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1
Cazillis, Michele, Vincent LeLievre, and Pierre Gressens. "Différenciation neurale des cellules souches embryonnaires." médecine/sciences 21, no. 5 (May 2005): 484–90. http://dx.doi.org/10.1051/medsci/2005215484.
2
Remaud, Sylvie, and Barbara Demeneix. "Les hormones thyroïdiennes régulent le destin des cellules souches neurales." Biologie Aujourd'hui 213, no. 1-2 (2019): 7–16. http://dx.doi.org/10.1051/jbio/2019007.
Анотація:
Les hormones thyroïdiennes (HT) sont essentielles pour le bon fonctionnement du cerveau tout au long de la vie des vertébrés, dès les stades précoces du neuro-développement. Des études épidémiologiques ont montré l’importance des HT de la mère pendant les premiers mois du développement fœtal : une déficience précoce en HT maternelles entraîne à long terme des altérations du développement cognitif et du comportement social de l’enfant. L’apport des modèles animaux, non seulement les modèles mammifères mais également les modèles alternatifs (poisson zèbre, xénope, poulet), a permis de décrypter les mécanismes cellulaires et moléculaires gouvernés par les HT lors du développement cérébral. En particulier le modèle rongeur a contribué à montrer que les HT ont également un rôle crucial chez l’adulte, principalement au sein de deux niches neurogéniques majeures, la zone sous-ventriculaire et la zone sous-granulaire de l’hippocampe où elles régulent finement le destin des cellules souches neurales (CSN). Une question essentielle en biologie des cellules souches est de comprendre, comment les HT gouvernent le devenir des CSN vers un destin neural ou glial et ce, afin de contribuer au développement du cerveau et de maintenir ses fonctions tout au long de la vie adulte dans des conditions physiologiques et lors d’un dommage cérébral (maladies neurodégénératives, maladies démyélinisantes ou accident vasculaire cérébral). Notre revue fait le point sur les connaissances actuelles sur le rôle d’un signal endocrinien clé, les HT, lors du développement du cerveau et de la neurogenèse adulte, et principalement chez les mammifères, notamment l’Homme.
3
Nguyen, Lam Son, Julien Fregeac, Christine Bole-Feysot, Patrick Nitschke, Oliver Pelle, and Laurence Colleaux. "Rôle de miR-146a dans la différenciation et l’acquisition de l’identité neurale des cellules souches humaines : pertinence pour les troubles du spectre autistique." Morphologie 101, no. 335 (December 2017): 242. http://dx.doi.org/10.1016/j.morpho.2017.07.010.
4
Hanna, Peter, Michael J. Dacey, Jaclyn Brennan, Alison Moss, Shaina Robbins, Sirisha Achanta, Natalia P. Biscola, et al. "Innervation and Neuronal Control of the Mammalian Sinoatrial Node a Comprehensive Atlas." Circulation Research 128, no. 9 (April 30, 2021): 1279–96. http://dx.doi.org/10.1161/circresaha.120.318458.
Анотація:
Rationale: Cardiac function is under exquisite intrinsic cardiac neural control. Neuroablative techniques to modulate control of cardiac function are currently being studied in patients, albeit with variable and sometimes deleterious results. Objective: Recognizing the major gaps in our understanding of cardiac neural control, we sought to evaluate neural regulation of impulse initiation in the sinoatrial node (SAN) as an initial discovery step. Methods and Results: We report an in-depth, multiscale structural and functional characterization of the innervation of the SAN by the right atrial ganglionated plexus (RAGP) in porcine and human hearts. Combining intersectional strategies, including tissue clearing, immunohistochemical, and ultrastructural techniques, we have delineated a comprehensive neuroanatomic atlas of the RAGP-SAN complex. The RAGP shows significant phenotypic diversity of neurons while maintaining predominant cholinergic innervation. Cellular and tissue-level electrophysiological mapping and ablation studies demonstrate interconnected ganglia with synaptic convergence within the RAGP to modulate SAN automaticity, atrioventricular conduction, and left ventricular contractility. Using this approach, we comprehensively demonstrate that intrinsic cardiac neurons influence the pacemaking site in the heart. Conclusions: This report provides an experimental demonstration of a discrete neuronal population controlling a specific geographic region of the heart (SAN) that can serve as a framework for further exploration of other parts of the intrinsic cardiac nervous system (ICNS) in mammalian hearts and for developing targeted therapies.
5
Yaple, Zachary A., and Rongjun Yu. "Functional and Structural Brain Correlates of Socioeconomic Status." Cerebral Cortex 30, no. 1 (May 2, 2019): 181–96. http://dx.doi.org/10.1093/cercor/bhz080.
Анотація:
Abstract Socioeconomic status (SES) is a multidimensional construct that includes not only measures of material wealth, but also education, social prestige, and neighborhood quality. Socioeconomic correlates between wealth and cognitive functions have been well established in behavioral studies. However, functional and structural brain correlates of SES remain unclear. Here, we sought to uncover the most likely neural regions to be affected by low SES, specifically associated with age. Using effect size–seed-based d Mapping, we compiled studies that examined individuals with low SES and performed functional magnetic resonance imaging and voxel-based morphometry meta-analyses. The results revealed that as from early to late age, individuals exposed to low SES are less likely to have sustained executive network activity yet a greater likelihood to enhanced activity within reward-related regions. A similar activity was shown for gray matter volume across early to older age. These findings provide the first quantitative integration of neuroimaging results pertaining to the neural basis of SES. Hypoactivation of the executive network and hyperactivation of the reward network in low SES individuals may support the scarcity hypothesis and animal models of the effects of early adversity.
6
Heinrichs-Graham, Elizabeth, Brittany K. Taylor, Yu-Ping Wang, Julia M. Stephen, Vince D. Calhoun, and Tony W. Wilson. "Parietal Oscillatory Dynamics Mediate Developmental Improvement in Motor Performance." Cerebral Cortex 30, no. 12 (July 24, 2020): 6405–14. http://dx.doi.org/10.1093/cercor/bhaa199.
Анотація:
Abstract Numerous recent studies have sought to determine the developmental trajectories of motor-related oscillatory responses from youth to adulthood. However, most of this work has relied on simple movements, and rarely have these studies linked developmental neural changes with maturational improvements in motor performance. In this study, we recorded magnetoencephalography during a complex finger-tapping task in a large sample of 107 healthy youth aged 9–15 years old. The relationships between region-specific neural activity, age, and performance metrics were examined using structural equation modeling. We found strong developmental effects on behavior and beta oscillatory activity during movement planning, as well as associations between planning-related beta activity and activity within the same region during the movement execution period. However, when all factors were tested, we found that only right parietal cortex beta dynamics mediated the relationship between age and performance on the task. These data suggest that strong, sustained beta activity within the right parietal cortex enhances motor performance, and that these sustained oscillations develop through childhood into early adolescence. In sum, these are the first data to link developmental trajectories in beta oscillatory dynamics with distinct motor performance metrics and implicate the right parietal cortex as a crucial hub in movement execution.
7
CASE, MICHAEL A., and HUGH R. MACMILLAN. "ON SIMULATING THE GENERATION OF MOSAICISM DURING MAMMALIAN CEREBRAL CORTICAL DEVELOPMENT." Journal of Biological Systems 17, no. 01 (March 2009): 27–62. http://dx.doi.org/10.1142/s0218339009002740.
Анотація:
Renewed calls for a systems biology reflect the hope hat enduring biological questions at single-cell and cell-population scales will be resolved as modern molecular biology, with its reductionist program, approaches a nearly-complete characterization of the molecular mechanisms of specific cellular processes. Due to the confounding complexity of biological organization across these scales, computational science is sought to complement the intuition of experimentalists. However, with respect to the molecular basis of cellular processes during development and disease, a gulf between feasible simulations and realistic biology persists. Formidable are the mathematical and computational challenges to conducting and validating cell population-scale simulations, drawn from single-cell level and molecular level details. Nonetheless, in some biological contexts, a focus on core processes crafted by evolution can yield coarse-grained mathematical models that retain explanatory potential despite drastic simplification of known biochemical kinetics. In this article, we bring this modeling philosophy to bear on the nature of neural progenitor cell decision making during mammalian cerebral cortical development. Specifically, we present the computational component to a research program addressing developmental links between (i) the cellular response to endogenous DNA damage, (ii) primary mechanisms of neuronal genetic heterogeneity, or mosaicism, and (iii) the cell fate decision making that defines the population kinetics of neurogenesis.
8
Herrera, Alejandro, Sara Morcuende, Rocío Talaverón, Beatriz Benítez-Temiño, Angel M. Pastor, and Esperanza R. Matarredona. "Purinergic Receptor Blockade with Suramin Increases Survival of Postnatal Neural Progenitor Cells In Vitro." International Journal of Molecular Sciences 22, no. 2 (January 12, 2021): 713. http://dx.doi.org/10.3390/ijms22020713.
Анотація:
Neural progenitor cells (NPCs) are self-renewing and multipotent cells that persist in the postnatal and adult brain in the subventricular zone and the hippocampus. NPCs can be expanded in vitro to be used in cell therapy. However, expansion is limited, since the survival and proliferation of adult NPCs decrease with serial passages. Many signaling pathways control NPC survival and renewal. Among these, purinergic receptor activation exerts differential effects on the biology of adult NPCs depending on the cellular context. In this study, we sought to analyze the effect of a general blockade of purinergic receptors with suramin on the proliferation and survival of NPCs isolated from the subventricular zone of postnatal rats, which are cultured as neurospheres. Treatment of neurospheres with suramin induced a significant increase in neurosphere diameter and in NPC number attributed to a decrease in apoptosis. Proliferation and multipotency were not affected. Suramin also induced an increase in the gap junction protein connexin43 and in vascular endothelial growth factor, which might be involved in the anti-apoptotic effect. Our results offer a valuable tool for increasing NPC survival before implantation in the lesioned brain and open the possibility of using this drug as adjunctive therapy to NPC transplantation.
9
Zhang, Furu, Kazuhiro Kurokawa, Ayoub Lassoued, James A. Crowell, and Donald T. Miller. "Cone photoreceptor classification in the living human eye from photostimulation-induced phase dynamics." Proceedings of the National Academy of Sciences 116, no. 16 (April 3, 2019): 7951–56. http://dx.doi.org/10.1073/pnas.1816360116.
