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To date, intracellular calcium reporters are the most commonly used optical probes for detecting neuron activity. Synthetic low molecular weight and genetically encoded protein compounds provide an enormous variety of accessible methods for recording signals of different intensity at different levels of studying the nervous system, from detecting activity in synaptic boutons and dendritic spines to recording the activity of the central nervous system in free behavior in vivo. This paper presents a comparative description of methods for optical recording of changes in the intracellular calcium concentration and compares original experimental data obtained by each of the methods described. Advantages and drawbacks are described, and the potential areas of application of each of the commercially available and widely used types of calcium-sensitive reporters are outlined. [ABSTRACT FROM AUTHOR]

The mechanical complexities of rotating an object through the gravity field present a formidable challenge to the human central nervous system (CNS). The current study documents the finger force patterns selected by the CNS when performing one-, two-, and four-finger grasping while holding an object statically at various orientations with respect to vertical. Numerous mechanically ‘‘unnecessary’’ behaviors were observed. These included: nonzero tangential forces for horizontal handle orientations, large internal forces (i.e., those in excess of equilibrium requirements) for all orientations, and safety margins between 50 and 90%. Additionally, none of the investigated measures were constant across orientations or could be represented as a simple trigonometric function of orientation. Nonetheless, all measures varied in systematic (and sometimes symmetric) ways with orientation. The results suggest that the CNS selects force patterns that are based on mechanical principles but also that are not simply related to object orientation. This study is complemented by a second paper that provides an in-depth analysis of the mechanics of nonvertical grasping and accounts for many of the observed results with numerical optimization (see Part II - current issue). Together, the papers demonstrate that the CNS is likely to utilize optimization processes when controlling prehensile actions. [ABSTRACT FROM AUTHOR]

Hetero-pentameric Cys-loop receptors constitute a major type of neurotransmitter receptors that enable signal transmission and processing in the nervous system. Despite intense investigations into their working mechanism and pharmaceutical potentials, how neurotransmitters activate these receptors remains unclear due to the lack of high-resolution structural information in the activated open state. Here we report near-atomic resolution structures resolved in digitonin consistent with all principle functional states of the human α1β GlyR, which is a major Cys-loop receptor that mediates inhibitory neurotransmission in the central nervous system of adults. Glycine binding induces cooperative and symmetric structural rearrangements in the neurotransmitter-binding extracellular domain but asymmetrical pore dilation in the transmembrane domain. Symmetric response in the extracellular domain is consistent with electrophysiological data showing cooperative glycine activation and contribution from both α1 and β subunits. A set of functionally essential but differentially charged amino acid residues in the transmembrane domain of the α1 and β subunits explains asymmetric activation. These findings provide a foundation for understanding how the gating of the Cys-loop receptor family members diverges to accommodate specific physiological environments. Despite essential roles in adult nervous systems, how heteromeric Cys-loop receptors work is unclear in the absence of an open state structure. Here, the authors report closed/open state structures and functional experiments, detailing an asymmetric gating mechanism driven by differing contributions from each subunit type. [ABSTRACT FROM AUTHOR]

Abstract  Drugs based on 5-phenyl-2,4 diamino pyrimidine and 6-phenyl-1,2,4 triazine derivatives are well known for their effects on the central nervous system. The study presented here provides detailed crystal structures of two pyrimidine derivatives which have neuroprotective properties in models of both grey and white matter ischemia. Recently published studies suggest that the compounds lamotrigine (a triazine derivative), and the two pyrimidines BW1003C87 (I) and sipatrigine (II) mediate their primary in vivo mode of action by inhibiting voltage-gated Na channels. The X-ray crystal structures will contribute valuable data for applications involving binding and modelling studies of the biological actions of these drugs. Graphical Abstract   X-ray crystallographic structures of neuroprotective pyrimidine derivatives: (I) the mesylate salt of BW1003C87 and (II) sipatrigine base Rex A. Palmer*, Brian S. Potter, Michael J. Leach and Babur Z. Chowdhry Surface representations, [20] are a useful tool with respect to considerations employed for the purposes of drug design. Shown here are the neuroprotective drug molecules (a) BW1003C87 and (b) Sipatrigine Base (BW619C89) derived from their solid state structures reported in this paper. The molecules are viewed edge on to ring B with the two adjacent Cl atoms uppermost on the left. [ABSTRACT FROM AUTHOR]

This paper describes a neuro-musculo-skeletal model of the human lower body which has been developed with the aim of studying the effects of spinal cord injury on locomotor abilities. The model represents spinal neural control modules corresponding to central pattern generators, muscle spindle based reflex pathways, golgi tendon organ based pathways and cutaneous reflex pathways, which are coupled to the lower body musculo-skeletal dynamics. As compared to other neuro-musculo-skeletal models which aim to provide a description of the possible mechanisms involved in the production of locomotion, the goal of the model here is to understand the role of the known spinal pathways in locomotion. Thus, while other models focus primarily on functionality at the overall system level, the model here emphasizes functional and topological correspondance with the biological system at the level of the subcomponents representing spinal pathways. Such a model is more suitable for the detailed investigation of clinical questions related to spinal control of locomotion. The model is used here to perform preliminary experiments addressing the following issues: (1) the significance of spinal reflex modalities for walking and (2) the relative criticality of the various reflex modalities. The results of these experiments shed new light on the possible role of the reflex modalities in the regulation of stance and walking speed. The results also demonstrate the use of the model for the generation of hypothesis which could guide clinical experimentation. In the future, such a model may have applications in clinical diagnosis, as it can be used to identify the internal state of the system which provides the closest behavioral fit to a patient’s pathological condition. [ABSTRACT FROM AUTHOR]

