Abnormal neuronal migration: radiologic-clinic study. Alteraciones en la migracion neural: estudio clinico-radiologico

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Martinez Fernandez, M.; Menor Serrano, F.; Bordon Ferre, F.; Garcia Tena, J.; Esteban Hernandez, E.; Sanguesa Nebot, C.; Marti Bonnati, L. (Hospital Infantil La Fe, Valencia (Spain))

1994-01-01

We present our experience in 18 pediatric patients with abnormal neuronal migration. Seven cases of heterotopia of the gray matter, 7 agyria-pachygyria complexes, 1 case of polymicrogyria, 2 cases of schizencephaly and 1 case of hemimegalencephaly were diagnosed by means of ultrasonography, computed tomography and magnetic resonance. The clinical picture was reviewed in each case, with special attention to the occurrence of convulsions, psycho motor development and visual changes. In general, the greater the morphological change, the greater the neurological involvement in these patients. However, the two cases of schizencephaly presented mild clinical expression. Magnetic resonance increases the diagnostic yield in neuronal migration disorders. Nevertheless, either ultrasonography or, especially, computed tomography is useful as a first diagnostic approach in these malformative disorders. (Author)

MR imaging of neuronal migration anomaly

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Hong, Hyun Sook; Choi, Eun Wan; Kim, Dae Ho; Chung, Moo Chan; Kwon, Kuy Hyang; Kim, Ki Jung

1991-01-01

Abnormalities of neuronal migration are characterized by anectopic location of neurons in the cerebral cortex. This broad group of anomalies includes agyria, pachygyria, schizencephaly, unilateral megalencephaly, and gray matter heterotopia. Patients with this anomaly present clinically with a variety of symptoms which are proportional to the extent of the brain involved. These abnormalities have characterized pathologically in vivo by sonography and CT scan. MR appears to be an imaging technique of choice in evaluating these anomalies because it is capable of exceptionally good differentiation between gray and white matter, high contrast resolution, multiplanar display of the anatomy, and lack of overlying bone artifac. The purpose of this paper is to describe the MR findings of neuronal migration anomaly. The results of our study support that MR appears to be the imaging method of choice for diagnosing migration anomalies and the primary screening method for infants or children who have seisure/and delayed development

Normal and abnormal neuronal migration in the developing cerebral cortex

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Sun, Xue-Zhi; Takahashi, Sentaro; Cui, Chun; Zhang, Rui; Sakata-Haga, Hiromi; Sawada, Kazuhiko; Fukui, Yoshihiro

2002-01-01

Neuronal migration is the critical cellular process which initiates histogenesis of cerebral cortex. Migration involves a series of complex cell interactions and transformation. After completing their final mitosis, neurons migrate from the ventricular zone into the cortical plate, and then establish neuronal lamina and settle onto the outermost layer, forming an “inside-out” gradient of maturation. This process is guided by radial glial fibers, requires proper receptors, ligands, other unkno...

Capture of microtubule plus-ends at the actin cortex promotes axophilic neuronal migration by enhancing microtubule tension in the leading process.

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Hutchins, B Ian; Wray, Susan

2014-01-01

Microtubules are a critical part of neuronal polarity and leading process extension, thus microtubule movement plays an important role in neuronal migration. However, the dynamics of microtubules during the forward movement of the nucleus into the leading process (nucleokinesis) is unclear and may be dependent on the cell type and mode of migration used. In particular, little is known about cytoskeletal changes during axophilic migration, commonly used in anteroposterior neuronal migration. We recently showed that leading process actin flow in migrating GnRH neurons is controlled by a signaling cascade involving IP3 receptors, CaMKK, AMPK, and RhoA. In the present study, microtubule dynamics were examined in GnRH neurons. Failure of the migration of these cells leads to the neuroendocrine disorder Kallmann Syndrome. Microtubules translocated forward along the leading process shaft during migration, but reversed direction and moved toward the nucleus when migration stalled. Blocking calcium release through IP3 receptors halted migration and induced the same reversal of microtubule translocation, while blocking cortical actin flow prevented microtubules from translocating toward the distal leading process. Super-resolution imaging revealed that microtubule plus-end tips are captured at the actin cortex through calcium-dependent mechanisms. This work shows that cortical actin flow draws the microtubule network forward through calcium-dependent capture in order to promote nucleokinesis, revealing a novel mechanism engaged by migrating neurons to facilitate movement.