Анотація:
Human color vision is achieved by mixing neural signals from cone photoreceptors sensitive to different wavelengths of light. The spatial arrangement and proportion of these spectral types in the retina set fundamental limits on color perception, and abnormal or missing types are responsible for color vision loss. Imaging provides the most direct and quantitative means to study these photoreceptor properties at the cellular scale in the living human retina, but remains challenging. Current methods rely on retinal densitometry to distinguish cone types, a prohibitively slow process. Here, we show that photostimulation-induced optical phase changes occur in cone cells and carry substantial information about spectral type, enabling cones to be differentiated with unprecedented accuracy and efficiency. Moreover, these phase dynamics arise from physiological activity occurring on dramatically different timescales (from milliseconds to seconds) inside the cone outer segment, thus exposing the phototransduction cascade and subsequent downstream effects. We captured these dynamics in cones of subjects with normal color vision and a deuteranope, and at different macular locations by: (i) marrying adaptive optics to phase-sensitive optical coherence tomography to avoid optical blurring of the eye, (ii) acquiring images at high speed that samples phase dynamics at up to 3 KHz, and (iii) localizing phase changes to the cone outer segment, where photoactivation occurs. Our method should have broad appeal for color vision applications in which the underlying neural processing of photoreceptors is sought and for investigations of retinal diseases that affect cone function.
10
Zhang, J. S., and F. M. Longo. "LAR tyrosine phosphatase receptor: alternative splicing is preferential to the nervous system, coordinated with cell growth and generates novel isoforms containing extensive CAG repeats." Journal of Cell Biology 128, no. 3 (February 1, 1995): 415–31. http://dx.doi.org/10.1083/jcb.128.3.415.
Анотація:
Receptor-linked tyrosine phosphatases regulate cell growth by dephosphorylating proteins involved in tyrosine kinase signal transduction. The leukocyte common antigen-related (LAR) tyrosine phosphatase receptor has sequence similarity to the neural cell adhesion molecule N-CAM and is located in a chromosomal region (1p32-33) frequently altered in neuroectodermal tumors. To understand the function of receptor-linked tyrosine phosphatases in neural development, we sought to identify LAR isoforms preferentially expressed in the nervous system and cellular processes regulating LAR alternative splicing. We report here the isolation of a series of rat LAR cDNA clones arising from complex combinatorial alternative splicing, not previously demonstrated for the tyrosine phosphatase-receptor gene family in general. Isoforms included: (a) deletions of the fourth, sixth and seventh fibronectin type III-like domains; (b) an alternatively spliced novel cassette exon in the fifth fibronectin type III-like domain; (c) two alternatively spliced novel cassette exons in the juxtamembrane region; (d) a retained intron in the extracellular region with in-frame stop codons predicting a secreted LAR isoform; and (e) an LAR transcript including an alternative 3' untranslated region containing multiple stretches of tandem CAG repeats up to 21 repeats in length. This number of repeats was in the range found in normal alleles of genes in which expansions of repeats are associated with neurodegenerative disease and the genetic phenomenon of anticipation. RT-PCR and Northern analysis demonstrated that LAR alternative splicing occurred preferentially in neuromuscular tissue in vivo and in neurons compared to astrocytes in vitro and was developmentally regulated. Alternative splicing was also regulated in PC12 cells by NGF, in 3T3 fibroblasts by cell confluence and in sciatic nerve and muscle subsequent to nerve transection. Western blot analysis demonstrated that alternatively spliced cassette exons result in the presence of corresponding amino acid segments of LAR protein in vivo. These studies suggest specialized functions of LAR isoforms in the nervous system and support our hypothesis that LAR-like tyrosine phosphatase receptors play a role in neural development and regeneration.
11
Singer, Benjamin D., Jason R. Mock, Franco R. D'Alessio, Neil R. Aggarwal, Pooja Mandke, Laura Johnston, and Mahendra Damarla. "Flow-cytometric method for simultaneous analysis of mouse lung epithelial, endothelial, and hematopoietic lineage cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 310, no. 9 (May 1, 2016): L796—L801. http://dx.doi.org/10.1152/ajplung.00334.2015.
Анотація:
Flow cytometry is a powerful tool capable of simultaneously analyzing multiple parameters on a cell-by-cell basis. Lung tissue preparation for flow cytometry requires creation of a single-cell suspension, which often employs enzymatic and mechanical dissociation techniques. These practices may damage cells and cause cell death that is unrelated to the experimental conditions under study. We tested methods of lung tissue dissociation and sought to minimize cell death in the epithelial, endothelial, and hematopoietic lineage cellular compartments. A protocol that involved flushing the pulmonary circulation and inflating the lung with Dispase, a bacillus-derived neutral metalloprotease, at the time of tissue harvest followed by mincing, digestion in a DNase and collagenase solution, and filtration before staining with fluorescent reagents concurrently maximized viable yields of epithelial, endothelial, and hematopoietic lineage cells compared with a standard method that did not use enzymes at the time of tissue harvest. Flow cytometry identified each population—epithelial (CD326+CD31−CD45−), endothelial (CD326−CD31+CD45−), and hematopoietic lineage (CD326−CD31−CD45+)—and measured cellular viability by 7-aminoactinomycin D (7-AAD) staining. The Dispase method permitted discrimination of epithelial vs. endothelial cell death in a systemic lipopolysaccharide model of increased pulmonary vascular permeability. We conclude that application of a dissociative enzyme solution directly to the cellular compartments of interest at the time of tissue harvest maximized viable cellular yields of those compartments. Investigators could employ this dissociation method to simultaneously harvest epithelial, endothelial, and hematopoietic lineage and other lineage-negative cells for flow-cytometric analysis.
12
ALEXANDER, JOHN K., BABETTE FUSS, and RAYMOND J. COLELLO. "Electric field-induced astrocyte alignment directs neurite outgrowth." Neuron Glia Biology 2, no. 2 (January 23, 2006): 93–103. http://dx.doi.org/10.1017/s1740925x0600010x.
Анотація:
The extension and directionality of neurite outgrowth are key to achieving successful target connections during both CNS development and during the re-establishment of connections lost after neural trauma. The degree of axonal elongation depends, in large part, on the spatial arrangement of astrocytic processes rich in growth-promoting proteins. Because astrocytes in culture align their processes on exposure to an electrical field of physiological strength, we sought to determine the extent to which aligned astrocytes affect neurite outgrowth. To this end, dorsal root ganglia cells were seeded onto cultured rat astrocytes that were pre-aligned by exposure to an electric field of physiological strength (500 mV mm−1). Using confocal microscopy and digital image analysis, we found that neurite outgrowth at 24 hours and at 48 hours is enhanced significantly and directed consistently along the aligned astrocyte processes. Moreover, this directed neurite outgrowth is maintained when grown on fixed, aligned astrocytes. Collectively, these results indicate that endogenous electric fields present within the developing CNS might act to align astrocyte processes, which can promote and direct neurite growth. Furthermore, these results demonstrate a simple method to produce an aligned cellular substrate, which might be used to direct regenerating neurites.
13
Srisongkram, Tarapong, Natthida Weerapreeyakul, Jussi Kärkkäinen, and Jarkko Rautio. "Role of L-Type Amino Acid Transporter 1 (LAT1) for the Selective Cytotoxicity of Sesamol in Human Melanoma Cells." Molecules 24, no. 21 (October 27, 2019): 3869. http://dx.doi.org/10.3390/molecules24213869.
Анотація:
Sesamol is effective against melanoma cells with less damage to normal cells. The underlying selective cytotoxicity of sesamol in melanoma vs. non-cancerous cells is undefined. Melanoma cells differ from normal cells by over-expression of the L-type amino acid transporter 1 (LAT1). We sought to clarify the transport mechanism on selective cytotoxicity of sesamol in melanoma cells. A human melanoma cell line (SK-MEL-2) and African monkey epithelial cell line (Vero) were used to study the cellular uptake and cytotoxicity of sesamol. The intracellular concentration of sesamol was quantified by UV-HPLC. The cytotoxicity was determined by neutral red uptake assay. Sesamol showed a higher distribution volume and uptake clearance in SK-MEL-2 than Vero cells. Sesamol was distributed by both carrier-mediated and passive transport by having greater carrier-mediated transport into SK-MEL-2 cells than Vero cells. Higher mRNA expression and function of LAT1 over LAT2 were evident in SK-MEL-2 cells compared to Vero cells. Sesamol uptake and sesamol cytotoxicity were inhibited by the LAT1 inhibitor, suggesting LAT1 had a role in sesamol transport and its bioactivity in melanoma. The LAT1-mediated transport of sesamol is indicative of how it engages cytotoxicity in melanoma cells with promising therapeutic benefits.
14
Ahmed, Shayan, Hugo Salmon, Nicholas Distasio, Hai Doan Do, Daniel Scherman, Khair Alhareth, Maryam Tabrizian, and Nathalie Mignet. "Viscous Core Liposomes Increase siRNA Encapsulation and Provides Gene Inhibition When Slightly Positively Charged." Pharmaceutics 13, no. 4 (April 1, 2021): 479. http://dx.doi.org/10.3390/pharmaceutics13040479.
Анотація:
Since its discovery, evidence that siRNA was able to act as an RNA interference effector, led to its acceptation as a novel medicine. The siRNA approach is very effective, due to its catalytic mechanism, but still the limitations of its cellular delivery should be addressed. One promising form of non-viral gene delivery system is liposomes. The variable and versatile nature of the lipids keeps the possibility to upgrade the liposomal structure, which makes them suitable for encapsulation and delivery of drugs. However, to avoid the limitation of fast release for the hydrophilic drug, we previously designed viscous core liposomes. We aimed in this work to evaluate if these viscous core liposomes (NvcLs) could be of interest for siRNA encapsulation. Then, we sought to add a limited amount of positive charges to provide cell interaction and transfection. Cationic lipid dimyristoylaminopropylaminopropyl or the polymer poly(ethylenimine) were incorporated in NvcL to produce positively charged viscous core liposomes (PvcL) by a customized microfluidic device. We found that NvcLs increased the encapsulation efficiency and loading content with regards to the neutral liposome. Both PvcLPEI and PvcLDMAPAP exhibited transfection and GFP knock-down (≈40%) in both 2D and 3D cell cultures. Finally, the addition of slight positive charges did not induce cell toxicity.
15
Siekmeier, Peter J. "An in Silico, Biomarker-Based Method for the Evaluation of Virtual Neuropsychiatric Drug Effects." Neural Computation 29, no. 4 (April 2017): 1021–52. http://dx.doi.org/10.1162/neco_a_00944.
