Neural Origin Research Articles

CRISPR/Cas9 nickase mediated targeting of urokinase receptor gene inhibits neuroblastoma cell proliferation.

Neuroblastoma is a tumor arising from pluripotent sympathoadrenal precursor cells of neural cell origin. Neuroblastoma is one of the most aggressive childhood tumors with highly invasive and metastatic potential. The increased expression of urokinase and its receptor is often associated with a negative prognosis in neuroblastoma patients.We have shown that targeting of the Plaur gene in mouse neuroblastoma Neuro 2A cells by CRISPR/Cas9n results in ~60% decrease in cell proliferation (p<0.05), reduction in the number of Ki-67 positive cells, caspase 3 activation and PARP-1 cleavage. Knockout of uPAR leads to downregulation of mRNA encoding full-length TrkC receptor, which is involved in p38MAPK and Akt signalling pathways. This finding provides a rationale to study a role of uPAR in neuroblastoma progression, since uPAR could be considered a potential therapeutic target in neuroblastoma treatment.

Contour interaction under photopic and scotopic conditions.

In the present study, we asked whether contour interaction undergoes significant changes for different luminance levels in the central and peripheral visual field. This study included nine normal observers at two laboratories (five at Palacky University Olomouc, Czech Republic and four at the University of Houston, USA). Observers viewed a randomly selected Sloan letter surrounded by four equally spaced bars for several separations measured edge-to-edge in min arc. Stimuli were viewed foveally under photopic and mesopic luminances and between 5° and 12° peripherally for four different background luminances of the display monitors, corresponding to photopic, mesopic, scotopic, and dim scotopic levels. The extent of the contour interaction in the fovea is approximately 20 times smaller than in the periphery. Whereas the magnitude of foveal contour interaction markedly decreases with decreasing luminance, no consistent luminance-induced change occurs in peripheral contour interaction. The extent of contour interaction does not scale with the size of the target letter, either in the fovea or peripherally. The results support a neural origin of contour interaction consistent with the properties of center-surround antagonism.

The neural crest and origin of the neurocranium in vertebrates.

Cranium of jawed vertebrates is composed of dorsal moiety that encapsulates the brain, or the neurocranium, and the is called the neurocranium, and the ventral moiety, the viscerocranium, that supports the pharynx. In modern jawed vertebrates (crown gnathostomes), the viscerocranium is predominantly of neural crest origin, and for the neurocranium, the rostral part is derived from neural crest cells, whereas the posterior part from the mesoderm. In the cyclostome cranium, the mesoderm/neural crest boundary of the neurocranium used to be enigmatic, let alone the morphological comparison of neurocranial between two cyclostome groups, lampreys and hagfishes. By examining the hagfish development it has become clear that cyclostomes share a common craniofacial embryonic pattern that is not shared by modern gnathostomes, and cyclostome cranium can be compared among the group as developmental modular units with comparable mesoderm/neural crest boundary within the neuroranium. Also, the dual origin of the jawed vertebrate neurocranium has now turned out to represent a derived condition, and ancestrally, the neurocranium would likely have been predominantly of mesodermal origin. Enlargement of the forebrain and reorganization of the oral apparatus seem to have led to the involvement of the neural crest in the rostral neurocranium.

Neural crest and the origin of species-specific pattern.

SummaryFor well over half of the 150 years since the discovery of the neural crest, the special ability of these cells to function as a source of species‐specific pattern has been clearly recognized. Initially, this observation arose in association with chimeric transplant experiments among differentially pigmented amphibians, where the neural crest origin for melanocytes had been duly noted. Shortly thereafter, the role of cranial neural crest cells in transmitting species‐specific information on size and shape to the pharyngeal arch skeleton as well as in regulating the timing of its differentiation became readily apparent. Since then, what has emerged is a deeper understanding of how the neural crest accomplishes such a presumably difficult mission, and this includes a more complete picture of the molecular and cellular programs whereby neural crest shapes the face of each species. This review covers studies on a broad range of vertebrates and describes neural‐crest‐mediated mechanisms that endow the craniofacial complex with species‐specific pattern. A major focus is on experiments in quail and duck embryos that reveal a hierarchy of cell‐autonomous and non‐autonomous signaling interactions through which neural crest generates species‐specific pattern in the craniofacial integument, skeleton, and musculature. By controlling size and shape throughout the development of these systems, the neural crest underlies the structural and functional integration of the craniofacial complex during evolution.