Principal components analysis (PCA) has not been very much in vogue within the field of movement coordination even though it is useful to reduce data dimensionality and to reveal underlying data structures. Traditionally, studies of coordination between two joints have predominantly made use of relative phase analyses. This has resulted in the identification of principal constraints that govern the Central Nervous System’s organization and the control of coordination patterns. However, relative phase analyses on pairwise joints have some drawbacks because they are not optimal for revealing convergent patterns among multijoint coordination modes and for unraveling generic control strategies. In this paper, we present a method to analyze multijoint coordination based on the properties of PC, more specifically the eigenvalues and eigenvectors of the covariance matrix. The comparison between relative phase analysis and PCA shows that both provide similar and consistent results, underscoring the latter technique’s sensitivity to the study of coordination performance. In addition, it provides a method for automatic pattern detection as well as an index of performance for each joint within the context of the global coordination pattern. Finally, the merit of the PCA technique within the context of central pattern generators (CPG) will be discussed. [ABSTRACT FROM AUTHOR]

The consensus of several studies on health among Gulf War (GW)-deployed veterans is that they have elevated symptom complaints. Central nervous system (CNS) symptoms among these veterans have been assessed in several investigations. Studies have disagreed as to whether there are neuropsychological deficits in GW-deployed veterans relative to controls. When differences between these groups have been found, they have often been attributed to stress or psychiatric factors, although exposures to neurotoxic substances present in the GW theatre have also been indicted as possible explanations. A review of the existing literature as well as the 5 papers contained in this issue of Journal of Psychopathology and Behavioral Assessment suggests that the neuropsychological and health symptom sequelae of GW zone service are multidetermined and cannot easily be explained on the basis of simplistic models of causation. Psychological, historical, and exposure parameters must be considered in the scientific evaluation of this problem. [ABSTRACT FROM AUTHOR]

This paper reviews the clinical diagnostic approach to hereditary neuropathies in adults by analysing: elements that point to a neuropathy of inherited origin, different modalities of presentation, laboratory and instrumental diagnostic tests, including molecular tests, symptoms and signs of involvement of other organs. Different phenotypes may be identified according to: disease course; involvement of motor, sensory, autonomic fibres; site of lesion (neuropathy versus neuronopathy); calibre of involved fibres (small-fibre versus large-fibre neuropathy); presence of distinctive symptoms (neuropathic pain); involvement of other organs or apparatus. Charcot-Marie-Tooth disease, Familial Amyloid Polyneuropathy, Hereditary Sensory and Autonomic Neuropathy, Fabry disease, Tangier disease, Porphyric Neuropathies, Refsum disease, Hereditary Neuropathy with liability to Pressure Palsies, Hereditary Neuralgic Amyotrophy, and other rare disorders involving the peripheral nervous system are reviewed. [ABSTRACT FROM AUTHOR]

HIV-1-associated en cephalopathy (HIVE) remains an important manifestation of advanced HIV infection despite recent advances in antiretroviral therapy. Special pharmacological and virological conditions predominate in the central nervous system (CNS). HIVE is characterized by "subcortical" dementia which becomes manifest as psychomotor slowing as well as mernory and concentration deficits. Deficits of central motor function are an invariable finding. Enhanced viral replication in immunocompetent CNS cells is believed to be the pathogenic basis of CNS disease. This process leads to neurotoxic effects elicited directly by viral products as well as indirectly by the immune response to the virus. HIV-1 associated myelopathy (HIVM) is the other CNS manifestion of advanced HIV-1 infection. The present consensus paper recommends diagnostic and therapeutic procedures in HIVE and HIVM and outlines the state of current research. [ABSTRACT FROM AUTHOR]

The potential of neuroimage databases to accelerate the dissemination and use of information about brain structure and function is enormous and ever increasing. Numerous efforts are now underway to further develop the technology and sociology that are necessary to support this revolution. Each effort has its own approach and tackles some of the complex problems that are associated with creating and providing access to a database. This paper introduces many of the recent successes and future challenges that are faced by the developers and users of neuroimage databases. [ABSTRACT FROM AUTHOR]

Morphogenesis of the Central Nervous System (CNS) is a complex process that obeys precise architectural rules. Yet, the mechanisms dictating these rules remain unknown. Analyzing morphogenesis of the Drosophila embryo Ventral Nerve Cord (VNC), we observe that a tight control of JNK signaling is essential for attaining the final VNC architecture. JNK signaling in a specific subset of pioneer neurons autonomously regulates the expression of Fasciclin 2 (Fas 2) and Neurexin IV (Nrx IV) adhesion molecules, probably via the transcription factor zfh1. Interfering at any step in this cascade affects fasciculation along pioneer axons, leading to secondary cumulative scaffolding defects during the structural organization of the axonal network. The global disorder of architectural landmarks ultimately influences nervous system condensation. In summary, our data point to JNK signaling in a subset of pioneer neurons as a key element underpinning VNC architecture, revealing critical milestones on the mechanism of control of its structural organization. The shape and size of the mature central nervous system is highly regular, implying precise architectural rules. The authors show that alterations in JNK signaling in selected neurons impact the overall 3-dimensional organization of the Drosophila ventral nerve cord in a cell non-autonomous fashion. [ABSTRACT FROM AUTHOR]

Paraneoplastic syndrome is a group of clinical symptoms that occur in the state of systemic malignant tumors. Paraneoplastic syndrome of the nervous system can affect any part of the central and peripheral nervous system and may also affect the eyes. In neuroophthalmology, paraneoplastic syndrome has a variety of manifestations that can affect both the afferent and efferent visual systems. The afferent system may involve the optic nerve, retina and uvea; the efferent system may involve eye movement, neuromuscular joints or involuntary eye movements and pupil abnormalities and may also have other neurological symptoms outside the visual system. This article discusses the clinical manifestations, pathological mechanisms, detection methods and treatment methods of paraneoplastic syndrome in neuroophthalmology. The performance of paraneoplastic syndrome is diverse, the diagnosis is difficult, and the treatment should be considered systematically. Differential diagnosis, optimal evaluation and management of these manifestations is not only the key to treatment but also a challenge. [ABSTRACT FROM AUTHOR]