Анотація:
The recent explosion in neuroscience research has markedly increased our understanding of the neurobiological correlates of many psychiatric illnesses, but this has unfortunately not translated into more effective pharmacologic treatments for these conditions. At the same time, researchers have increasingly sought out biological markers, or biomarkers, as a way to categorize psychiatric illness, as these are felt to be closer to underlying genetic and neurobiological vulnerabilities. While biomarker-based drug discovery approaches have tended to employ in vivo (e.g., rodent) or in vitro test systems, relatively little attention has been paid to the potential of computational, or in silico, methodologies. Here we describe such a methodology, using as an example a biophysically detailed computational model of hippocampus that is made to generate putative schizophrenia biomarkers by the inclusion of a number of neuropathological changes that have been associated with the illness (NMDA system deficit, decreased neural connectivity, hyperdopaminergia). We use the specific inability to attune to gamma band (40 Hz) auditory stimulus as our illness biomarker. We expose this system to a large number of virtual medications, defined by systematic variation of model parameters corresponding to five cellular-level effects. The potential efficacy of virtual medications is determined by a wellness metric (WM) that we have developed. We identify a number of virtual agents that consist of combinations of mechanisms, which are not simply reversals of the causative lesions. The manner in which this methodology could be extended to other neuropsychiatric conditions, such as Alzheimer’s disease, autism, and fragile X syndrome, is discussed.
16
Saude, L., K. Woolley, P. Martin, W. Driever, and D. L. Stemple. "Axis-inducing activities and cell fates of the zebrafish organizer." Development 127, no. 16 (August 15, 2000): 3407–17. http://dx.doi.org/10.1242/dev.127.16.3407.
Анотація:
We have investigated axis-inducing activities and cellular fates of the zebrafish organizer using a new method of transplantation that allows the transfer of both deep and superficial organizer tissues. Previous studies have demonstrated that the zebrafish embryonic shield possesses classically defined dorsal organizer activity. When we remove the morphologically defined embryonic shield, embryos recover and are completely normal by 24 hours post-fertilization. We find that removal of the morphological shield does not remove all goosecoid- and floating head-expressing cells, suggesting that the morphological shield does not comprise the entire organizer region. Complete removal of the embryonic shield and adjacent marginal tissue, however, leads to a loss of both prechordal plate and notochord. In addition, these embryos are cyclopean, show a significant loss of floor plate and primary motorneurons and display disrupted somite patterning. Motivated by apparent discrepancies in the literature we sought to test the axis-inducing activity of the embryonic shield. A previous study suggested that the shield is capable of only partial axis induction, specifically being unable to induce the most anterior neural tissues. Contrary to this study, we find shields can induce complete secondary axes when transplanted into host ventral germ-ring. In induced secondary axes donor tissue contributes to notochord, prechordal plate and floor plate. When explanted shields are divided into deep and superficial fragments and separately transplanted we find that deep tissue is able to induce the formation of ectopic axes with heads but lacking posterior tissues. We conclude that the deep tissue included in our transplants is important for proper head formation.
17
Belzile, Jean-Philippe, Maite Sabalza, Megan Craig, Alex E. Clark, Christopher S. Morello, and Deborah H. Spector. "Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types." Journal of Virology 90, no. 3 (November 11, 2015): 1259–77. http://dx.doi.org/10.1128/jvi.02651-15.
Анотація:
ABSTRACT Human cytomegalovirus (HCMV) is the major viral cause of birth defects and a serious problem in immunocompromised individuals and has been associated with atherosclerosis. Previous studies have shown that the induction of autophagy can inhibit the replication of several different types of DNA and RNA viruses. The goal of the work presented here was to determine whether constitutive activation of autophagy would also block replication of HCMV. Most prior studies have used agents that induce autophagy via inhibition of the mTOR pathway. However, since HCMV infection alters the sensitivity of mTOR kinase-containing complexes to inhibitors, we sought an alternative method of inducing autophagy. We chose to use trehalose, a nontoxic naturally occurring disaccharide that is found in plants, insects, microorganisms, and invertebrates but not in mammals and that induces autophagy by an mTOR-independent mechanism. Given the many different cell targets of HCMV, we proceeded to determine whether trehalose would inhibit HCMV infection in human fibroblasts, aortic artery endothelial cells, and neural cells derived from human embryonic stem cells. We found that in all of these cell types, trehalose induces autophagy and inhibits HCMV gene expression and production of cell-free virus. Treatment of HCMV-infected neural cells with trehalose also inhibited production of cell-associated virus and partially blocked the reduction in neurite growth and cytomegaly. These results suggest that activation of autophagy by the natural sugar trehalose or other safe mTOR-independent agents might provide a novel therapeutic approach for treating HCMV disease. IMPORTANCE HCMV infects multiple cell types in vivo, establishes lifelong persistence in the host, and can cause serious health problems for fetuses and immunocompromised individuals. HCMV, like all other persistent pathogens, has to finely tune its interplay with the host cellular machinery to replicate efficiently and evade detection by the immune system. In this study, we investigated whether modulation of autophagy, a host pathway necessary for the recycling of nutrients and removal of protein aggregates, misfolded proteins, and pathogens, could be used to target HCMV. We found that autophagy could be significantly increased by treatment with the nontoxic, natural disaccharide trehalose. Importantly, trehalose had a profound inhibitory effect on viral gene expression and strongly impaired viral spread. These data constitute a proof-of-concept for the use of natural products targeting host pathways rather than the virus itself, thus reducing the risk of the development of resistance to treatment.
18
Save, Akshay, Todd Hollon, Zia Farooq, Deborah Boyett, Andrea Hawkins-Daarud, Hyunsoo Yoon, Kyle Singleton, et al. "TMOD-14. RADIOGRAPHIC, STIMULATED RAMAN HISTOLOGIC, AND MULTIPLEXED RNA-SEQUENCING ANALYSIS OF POST-TREATMENT RECURRENT HIGH-GRADE GLIOMAS." Neuro-Oncology 21, Supplement_6 (November 2019): vi265. http://dx.doi.org/10.1093/neuonc/noz175.1113.
Анотація:
Abstract High-grade gliomas (HGGs) nearly always recur after standard initial treatment, and the resulting mixture of recurrent tumor and treatment-induced reactive changes presents major diagnostic challenges. Anatomical imaging, such as MRI, cannot adequately distinguish progressive disease from treatment effect (pseudo-progression). Furthermore, there is marked intra-tumoral heterogeneity, such that some areas of a tumor may demonstrate necrotic treatment effect and others frank recurrence. Due to this difficulty reliably differentiating between these two clinical findings, analytic methods using multiple modalities are necessary to further our understanding of this disease process. To this end, we sought to correlate radiographic, histopathologic and molecular features of surgically sampled post-treatment suspected recurrence to identify markers distinguishing tumor growth from treatment effect. We performed Stimulated Raman Histology (SRH) imaging and highly multiplexed RNA-sequencing (PLATE-seq) on 84 MRI-localized biopsies from 39 patients with clinically suspected recurrent HGG. The SRH images were classified as recurrent tumor or gliotic/reactive tissue using a convolutional neural network trained on an independent cohort including a large set of recurrent HGG, and an automated cell-counting algorithm was used to quantify cellularity from the SRH image of each sample. Differential gene expression analysis of the PLATE-seq data was used to identify gene sets that distinguish recurrent tumor from treatment effect, and single sample gene set variation analysis (GSVA) was used to further assess the molecular and cellular composition of each MRI-localized sample. The histopathologic and molecular features of each sample were also correlated with the MRI features of the corresponding biopsy sites, and this data is currently being used to train machine learning models that predict the distribution of recurrent tumor and treatment-induced reactive changes within a patient’s radiographic lesion. These predictive radiomic models will help to guide neurosurgical sampling, and improve our ability to monitor glioma progression and response to therapy.
19
Peralta, O., W. Huckle, M. Martinez, J. Correa, R. Gatica, and W. Eyestone. "262 TISSUE-SPECIFIC ANALYSIS OF PRION EXPRESSION IN EARLY BOVINE FETUSES." Reproduction, Fertility and Development 18, no. 2 (2006): 238. http://dx.doi.org/10.1071/rdv18n2ab262.
Анотація:
The prion protein (PrP) is best known for its mis-folded, pathogenic isoform, which is widely regarded as the infectious agent in transmissable spongiform encephalopathies. However, the role of normal, cellular PrP, a host-encoded 29-kD glycoprotein tethered to the cell membrane by a phosphatidyl-inositol glycane (GPI) anchor, is poorly understood. PrP binds copper with high affinity, has antioxidant activity and may play a role in cell adhesion and/or signaling. PrP is expressed in mouse embryos on 6.5 days post-coitum in extra-embryonic tissue and at 13.5 days in the central and peripheral nervous system, intestine, and dental lamina. Our previous data revealed PrP gene expression in bovine embryos throughout pre-implantation embryo development. As part of a larger effort to map the ontogeny of cellular PrP expression in cattle, we sought here to analyze in early bovine fetuses (1) total PrP gene expression by real-time quantitative PCR (QPCR), and (2) tissue-specific PrP expression by immunohistochemistry. Fetuses were obtained from donor cattle bred by artificial insemination (AI; Day 0) and subjected to mid-ventral laparotomy on Days 32 (n = 2) and 39 (n = 2). Immediately upon recovery, one fetus from each stage was placed in RNAlater for RNA isolation and the other fixed in 10% formalin for immunohistochemistry. RNA was isolated using an RNeasy� mini kit (Qiagen, Valencia, CA, USA). cDNA was generated by reverse transcription with random hexamer priming and used the ΔΔcT method for estimation of PrP expression by QPCR. Tissue-specific expression was determined by immunohistochemistry. Formalin-fixed fetuses were embedded in paraffin, sagittally sectioned, dehydrated, and subjected to an unmasking protocol that employed Vectorlab unmasking solution and autoclaving. Tissues were then probed with a primary anti-PrP monoclonal antibody (SAF 32; Cayman Chemical Company, Ann Arbor, MI, USA). Bound primary antibody was detected with a biotinylated horse anti-mouse secondary antibody complexed to horseradish peroxidase using the ABC kit (Vector Laboratories, Burlingame, CA, USA). Probed sections were then counterstained with hematoxolin and eosin. Neighboring sections, processed identically but to which no primary antibody was added, served as controls. PrP gene expression was detected by QPCR at both stages examined and tended to be higher in Day 39 compared to Day 32 fetuses. PrP immunoreactivity was found throughout the central and peripheral nervous systems, ganglia, nerve trunks, and neural cell populations of sensory organs in both Day 32 and Day 39 fetuses. PrP immunolabeling was also observed in the mesonephric kidney, liver, and heart in the Day 39 fetus. At both stages, immunoreactivity was most intense in the nervous system. Thus, PrP is expressed in a tissue-specific pattern in early bovine fetuses. Tissue distribution of fetal PrP expression appears similar to that of adult PrP. Moreover, PrP appears to be expressed in a developmentally regulated fashion in some tissues.
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Povinelli, Benjamin, and Michael J. Nemeth. "Non-Canonical Wnt Signaling Regulates Hematopooetic Repopulation Through the Ryk Receptor." Blood 120, no. 21 (November 16, 2012): 852. http://dx.doi.org/10.1182/blood.v120.21.852.852.