Differentiation of neural crest stem cells from nasal mucosa into motor neuron-like cells

Cell transplantation is a potential therapeutic approach for repairing neuropathological and neurodegenerative disorders of central nervous system by replacing the degenerated cells with new ones. Among a variety of stem cell candidates to provide these new cells, olfactory ectomesenchymal stem cells (OE-MSCs) have attracted a great attention due to their neural crest origin, easy harvest, high proliferation, and autologous transplantation. Since there is no report on differentiation potential of these cells into motor neuron-like cells, we evaluated this potential using Real-time PCR, flowcytometry and immunocytochemistry after the treatment with differentiation cocktail containing retinoic acid and Sonic Hedgehog. Immunocytochemistry staining of the isolated OE-MSCs demonstrated their capability to express nestin and vimentin, as the two markers of primitive neuroectoderm. The motor neuron differentiation of OE-MSCs resulted in changing their morphology into bipolar cells with high expression of motor neuron markers of ChAT, Hb-9 and Islet-1 at the level of mRNA and protein. Consequently, we believe that the OE-MSCs have great potential to differentiate into motor neuron-like cells and can be an ideal stem cell source for the treatment of motor neuron-related disorders of central nervous system.

Measuring peripheral oxytocin and vasopressin in nonhuman primates.

Studying the neural and hormonal changes that modulate behavior is critical to understanding social relationships. Of particular interest is measuring oxytocin (OT) and arginine vasopressin (AVP) peripherally, and preferably, non-invasively, in nonhuman primates. Due to these peptides' neural origin and their stimulation of brain areas that influence social behavior, there has been debate whether peripheral measures in blood, urine, and saliva reflect central levels in the brain. This review elucidates the challenges of OT measurement and the solutions that provide valuable data on OT's role in social behavior. This review discusses the recent studies in rhesus macaques which indicate that exogenous OT delivered by nasal spray results in increased OT in cerebrospinal fluid, and it notes the new methodologies that can measure both endogenous and exogenous OT simultaneously, which thereby determine the source of measured OT in biological fluids. Next, this review highlights the utility of measuring urinary OT by summarizing the results of clearance rate studies in humans and marmosets, which characterize the timing that circulating OT enters urine and illustrate that endogenous releasers of OT also increase urinary OT. With the ability to reliably measure OT and AVP in urine and in blood, we can now study free-ranging captive, and non-captive primates to answer questions about the biology of social bonding that were not possible before. One procedural concern that this review also highlights is whether extraction of the peptides prior to assay is needed, as the values are higher in samples that have not been extracted. Studies indicate that extractions eliminate the interfering compounds that cause higher values. Across studies, to ensure the reliability of measuring OT for nonhuman primates, this review makes suggestions based on empirical evidence for how to correctly preserve samples and emphasizes the need to validate each assay for individual species.

Dental Pulp Stem Cells - Exploration in a Novel Animal Model: the Tasmanian Devil (Sarcophilus harrisii).