This review is devoted to the analysis of works that investigated the long-term effects of species-specific forms of intensive locomotion on the cognitive functions of animals and humans, which can be transmitted to the next generation. To date, the anxiolytic and cognitive-enhancing long-term effects of intensive locomotion have been demonstrated in humans, rodents, fish, insects, mollusks, and nematodes. In rodents, changes in the central nervous system caused by intense locomotion can be transmitted through the maternal and paternal line to the descendants of the first generation. These include reduced anxiety, improved spatial learning and memory, increased levels of brain neurotrophic factor and vascular endothelial growth factor in the hippocampus and frontal cortex. The shift of the balance of histone acetylation in the hippocampus of rodents towards hyperacetylation, and the balance of DNA methylation towards demethylation manifests itself both as a direct and as a first-generation inherited effect of motor activity. The question about the mechanisms that link locomotion with an increase in the plasticity of a genome in the brain of descendants remains poorly understood, and invertebrate model organisms can be an ideal object for its study. Currently, there is a lack of a theoretical model explaining why motor activity leads to long-term improvement of some cognitive functions that can be transmitted to the next generation and why such an influence could have appeared in evolution. The answer to these questions is not only of fundamental interest, but it is necessary for predicting therapeutic and possible side effects of motor activity in humans. In this regard, the article pays special attention to the review of ideas on the evolutionary aspects of the problem. We propose our own hypothesis, according to which the activating effect of intensive locomotion on the function of the nervous system could have been formed in evolution as a preadaptation to a possible entry into a new environment. [ABSTRACT FROM AUTHOR]

Axonal characterizations of connectomes in healthy and disease phenotypes are surprisingly incomplete and biased because unmyelinated axons, the most prevalent type of fibers in the nervous system, have largely been ignored as their quantitative assessment quickly becomes unmanageable as the number of axons increases. Herein, we introduce the first prototype of a high-throughput processing pipeline for automated segmentation of unmyelinated fibers. Our team has used transmission electron microscopy images of vagus and pelvic nerves in rats. All unmyelinated axons in these images are individually annotated and used as labeled data to train and validate a deep instance segmentation network. We investigate the effect of different training strategies on the overall segmentation accuracy of the network. We extensively validate the segmentation algorithm as a stand-alone segmentation tool as well as in an expert-in-the-loop hybrid segmentation setting with preliminary, albeit remarkably encouraging results. Our algorithm achieves an instance-level F 1 score of between 0.7 and 0.9 on various test images in the stand-alone mode and reduces expert annotation labor by 80% in the hybrid setting. We hope that this new high-throughput segmentation pipeline will enable quick and accurate characterization of unmyelinated fibers at scale and become instrumental in significantly advancing our understanding of connectomes in both the peripheral and the central nervous systems. [ABSTRACT FROM AUTHOR]

Aside from the respiratory distress as the predominant clinical presentation of SARS-CoV-2 infection, various neurological complications have been reported with the infection during the ongoing pandemic, some of which cause serious morbidity and mortality. Herein, we gather the latest anatomical evidence of the virus's presence within the central nervous system. We then delve into the possible SARS-CoV-2 entry routes into the neurological tissues, with the hematogenous and the neuronal routes as the two utmost passage routes into the nervous system. We then give a comprehensive review of the neurological manifestations of the SARS-CoV-2 invasion in both the central and peripheral nervous system and its underlying pathophysiology via investigating large studies in the field and case reports in cases of study scarcity. [ABSTRACT FROM AUTHOR]

A variety of neural networks in the central nervous system is determined by the heterogeneity of its constituent neuronal populations. Calcium-binding proteins can be used as markers of different neuronal morphotypes. One of the most common calcium-binding proteins in the nervous system is calretinin. In the present work, using an indirect immunohistochemical method, calretinin-immunopositive neuronal populations were labeled in lumbar segments of the cat (Felis catus) spinal cord. We identified nineteen morphotypes of neurons with strictly segmental and laminar distribution patterns, and attempted to compare putative functions of these neurons with the available literature data. Three morphotypes are located in lamina I, corresponding to neurons involved in nociceptive and temperature processing. Lamina II contains neurons of a single morphotype, on which nociceptive afferents converge. Laminae III–IV comprise three types of projection neurons transmitting information from peripheral mechanoreceptors and nociceptors to supraspinal structures. Laminae V–VI are characterized by functionally different neurons of five morphotypes: two types of interneurons localized to the Clarke's column and analogous zone of the caudal lumbar segments, which collect proprioceptive information; one type of neurons located at the lateral border between the white and gray matter and responding to pain and tactile signals; and two types of irregularly distributed interneurons (projection or propriospinal neurons) that receive heterogeneous afferent signals from muscle spindles. In laminae VII–VIII, there are two types of sympathetic preganglionic neurons (in the intermediolateral and intercalated nuclei), Renshaw interneurons, and three types of multi-sized dispersedly distributed multipolar cells with unidentified functions. No calretinin-immunopositive neurons were found in lamina IX represented by motoneuron pools. In lamina X, sparse neurons reside around the central canal; their function is also obscure due to the paucity of morphological traits. [ABSTRACT FROM AUTHOR]

Stem cell technologies including self-assembling 3D tissue models provide access to early human neurodevelopment and fundamental insights into neuropathologies. Gastruloid models have not been used to investigate co-developing central and peripheral neuronal systems with trunk mesendoderm which we achieve here in elongating multi-lineage organized (EMLO) gastruloids. We evaluate EMLOs over a forty-day period, applying immunofluorescence of multi-lineage and functional biomarkers, including day 16 single-cell RNA-Seq, and evaluation of ectodermal and non-ectodermal neural crest cells (NCCs). We identify NCCs that differentiate to form peripheral neurons integrated with an upstream spinal cord region after day 8. This follows initial EMLO polarization events that coordinate with endoderm differentiation and primitive gut tube formation during multicellular spatial reorganization. This combined human central-peripheral nervous system model of early organogenesis highlights developmental events of mesendoderm and neuromuscular trunk regions and enables systemic studies of tissue interactions and innervation of neuromuscular, enteric and cardiac relevance. The authors generate EMLOs (elongating multi-lineage organized gastruloids): organoids that self-organize to form compartments with characteristics of the central nervous system, peripheral nervous system, mesenchyme, and gut tube. [ABSTRACT FROM AUTHOR]