Анотація:
Abstract Abstract 852 Proper regulation of the balance between quiescence and proliferation is implicated in long-term maintenance of hematopoietic stem cell (HSC) function. Our lab has demonstrated that Wnt5a, a member of the Wnt family of ligands, induces HSC quiescence in vitro and enhances short and long-term hematopoietic repopulation (Nemeth, et al. 2007). To determine the mechanisms of Wnt5a signaling in HSCs we sought to identify potential Wnt5a receptors. The Ryk gene encodes a non-canonical Wnt receptor in lineage-negative, Sca-1+, c-kit+ (LSK) cells. Previous research using neural crest cells identified Ryk as a receptor for Wnt5a. We hypothesized that the ability of Wnt5a to enhance HSC quiescence and hematopoietic repopulation required the Ryk receptor. To test this hypothesis, we cultured C57BL/6 LSK cells in serum-free media with 25ng/ml SCF and Flt3, 250ng/ml recombinant Wnt5a (rWnt5a), and 1.0 μg/ml anti-Ryk neutralizing antibody (α-Ryk) for four days. We observed that compared to control treatment, rWnt5a significantly inhibited cellular expansion (control: 5.9 ± 0.1-fold; rWnt5a: 3.1 ± 0.3-fold; n = 4, p <0.01). The effect of Wnt5a on cellular expansion was blocked by the inhibition of Ryk with α-Ryk (α-Ryk + rWnt5a: 3.1 ± 0.3-fold; n = 4, p = 0.01 compared to rWnt5a alone). We confirmed these data using a genetic approach in which we transduced LSK cells with a lentiviral vector expressing a dominant-negative Ryk mutant; LSK cells transduced with this vector did not respond to rWnt5a treatment as measured by cell expansion. We measured the effects of rWnt5a and α-Ryk treatment on the cell cycle. rWnt5a treatment resulted in a modest decrease in the percentage of cells in the S/G2/M phases (control: 35.0 ± 1.9%; rWnt5a: 29.1 ± 0.5%, n=3, p < 0.01). Treatment with α-Ryk partially restored this response (α-Ryk + rWnt5a; 32.2 ± 2.0%, n=3, p = 0.06 compared to rWnt5a). We then tested the effects of rWnt5a and α-Ryk treatment on cell quiescence. As expected, rWnt5a treatment increased the percentage of cells in G0 compared to control (control: 11.3 ± 6.7%; rWnt5a: 26.1 ± 0.9%, n=3, p < 0.01). The effect of rWnt5a on quiescence was blocked by the addition of α-Ryk (α-Ryk + rWnt5a; 21.1 ± 1.4%, n=3, p < 0.05 compared to rWnt5a). To test the effects of inhibiting Ryk on Wnt5a-mediated enhancement of hematopoietic repopulation, we performed competitive bone marrow transplant assays. We cultured C57BL/6 LSK cells for 4 days and transplanted 1 × 104 cells along with 5 × 105 whole bone marrow cells from Ubc-GFP transgenic mice (C57BL/6 background) into lethally irradiated B6.SJL mice. At 4 and 16 weeks, we measured the contribution of cultured LSK cells to hematopoietic repopulation by determining the percentage of peripheral blood cells that were CD45.2+, GFP-. rWnt5a increased the contribution of cultured LSK cells to hematopoietic repopulation after 4 weeks (control: 5.3 ± 1.4%, n = 8, rWnt5a: 19.5 ± 7.1%, n = 6, p < 0.05) and 16 weeks (control: 4.5 ± 1.6% n = 8, rWnt5a: 32.0 ± 13.1%, n = 6, p = 0.01). Inhibiting Ryk blocked the effects of rWnt5a on reconstitution after 4 and 16 weeks (4 weeks: α-Ryk + rWnt5a; 5.8 ± 2.1% n = 6, p < 0.05 compared to rWnt5a; 16 weeks: α-Ryk + rWnt5a; 11.9 ± 7.1%, n = 6, p < 0.05 compared to rWnt5a). These data indicate that the effects of rWnt5a on hematopoietic cell proliferation and HSC engraftment are regulated by the Ryk receptor. To determine a mechanism by which Wnt5a induces quiescence and hematopoietic repopulation, we tested whether Wnt5a regulates production of reactive oxygen species (ROS). Excessive ROS production is linked to decreased HSC quiescence and reduced long-term function. We measured the level of ROS in our sorted LSK cells using the ROS probe dihydrodichlorofluorescein. We observed that treatment of LSK cells with rWnt5a resulted in a 1.6 ± 0.3-fold reduction in ROS levels compared to control (n = 3); this reduction was comparable to that observed using the proto-typical anti-oxidant N-acetyl cysteine. This reduction in ROS production was inhibited by the addition of α-Ryk (1.04 ± 0.1-fold compared to control, n = 3). Together, our data indicate that the Ryk receptor functionally interacts with Wnt5a to regulate hematopoietic stem and progenitor quiescence and function and that regulation of ROS production is a potential mechanism by which Wnt5a regulates HSC function. Disclosures: No relevant conflicts of interest to declare.
21
Vicario, Nunzio, Federica M. Spitale, Daniele Tibullo, Cesarina Giallongo, Angela M. Amorini, Grazia Scandura, Graziana Spoto, et al. "Clobetasol promotes neuromuscular plasticity in mice after motoneuronal loss via sonic hedgehog signaling, immunomodulation and metabolic rebalancing." Cell Death & Disease 12, no. 7 (June 16, 2021). http://dx.doi.org/10.1038/s41419-021-03907-1.
Анотація:
AbstractMotoneuronal loss is the main feature of amyotrophic lateral sclerosis, although pathogenesis is extremely complex involving both neural and muscle cells. In order to translationally engage the sonic hedgehog pathway, which is a promising target for neural regeneration, recent studies have reported on the neuroprotective effects of clobetasol, an FDA-approved glucocorticoid, able to activate this pathway via smoothened. Herein we sought to examine functional, cellular, and metabolic effects of clobetasol in a neurotoxic mouse model of spinal motoneuronal loss. We found that clobetasol reduces muscle denervation and motor impairments in part by restoring sonic hedgehog signaling and supporting spinal plasticity. These effects were coupled with reduced pro-inflammatory microglia and reactive astrogliosis, reduced muscle atrophy, and support of mitochondrial integrity and metabolism. Our results suggest that clobetasol stimulates a series of compensatory processes and therefore represents a translational approach for intractable denervating and neurodegenerative disorders.
22
Yamada, Shunji, Nienke van Kooten, Takuma Mori, Katsutoshi Taguchi, Atsushi Tsujimura, and Masaki Tanaka. "Efferent and Afferent Connections of Neuropeptide Y Neurons in the Nucleus Accumbens of Mice." Frontiers in Neuroanatomy 15 (September 10, 2021). http://dx.doi.org/10.3389/fnana.2021.741868.
Анотація:
Neuropeptide Y (NPY) is a neural peptide distributed widely in the brain and has various functions in each region. We previously reported that NPY neurons in the nucleus accumbens (NAc) are involved in the regulation of anxiety behavior. Anterograde and retrograde tracing studies suggest that neurons in the NAc project to several areas, such as the lateral hypothalamus (LH) and ventral pallidum (VP), and receive afferent projections from the cortex, thalamus, and amygdala. However, the neural connections between accumbal NPY neurons and other brain areas in mice remain unclear. In this study, we sought to clarify these anatomical connections of NPY neurons in the NAc by investigating their neural outputs and inputs. To selectively map NPY neuronal efferents from the NAc, we injected Cre-dependent adeno-associated viruses (AAVs) into the NAc of NPY-Cre mice. This revealed that NAc NPY neurons exclusively projected to the LH. We confirmed this by injecting cholera toxin b subunit (CTb), a retrograde tracer, into the LH and found that approximately 7–10% of NPY neurons in the NAc were double-labeled for mCherry and CTb. Moreover, retrograde tracing using recombinant rabies virus (rRABV) also identified NAc NPY projections to the LH. Finally, we investigated monosynaptic input to the NPY neurons in the NAc using rRABV. We found that NPY neurons in the NAc received direct synaptic connections from the midline thalamic nuclei and posterior basomedial amygdala. These findings provide new insight into the neural networks of accumbal NPY neurons and should assist in elucidating their functional roles.
23
Islam, Rehnuma, Stasja Drecun, Balazs V. Varga, Ilan Vonderwalde, Ricky Siu, Andras Nagy, and Cindi M. Morshead. "Transplantation of Human Cortically-Specified Neuroepithelial Progenitor Cells Leads to Improved Functional Outcomes in a Mouse Model of Stroke." Frontiers in Cellular Neuroscience 15 (April 29, 2021). http://dx.doi.org/10.3389/fncel.2021.654290.
Анотація:
Stroke is a leading cause of death and long-term disability worldwide. Current therapeutic options are limited in terms of their time for implementation and efficacy in promoting recovery. Cell transplantation has been shown to have promise in several animal models however significant challenges remain, including the optimal source of cells to promote neural repair. Here, we report on the use of a population of human ESC derived, cortically specified, neuroepithelial precursor cells (cNEPs) that are neurally restricted in their lineage potential. CNEPs have the potential to give rise to mature neural cell types following transplantation, including neurons, astrocytes and oligodendrocytes. With a view towards translation, we sought to determine whether this human cell source was effective in promoting improved functional outcomes following stroke. Undifferentiated cNEPs were transplanted in a pre-clinical endothelin-1 (ET-1) model of ischemic motor cortical stroke in immunocompromised SCID-beige mice and cellular and functional outcomes were assessed. We demonstrate that cNEP transplantation in the acute phase (4 days post-stroke) improves motor function as early as 20 days post-stroke, compared to stroke-injured, non-transplanted mice. At the time of recovery, a small fraction (<6%) of the transplanted cNEPs are observed within the stroke injury site. The surviving cells expressed the immature neuronal marker, doublecortin, with no differentiation into mature neural phenotypes. At longer survival times (40 days), the majority of recovered, transplanted mice had a complete absence of surviving cNEPS. Hence, human cNEPs grafted at early times post-stroke support the observed functional recovery following ET-1 stroke but their persistence is not required, thereby supporting a by-stander effect rather than cell replacement.
24
Shah, Sumedh S., Garima Yagnik, Alan T. Nguyen, Harsh Wadhwa, Jordan Spatz, Michael Safaee, Justin Cheng, and Manish K. Aghi. "Pro-tumoral Effects of Intra-tumoral Neutrophils in the Glioblastoma Microenvironment." Neurosurgery 66, Supplement_1 (August 20, 2019). http://dx.doi.org/10.1093/neuros/nyz310_314.