Dental pulp stem cells (DPSC) are a heterogeneous population of highly proliferative stem cells located in the soft inner pulp tissue of the tooth. Demonstrated to have an affinity for neural differentiation, DPSC have been reported to generate functional Schwann cells (SC) through in vitro differentiation. Both DPSC and SC have neural crest origins, recently a significant population of DPSC have been reported to derive from peripheral nerve-associated glia. The predisposition DPSC have towards the SC lineage is not only a very useful tool for neural regenerative therapies in the medical field, it also holds great promise in the veterinary field. Devil Facial Tumour (DFT) is a clonally transmissible cancer of SC origin responsible for devastating wild populations of the Tasmanian devil. Very few studies have investigated the healthy Tasmanian devil SC (tdSC) for comparative studies between tdSC and DFT cells, and the development and isolation of a tdSC population is yet to be undertaken. A Tasmanian devil DPSC model offers a promising new outlook for DFT research, and the link between SC and DPSC may provide a potential explanation as to how a cancerous SC initially arose in a single Tasmanian devil to then go on to infect others as a parasitic clonal cell line. In this review we explore the current role of DPSC in human regenerative medicine, provide an overview of the Tasmanian devil and the devastating effect of DFT, and highlight the promising potential DPSC techniques pose for DFT research and our current understanding of DFT.

Group Analysis in FieldTrip of Time-Frequency Responses: A Pipeline for Reproducibility at Every Step of Processing, Going From Individual Sensor Space Representations to an Across-Group Source Space Representation

An important aim of an analysis pipeline for magnetoencephalographic (MEG) data is that it allows for the researcher spending maximal effort on making the statistical comparisons that will answer his or her questions. The example question being answered here is whether the so-called beta rebound differs between novel and repeated stimulations. Two analyses are presented: going from individual sensor space representations to, respectively, an across-group sensor space representation and an across-group source space representation. The data analyzed are neural responses to tactile stimulations of the right index finger in a group of 20 healthy participants acquired from an Elekta Neuromag System. The processing steps covered for the first analysis are MaxFiltering the raw data, defining, preprocessing and epoching the data, cleaning the data, finding and removing independent components related to eye blinks, eye movements and heart beats, calculating participants' individual evoked responses by averaging over epoched data and subsequently removing the average response from single epochs, calculating a time-frequency representation and baselining it with non-stimulation trials and finally calculating a grand average, an across-group sensor space representation. The second analysis starts from the grand average sensor space representation and after identification of the beta rebound the neural origin is imaged using beamformer source reconstruction. This analysis covers reading in co-registered magnetic resonance images, segmenting the data, creating a volume conductor, creating a forward model, cutting out MEG data of interest in the time and frequency domains, getting Fourier transforms and estimating source activity with a beamformer model where power is expressed relative to MEG data measured during periods of non-stimulation. Finally, morphing the source estimates onto a common template and performing group-level statistics on the data are covered. Functions for saving relevant figures in an automated and structured manner are also included. The protocol presented here can be applied to any research protocol where the emphasis is on source reconstruction of induced responses where the underlying sources are not coherent.

72 - Orbital fat derived mesenchymal stem cells rescue RPE from necrosis and differentiate towards RPE

Purpose: Oxidative stress leads to degeneration of retinal pigment epithelial cells (RPE) in age related macular degeneration. Orbital adipose tissue is of neural crest origin similar to most of the ocular and orbital components including the RPE. Here we isolated a orbital fat derived mesenchymal stem cells (OMSCs), evaluated the protective effect of OMSCs on necrosis of RPE, as well as the potential of OMSCs to differentiate towards RPE.

Model-based deconstruction of cortical evoked potentials generated by subthalamic nucleus deep brain stimulation.