Cytoskeletal Regulation by AUTS2 in Neuronal Migration and Neuritogenesis

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Kei Hori

2014-12-01

Full Text Available Mutations in the Autism susceptibility candidate 2 gene (AUTS2, whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development. Immunohistochemistry and fractionation studies show that AUTS2 localizes not only in nuclei, but also in the cytoplasm, including in the growth cones in the developing brain. AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These findings suggest that cytoplasmic AUTS2 acts as a regulator of Rho family GTPases to contribute to brain development and give insight into the pathology of human psychiatric disorders with AUTS2 mutations.

Absence of Tangentially Migrating Glutamatergic Neurons in the Developing Avian Brain

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Fernando García-Moreno

2018-01-01

Full Text Available Summary: Several neuronal populations orchestrate neocortical development during mammalian embryogenesis. These include the glutamatergic subplate-, Cajal-Retzius-, and ventral pallium-derived populations, which coordinate cortical wiring, migration, and proliferation, respectively. These transient populations are primarily derived from other non-cortical pallial sources that migrate to the dorsal pallium. Are these migrations to the dorsal pallium conserved in amniotes or are they specific to mammals? Using in ovo electroporation, we traced the entire lineage of defined chick telencephalic progenitors. We found that several pallial sources that produce tangential migratory neurons in mammals only produced radially migrating neurons in the avian brain. Moreover, ectopic expression of VP-specific mammalian Dbx1 in avian brains altered neurogenesis but did not convert the migration into a mammal-like tangential movement. Together, these data indicate that tangential cellular contributions of glutamatergic neurons originate from outside the dorsal pallium and that pallial Dbx1 expression may underlie the generation of the mammalian neocortex during evolution. : Neocortical formation crucially depends on the early tangential arrival of several transient glutamatergic neuronal populations. García-Moreno et al. find that these neuronal migrations are absent in the developing brain of chicks. The mammalian uniqueness of these developing migrations suggests a crucial role of these cells in the evolutionary origin of the neocortex. Keywords: neocortex, chick, pallium, ventral pallium, evo-devo, evolution, Dbx1, telencephalon

Visualization of migration of human cortical neurons generated from induced pluripotent stem cells.

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Bamba, Yohei; Kanemura, Yonehiro; Okano, Hideyuki; Yamasaki, Mami

2017-09-01

Neuronal migration is considered a key process in human brain development. However, direct observation of migrating human cortical neurons in the fetal brain is accompanied by ethical concerns and is a major obstacle in investigating human cortical neuronal migration. We established a novel system that enables direct visualization of migrating cortical neurons generated from human induced pluripotent stem cells (hiPSCs). We observed the migration of cortical neurons generated from hiPSCs derived from a control and from a patient with lissencephaly. Our system needs no viable brain tissue, which is usually used in slice culture. Migratory behavior of human cortical neuron can be observed more easily and more vividly by its fluorescence and glial scaffold than that by earlier methods. Our in vitro experimental system provides a new platform for investigating development of the human central nervous system and brain malformation. Copyright © 2017 Elsevier B.V. All rights reserved.

TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway

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Falace, Antonio; Buhler, Emmanuelle; Fadda, Manuela; Watrin, Françoise; Lippiello, Pellegrino; Pallesi-Pocachard, Emilie; Baldelli, Pietro; Benfenati, Fabio; Zara, Federico; Represa, Alfonso; Fassio, Anna; Cardoso, Carlos

2014-01-01

Alterations in the formation of brain networks are associated with several neurodevelopmental disorders. Mutations in TBC1 domain family member 24 (TBC1D24) are responsible for syndromes that combine cortical malformations, intellectual disability, and epilepsy, but the function of TBC1D24 in the brain remains unknown. We report here that in utero TBC1D24 knockdown in the rat developing neocortex affects the multipolar-bipolar transition of neurons leading to delayed radial migration. Furthermore, we find that TBC1D24-knockdown neurons display an abnormal maturation and retain immature morphofunctional properties. TBC1D24 interacts with ADP ribosylation factor (ARF)6, a small GTPase crucial for membrane trafficking. We show that in vivo, overexpression of the dominant-negative form of ARF6 rescues the neuronal migration and dendritic outgrowth defects induced by TBC1D24 knockdown, suggesting that TBC1D24 prevents ARF6 activation. Overall, our findings demonstrate an essential role of TBC1D24 in neuronal migration and maturation and highlight the physiological relevance of the ARF6-dependent membrane-trafficking pathway in brain development. PMID:24469796

ApoER2 Controls Not Only Neuronal Migration in the Intermediate Zone But Also Termination of Migration in the Developing Cerebral Cortex.