Анотація:
Abstract INTRODUCTION The glioblastoma microenvironment contains immune cells, particularly well-defined macrophage populations; however, intratumoral neutrophils and their effects on GBM biology are under-characterized. While tumor-associated neutrophils (TANs) were initially thought as passive bystanders due to their short-lived nature, current investigation of TANs in other cancer types revealed distinct pro-tumoral roles. Therefore, we sought to characterize TANs in the glioblastoma microenvironment and define their oncologic effects. METHODS Following informed consent, patient-derived GBM samples were collected for flow cytometry of TANs, which were then used to produce conditioned media (CM) for in Vitro studies on tumor cell proliferation and ELISA quantification of TAN-secreted factors. Single-cell RNA sequencing was performed on TANs to identify pro-tumoral factors. RESULTS Flow cytometric analysis (CD11b+/CD15+ /CD66b+) indicated higher percentages of TAN-infiltration to glioblastoma compared to low-grade gliomas (1.76% [n = 13] vs 0.33% [n = 6], P = .03). Using the Transwell migration assay with glioblastoma tumor CM, we found recruitment of circulating neutrophils to tumor sites is mediated by leukotriene-B4 and that this chemoattraction can be blocked with an LtB4 receptor antagonist, LY293111. We then performed single-cell RNA sequencing of isolated TANs and identified upregulation of osteopontin. Osteopontin is linked to GBM stem cell-like phenotype maintenance, thus, we decided to investigate osteopontin as a possible driver of pro-tumoral signaling. Osteopontin concentration was significantly higher in TAN CM than in patient-matched peripheral blood neutrophil CM (3.2 ng/mL [n = 3] vs 0.02 ng/mL [n = 3], P < .05). In Vitro, TAN CM led to significantly increased GBM cell proliferation and increased stem marker expression (Nanog, Oct4, Sox2) when incubated with neurospheres from an established GBM line. Pro-tumoral effects were lost in presence of osteopontin-neutralizing antibodies. CONCLUSION This study elucidates a possible mechanism of neutrophil-mediated pro-tumoral signaling. We found that neutrophils are recruited to tumor sites and play a biologically relevant role in GBM cellular proliferation and maintenance of a stem cell phenotype via osteopontin secretion.
25
Daniel K, Michelle L. Olsen, Mengchan Ou, Colin M. Cleary, and Guizhi Du. "Putative roles of astrocytes in general anesthesia." Current Neuropharmacology 19 (February 15, 2021). http://dx.doi.org/10.2174/1570159x19666210215120755.
Анотація:
: General anesthetics are a mainstay of modern medicine, and although much progress has been made towards identifying molecular targets of anesthetics and neural networks contributing to endpoints of general anesthesia, our understanding of how anesthetics work remains unclear. Reducing this knowledge gap is of fundamental importance to prevent unwanted and life-threatening side-effects associated with general anesthesia. General anesthetics are chemically diverse, yet they all have similar behavioral endpoints, and so for decades research has sought to identify a single underlying mechanism to explain how anesthetics work. However, this effort has given way to the ‘multiple target hypothesis’ as it has become clear that anesthetics target many cellular proteins including GABAA receptors, glutamate receptors, voltage-independent K+ channels and voltage-dependent K+, Ca2+ and Na+ channels, to name a few. Yet, despite evidence that astrocytes are capable of modulating multiple aspects of neural function and express many anesthetic target proteins, they have been largely ignored as potential targets of anesthesia. The purpose of this brief review is to highlight effects of anesthetic on astrocyte processes and identify potential roles of astrocytes in behavioral endpoints of anesthesia (hypnosis, amnesia, analgesia and immobilization).
26
Shapiro, Jared T., Nicole M. Michaud, Jillian L. King, and Nathan A. Crowder. "Optogenetic Activation of Interneuron Subtypes Modulates Visual Contrast Responses of Mouse V1 Neurons." Cerebral Cortex, August 19, 2021. http://dx.doi.org/10.1093/cercor/bhab269.
Анотація:
Abstract Interneurons are critical for information processing in the cortex. In vitro optogenetic studies in mouse primary visual cortex (V1) have sketched the connectivity of a local neural circuit comprising excitatory pyramidal neurons and distinct interneuron subtypes that express parvalbumin (Pvalb+), somatostatin (SOM+), or vasoactive intestinal peptide (VIP+). However, in vivo studies focusing on V1 orientation tuning have ascribed discrepant computational roles to specific interneuron subtypes. Here, we sought to clarify the differences between interneuron subtypes by examining the effects of optogenetic activation of Pvalb+, SOM+, or VIP+ interneurons on contrast tuning of V1 neurons while also accounting for cortical depth and photostimulation intensity. We found that illumination of the cortical surface produced a similar spectrum of saturating additive photostimulation effects in all 3 interneuron subtypes, which varied with cortical depth rather than light intensity in Pvalb+ and SOM+ cells. Pyramidal cell modulation was well explained by a conductance-based model that incorporated these interneuron photostimulation effects.
27
Becker, Martin, Francesca Mastropasqua, Jan Philipp Reising, Simon Maier, Mai-Lan Ho, Ielyzaveta Rabkina, Danyang Li, et al. "Presynaptic dysfunction in CASK-related neurodevelopmental disorders." Translational Psychiatry 10, no. 1 (September 14, 2020). http://dx.doi.org/10.1038/s41398-020-00994-0.
Анотація:
Abstract CASK-related disorders are genetically defined neurodevelopmental syndromes. There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK-mutation consequences and neuronal effects using induced pluripotent stem cell-derived neurons from two mutation carriers. One male case with autism spectrum disorder carried a novel splice-site mutation and a female case with intellectual disability carried an intragenic tandem duplication. We show reduction of CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of genes involved in presynaptic development and of CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory–inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in the brain. Our data show that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.
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Zaben, Malik, Niels Haan, Feras Sharouf, Aminul Ahmed, Lars E. Sundstrom та William P. Gray. "IL-1β and HMGB1 are anti-neurogenic to endogenous neural stem cells in the sclerotic epileptic human hippocampus". Journal of Neuroinflammation 18, № 1 (21 вересня 2021). http://dx.doi.org/10.1186/s12974-021-02265-1.
Анотація:
Abstract Background The dentate gyrus exhibits life-long neurogenesis of granule-cell neurons, supporting hippocampal dependent learning and memory. Both temporal lobe epilepsy patients and animal models frequently have hippocampal-dependent learning and memory difficulties and show evidence of reduced neurogenesis. Animal and human temporal lobe epilepsy studies have also shown strong innate immune system activation, which in animal models reduces hippocampal neurogenesis. We sought to determine if and how neuroinflammation signals reduced neurogenesis in the epileptic human hippocampus and its potential reversibility. Methods We isolated endogenous neural stem cells from surgically resected hippocampal tissue in 15 patients with unilateral hippocampal sclerosis. We examined resultant neurogenesis after growing them either as neurospheres in an ideal environment, in 3D cultures which preserved the inflammatory microenvironment and/or in 2D cultures which mimicked it. Results 3D human hippocampal cultures largely replicated the cellular composition and inflammatory environment of the epileptic hippocampus. The microenvironment of sclerotic human epileptic hippocampal tissue is strongly anti-neurogenic, with sustained release of the proinflammatory proteins HMGB1 and IL-1β. IL-1β and HMGB1 significantly reduce human hippocampal neurogenesis and blockade of their IL-1R and TLR 2/4 receptors by IL1Ra and Box-A respectively, significantly restores neurogenesis in 2D and 3D culture. Conclusion Our results demonstrate a HMGB1 and IL-1β-mediated environmental anti-neurogenic effect in human TLE, identifying both the IL-1R and TLR 2/4 receptors as potential drug targets for restoring human hippocampal neurogenesis in temporal lobe epilepsy.
29
Bisese, Eleanor C., Chandler M. Ciuba, Amelia L. Davidson, Akanksha Kaushik, Sabrina M. Mullen, Jeremy L. Barth, E. Starr Hazard, Robert C. Wilson, Gary Hardiman, and David M. Hollis. "The acute transcriptome response of the midbrain/diencephalon to injury in the adult mummichog (Fundulus heteroclitus)." Molecular Brain 12, no. 1 (December 2019). http://dx.doi.org/10.1186/s13041-019-0542-4.
Анотація:
AbstractAdult fish produce new cells throughout their central nervous system during the course of their lives and maintain a tremendous capacity to repair damaged neural tissue. Much of the focus on understanding brain repair and regeneration in adult fish has been directed at regions of the brainstem and forebrain; however, the mesencephalon (midbrain) and diencephalon have received little attention. We sought to examine differential gene expression in the midbrain/diencephalon in response to injury in the adult fish using RNA-seq. Using the mummichog (Fundulus heteroclitus), we administered a mechanical lesion to the midbrain/diencephalon and examined differentially expressed genes (DEGs) at an acute recovery time of 1 h post-injury. Comparisons of whole transcriptomes derived from isolated RNA of intact and injured midbrain/diencephalic tissue identified 404 DEGs with the vast majority being upregulated. Using qPCR, we validated the upregulation of DEGs pim-2-like, syndecan-4-like, and cd83. Based on genes both familiar and novel regarding the adult brain response to injury, these data provide an extensive molecular profile giving insight into a range of cellular processes involved in the injury response of a brain regenerative-capable vertebrate.
30
Weaver, Cory J., and Fabienne E. Poulain. "From whole organism to ultrastructure: progress in axonal imaging for decoding circuit development." Development 148, no. 18 (July 30, 2021). http://dx.doi.org/10.1242/dev.199717.
Анотація:
ABSTRACT Since the pioneering work of Ramón y Cajal, scientists have sought to unravel the complexities of axon development underlying neural circuit formation. Micrometer-scale axonal growth cones navigate to targets that are often centimeters away. To reach their targets, growth cones react to dynamic environmental cues that change in the order of seconds to days. Proper axon growth and guidance are essential to circuit formation, and progress in imaging has been integral to studying these processes. In particular, advances in high- and super-resolution microscopy provide the spatial and temporal resolution required for studying developing axons. In this Review, we describe how improved microscopy has revolutionized our understanding of axonal development. We discuss how novel technologies, specifically light-sheet and super-resolution microscopy, led to new discoveries at the cellular scale by imaging axon outgrowth and circuit wiring with extreme precision. We next examine how advanced microscopy broadened our understanding of the subcellular dynamics driving axon growth and guidance. We finally assess the current challenges that the field of axonal biology still faces for imaging axons, and examine how future technology could meet these needs.
31
Belloy, Michaël E., Jacob Billings, Anzar Abbas, Amrit Kashyap, Wen-Ju Pan, Rukun Hinz, Verdi Vanreusel, et al. "Resting Brain Fluctuations Are Intrinsically Coupled to Visual Response Dynamics." Cerebral Cortex, October 27, 2020. http://dx.doi.org/10.1093/cercor/bhaa305.