Parkinson's disease is associated with altered neural activity in the motor cortex. Chronic high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in suppressing parkinsonian motor symptoms and modulates cortical activity. However, the anatomical pathways responsible for STN DBS-mediated cortical modulation remain unclear. Cortical evoked potentials (cEP) generated by STN DBS reflect the response of cortex to subcortical stimulation, and the goal of this study was to determine the neural origin of STN DBS-generated cEP using a two-step approach. First, we recorded cEP over ipsilateral primary motor cortex during different frequencies of STN DBS in awake healthy and unilateral 6-OHDA-lesioned parkinsonian rats. Second, we used a detailed, biophysically based model of the thalamocortical network to deconstruct the neural origin of the recorded cEP. The in vivo cEP included short (R1)-, intermediate (R2)-, and long-latency (R3) responses. Model-based cortical responses to simulated STN DBS matched remarkably well the in vivo responses. The short-latency response was generated by antidromic activation of layer 5 pyramidal neurons, whereas recurrent activation of layer 5 pyramidal neurons via excitatory axon collaterals reproduced the intermediate-latency response. The long-latency response was generated by polysynaptic activation of layer 2/3 pyramidal neurons via the cortico-thalamic-cortical pathway. Antidromic activation of the hyperdirect pathway and subsequent intracortical and cortico-thalamo-cortical synaptic interactions were sufficient to generate cortical potential evoked by STN DBS, and orthodromic activation through basal ganglia-thalamus-cortex pathways was not required. These results demonstrate the utility of cEP to determine the neural elements activated by STN DBS that might modulate cortical activity and contribute to the suppression of parkinsonian symptoms. NEW & NOTEWORTHY Subthalamic nucleus (STN) deep brain stimulation (DBS) is increasingly used to treat Parkinson's disease (PD). Cortical potentials evoked by STN DBS in patients with PD exhibit consistent short-latency (1-3 ms), intermediate-latency (5-15 ms), and long-latency (18-25 ms) responses. The short-latency response occurs as a result of antidromic activation of the hyperdirect pathway comprising corticosubthalamic axons. However, the neural origins of intermediate- and long-latency responses remain elusive, and the dominant view is that these are produced through the orthodromic pathway (basal ganglia-thalamus-cortex). By combining in vivo electrophysiology with computational modeling, we demonstrate that antidromic activation of the cortico-thalamic-cortical pathway is sufficient to generate the intermediate- and long-latency cortical responses to STN DBS.

Identity prediction errors in the human midbrain update reward-identity expectations in the orbitofrontal cortex

There is general consensus that dopaminergic midbrain neurons signal reward prediction errors, computed as the difference between expected and received reward value. However, recent work in rodents shows that these neurons also respond to errors related to inferred value and sensory features, indicating an expanded role for dopamine beyond learning cached values. Here we utilize a transreinforcer reversal learning task and functional magnetic resonance imaging (fMRI) to test whether prediction error signals in the human midbrain are evoked when the expected identity of an appetitive food odor reward is violated, while leaving value matched. We found that midbrain fMRI responses to identity and value errors are correlated, suggesting a common neural origin for these error signals. Moreover, changes in reward-identity expectations, encoded in the orbitofrontal cortex (OFC), are directly related to midbrain activity, demonstrating that identity-based error signals in the midbrain support the formation of outcome identity expectations in OFC.

Subcortical sources dominate the neuroelectric auditory frequency-following response to speech

Frequency-following responses (FFRs) are neurophonic potentials that provide a window into the encoding of complex sounds (e.g., speech/music), auditory disorders, and neuroplasticity. While the neural origins of the FFR remain debated, renewed controversy has reemerged after demonstration that FFRs recorded via magnetoencephalography (MEG) are dominated by cortical rather than brainstem structures as previously assumed. Here, we recorded high-density (64 ch) FFRs via EEG and applied state-of-the art source imaging techniques to multichannel data (discrete dipole modeling, distributed imaging, independent component analysis, computational simulations). Our data confirm a mixture of generators localized to bilateral auditory nerve (AN), brainstem inferior colliculus (BS), and bilateral primary auditory cortex (PAC). However, frequency-specific scrutiny of source waveforms showed the relative contribution of these nuclei to the aggregate FFR varied across stimulus frequencies. Whereas AN and BS sources produced robust FFRs up to ∼700 Hz, PAC showed weak phase-locking with little FFR energy above the speech fundamental (100 Hz). Notably, CLARA imaging further showed PAC activation was eradicated for FFRs >150 Hz, above which only subcortical sources remained active. Our results show (i) the site of FFR generation varies critically with stimulus frequency; and (ii) opposite the pattern observed in MEG, subcortical structures make the largest contribution to electrically recorded FFRs (AN ≥ BS > PAC). We infer that cortical dominance observed in previous neuromagnetic data is likely due to the bias of MEG to superficial brain tissue, underestimating subcortical structures that drive most of the speech-FFR. Cleanly separating subcortical from cortical FFRs can be achieved by ensuring stimulus frequencies are >150–200 Hz, above the phase-locking limit of cortical neurons.