The Hippo signaling pathway is highly conserved from Drosophila melanogaster to mammals and plays a crucial role in organ size control, tissue regeneration, and tumor suppression. The Yes-associated protein (YAP) is an important transcriptional co-activator that is negatively regulated by the Hippo signaling pathway. The Hippo signaling pathway is also regulated by various upstream regulators, such as cell polarity, adhesion proteins, and other signaling pathways (the Wnt/β-catenin, Notch, and MAPK pathways). Recently, accumulated evidence suggests that the Hippo/YAP signaling pathway plays important roles in central nervous system development and brain tumor, including glioma. In this review, we summarize the results of recent studies on the physiological effect of the Hippo/YAP signaling pathway in neural stem cells, neural progenitor cells, and glial cells. In particular, we also focus on the expression of MST1/2, LATS1/2, and the downstream effector YAP, in glioma, and offer a review of the latest research of the Hippo/YAP signaling pathway in glioma pathogenesis. Finally, we also present future research directions and potential therapeutic strategies for targeting the Hippo/YAP signaling in glioma. [ABSTRACT FROM AUTHOR]

A 7-year-old boy that presented an encephalomyeloradiculitis and no classic symptoms of arboviruses. Zika virus (ZIKV) was confirmed by molecular analyses of cerebrospinal fluid and 1 year later by plaque reduction neutralization test. This case demonstrates that ZIKV can be associated with diffuse nervous system infection in children. [ABSTRACT FROM AUTHOR]

A two-dimensional shadow may encompass more information than its corresponding three-dimensional object. Indeed, if we rotate the object, we achieve a pool of observed shadows from different angulations, gradients, shapes and variable length contours that make it possible for us to increase our available information. Starting from this simple observation, we show how informational entropies might turn out to be useful in the evaluation of scale-free dynamics in the brain. Indeed, brain activity exhibits a scale-free distribution that leads to the variations in the power law exponent typical of different functional neurophysiological states. Here we show that modifications in scaling slope are associated with variations in Rényi entropy, a generalization of Shannon informational entropy. From a three-dimensional object’s perspective, by changing its orientation (standing for the cortical scale-free exponent), we detect different two-dimensional shadows from different perception angles (standing for Rényi entropy in different brain areas). We show how, starting from known values of Rényi entropy (easily detectable in brain fMRIs or EEG traces), it is feasible to calculate the scaling slope in a given moment and in a given brain area. Because changes in scale-free cortical dynamics modify brain activity, this issue points towards novel approaches to mind reading and description of the forces required for transcranial stimulation. [ABSTRACT FROM AUTHOR]

The small-world architecture has gained considerable attention in anatomical brain connectivity studies. However, how to adequately quantify small-worldness in diffusion networks has remained a problem. We addressed the limits of small-world measures and defined new metric indices: the small-world efficiency (SWE) and the small-world angle (SWA), both based on the tradeoff between high global and local efficiency. To confirm the validity of the new indices, we examined the behavior of SWE and SWA of networks based on the Watts-Strogatz model as well as the diffusion tensor imaging (DTI) data from 75 healthy old subjects (aged 50-70). We found that SWE could classify the subjects into different age groups, and was correlated with individual performance on the WAIS-IV test. Moreover, to evaluate the sensitivity of the proposed measures to network, two network attack strategies were applied. Our results indicate that the new indices outperform their predecessors in the analysis of DTI data. [ABSTRACT FROM AUTHOR]

A comparison has been made for the first time between the cholinergic components of the nervous system of important human digeneans namely Schistosoma mansoni and Schistosoma haematobium from infected hamster ( Cricentus auratus) in Egypt. In each parasite, the central nervous system consists of two cerebral ganglia and three pairs of nerve cords (ventral, lateral, and dorsal) linked together by some transverse connectives and numerous ring commissures. Peripheral cholinergic innervation was detected in oral and ventral suckers and in some parts of female reproductive system in both species, but there were some differences. The possible functions of some of these nervous components are discussed. [ABSTRACT FROM AUTHOR]

The article focuses on atypical granular cell tumour of the sural nerve mimicking. Granular cell tumours are usually found in the skin of head, neck, and tongue and may be multiple. Other less common sites are breast, gastrointestinal tract, vulva, peripheral and central nervous system, spermatic cord, and upper respiratory tract. Granular cell tumours in the upper and lower extremities are mostly located in the skin and subcutaneous tissue. Reports of granular cell tumours of peripheral nerves are extremely rare, and there are only few cases involving the median, radial, ulnar, digital, sciatic, trigeminal, and recurrent laryngeal nerves.

Peripheral cytokines affect central nervous system (CNS) function, manifesting in symptoms of anxiety and cognitive decline. Although the peripheral blockage of tumor necrosis factor (TNF)-α has been effective in alleviating depression and rheumatoid arthritis, it is yet unknown whether central blockade of TNF-α is beneficial for immune-challenged CNS function. This study investigated the effects of central etanercept administration following a peripheral immune challenge on anxiety-like and cognition-like behaviors and microglia and astrocyte numbers. Twelve-week-old C57BL/6 mice (n=40) were treated with either LPS or saline administered peripherally 24 h before being treated with either etanercept or artificial CSF (aCSF) by intracerebroventricular injection. Mice underwent behavioral analyses for locomotion, memory, and anxiety-like behavior 24 h post-etanercept/aCSF treatment, and tissue was collected to estimate the numbers of hippocampal microglia and astrocytes. Following peripheral immune challenge with LPS, mice showed increased anxiety-like behavior, which was significantly improved following treatment with etanercept (two-way ANOVA: Interaction: F(1,30)=0.60, P=0.44; Saline/LPS challenge: F(1,30)=23.92, P<0.0001, etanercept vs aCSF: F(1,30)=11.09, P=0.0023). For cognition, a significant interaction effect found by two-way ANOVA (Interaction: F(1,20)=4.96, P=0.037, Saline/LPS challenge: F(1,20)=4.966, P=0.31, aCSF/etanercept treatment: F(1,20)=0.06, P=0.80) and post-hoc analysis revealed a significant decrease in cognition in LPS-aCSF compared with Sal-aCSF mice (P=0.038), but no significant difference was noted between LPS-aCSF and LPS-Etan mice (P>0.9). A significant reduction in the number of microglia within the hippocampus of these mice was noted (two-way ANOVA: Interaction: F(1,15)=11.41, P=0.0041; Saline/LPS challenge: F(1,15)=50.13, P<0.0001, etanercept vs aCSF: F(1,15)=3.36, P=0.08). Centrally administered etanercept improved anxiety-like behavior but not spatial memory under a peripheral immune challenge and was associated with a decrease in the hippocampal microglia numbers. This suggests that etanercept recovers anxiety-like behavior possibly mediated by a reduction of TNF-α-related central inflammation. [ABSTRACT FROM AUTHOR]