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Hirota, Yuki; Kubo, Ken-Ichiro; Fujino, Takahiro; Yamamoto, Tokuo T; Nakajima, Kazunori

2018-01-01

Neuronal migration contributes to the establishment of mammalian brain. The extracellular protein Reelin sends signals to various downstream molecules by binding to its receptors, the apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor and exerts essential roles in the neuronal migration and formation of the layered neocortex. However, the cellular and molecular functions of Reelin signaling in the cortical development are not yet fully understood. Here, to gain insight into the role of Reelin signaling during cortical development, we examined the migratory behavior of Apoer2-deficient neurons in the developing brain. Stage-specific labeling of newborn neurons revealed that the neurons ectopically invaded the marginal zone (MZ) and that neuronal migration of both early- and late-born neurons was disrupted in the intermediate zone (IZ) in the Apoer2 KO mice. Rescue experiments showed that ApoER2 functions both in cell-autonomous and noncell-autonomous manners, that Rap1, integrin, and Akt are involved in the termination of migration beneath the MZ, and that Akt also controls neuronal migration in the IZ downstream of ApoER2. These data indicate that ApoER2 controls multiple processes in neuronal migration, including the early stage of radial migration and termination of migration beneath the MZ in the developing neocortex. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Differential regulation of microtubule severing by APC underlies distinct patterns of projection neuron and interneuron migration

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Eom, Tae-Yeon; Stanco, Amelia; Guo, Jiami; Wilkins, Gary; Deslauriers, Danielle; Yan, Jessica; Monckton, Chase; Blair, Josh; Oon, Eesim; Perez, Abby; Salas, Eduardo; Oh, Adrianna; Ghukasyan, Vladimir; Snider, William D.; Rubenstein, John L. R.; Anton, E. S.

2014-01-01

Coordinated migration of distinct classes of neurons to appropriate positions leads to the formation of functional neuronal circuitry in the cerebral cortex. Two major classes of cortical neurons, interneurons and projection neurons, utilize distinctly different modes (radial vs. tangential) and routes of migration to arrive at their final positions in the cerebral cortex. Here, we show that adenomatous polyposis coli (APC) modulates microtubule (MT) severing in interneurons to facilitate tangential mode of interneuron migration, but not the glial-guided, radial migration of projection neurons. APC regulates the stability and activity of the MT severing protein p60-katanin in interneurons to promote the rapid remodeling of neuronal processes necessary for interneuron migration. These findings reveal how severing and restructuring of MTs facilitate distinct modes of neuronal migration necessary for laminar organization of neurons in the developing cerebral cortex. PMID:25535916

Low level prenatal exposure to methylmercury disrupts neuronal migration in the developing rat cerebral cortex

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Guo, Bao-Qiang; Yan, Chong-Huai; Cai, Shi-Zhong; Yuan, Xiao-Bing; Shen, Xiao-Ming

2013-01-01

Highlights: ► Low level MeHg exposure causes migratory defect of rat cerebrocortical neurons. ► The migration defect is due to the impact of MeHg on the neuronal migration itself. ► Rho GTPases seem to be involved in MeHg-induced disruption of neuronal migration. -- Abstract: We determined the effects of low-level prenatal MeHg exposure on neuronal migration in the developing rat cerebral cortex using in utero electroporation. We used offspring rats born to dams that had been exposed to saline or various doses of MeHg (0.01 mg/kg/day, 0.1 mg/kg/day, and 1 mg/kg/day) from gestational day (GD) 11–21. Immunohistochemical examination of the brains of the offspring was conducted on postnatal day (PND) 0, PND3, and PND7. Our results showed that prenatal exposure to low levels of MeHg (0.1 mg/kg/day or 1 mg/kg/day) during the critical stage in neuronal migration resulted in migration defects of the cerebrocortical neurons in offspring rats. Importantly, our data revealed that the abnormal neuronal distribution induced by MeHg was not caused by altered proliferation of neural progenitor cells (NPCs), induction of apoptosis of NPCs and/or newborn neurons, abnormal differentiation of NPCs, and the morphological changes of radial glial scaffold, indicating that the defective neuronal positioning triggered by exposure to low-dose of MeHg is due to the impacts of MeHg on the process of neuronal migration itself. Moreover, we demonstrated that in utero exposure to low-level MeHg suppresses the expression of Rac1, Cdc42, and RhoA, which play key roles in the migration of cerebrocortical neurons during the early stage of brain development, suggesting that the MeHg-induced migratory disturbance of cerebrocortical neurons is likely associated with the Rho GTPases signal pathway. In conclusion, our results provide a novel perspective on clarifying the mechanisms underlying the impairment of neuronal migration induced by MeHg

