators has shown that pancreatic sensory neurons are required for the progression of PDA, as ablation of this cell type significantly prolongs survival. Interestingly, tuft cells in the metaplastic pancreas have been shown to appear during transdifferentiation and progression to PDA. These tuft cells also possess key signaling elements that have the potential to mediate the response to extracellular signals, such as α-gustducin and TRPM5. Metaplastic tuft cells also produce the proteins necessary to make or release prostaglandins, acetylcholine and ATP, all of which can stimulate either a direct immunomodulatory signal or activate sensory nerve fibers. This leads us to hypothesize that tuft cells are a key mediator of signals to the stromal immune compartment and to sensory neurons in order to promote a robust immune response. In order to answer this question we are using chemosensory knockout animals to ablate critical signaling components of the chemosensory cascade to study the progression of PDA. Citation Format: Megan T. Hoffman, Shan Gao, Howard Crawford.{Authors}. Tuft cell signaling can induce pancreatic inflammation and promote pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B69.

Inhibition in the auditory brainstem enhances signal representation and regulates gain in complex acoustic environments.

Inhibition plays a crucial role in neural signal processing, shaping and limiting responses. In the auditory system, inhibition already modulates second order neurons in the cochlear nucleus, e.g. spherical bushy cells (SBCs). While the physiological basis of inhibition and excitation is well described, their functional interaction in signal processing remains elusive. Using a combination of in vivo loose-patch recordings, iontophoretic drug application, and detailed signal analysis in the Mongolian Gerbil, we demonstrate that inhibition is widely co-tuned with excitation, and leads only to minor sharpening of the spectral response properties. Combinations of complex stimuli and neuronal input-output analysis based on spectrotemporal receptive fields revealed inhibition to render the neuronal output temporally sparser and more reproducible than the input. Overall, inhibition plays a central role in improving the temporal response fidelity of SBCs across a wide range of input intensities and thereby provides the basis for high-fidelity signal processing.

Improved Auditory Nerve Survival with Nanoengineered Supraparticles for Neurotrophin Delivery into the Deafened Cochlea

Cochlear implants electrically stimulate spiral ganglion neurons (SGNs) in order to provide speech cues to severe-profoundly deaf patients. In normal hearing cochleae the SGNs depend on endogenous neurotrophins secreted by sensory cells in the organ of Corti for survival. SGNs gradually degenerate following deafness and consequently there is considerable interest in developing clinically relevant strategies to provide exogenous neurotrophins to preserve SGN survival. The present study investigated the safety and efficacy of a drug delivery system for the cochlea using nanoengineered silica supraparticles. In the present study we delivered Brain-derived neurotrophic factor (BDNF) over a period of four weeks and evaluated SGN survival as a measure of efficacy. Supraparticles were bilaterally implanted into the basal turn of cochleae in profoundly deafened guinea pigs. One ear received BDNF-loaded supraparticles and the other ear control (unloaded) supraparticles. After one month of treatment the cochleae were examined histologically. There was significantly greater survival of SGNs in cochleae that received BDNF supraparticles compared to the contralateral control cochleae (repeated measures ANOVA, p = 0.009). SGN survival was observed over a wide extent of the cochlea. The supraparticles were well tolerated within the cochlea with a tissue response that was localised to the site of implantation in the cochlear base. Although mild, the tissue response was significantly greater in cochleae treated with BDNF supraparticles compared to the controls (repeated measures ANOVA, p = 0.003). These data support the clinical potential of this technology particularly as the supraparticles can be loaded with a variety of therapeutic drugs.

ATP-sensitive muscle afferents activate spinal trigeminal neurons with meningeal afferent input in rat - pathophysiological implications for tension-type headache.

BackgroundTension-type headache and other primary headaches may be triggered or aggravated by disorders of pericranial muscles, which is possibly due to convergent or collateral afferent input from meningeal and muscular receptive areas. In rodent models high extracellular concentrations of ATP caused muscle nociception and central sensitization of second order neurons. In a rat model of meningeal nociception we asked if spinal trigeminal activity induced by ATP can be modulated by local anaesthesia of distinct muscles.MethodsOngoing activity was recorded from spinal trigeminal neurons with afferent input from the cranial dura mater, the temporal muscle and neck muscles. The stable ATP analogue α,β-methylene adenosine 5′-triphosphate (α,β-meATP, 10 mM) was injected into the ipsilateral temporal muscle, 30 min later followed by injection of local anaesthetics (lidocaine, 2 %) into the ipsilateral neck muscles and/or the temporal muscle.ResultsInjection of α,β-meATP into the temporal muscle caused progressive increase in ongoing activity of most of the spinal trigeminal neurons within 30 min. Injection of lidocaine into the neck muscles and/or the temporal muscle reduced this activation to previous levels within 10 min.ConclusionsDistinct spinal trigeminal neurons processing meningeal nociceptive information are under the control of convergent afferent input from several pericranial muscles. Blockade of at least one of these inputs can normalize central trigeminal activity. This may explain why therapeutic manipulations of head muscles can be beneficial in primary headaches.

Evaluation of micro Electroretinograms Recorded with Multiple Electrode Array to Assess Focal Retinal Function.

Full-field electroretinograms (ERGs) are used to objectively assess the mass function of the retina, whereas focal ERGs are used to evaluate the focal retinal function. The purpose of this study was to determine the usefulness of a multiple electrode array (MEA) system for recording ex vivo micro ERGs (mERGs) together with multiunit spike responses of the retinal ganglion cells (RGCs) to assess focal retinal function in isolated mouse retinas. The a- and b-waves of the full-field ERGs were present in the mERG. The b-wave was blocked by L-AP4, an inhibitor of the mGluR6 receptor, and the OFF-component was blocked by exposure to PDA, an antagonist of ionotropic glutamate receptors, with a corresponding RGC responses. mERGs were also recorded from mice with progressive retinal degeneration, the C57BL/6J-Pde6brd1-2J/J (rd1) mice, from which conventional full-field ERGs are non-recordable. A blockade of the glutamate receptors indicated that the negative wave of rd1 mice do not originate from the photoreceptors but from the second or third order neurons. This technique of recording mERGs will be useful in assessing the focal properties of the retinas obtained from eyes with pathology and also to follow the recovery of the physiology of the retina in regenerative studies.