Throughout the CNS, gap junction-mediated electrical signals synchronize neural activity on millisecond timescales via cooperative interactions with chemical synapses. However, gap junction-mediated synchrony has rarely been studied in the context of varying spatiotemporal patterns of electrical and chemical synaptic activity. Thus, the mechanism underlying fine-scale synchrony and its relationship to neural coding remain unclear. We examined spike synchrony in pairs of genetically identified, electrically coupled ganglion cells in mouse retina. We found that coincident electrical and chemical synaptic inputs, but not electrical inputs alone, elicited synchronized dendritic spikes in subregions of coupled dendritic trees. The resulting nonlinear integration produced fine-scale synchrony in the cells' spike output, specifically for light stimuli driving input to the regions of dendritic overlap. In addition, the strength of synchrony varied inversely with spike rate. Together, these features may allow synchronized activity to encode information about the spatial distribution of light that is ambiguous on the basis of spike rate alone. [ABSTRACT FROM AUTHOR]

Because cerebrospinal fluid (CSF) is the biofluid which interacts most closely with the central nervous system, it holds promise as a reporter of neurological disease, for example multiple sclerosis (MScl). To characterize the metabolomics profile of neuroinflammatory aspects of this disease we studied an animal model of MScl-experimental autoimmune/allergic encephalomyelitis (EAE). Because CSF also exchanges metabolites with blood via the blood-brain barrier, malfunctions occurring in the CNS may be reflected in the biochemical composition of blood plasma. The combination of blood plasma and CSF provides more complete information about the disease. Both biofluids can be studied by use of NMR spectroscopy. It is then necessary to perform combined analysis of the two different datasets. Mid-level data fusion was therefore applied to blood plasma and CSF datasets. First, relevant information was extracted from each biofluid dataset by use of linear support vector machine recursive feature elimination. The selected variables from each dataset were concatenated for joint analysis by partial least squares discriminant analysis (PLS-DA). The combined metabolomics information from plasma and CSF enables more efficient and reliable discrimination of the onset of EAE. Second, we introduced hierarchical models fusion, in which previously developed PLS-DA models are hierarchically combined. We show that this approach enables neuroinflamed rats (even on the day of onset) to be distinguished from either healthy or peripherally inflamed rats. Moreover, progression of EAE can be investigated because the model separates the onset and peak of the disease. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Chromaffin cells probably are the most intensively studied of the neural crest derivates. They are closely related to the nervous system, share with neurons some fundamental mechanisms and thus were the ideal model to study the basic mechanisms of neurobiology for many years. The lessons we have learned from chromaffin cell biology as a peripheral model for the brain and brain diseases pertain more than ever to the cutting edge research in neurobiology. Here, we highlight how studying this cell model can help unravel the basic mechanisms of cell renewal and regeneration both in the central nervous system (CNS) and neuroendocrine tissue and also can help in designing new strategies for regenerative therapies of the CNS. [ABSTRACT FROM AUTHOR]

The intermediate filament (IF) synemin gene encodes three IF proteins (H 180, M 150, L 41 kDa) with overlapping distributions. Synemin M was present early with vimentin and nestin. Synemin H was found later in the nervous system and mesodermic derivatives concomitantly with angiogenesis and the migration of neural crest cells. Synemin L appeared later in neurons. A series of in vitro cell cultures were done to identify the linkage between synemin isoforms and specific cell types of the central nervous system (CNS). The neurons and glia from the brains of humans and rats were cultured and double immunostaining done with antibodies against the H/M or L synemin isoforms and neural cell types (βIII-tubulin or NeuN) or astrocyte intermediate filaments (GFAP or vimentin). In neurons of the CNS, synemin H/M were co-expressed with GFAP, vimentin or nestin in glial cells, whereas synemin L was found in neurons. [ABSTRACT FROM AUTHOR]

Circulating immune cells support hippocampal neurogenesis, spatial memory, expression of brain-derived neurotrophic factor, and resilience to stress. Nevertheless, considering the immune privileged status of the central nervous system (CNS), such cells were assumed to be excluded from the healthy brain. It is evident, however, that the CNS is continuously surveyed by leukocytes, though their function is still a mystery. Coupling this routine leukocyte trafficking with the function attributed to circulating T cells in brain plasticity led us to propose here that CNS immunosurveillance is an integral part of the functioning brain. Anatomical restriction of selected self-recognizing leukocytes to the brain's borders and fluids (cerebrospinal fluid) not only supports the brain's activity, but also controls the potential aggressiveness of such cells. Accordingly, the brain's ‘privilege’ is its acquisition of a private peripheral immunological niche under its own control, which supports brain function. Immune malfunction may comprise a missing link between a healthy and diseased mind. [ABSTRACT FROM AUTHOR]

Neural representations of limb movement kinematic parameters are common among central nervous system structures involved in motor control, such as the interpositus nucleus of the cerebellum. Much experimental evidence indicates that neurons in the interpositus may encode limb kinematic parameters both during active, voluntary actions and during limb motion imposed passively, which entrains only sensory afferents. With respect to the sensory processing of information related to movement kinematics, we show that interpositus neuronal activity can parse out the directional from the scalar component (i.e., the movement speed) of the velocity vector. Moreover, a differential role for the anterior and posterior portion of interpositus in encoding these parameters emerged from these data, since the activity of the posterior interpositus was specifically associated to changes of movement speed. Limb movement representations in the interpositus nucleus may be instrumental for the control of goal-directed movements such as shaping hand during grasping or precise foot placement during gait. Finally, we discuss the idea that sensory information about the movement kinematics contribute to both feedback and anticipatory processes for limb movement control. [ABSTRACT FROM AUTHOR]

Presents the results of a study on the contribution of gene evolution to the development of the brain. Comparison of the rates of evolution of genes in the primate lineage and non-primate lineage; Factors that influenced the role of genes in nervous system function; Details of the developmental process involved in evolutionary changes in brain size.