Riding the glial monorail: a common mechanism for glial-guided neuronal migration in different regions of the developing mammalian brain.

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Hatten, M E

1990-05-01

In vitro studies from our laboratory indicate that granule neurons, purified from early postnatal mouse cerebellum, migrate on astroglial fibers by forming a 'migration junction' with the glial fiber along the length of the neuronal soma and extending a motile 'leading process' in the direction of migration. Similar dynamics are seen for hippocampal neurons migrating along hippocampal astroglial fibers in vitro. In heterotypic recombinations of neurons and glia from mouse cerebellum and rat hippocampus, neurons migrate on astroglial processes with a cytology and neuron-glia relationship identical to that of homotypic neuronal migration in vitro. In all four cases, the migrating neuron presents a stereotyped posture, speed and mode of movement, suggesting that glial fibers provide a generic pathway for neuronal migration in developing brain. Studies on the molecular basis of glial-guided migration suggest that astrotactin, a neuronal antigen that functions as a neuron-glia ligand, is likely to play a crucial role in the locomotion of the neuron along glial fibers. The navigation of neurons from glial fibers into cortical layers, in turn, is likely to involve neuron-neuron adhesion ligands.

Asymmetry of radial and symmetry of tangential neuronal migration pathways in developing human fetal brains

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Yuta eMiyazaki

2016-01-01

Full Text Available AbstractThe radial and tangential neural migration pathways are two major neuronal migration streams in humans that are critical during corticogenesis. Corticogenesis is a complex process of neuronal proliferation that is followed by neuronal migration and the formation of axonal connections. Existing histological assessments of these two neuronal migration pathways have limitations inherent to microscopic studies and are confined to small anatomic regions of interest. Thus, little evidence is available about their three-dimensional fiber pathways and development throughout the entire brain. In this study, we imaged and analyzed radial and tangential migration pathways in the whole human brain using high-angular resolution diffusion MR imaging (HARDI tractography. We imaged ten fixed, postmortem fetal (17 gestational weeks (GW, 18 GW, 19 GW, three 20 GW, three 21 GW and 22 GW and eight in vivo newborn (two 30 GW, 34 GW, 35 GW and four 40 GW brains with no neurological/pathological conditions. We statistically compared the volume of the left and right radial and tangential migration pathways, and the volume of the radial migration pathways of the anterior and posterior regions of the brain. In specimens 22 GW or younger, the volume of radial migration pathways of the left hemisphere was significantly larger than that of the right hemisphere. The volume of posterior radial migration pathways was also larger when compared to the anterior pathways in specimens 22 GW or younger. In contrast, no significant differences were observed in the radial migration pathways of brains older than 22 GW. Moreover, our study did not identify any significant differences in volumetric laterality in the tangential migration pathways. These results suggest that these two neuronal migration pathways develop and regress differently, and radial neuronal migration varies regionally based on hemispheric and anterior-posterior laterality, potentially explaining regional

Nonautonomous Regulation of Neuronal Migration by Insulin Signaling, DAF-16/FOXO, and PAK-1

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Lisa M. Kennedy

2013-09-01

Full Text Available Neuronal migration is essential for nervous system development in all organisms and is regulated in the nematode, C. elegans, by signaling pathways that are conserved in humans. Here, we demonstrate that the insulin/IGF-1-PI3K signaling pathway modulates the activity of the DAF-16/FOXO transcription factor to regulate the anterior migrations of the hermaphrodite-specific neurons (HSNs during embryogenesis of C. elegans. When signaling is reduced, DAF-16 is activated and promotes migration; conversely, when signaling is enhanced, DAF-16 is inactivated, and migration is inhibited. We show that DAF-16 acts nonautonomously in the hypodermis to promote HSN migration. Furthermore, we identify PAK-1, a p21-activated kinase, as a downstream mediator of insulin/IGF-1-DAF-16 signaling in the nonautonomous control of HSN migration. Because a FOXO-Pak1 pathway was recently shown to regulate mammalian neuronal polarity, our findings indicate that the roles of FOXO and Pak1 in neuronal migration are most likely conserved from C. elegans to higher organisms.