Source Reconstruction of Brain Potentials Using Bayesian Model Averaging to Analyze Face Intra-Domain vs. Face-Occupation Cross-Domain Processing.

We investigated the neural correlates of the access to and retrieval of face structure information in contrast to those concerning the access to and retrieval of person-related verbal information, triggered by faces. We experimentally induced stimulus familiarity via a systematic learning procedure including faces with and without associated verbal information. Then, we recorded event-related potentials (ERPs) in both intra-domain (face-feature) and cross-domain (face-occupation) matching tasks while N400-like responses were elicited by incorrect eyes-eyebrows completions and occupations, respectively. A novel Bayesian source reconstruction approach plus conjunction analysis of group effects revealed that in both cases the generated N170s were of similar amplitude but had different neural origin. Thus, whereas the N170 of faces was associated predominantly to right fusiform and occipital regions (the so-called “Fusiform Face Area”, “FFA” and “Occipital Face Area”, “OFA”, respectively), the N170 of occupations was associated to a bilateral very posterior activity, suggestive of basic perceptual processes. Importantly, the right-sided perceptual P200 and the face-related N250 were evoked exclusively in the intra-domain task, with sources in OFA and extensively in the fusiform region, respectively. Regarding later latencies, the intra-domain N400 seemed to be generated in right posterior brain regions encompassing mainly OFA and, to some extent, the FFA, likely reflecting neural operations triggered by structural incongruities. In turn, the cross-domain N400 was related to more anterior left-sided fusiform and temporal inferior sources, paralleling those described previously for the classic verbal N400. These results support the existence of differentiated neural streams for face structure and person-related verbal processing triggered by faces, which can be activated differentially according to specific task demands.

Radial glial cells in the adult dentate gyrus: what are they and where do they come from?

Adult neurogenesis occurs in the dentate gyrus in the mammalian hippocampus. These new neurons arise from neural precursor cells named radial glia-like cells, which are situated in the subgranular zone of the dentate gyrus. Here, we review the emerging topic of precursor heterogeneity in the adult subgranular zone. We also discuss how this heterogeneity may be established during development and focus on the embryonic origin of the dentate gyrus and radial glia-like stem cells. Finally, we discuss recently developed single-cell techniques, which we believe will be critical to comprehensively investigate adult neural stem cell origin and heterogeneity.

Explicit and Implicit Factors That Determine Private Labels’ Possible Purchase: Eyetracking and EEG Research

Abstract Objective: This paper investigates the explicit and implicit factors affecting private-label (PL) products’ possible purchase decision for different retailers. Design: The study uses eyetracking and electroencephalography (EEG) to explore the differences in eye movement and brain activity for PL products. This article examines how approach motivation, measured by total fixation duration and by EEG asymmetry over the frontal hemisphere of the brain, predicts PL purchase decision. Findings: This study investigates implicit variables that can influence consumers’ willingness to PL purchase. The relatively greater left frontal activation (i.e., higher approach motivation) during the predecision period predicted an affirmative purchase decision in some cases. The eyetracking study did not reveal differences between women’s and men’s esthetics sensitivity toward the presented PL products. EEG research proved that consumers were not influenced by the PL product price. Originality/value: Literature lacks credible information on young buyers’ behavior in the context of PL products. This paper elaborates on PL perception, revealing the neural origins of the associated psychological processes.

Second Commentary on "Partial Wrist Denervation: The Evidence Behind a Small Fix for Big Problems".

Second Commentary on "Partial Wrist Denervation: The Evidence Behind a Small Fix for Big Problems".

Neurophysiological adaptations in the untrained side in conjunction with cross-education of muscle strength: a systematic review and meta-analysis.