The signalling pathways controlling both the evolution and development of language in the human brain remain unknown. So far, the transcription factor FOXP2 (forkhead box P2) is the only gene implicated in Mendelian forms of human speech and language dysfunction. It has been proposed that the amino acid composition in the human variant of FOXP2 has undergone accelerated evolution, and this two-amino-acid change occurred around the time of language emergence in humans. However, this remains controversial, and whether the acquisition of these amino acids in human FOXP2 has any functional consequence in human neurons remains untested. Here we demonstrate that these two human-specific amino acids alter FOXP2 function by conferring differential transcriptional regulation in vitro. We extend these observations in vivo to human and chimpanzee brain, and use network analysis to identify novel relationships among the differentially expressed genes. These data provide experimental support for the functional relevance of changes in FOXP2 that occur on the human lineage, highlighting specific pathways with direct consequences for human brain development and disease in the central nervous system (CNS). Because FOXP2 has an important role in speech and language in humans, the identified targets may have a critical function in the development and evolution of language circuitry in humans. [ABSTRACT FROM AUTHOR]

Previous studies have shown that axonal outgrowth in the damaged central nervous system is closely related to the local microenvironment. Transplantation of bone marrow stromal cells (BMSC) or BMSC with some biomaterials has been used to treat various central nervous system diseases with some success. In the current study, we investigated if BMSC on denuded human amniotic membrane (DhAM) as a composite matrix could stimulate axonal outgrowth or not. After completely removing the cells on the amniotic membrane with a tryptic and mechanical approach, we seeded BMSC on it. The MTS was applied to test the cytotoxicity of DhAM compared with PLGA and PLL. The morphology of the BMSC was observed by light, electronic and laser confocal microscopy. We also used four kinds of substance (PLL, DhAM, BMSC + PLL, BMSC + DhAM) to coculturing with the cortical neurons. Finally, the lengths of axons in each group were studied using the positive axon-specific marker NF–H. The DhAM was devoid of cellular components and only its intact basement membrane was left. BMSC grew on the substrate and proliferated with a flat to fusiform morphology. In the MTS test, the results indicated that BMSC cultured in DhAM extract had a high survival rate (> 80%). Moreover, the cortical neural axons in the experimental group (BMSC + DhAM) were longer (287.37 ± 12.72 μm) than in the other groups ( P < 0.01). This study demonstrates that the DhAM was a good carrier to support growth of BMSC and BMSC on DhAM was an effective composite matrix to support the outgrowth of the axons of rat cortical neurons in vitro. Future studies of the use of the composite matrix in disorders are planned. [ABSTRACT FROM AUTHOR]

T-cell acute lymphoblastic leukaemia (T-ALL) is a blood malignancy afflicting mainly children and adolescents. T-ALL patients present at diagnosis with increased white cell counts and hepatosplenomegaly, and are at an increased risk of central nervous system (CNS) relapse. For that reason, T-ALL patients usually receive cranial irradiation in addition to intensified intrathecal chemotherapy. The marked increase in survival is thought to be worth the considerable side-effects associated with this therapy. Such complications include secondary tumours, neurocognitive deficits, endocrine disorders and growth impairment. Little is known about the mechanism of leukaemic cell infiltration of the CNS, despite its clinical importance. Here we show, using T-ALL animal modelling and gene-expression profiling, that the chemokine receptor CCR7 (ref. 5) is the essential adhesion signal required for the targeting of leukaemic T-cells into the CNS. Ccr7 gene expression is controlled by the activity of the T-ALL oncogene Notch1 and is expressed in human tumours carrying Notch1-activating mutations. Silencing of either CCR7 or its chemokine ligand CCL19 (ref. 6) in an animal model of T-ALL specifically inhibits CNS infiltration. Furthermore, murine CNS-targeting by human T-ALL cells depends on their ability to express CCR7. These studies identify a single chemokine–receptor interaction as a CNS ‘entry’ signal, and open the way for future pharmacological targeting. Targeted inhibition of CNS involvement in T-ALL could potentially decrease the intensity of CNS-targeted therapy, thus reducing its associated short- and long-term complications. [ABSTRACT FROM AUTHOR]

Discusses various parallels that can be drawn between axon guidance mechanisms in flies and vertebrates. Significance of the interaction between the Slit repellents and the Roundabout family of receptors for guiding axons across central nervous system midline in Drosophila melanogaster; Information on the two populations of interneurons recognized in the vertebrate central nervous system.