Reelin signaling in the migration of ventral brain stem and spinal cord neurons

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Sandra eBlaess

2016-03-01

Full Text Available The extracellular matrix protein Reelin is an important orchestrator of neuronal migration during the development of the central nervous system. While its role and mechanism of action have been extensively studied and reviewed in the formation of dorsal laminar brain structures like the cerebral cortex, hippocampus, and cerebellum, its functions during the neuronal migration events that result in the nuclear organization of the ventral central nervous system are less well understood. In an attempt to delineate an underlying pattern of Reelin action in the formation of neuronal cell clusters, this review highlights the role of Reelin signaling in the migration of neuronal populations that originate in the ventral brain stem and the spinal cord.

Kisspeptin Activates Ankrd 26 Gene Expression in Migrating Embryonic GnRH Neurons

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Tomoko eSoga

2016-03-01

Full Text Available Kisspeptin, a newly discovered neuropeptide regulates gonadotropin-releasing hormone (GnRH. Kisspeptins are a large RF-amide family of peptides. The kisspeptin coded by kiss1 gene is a 145-amino acid- protein that is cleaved to C-terminal peptide kisspeptin-10. G-protein coupled receptor 54 (GPR54 has been identified as a kisspeptin receptor, and it is expressed in GnRH neurons and in a variety of cancer cells. In this study, enhanced green fluorescent protein (EGFP labelled GnRH cells with migratory properties, which express GPR54, served as a model to study the effects of kisspeptin on cell migration. We monitored EGFP–GnRH neuronal migration in brain slide culture of embryonic day 14 transgenic rat by live cell imaging system and studied the effects of kisspeptin-10 (1nM treatment for 36h on GnRH migration. Furthermore to determine kisspeptin-induced molecular pathways related with apoptosis, and cytoskeletal changes during neuronal migration, we studied the expression levels of candidate genes in laser captured EGFP–GnRH neurons by real time PCR. We found that there was no change in the expression level of genes related to cell proliferation and apoptosis. The expression of ankyrin repeat domain-containing protein (ankrd 26 in EGFP–GnRH neurons was up-regulated by the exposure to kisspeptin. These studies suggest that ankrd26 gene plays an unidentified role in regulating neuronal movement mediated by kisspeptin-GPR54 signaling, which could be a potential pathway to suppress cell migration.

Cellullar insights into cerebral cortical development: focusing on the locomotion mode of neuronal migration

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Takeshi eKawauchi

2015-10-01

Full Text Available The mammalian brain consists of numerous compartments that are closely connected with each other via neural networks, comprising the basis of higher order brain functions. The highly specialized structure originates from simple pseudostratified neuroepithelium-derived neural progenitors located near the ventricle. A long journey by neurons from the ventricular side is essential for the formation of a sophisticated brain structure, including a mammalian-specific six-layered cerebral cortex. Neuronal migration consists of several contiguous steps, but the locomotion mode comprises a large part of the migration. The locomoting neurons exhibit unique features; a radial glial fiber-dependent migration requiring the endocytic recycling of N-cadherin and a neuron-specific migration mode with dilation/swelling formation that requires the actin and microtubule organization possibly regulated by cyclin-dependent kinase 5 (Cdk5, Dcx, p27kip1, Rac1 and POSH. Here I will introduce the roles of various cellular events, such as cytoskeletal organization, cell adhesion and membrane trafficking, in the regulation of the neuronal migration, with particular focus on the locomotion mode.