Анотація:
Abstract How do intrinsic brain dynamics interact with processing of external sensory stimuli? We sought new insights using functional magnetic resonance imaging to track spatiotemporal activity patterns at the whole brain level in lightly anesthetized mice, during both resting conditions and visual stimulation trials. Our results provide evidence that quasiperiodic patterns (QPPs) are the most prominent component of mouse resting brain dynamics. These QPPs captured the temporal alignment of anticorrelation between the default mode (DMN)- and task-positive (TPN)-like networks, with global brain fluctuations, and activity in neuromodulatory nuclei of the reticular formation. Specifically, the phase of QPPs prior to stimulation could significantly stratify subsequent visual response magnitude, suggesting QPPs relate to brain state fluctuations. This is the first observation in mice that dynamics of the DMN- and TPN-like networks, and particularly their anticorrelation, capture a brain state dynamic that affects sensory processing. Interestingly, QPPs also displayed transient onset response properties during visual stimulation, which covaried with deactivations in the reticular formation. We conclude that QPPs appear to capture a brain state fluctuation that may be orchestrated through neuromodulation. Our findings provide new frontiers to understand the neural processes that shape functional brain states and modulate sensory input processing.
32
Hanson, Elizabeth, Katie L. Brandel-Ankrapp, and Benjamin R. Arenkiel. "Dynamic Cholinergic Tone in the Basal Forebrain Reflects Reward-Seeking and Reinforcement During Olfactory Behavior." Frontiers in Cellular Neuroscience 15 (February 2, 2021). http://dx.doi.org/10.3389/fncel.2021.635837.
Анотація:
Sensory perception underlies how we internalize and interact with the external world. In order to adapt to changing circumstances and interpret signals in a variety of contexts, sensation needs to be reliable, but perception of sensory input needs to be flexible. An important mediator of this flexibility is top-down regulation from the cholinergic basal forebrain. Basal forebrain projection neurons serve as pacemakers and gatekeepers for downstream neural networks, modulating circuit activity across diverse neuronal populations. This top-down control is necessary for sensory cue detection, learning, and memory, and is disproportionately disrupted in neurodegenerative diseases associated with cognitive decline. Intriguingly, cholinergic signaling acts locally within the basal forebrain to sculpt the activity of basal forebrain output neurons. To determine how local cholinergic signaling impacts basal forebrain output pathways that participate in top-down regulation, we sought to define the dynamics of cholinergic signaling within the basal forebrain during motivated behavior and learning. Toward this, we utilized fiber photometry and the genetically encoded acetylcholine indicator GAChR2.0 to define temporal patterns of cholinergic signaling in the basal forebrain during olfactory-guided, motivated behaviors and learning. We show that cholinergic signaling reliably increased during reward seeking behaviors, but was strongly suppressed by reward delivery in a go/no-go olfactory-cued discrimination task. The observed transient reduction in cholinergic tone was mirrored by a suppression in basal forebrain GABAergic neuronal activity. Together, these findings suggest that cholinergic tone in the basal forebrain changes rapidly to reflect reward-seeking behavior and positive reinforcement and may impact downstream circuitry that modulates olfaction.
33
Hollomon, Jeffrey M., Nora Grahl, Sven D. Willger, Katja Koeppen, and Deborah A. Hogan. "Global Role of Cyclic AMP Signaling in pH-Dependent Responses in Candida albicans." mSphere 1, no. 6 (November 30, 2016). http://dx.doi.org/10.1128/msphere.00283-16.
Анотація:
ABSTRACT Candida albicans is a human commensal and the causative agent of candidiasis, a potentially invasive and life-threatening infection. C. albicans experiences wide changes in pH during both benign commensalism (a common condition) and pathogenesis, and its morphology changes in response to this stimulus. Neutral pH is considered an activator of hyphal growth through Rim101, but the effect of low pH on other morphology-related pathways has not been extensively studied. We sought to determine the role of cyclic AMP signaling, a central regulator of morphology, in the sensing of pH. In addition, we asked broadly what cellular processes were altered by pH in both the presence and absence of this important signal integration system. We concluded that cAMP signaling is impacted by pH and that cAMP broadly impacts C. albicans physiology in both pH-dependent and -independent ways. Candida albicans behaviors are affected by pH, an important environmental variable. Filamentous growth is a pH-responsive behavior, where alkaline conditions favor hyphal growth and acid conditions favor growth as yeast. We employed filamentous growth as a tool to study the impact of pH on the hyphal growth regulator Cyr1, and we report that downregulation of cyclic AMP (cAMP) signaling by acidic pH contributes to the inhibition of hyphal growth in minimal medium with GlcNAc. Ras1 and Cyr1 are generally required for efficient hyphal growth, and the effects of low pH on Ras1 proteolysis and GTP binding are consistent with diminished cAMP output. Active alleles of ras1 do not suppress the hyphal growth defect at low pH, while dibutyryl cAMP partially rescues filamentous growth at low pH in a cyr1 mutant. These observations are consistent with Ras1-independent downregulation of Cyr1 by low pH. We also report that extracellular pH leads to rapid and prolonged decreases in intracellular pH, and these changes may contribute to reduced cAMP signaling by reducing intracellular bicarbonate pools. Transcriptomics analyses found that the loss of Cyr1 at either acidic or neutral pH leads to increases in transcripts involved in carbohydrate catabolism and protein translation and glycosylation and decreases in transcripts involved in oxidative metabolism, fluconazole transport, metal transport, and biofilm formation. Other pathways were modulated in pH-dependent ways. Our findings indicate that cAMP has a global role in pH-dependent responses, and this effect is mediated, at least in part, through Cyr1 in a Ras1-independent fashion. IMPORTANCE Candida albicans is a human commensal and the causative agent of candidiasis, a potentially invasive and life-threatening infection. C. albicans experiences wide changes in pH during both benign commensalism (a common condition) and pathogenesis, and its morphology changes in response to this stimulus. Neutral pH is considered an activator of hyphal growth through Rim101, but the effect of low pH on other morphology-related pathways has not been extensively studied. We sought to determine the role of cyclic AMP signaling, a central regulator of morphology, in the sensing of pH. In addition, we asked broadly what cellular processes were altered by pH in both the presence and absence of this important signal integration system. We concluded that cAMP signaling is impacted by pH and that cAMP broadly impacts C. albicans physiology in both pH-dependent and -independent ways.
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Khateb, Mohamed, Noam Bosak, and Moshe Herskovitz. "The Effect of Anti-seizure Medications on the Propagation of Epileptic Activity: A Review." Frontiers in Neurology 12 (May 27, 2021). http://dx.doi.org/10.3389/fneur.2021.674182.
Анотація:
The propagation of epileptiform events is a highly interesting phenomenon from the pathophysiological point of view, as it involves several mechanisms of recruitment of neural networks. Extensive in vivo and in vitro research has been performed, suggesting that multiple networks as well as cellular candidate mechanisms govern this process, including the co-existence of wave propagation, coupled oscillator dynamics, and more. The clinical importance of seizure propagation stems mainly from the fact that the epileptic manifestations cannot be attributed solely to the activity in the seizure focus itself, but rather to the propagation of epileptic activity to other brain structures. Propagation, especially when causing secondary generalizations, poses a risk to patients due to recurrent falls, traumatic injuries, and poor neurological outcome. Anti-seizure medications (ASMs) affect propagation in diverse ways and with different potencies. Importantly, for drug-resistant patients, targeting seizure propagation may improve the quality of life even without a major reduction in simple focal events. Motivated by the extensive impact of this phenomenon, we sought to review the literature regarding the propagation of epileptic activity and specifically the effect of commonly used ASMs on it. Based on this body of knowledge, we propose a novel classification of ASMs into three main categories: major, minor, and intermediate efficacy in reducing the propagation of epileptiform activity.
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Whitely, Michael E., Patrick B. Collins, Masahiro Iwamoto та Joseph C. Wenke. "Administration of a selective retinoic acid receptor-γ agonist improves neuromuscular strength in a rodent model of volumetric muscle loss". Journal of Experimental Orthopaedics 8, № 1 (12 серпня 2021). http://dx.doi.org/10.1186/s40634-021-00378-3.
Анотація:
Abstract Purpose Volumetric muscle loss is a uniquely challenging pathology that results in irrecoverable functional deficits. Furthermore, a breakthrough drug or bioactive factor has yet to be established that adequately improves repair of these severe skeletal muscle injuries. This study sought to assess the ability of an orally administered selective retinoic acid receptor-γ agonist, palovarotene, to improve recovery of neuromuscular strength in a rat model of volumetric muscle loss. Methods An irrecoverable, full thickness defect was created in the tibialis anterior muscle of Lewis rats and animals were survived for 4 weeks. Functional recovery of the tibialis anterior muscle was assessed in vivo via neural stimulation and determination of peak isometric torque. Histological staining was performed to qualitatively assess fibrous scarring of the defect site. Results Treatment with the selective retinoic acid receptor-γ agonist, palovarotene, resulted in a 38% improvement of peak isometric torque in volumetric muscle loss affected limbs after 4 weeks of healing compared to untreated controls. Additionally, preliminary histological assessment suggests that oral administration of palovarotene reduced fibrous scarring at the defect site. Conclusions These results highlight the potential role of selective retinoic acid receptor-γ agonists in the design of regenerative medicine platforms to maximize skeletal muscle healing. Additional studies are needed to further elucidate cellular responses, optimize therapeutic delivery, and characterize synergistic potential with adjunct therapies.
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Yamashiro, Kotaro, Jiayan Liu, Nobuyoshi Matsumoto, and Yuji Ikegaya. "Deep Learning-Based Classification of GAD67-Positive Neurons Without the Immunosignal." Frontiers in Neuroanatomy 15 (March 31, 2021). http://dx.doi.org/10.3389/fnana.2021.643067.
Анотація:
Excitatory neurons and GABAergic interneurons constitute neural circuits and play important roles in information processing. In certain brain regions, such as the neocortex and the hippocampus, there are fewer interneurons than excitatory neurons. Interneurons have been quantified via immunohistochemistry, for example, for GAD67, an isoform of glutamic acid decarboxylase. Additionally, the expression level of other proteins varies among cell types. For example, NeuN, a commonly used marker protein for postmitotic neurons, is expressed differently across brain regions and cell classes. Thus, we asked whether GAD67-immunopositive neurons can be detected using the immunofluorescence signals of NeuN and the fluorescence signals of Nissl substances. To address this question, we stained neurons in layers 2/3 of the primary somatosensory cortex (S1) and the primary motor cortex (M1) of mice and manually labeled the neurons as either cell type using GAD67 immunosignals. We then sought to detect GAD67-positive neurons without GAD67 immunosignals using a custom-made deep learning-based algorithm. Using this deep learning-based model, we succeeded in the binary classification of the neurons using Nissl and NeuN signals without referring to the GAD67 signals. Furthermore, we confirmed that our deep learning-based method surpassed classic machine-learning methods in terms of binary classification performance. Combined with the visualization of the hidden layer of our deep learning algorithm, our model provides a new platform for identifying unbiased criteria for cell-type classification.