Internal brain states form key determinants for sensory perception, sensorimotor coordination and learning. A prominent reflection of different brain states in the mammalian central nervous system is the presence of distinct patterns of cortical synchrony, as revealed by extracellular recordings of the electroencephalogram, local field potential and action potentials. Such temporal correlations of cortical activity are thought to be fundamental mechanisms of neuronal computation. However, it is unknown how cortical synchrony is reflected in the intracellular membrane potential (Vm) dynamics of behaving animals. Here we show, using dual whole-cell recordings from layer 2/3 primary somatosensory barrel cortex in behaving mice, that the Vm of nearby neurons is highly correlated during quiet wakefulness. However, when the mouse is whisking, an internally generated state change reduces the Vm correlation, resulting in a desynchronized local field potential and electroencephalogram. Action potential activity was sparse during both quiet wakefulness and active whisking. Single action potentials were driven by a large, brief and specific excitatory input that was not present in the Vm of neighbouring cells. Action potential initiation occurs with a higher signal-to-noise ratio during active whisking than during quiet periods. Therefore, we show that an internal brain state dynamically regulates cortical membrane potential synchrony during behaviour and defines different modes of cortical processing. [ABSTRACT FROM AUTHOR]

Our movements can hinder our ability to sense the world. Movements can induce sensory input (for example, when you hit something) that is indistinguishable from the input that is caused by external agents (for example, when something hits you). It is critical for nervous systems to be able to differentiate between these two scenarios. A ubiquitous strategy is to route copies of movement commands to sensory structures. These signals, which are referred to as corollary discharge (CD), influence sensory processing in myriad ways. Here we review the CD circuits that have been uncovered by neurophysiological studies and suggest a functional taxonomic classification of CD across the animal kingdom. This broad understanding of CD circuits lays the groundwork for more challenging studies that combine neurophysiology and psychophysics to probe the role of CD in perception. [ABSTRACT FROM AUTHOR]

Recent functional neuroimaging and lesion studies demonstrate the involvement of the orbitofrontal/ventromedial prefrontal cortex as a key structure in decision making processes. This region seems to be particularly crucial when contingencies between options and consequences are unknown but have to be learned by the use of feedback following previous decisions (decision making under ambiguity). However, little is known about the neural correlates of decision making under risk conditions in which information about probabilities and potential outcomes is given. In the present study, we used functional magnetic resonance imaging to measure blood-oxygenation-level-dependent (BOLD) responses in 12 subjects during a decision making task. This task provided explicit information about probabilities and associated potential incentives. The responses were compared to BOLD signals in a control condition without information about incentives. In contrast to previous decision making studies, we completely removed the outcome phase following a decision to exclude the potential influence of feedback previously received on current decisions. The results indicate that the integration of information about probabilities and incentives leads to activations within the dorsolateral prefrontal cortex, the posterior parietal lobe, the anterior cingulate and the right lingual gyrus. We assume that this pattern of activation is due to the involvement of executive functions, conflict detection mechanisms and arithmetic operations during the deliberation phase of decisional processes that are based on explicit information. [ABSTRACT FROM AUTHOR]

Collections of human postmortem brains gathered in brain banks have underpinned many significant developments in the understanding of central nervous system (CNS) disorders and continue to support current research. Unfortunately, the worldwide decline in postmortem examinations has had an adverse effect on research tissue procurement, particularly from control cases (non-diseased brains). Recruitment to brain donor programmes partially addresses this problem and has been successful for dementing and neurodegenerative conditions. However, the collection of brains from control subjects, particularly from younger individuals, and from CNS disorders of sudden onset, remains a problem. Brain banks need to adopt additional strategies to circumvent such shortages. The establishment of brain bank networks allows data on, and access to, control cases and unusual CNS disorders to be shared, providing a larger resource for potential users. For the brain banks themselves, inclusion in a network fosters the sharing of protocols and development of best practice and quality control. One aspect of this collective experience concerns brain bank management, excellence in which is a prerequisite not only for gaining the trust of potential donors and of society in general, but also for ensuring equitable distribution to researchers of high quality tissue samples. This review addresses the legal, ethical and governance issues, tissue quality, and health and safety aspects of brain bank management and data management in a network, as well as the needs of users, brain bank staffing, donor programs, funding issues and public relations. Recent developments in research methodology present new opportunities for researchers who use brain tissue samples, but will require brain banks to adopt more complex protocols for tissue collection, preparation and storage, with inevitable cost implications for the future. [ABSTRACT FROM AUTHOR]

Understanding the transmission of sensory information at individual synaptic connections requires knowledge of the properties of presynaptic terminals and their patterns of firing evoked by sensory stimuli. Such information has been difficult to obtain because of the small size and inaccessibility of nerve terminals in the central nervous system. Here we show, by making direct patch-clamp recordings in vivo from cerebellar mossy fibre boutons—the primary source of synaptic input to the cerebellar cortex—that sensory stimulation can produce bursts of spikes in single boutons at very high instantaneous firing frequencies (more than 700 Hz). We show that the mossy fibre–granule cell synapse exhibits high-fidelity transmission at these frequencies, indicating that the rapid burst of excitatory postsynaptic currents underlying the sensory-evoked response of granule cells can be driven by such a presynaptic spike burst. We also demonstrate that a single mossy fibre can trigger action potential bursts in granule cells in vitro when driven with in vivo firing patterns. These findings suggest that the relay from mossy fibre to granule cell can act in a ‘detonator’ fashion, such that a single presynaptic afferent may be sufficient to transmit the sensory message. This endows the cerebellar mossy fibre system with remarkable sensitivity and high fidelity in the transmission of sensory information. [ABSTRACT FROM AUTHOR]