β1 integrin signaling promotes neuronal migration along vascular scaffolds in the post-stroke brain

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Teppei Fujioka

2017-02-01

Full Text Available Cerebral ischemic stroke is a main cause of chronic disability. However, there is currently no effective treatment to promote recovery from stroke-induced neurological symptoms. Recent studies suggest that after stroke, immature neurons, referred to as neuroblasts, generated in a neurogenic niche, the ventricular-subventricular zone, migrate toward the injured area, where they differentiate into mature neurons. Interventions that increase the number of neuroblasts distributed at and around the lesion facilitate neuronal repair in rodent models for ischemic stroke, suggesting that promoting neuroblast migration in the post-stroke brain could improve efficient neuronal regeneration. To move toward the lesion, neuroblasts form chain-like aggregates and migrate along blood vessels, which are thought to increase their migration efficiency. However, the molecular mechanisms regulating these migration processes are largely unknown. Here we studied the role of β1-class integrins, transmembrane receptors for extracellular matrix proteins, in these migrating neuroblasts. We found that the neuroblast chain formation and blood vessel-guided migration critically depend on β1 integrin signaling. β1 integrin facilitated the adhesion of neuroblasts to laminin and the efficient translocation of their soma during migration. Moreover, artificial laminin-containing scaffolds promoted neuroblast chain formation and migration toward the injured area. These data suggest that laminin signaling via β1 integrin supports vasculature-guided neuronal migration to efficiently supply neuroblasts to injured areas. This study also highlights the importance of vascular scaffolds for cell migration in development and regeneration.

Planar polarity pathway and Nance-Horan syndrome-like 1b have essential cell-autonomous functions in neuronal migration.

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Walsh, Gregory S; Grant, Paul K; Morgan, John A; Moens, Cecilia B

2011-07-01

Components of the planar cell polarity (PCP) pathway are required for the caudal tangential migration of facial branchiomotor (FBM) neurons, but how PCP signaling regulates this migration is not understood. In a forward genetic screen, we identified a new gene, nhsl1b, required for FBM neuron migration. nhsl1b encodes a WAVE-homology domain-containing protein related to human Nance-Horan syndrome (NHS) protein and Drosophila GUK-holder (Gukh), which have been shown to interact with components of the WAVE regulatory complex that controls cytoskeletal dynamics and with the polarity protein Scribble, respectively. Nhsl1b localizes to FBM neuron membrane protrusions and interacts physically and genetically with Scrib to control FBM neuron migration. Using chimeric analysis, we show that FBM neurons have two modes of migration: one involving interactions between the neurons and their planar-polarized environment, and an alternative, collective mode involving interactions between the neurons themselves. We demonstrate that the first mode of migration requires the cell-autonomous functions of Nhsl1b and the PCP components Scrib and Vangl2 in addition to the non-autonomous functions of Scrib and Vangl2, which serve to polarize the epithelial cells in the environment of the migrating neurons. These results define a role for Nhsl1b as a neuronal effector of PCP signaling and indicate that proper FBM neuron migration is directly controlled by PCP signaling between the epithelium and the migrating neurons.

Non-autonomous Regulation of Neuronal Migration by Insulin Signaling, DAF-16/FOXO and PAK-1

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Kennedy, Lisa M.; Pham, Steven C.D.L.; Grishok, Alla

2013-01-01

SUMMARY Neuronal migration is essential for nervous system development in all organisms and is regulated in the nematode, C. elegans, by signaling pathways that are conserved in humans. Here, we demonstrate that the Insulin/IGF-1-PI3K signaling pathway modulates the activity of the DAF-16/FOXO transcription factor to promote the anterior migrations of the hermaphrodite-specific neurons (HSNs) during embryogenesis of C. elegans. When signaling is reduced, DAF-16 is activated and promotes migration, conversely, when signaling is enhanced, DAF-16 is inactivated and migration is inhibited. We show that DAF-16 acts non-autonomously in the hypodermis to promote HSN migration. Furthermore, we identify PAK-1, a p21-activated kinase, as a downstream mediator of Insulin/IGF-1-DAF-16 signaling in the non-autonomous control of HSN migration. As a FOXO-Pak1 pathway was recently shown to regulate mammalian neuronal polarity, our findings indicate that the roles of FOXO and Pak1 in neuronal migration are likely conserved from C. elegans to higher organisms. PMID:23994474

Drebrin controls neuronal migration through the formation and alignment of the leading process.