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Earp, Brian D., and Jim A. C. Everett. "Is the N170 face specific? Controversy, context, and theory." Neuropsychological Trends, no. 13 (April 2013). http://dx.doi.org/10.7358/neur-2013-013-earp.
Анотація:
In cognitive science, there is an ongoing debate about the architecture of the mind: does it consist of a number of mental organs each managing a different function in isolation, or is it more of general processor, adaptable to a wide range of tasks? One corner of this debate has centered on face processing. This is because face-perception is crucial to normal human functioning and some evidence shows that faces may be processed by the brain in a privileged way compared to other types of stimuli. For example, in EEG brain recordings, the N170 is a characteristic signal that occurs after a participant is exposed to an image of a face, but it is much less pronounced when other stimuli are shown. More than 15 years of research on the N170 face effect have yielded the standard view that the N170 is at the very least face-sensitive, and possibly even face-specific, that is, indexing modular processes tied exclusively to facial geometries. The specificity claim is clearly stronger, and hence subject to significant controversy; while the more conservative sensitivity claim had been regarded (until recently) as effectively settled. Nevertheless, Thierry and colleagues, in a contentious 2007 article, sought to undermine even this conservative consensus: they argued that the apparent face-responsiveness of the N170 in prior research was due to systematic flaws in experimental design. Fiery debate has followed. In this review, we put the debate in its historical and philosophical context, and try to spell out some of the theoretical and logical assumptions that underlie the claims of the competing camps. We then show that the best available evidence counts, at least partially, against the Thierry et al. construal of the N170. Accordingly, it would be premature to abandon the conservative account of the N170, according to which it is – minimally – responsive to faces. We conclude by returning to the more controversial claim about face-specificity, and try to clarify what such a view would entail from a theoretical standpoint.
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Hsu, Chih-Chien, Ke-Hung Chien, Aliaksandr A. Yarmishyn, Waradee Buddhakosai, Wen-Ju Wu, Tai-Chi Lin, Shih-Hwa Chiou, et al. "Modulation of osmotic stress-induced TRPV1 expression rescues human iPSC-derived retinal ganglion cells through PKA." Stem Cell Research & Therapy 10, no. 1 (September 23, 2019). http://dx.doi.org/10.1186/s13287-019-1363-1.
Анотація:
Abstract Background Transient receptor potential vanilloid 1 (TRPV1), recognized as a hyperosmolarity sensor, is a crucial ion channel involved in the pathogenesis of neural and glial signaling. Recently, TRPV1 was determined to play a role in retinal physiology and visual transmission. In this study, we sought to clarify the role of TRPV1 and the downstream pathway in the osmotic stress-related retina ganglion cell (RGC) damage. Methods First, we modified the RGC differentiation protocol to obtain a homogeneous RGC population from human induced pluripotent stem cells (hiPSCs). Subsequently, we induced high osmotic pressure in the hiPSC-derived RGCs by administering NaCl solution and observed the behavior of the TRPV1 channel and its downstream cascade. Results We obtained a purified RGC population from the heterogeneous retina cell population using our modified method. Our findings revealed that TRPV1 was activated after 24 h of NaCl treatment. Upregulation of TRPV1 was noted with autophagy and apoptosis induction. Downstream protein expression analysis indicated increased phosphorylation of CREB and downregulated brain-derived neurotrophic factor (BDNF). However, hyperosmolarity-mediated defective morphological change and apoptosis of RGCs, CREB phosphorylation, and BDNF downregulation were abrogated after concomitant treatment with the PKA inhibitor H89. Conclusion Collectively, our study results indicated that the TRPV1–PKA pathway contributed to cellular response under high levels of osmolarity stress; furthermore, the PKA inhibitor had a protective effect on RGCs exposed to this stress. Therefore, our findings may assist in the treatment of eye diseases involving RGC damage.
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Romer, Adrienne L., Annchen R. Knodt, Maria L. Sison, David Ireland, Renate Houts, Sandhya Ramrakha, Richie Poulton, et al. "Replicability of structural brain alterations associated with general psychopathology: evidence from a population-representative birth cohort." Molecular Psychiatry, December 3, 2019. http://dx.doi.org/10.1038/s41380-019-0621-z.
Анотація:
AbstractTransdiagnostic research has identified a general psychopathology factor—often called the ‘p’ factor—that accounts for shared variation across internalizing, externalizing, and thought disorders in diverse samples. It has been argued that the p factor may reflect dysfunctional thinking present in serious mental illness. In support of this, we previously used a theory-free, data-driven multimodal neuroimaging approach to find that higher p factor scores are associated with structural alterations within a cerebello-thalamo-cortical circuit (CTCC) and visual association cortex, both of which are important for monitoring and coordinating information processing in the service of executive control. Here we attempt to replicate these associations by conducting region-of-interest analyses using data from 875 members of the Dunedin Longitudinal Study, a five-decade study of a population-representative birth cohort, collected when they were 45 years old. We further sought to replicate a more recent report that p factor scores can be predicted by patterns of distributed cerebellar morphology as estimated through independent component analysis. We successfully replicated associations between higher p factor scores and both reduced gray matter volume of the visual association cortex and fractional anisotropy of pontine white matter pathways within the CTCC. In contrast, we failed to replicate prior associations between cerebellar structure and p factor scores. Collectively, our findings encourage further focus on the CTCC and visual association cortex as core neural substrates and potential biomarkers of general psychopathology.
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Dey, Arindam K., Adrien Nougarède, Flora Clément, Carole Fournier, Evelyne Jouvin-Marche, Marie Escudé, Dorothée Jary, Fabrice P. Navarro, and Patrice N. Marche. "Tuning the Immunostimulation Properties of Cationic Lipid Nanocarriers for Nucleic Acid Delivery." Frontiers in Immunology 12 (August 23, 2021). http://dx.doi.org/10.3389/fimmu.2021.722411.
Анотація:
Nonviral systems, such as lipid nanoparticles, have emerged as reliable methods to enable nucleic acid intracellular delivery. The use of cationic lipids in various formulations of lipid nanoparticles enables the formation of complexes with nucleic acid cargo and facilitates their uptake by target cells. However, due to their small size and highly charged nature, these nanocarrier systems can interact in vivo with antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages. As this might prove to be a safety concern for developing therapies based on lipid nanocarriers, we sought to understand how they could affect the physiology of APCs. In the present study, we investigate the cellular and metabolic response of primary macrophages or DCs exposed to the neutral or cationic variant of the same lipid nanoparticle formulation. We demonstrate that macrophages are the cells affected most significantly and that the cationic nanocarrier has a substantial impact on their physiology, depending on the positive surface charge. Our study provides a first model explaining the impact of charged lipid materials on immune cells and demonstrates that the primary adverse effects observed can be prevented by fine-tuning the load of nucleic acid cargo. Finally, we bring rationale to calibrate the nucleic acid load of cationic lipid nanocarriers depending on whether immunostimulation is desirable with the intended therapeutic application, for instance, gene delivery or messenger RNA vaccines.
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Arzua, Thiago, Yasheng Yan, Congshan Jiang, Sarah Logan, Reilly L. Allison, Clive Wells, Suresh N. Kumar, Richard Schäfer, and Xiaowen Bai. "Modeling alcohol-induced neurotoxicity using human induced pluripotent stem cell-derived three-dimensional cerebral organoids." Translational Psychiatry 10, no. 1 (October 13, 2020). http://dx.doi.org/10.1038/s41398-020-01029-4.
Анотація:
Abstract Maternal alcohol exposure during pregnancy can substantially impact the development of the fetus, causing a range of symptoms, known as fetal alcohol spectrum disorders (FASDs), such as cognitive dysfunction and psychiatric disorders, with the pathophysiology and mechanisms largely unknown. Recently developed human cerebral organoids from induced pluripotent stem cells are similar to fetal brains in the aspects of development and structure. These models allow more relevant in vitro systems to be developed for studying FASDs than animal models. Modeling binge drinking using human cerebral organoids, we sought to quantify the downstream toxic effects of alcohol (ethanol) on neural pathology phenotypes and signaling pathways within the organoids. The results revealed that alcohol exposure resulted in unhealthy organoids at cellular, subcellular, bioenergetic metabolism, and gene expression levels. Alcohol induced apoptosis on organoids. The apoptotic effects of alcohol on the organoids depended on the alcohol concentration and varied between cell types. Specifically, neurons were more vulnerable to alcohol-induced apoptosis than astrocytes. The alcohol-treated organoids exhibit ultrastructural changes such as disruption of mitochondria cristae, decreased intensity of mitochondrial matrix, and disorganized cytoskeleton. Alcohol exposure also resulted in mitochondrial dysfunction and metabolic stress in the organoids as evidenced by (1) decreased mitochondrial oxygen consumption rates being linked to basal respiration, ATP production, proton leak, maximal respiration and spare respiratory capacity, and (2) increase of non-mitochondrial respiration in alcohol-treated organoids compared with control groups. Furthermore, we found that alcohol treatment affected the expression of 199 genes out of 17,195 genes analyzed. Bioinformatic analyses showed the association of these dysregulated genes with 37 pathways related to clinically relevant pathologies such as psychiatric disorders, behavior, nervous system development and function, organismal injury and abnormalities, and cellular development. Notably, 187 of these genes are critically involved in neurodevelopment, and/or implicated in nervous system physiology and neurodegeneration. Furthermore, the identified genes are key regulators of multiple pathways linked in networks. This study extends for the first time animal models of binge drinking-related FASDs to a human model, allowing in-depth analyses of neurotoxicity at tissue, cellular, subcellular, metabolism, and gene levels. Hereby, we provide novel insights into alcohol-induced pathologic phenotypes, cell type-specific vulnerability, and affected signaling pathways and molecular networks, that can contribute to a better understanding of the developmental neurotoxic effects of binge drinking during pregnancy.
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Li, Ya-Dong, Yan-Jia Luo, Wei Xu, Jing Ge, Yoan Cherasse, Yi-Qun Wang, Michael Lazarus, Wei-Min Qu, and Zhi-Li Huang. "Ventral pallidal GABAergic neurons control wakefulness associated with motivation through the ventral tegmental pathway." Molecular Psychiatry, October 14, 2020. http://dx.doi.org/10.1038/s41380-020-00906-0.