Abstract Purpose  Neurons in post-traumatized mammalian central nervous system show only limited degree of regeneration, which can be attributed to the presence of neurite outgrowth inhibitors in damaged myelin and glial scar, and to the apoptosis of severed central neurons and glial cells during secondary Wallerian degeneration. RhoA GTPase has been implicated as the common denominator in these counter-regeneration events, which shows significant and persistent up-regulation for weeks in injured spinal cord and cerebral infarct after stroke. While the exoenzyme C3 transferase is a potent RhoA inhibitor, its extremely low efficiency of cell entry and degradation in vivo has restricted the therapeutic value. This study aims to circumvent these problems by developing a membrane-permeating form of C3 transferase and a biopolymer-based microsphere depot system for sustainable controlled release of the protein. Materials and Methods  A membrane-permeating form of C3 transferase was developed by fusing a Tat (trans-activating transcription factor) transduction domain of human immunodeficiency virus to its amino terminal using standard molecular cloning techniques. After confirming efficient cell entry into epithelial and neuroblastoma cells, the resulting recombinant protein TAT-C3 was encapsulated in biocompatible polymer poly(d,l-lactide-co-glycolide) in the form of microspheres by a water-in-oil-in-water (W/O/W) emulsion method. By blending capped and uncapped form of the polymer at different ratios, TAT-C3 protein release profile was modified to suit the expression pattern of endogenous RhoA during CNS injuries. Bioactivity of TAT-C3 released from microspheres was assessed by RhoA ribosylation assay. Results  In contrast to wild-type C3 transferase, the modified TAT-C3 protein was found to efficiently enter NIH3T3 and N1E-115 neuroblastoma cells as early as 6 hours of incubation. The fusion of TAT sequence to C3 transferase imposed no appreciable effects on its biological activity in promoting neurite outgrowth through RhoA inhibition. Characterization of TAT-C3 encapsulation in various blends of capped/uncapped PLGA polymer revealed the 30:70 formulation to be optimal in attaining a mild initial burst release of 25%, followed by a subsequent average daily release of 2.3% of encapsulated protein over one month, matching the change in RhoA level in severed brain and spinal cord. Importantly, TAT-C3 released from the microspheres remained active up to the first three weeks of incubation. Conclusion  Enhanced cell entry of TAT-C3 circumvents the need to administer high dose of the protein to site of injury. The encapsulation of TAT-C3 in different blends of capped/uncapped PLGA microspheres allows adjustment of protein release profile to suit the pattern of RhoA expression in injured CNS. [ABSTRACT FROM AUTHOR]

It has been postulated that the central nervous system (CNS) can tune the mechanical behavior of a joint by altering reflex stiffness in a task-dependant manner. However, most of the evidence supporting this hypothesis has come from the analysis of H-reflexes or electromyogram (EMG) responses. Changes in overall stiffness have been documented but, as yet, there is no direct evidence that the CNS can control reflex stiffness independently of the intrinsic stiffness. We have used a novel identification algorithm to estimate intrinsic and reflex stiffness and feed it back to subjects in real-time. Using this biofeedback, subjects could learn to control reflex stiffness independently of intrinsic stiffness. At low torque levels, subjects could vary their reflex stiffness gain by a factor of 4, while maintaining elastic stiffness and torque constant. EMG measurements confirmed that the contraction levels of the ankle muscles remained constant. Further experiments showed that subjects could change their reflexes rapidly on command. Thus, we conclude that the CNS can control reflex stiffness independently and so has great flexibility in adjusting the mechanical properties of a joint to meet functional requirements. [ABSTRACT FROM AUTHOR]

Channels and developmental genes belong to the molecular key players in the human central nervous system (CNS). Mutations in these genes often cause monogenic neurological disease and interspecies comparisons had shown reduced divergence. On the other hand, accelerated evolution of genes with roles in neurotransmission and development had indicated widespread positive selection in hominids. In the present study, we hypothesized that recombination hotspots could be enriched at genes with particularly important role in the CNS, because at those loci beneficial mutations may occur on a highly constrained background and consequently increased recombination could promote their fixation. To test this hypothesis, we retrieved CNS genes based on keyword search, expression data and expert knowledge. Consistent with our hypothesis, we find an enrichment of hotspot predictions around genes that are retrieved by all three strategies. Moreover, when comparing human genes based on their Gene Ontology annotations, we find hotspot predictions preferentially located around channels and neurodevelopmental genes. Taken together with the distinct sequence evolution that was reported by comparative genomic studies, this finding indicates continued positive selection at many CNS gene loci. In support of this interpretation, we also find an enrichment of recombination hotspot predictions around conserved noncoding regions that were reported to display a signature of accelerated evolution in the human lineage. Widespread positive selection acting on CNS gene loci could relate to the high prevalence of human nervous system disorders with genetically complex inheritance, potentially under an ancestral susceptibility allele model.European Journal of Human Genetics (2007) 15, 1071–1078; doi:10.1038/sj.ejhg.5201876; published online 13 June 2007 [ABSTRACT FROM AUTHOR]

Deals with the solution to the difficulty in the repair of the regenerative capacity of axons in the central nervous system (CNS). Characteristics of the primary sensory neurons of the dorsal root ganglion neurons; Factor that allows CNS neurons to grow on myelin; Impact of the presence of a cyclic AMP on a peripheral lesion.

Discusses research being done on oligodendrocytes, the myelinating cells of the central nervous system. Reference to a study by H. Fu et al, published in the 2002 issue of the "Development" journal; Origin of oligodendrocytes; Description of the dorsoventral axis of the developing spinal cord.

We have developed a tri-axial model of spatial orientation applicable to static 1 g and non-1 g environments. The model attempts to capture the mechanics of otolith organ transduction of static linear forces and the perceptual computations performed on these sensor signals to yield subjective orientation of the vertical direction relative to the head. Our model differs from other treatments that involve computing the gravitoinertial force (GIF) vector in three independent dimensions. The perceptual component of our model embodies the idea that the central nervous system processes utricular and saccular stimuli as if they were produced by a GIF vector equal to 1 g, even when it differs in magnitude, because in the course of evolution living creatures have always experienced gravity as a constant. We determine just two independent angles of head orientation relative to the vertical that are GIF dependent, the third angle being derived from the first two and being GIF independent. Somatosensory stimulation is used to resolve our vestibular model's ambiguity of the up–down directions. Our otolith mechanical model takes into account recently established non-linear behavior of the force–displacement relationship of the otoconia, and possible otoconial deflections that are not co-linear with the direction of the input force (cross-talk). The free parameters of our model relate entirely to the mechanical otolith model. They were determined by fitting the integrated mechanical/perceptual model to subjective indications of the vertical obtained during pitch and roll body tilts in 1 g and 2 g force backgrounds and during recumbent yaw tilts in 1 g. The complete data set was fit with very little residual error. A novel prediction of the model is that background force magnitude either lower or higher than 1 g will not affect subjective vertical judgments during recumbent yaw tilt. These predictions have been confirmed in recent parabolic flight experiments. [ABSTRACT FROM AUTHOR]