We reviewed the evidence from randomized controlled trials (RCTs) focusing on the neurophysiological adaptations in the untrained side associated with cross-education of strength (CE) and pooled data into definite effect estimates for neurophysiological variables assessed in chronic CE studies. Furthermore, scoping directions for future research were provided to enhance the homogeneity and comparability of studies investigating the neural responses to CE. The magnitude of CE was 21.1 ± 18.2% (mean ± SD; P < 0.0001) in 22 RCTs ( n = 467 subjects) that measured at least 1 neurophysiological variable in the untrained side, including the following: electromyography (EMG; 14 studies); motor evoked potential (MEP; 8 studies); short-interval intracortical inhibition (SICI), recruitment curve, and M wave (6 studies); cortical silent period (cSP; 5 studies); interhemispheric inhibition, intracortical facilitation (ICF), and H reflex (2 studies); and V wave, short-interval ICF, short-latency afferent inhibition, and long-latency afferent inhibition (1 study). Only EMG, MEP, ICF, cSP, and SICI could be included in the meta-analysis (18 studies, n = 387). EMG ( P = 0.26, n = 235) and MEP amplitude ( P = 0.11, n = 145) did not change in the untrained limb after CE. cSP duration ( P = 0.02, n = 114) and SICI ( P = 0.001, n = 95) decreased in the untrained hemisphere according to body region and type and intensity of training. The magnitude of CE did not correlate with changes in these transcranial magnetic stimulation (TMS) measures. The design of this meta-analytical study and the lack of correlations prevented the ability to link mechanistically the observed neurophysiological changes to CE. Notwithstanding the limited amount of data available for pooling, the use of TMS to assess the ipsilateral neurophysiological responses to unilateral training still confirms the central neural origin hypothesis of chronic CE induced by strength training. However, how these neural adaptations contribute to CE remains unclear.

From Tissue Engineering to Regenerative Surgery

From Tissue Engineering to Regenerative Surgery

Liponeurofibroma: Clinicopathological features and histogenesis.

A neurofibroma is a common cutaneous benign tumor of neural origin. Various histological variants have been reported. Recently, sporadic reports of fatty variants have been reported but their clinicopathological features have not been well studied. The purpose of this study was to examine liponeurofibroma, and to report the distinctive clinicopathological features and histogenesis in comparison with the classic form. A retrospective study was performed on 130 cases. Immunohistochemical staining was performed for S100, factor VIIIa, perilipin and vascular endothelial growth factor. Masson's trichrome stain was also used. Intratumoral adipocytes were examined with transmission electron microscopy. Thirty-two (24.6%) cases were classified as liponeurofibroma on microscopic examination. This variant was more common in patients with neurofibromatosis type 1, older age and female sex. The most prevalent location was the head and neck. Intratumoral fat deposits showed differences in morphology and size compared with subcutaneous fat on light microscopy. Neurofibromatosis type 1 had the highest odds of fatty change in liponeurofibroma. In sporadic cases, fatty change can be caused by senescence, chronic injury, or tissue hypoxia secondary to internal or external stimuli. Further investigation is needed to identify the pathomechanism of fatty change in various cutaneous neoplasms, including neurofibroma.

Two case studies of 129/Sv testicular teratoma

Testicular teratoma is classified among testicular germ cells tumors. While its incidence is relatively low among animals, in 129/Sv mice is presented in relatively high prevalence. It has been revealed that murine teratoma arises from genetically altered germ cells that undergo malignant transformation during embryogenesis. A point mutation on the 129/Sv genome has been incriminated for failing to regulate normal pathways in germ cell development leading in high teratocarcinogenic risk. For a neoplasm to be characterized as teratoma, derivatives from at least two germ cell layers have to be detected. In the present study, two cases exhibiting all three layers (mesoderm, endoderm, ectoderm) are presented while the tissues observed were of epithelial, connective, muscular, and neural origin. Findings include an almost fully shaped large intestine, a structure closely resembling the heart (blood, endocardium, myocardium) and endochondral ossification.