Анотація:
Abstract The ventral pallidum (VP) regulates motivation, drug addiction, and several behaviors that rely on heightened arousal. However, the role and underlying neural circuits of the VP in the control of wakefulness remain poorly understood. In the present study, we sought to elucidate the specific role of VP GABAergic neurons in controlling sleep–wake behaviors in mice. Fiber photometry revealed that the population activity of VP GABAergic neurons was increased during physiological transitions from non-rapid eye movement (non-REM, NREM) sleep to either wakefulness or REM sleep. Moreover, chemogenetic and optogenetic manipulations were leveraged to investigate a potential causal role of VP GABAergic neurons in initiating and/or maintaining arousal. In vivo optogenetic stimulation of VP GABAergic neurons innervating the ventral tegmental area (VTA) strongly promoted arousal via disinhibition of VTA dopaminergic neurons. Functional in vitro mapping revealed that VP GABAergic neurons, in principle, inhibited VTA GABAergic neurons but also inhibited VTA dopaminergic neurons. In addition, optogenetic stimulation of terminals of VP GABAergic neurons revealed that they promoted arousal by innervating the lateral hypothalamus, but not the mediodorsal thalamus or lateral habenula. The increased wakefulness chemogenetically evoked by VP GABAergic neuronal activation was completely abolished by pretreatment with dopaminergic D1 and D2/D3 receptor antagonists. Furthermore, activation of VP GABAergic neurons increased exploration time in both the open-field and light–dark box tests but did not modulate depression-like behaviors or food intake. Finally, chemogenetic inhibition of VP GABAergic neurons decreased arousal. Taken together, our findings indicate that VP GABAergic neurons are essential for arousal related to motivation.
43
Ely, Benjamin A., Qi Liu, Samuel J. DeWitt, Lushna M. Mehra, Carmen M. Alonso, and Vilma Gabbay. "Data-driven parcellation and graph theory analyses to study adolescent mood and anxiety symptoms." Translational Psychiatry 11, no. 1 (May 3, 2021). http://dx.doi.org/10.1038/s41398-021-01321-x.
Анотація:
AbstractAdolescence is a period of rapid brain development when psychiatric symptoms often first emerge. Studying adolescents may therefore facilitate the identification of neural alterations early in the course of psychiatric conditions. Here, we sought to utilize new, high-quality brain parcellations and data-driven graph theory approaches to characterize associations between resting-state networks and the severity of depression, anxiety, and anhedonia symptoms—salient features across psychiatric conditions. As reward circuitry matures considerably during adolescence, we examined both Whole Brain and three task-derived reward networks. Subjects were 87 psychotropic-medication-free adolescents (age = 12–20) with diverse psychiatric conditions (n = 68) and healthy controls (n = 19). All completed diagnostic interviews, dimensional clinical assessments, and 3T resting-state fMRI (10 min/2.3 mm/TR = 1 s). Following high-quality Human Connectome Project-style preprocessing, multimodal surface matching (MSMAll) alignment, and parcellation via the Cole-Anticevic Brain-wide Network Partition, weighted graph theoretical metrics (Strength Centrality = CStr; Eigenvector Centrality = CEig; Local Efficiency = ELoc) were estimated within each network. Associations with symptom severity and clinical status were assessed non-parametrically (two-tailed pFWE < 0.05). Across subjects, depression scores correlated with ventral striatum CStr within the Reward Attainment network, while anticipatory anhedonia correlated with CStr and ELoc in the subgenual anterior cingulate, dorsal anterior cingulate, orbitofrontal cortex, caudate, and ventral striatum across multiple networks. Group differences and associations with anxiety were not detected. Using detailed functional and clinical measures, we found that adolescent depression and anhedonia involve increased influence and communication efficiency in prefrontal and limbic reward areas. Resting-state network properties thus reflect positive valence system anomalies related to discrete reward sub-systems and processing phases early in the course of illness.
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Scarpazza, Cristina, Livio Finos, Sarah Genon, Laura Masiero, Elena Bortolato, Camilla Cavaliere, Jessica Pezzaioli, et al. "Idiopathic and acquired pedophilia as two distinct disorders: an insight from neuroimaging." Brain Imaging and Behavior, January 28, 2021. http://dx.doi.org/10.1007/s11682-020-00442-z.
Анотація:
AbstractPedophilia is a disorder of public concern because of its association with child sexual offense and recidivism. Previous neuroimaging studies of potential brain abnormalities underlying pedophilic behavior, either in idiopathic or acquired (i.e., emerging following brain damages) pedophilia, led to inconsistent results. This study sought to explore the neural underpinnings of pedophilic behavior and to determine the extent to which brain alterations may be related to distinct psychopathological features in pedophilia. To this aim, we run a coordinate based meta-analysis on previously published papers reporting whole brain analysis and a lesion network analysis, using brain lesions as seeds in a resting state connectivity analysis. The behavioral profiling approach was applied to link identified regions with the corresponding psychological processes. While no consistent neuroanatomical alterations were identified in idiopathic pedophilia, the current results support that all the lesions causing acquired pedophilia are localized within a shared resting state network that included posterior midlines structures, right inferior temporal gyrus and bilateral orbitofrontal cortex. These regions are associated with action inhibition and social cognition, abilities that are consistently and severely impaired in acquired pedophiles. This study suggests that idiopathic and acquired pedophilia may be two distinct disorders, in line with their distinctive clinical features, including age of onset, reversibility and modus operandi. Understanding the neurobiological underpinnings of pedophilic behavior may contribute to a more comprehensive characterization of these individuals on a clinical ground, a pivotal step forward for the development of more efficient therapeutic rehabilitation strategies.
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Intskirveli, Irakli, and Raju Metherate. "Nicotine Enhances Amplitude and Consistency of Timing of Responses to Acoustic Trains in A1." Frontiers in Neural Circuits 15 (February 18, 2021). http://dx.doi.org/10.3389/fncir.2021.597401.
Анотація:
Systemic nicotine enhances neural processing in primary auditory cortex (A1) as determined using tone-evoked, current-source density (CSD) measurements. For example, nicotine enhances the characteristic frequency (CF)-evoked current sink in layer 4 of A1, increasing amplitude and decreasing latency. However, since presenting auditory stimuli within a stream of stimuli increases the complexity of response dynamics, we sought to determine the effects of nicotine on CSD responses to trains of CF stimuli (one-second trains at 2–40 Hz; each train repeated 25 times). CSD recordings were obtained using a 16-channel multiprobe inserted in A1 of urethane/xylazine-anesthetized mice, and analysis focused on two current sinks in the middle (layer 4) and deep (layers 5/6) layers. CF trains produced adaptation of the layer 4 response that was weak at 2 Hz, stronger at 5–10 Hz and complete at 20–40 Hz. In contrast, the layer 5/6 current sink exhibited less adaptation at 2–10 Hz, and simultaneously recorded auditory brainstem responses (ABRs) showed no adaptation even at 40 Hz. Systemic nicotine (2.1 mg/kg) enhanced layer 4 responses throughout the one-second stimulus train at rates ≤10 Hz. Nicotine enhanced both response amplitude within each train and the consistency of response timing across 25 trials. Nicotine did not alter the degree of adaptation over one-second trials, but its effect to increase amplitudes revealed a novel, slower form of adaptation that developed over multiple trials. Nicotine did not affect responses that were fully adapted (20–40 Hz trains), nor did nicotine affect any aspect of the layer 5/6 current sink or ABRs. The overall effect of nicotine in layer 4 was to enhance all responses within each train, to emphasize earlier trials across multiple trials, and to improve the consistency of timing across all trials. These effects may improve processing of complex acoustic streams, including speech, that contain information in the 2–10 Hz range.
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Linden, Jennifer R., Yinghua Ma, Baohua Zhao, Jason Michael Harris, Kareem Rashid Rumah, Nicole Schaeren-Wiemers, and Timothy Vartanian. "Clostridium perfringens Epsilon Toxin Causes Selective Death of Mature Oligodendrocytes and Central Nervous System Demyelination." mBio 6, no. 3 (June 16, 2015). http://dx.doi.org/10.1128/mbio.02513-14.
Анотація:
ABSTRACTClostridium perfringensepsilon toxin (ε-toxin) is responsible for a devastating multifocal central nervous system (CNS) white matter disease in ruminant animals. The mechanism by which ε-toxin causes white matter damage is poorly understood. In this study, we sought to determine the molecular and cellular mechanisms by which ε-toxin causes pathological changes to white matter. In primary CNS cultures, ε-toxin binds to and kills oligodendrocytes but not astrocytes, microglia, or neurons. In cerebellar organotypic culture, ε-toxin induces demyelination, which occurs in a time- and dose-dependent manner, while preserving neurons, astrocytes, and microglia. ε-Toxin specificity for oligodendrocytes was confirmed using enriched glial culture. Sensitivity to ε-toxin is developmentally regulated, as only mature oligodendrocytes are susceptible to ε-toxin; oligodendrocyte progenitor cells are not. ε-Toxin sensitivity is also dependent on oligodendrocyte expression of the proteolipid myelin and lymphocyte protein (MAL), as MAL-deficient oligodendrocytes are insensitive to ε-toxin. In addition, ε-toxin binding to white matter follows the spatial and temporal pattern of MAL expression. A neutralizing antibody against ε-toxin inhibits oligodendrocyte death and demyelination. This study provides several novel insights into the action of ε-toxin in the CNS. (i) ε-Toxin causes selective oligodendrocyte death while preserving all other neural elements. (ii) ε-Toxin-mediated oligodendrocyte death is a cell autonomous effect. (iii) The effects of ε-toxin on the oligodendrocyte lineage are restricted to mature oligodendrocytes. (iv) Expression of the developmentally regulated proteolipid MAL is required for the cytotoxic effects. (v) The cytotoxic effects of ε-toxin can be abrogated by an ε-toxin neutralizing antibody.IMPORTANCEOur intestinal tract is host to trillions of microorganisms that play an essential role in health and homeostasis. Disruption of this symbiotic relationship has been implicated in influencing or causing disease in distant organ systems such as the brain. Epsilon toxin (ε-toxin)-carryingClostridium perfringensstrains are responsible for a devastating white matter disease in ruminant animals that shares similar features with human multiple sclerosis. In this report, we define the mechanism by which ε-toxin causes white matter disease. We find that ε-toxin specifically targets the myelin-forming cells of the central nervous system (CNS), oligodendrocytes, leading to cell death. The selectivity of ε-toxin for oligodendrocytes is remarkable, as other cells of the CNS are unaffected. Importantly, ε-toxin-induced oligodendrocyte death results in demyelination and is dependent on expression of myelin and lymphocyte protein (MAL). These results help complete the mechanistic pathway from bacteria to brain by explaining the specific cellular target of ε-toxin within the CNS.