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Dun, Xin-peng; Bandeira de Lima, Tiago; Allen, James; Geraldo, Sara; Gordon-Weeks, Phillip; Chilton, John K

2012-03-01

Formation of a functional nervous system requires neurons to migrate to the correct place within the developing brain. Tangentially migrating neurons are guided by a leading process which extends towards the target and is followed by the cell body. How environmental cues are coupled to specific cytoskeletal changes to produce and guide leading process growth is unknown. One such cytoskeletal modulator is drebrin, an actin-binding protein known to induce protrusions in many cell types and be important for regulating neuronal morphology. Using the migration of oculomotor neurons as a model, we have shown that drebrin is necessary for the generation and guidance of the leading process. In the absence of drebrin, leading processes are not formed and cells fail to migrate although axon growth and pathfinding appear grossly unaffected. Conversely, when levels of drebrin are elevated the leading processes turn away from their target and as a result the motor neuron cell bodies move along abnormal paths within the brain. The aberrant trajectories were highly reproducible suggesting that drebrin is required to interpret specific guidance cues. The axons and growth cones of these neurons display morphological changes, particularly increased branching and filopodial number but despite this they extend along normal developmental pathways. Collectively these results show that drebrin is initially necessary for the formation of a leading process and subsequently for this to respond to navigational signals and grow in the correct direction. Furthermore, we have shown that the actions of drebrin can be segregated within individual motor neurons to direct their migration independently of axon guidance. Copyright © 2012 Elsevier Inc. All rights reserved.

Leading tip drives soma translocation via forward F-actin flow during neuronal migration.

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He, Min; Zhang, Zheng-hong; Guan, Chen-bing; Xia, Di; Yuan, Xiao-bing

2010-08-11

Neuronal migration involves coordinated extension of the leading process and translocation of the soma, but the relative contribution of different subcellular regions, including the leading process and cell rear, in driving soma translocation remains unclear. By local manipulation of cytoskeletal components in restricted regions of cultured neurons, we examined the molecular machinery underlying the generation of traction force for soma translocation during neuronal migration. In actively migrating cerebellar granule cells in culture, a growth cone (GC)-like structure at the leading tip exhibits high dynamics, and severing the tip or disrupting its dynamics suppressed soma translocation within minutes. Soma translocation was also suppressed by local disruption of F-actin along the leading process but not at the soma, whereas disrupting microtubules along the leading process or at the soma accelerated soma translocation. Fluorescent speckle microscopy using GFP-alpha-actinin showed that a forward F-actin flow along the leading process correlated with and was required for soma translocation, and such F-actin flow depended on myosin II activity. In migrating neurons, myosin II activity was high at the leading tip but low at the soma, and increasing or decreasing this front-to-rear difference accelerated or impeded soma advance. Thus, the tip of the leading process actively pulls the soma forward during neuronal migration through a myosin II-dependent forward F-actin flow along the leading process.

Comparison of slow and fast neocortical neuron migration using a new in vitro model

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Carney Laurel H

2008-06-01

Full Text Available Abstract Background Mutations, toxic insults and radiation exposure are known to slow or arrest the migration of cortical neurons, in most cases by unknown mechanisms. The movement of migrating neurons is saltatory, reflecting the intermittent movement of the nucleus (nucleokinesis within the confines of the plasma membrane. Each nucleokinetic movement is analogous to a step. Thus, average migration speed could be reduced by lowering step frequency and/or step distance. Results To assess the kinetic features of cortical neuron migration we developed a cell culture system that supports fiber-guided migration. In this system, the majority of fiber-apposed cells were neurons, expressed age-appropriate cortical-layer specific markers and migrated during a 30 min imaging period. Comparison of the slowest and fastest quartiles of cells revealed a 5-fold difference in average speed. The major determinant of average speed in slower cells (6–26 μm/hr was step frequency, while step distance was the critical determinant of average speed in faster cells (>26 μm/hr. Surprisingly, step distance was largely determined by the average duration of the step, rather than the speed of nucleokinesis during the step, which differed by only 1.3-fold between the slowest and fastest quartiles. Conclusion Saltatory event frequency and duration, not nucleokinetic speed, are the major determinants of average migration speed in healthy neurons. Alteration of either saltatory event frequency or duration should be considered along with nucleokinetic abnormalities as possible contributors to pathological conditions.

Roles of Fukutin, the Gene Responsible for Fukuyama-Type Congenital Muscular Dystrophy, in Neurons: Possible Involvement in Synaptic Function and Neuronal Migration

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Hiroi, Atsuko; Yamamoto, Tomoko; Shibata, Noriyuki; Osawa, Makiko; Kobayashi, Makio

2011-01-01

Fukutin is a gene responsible for Fukuyama-type congenital muscular dystrophy (FCMD), accompanying ocular and brain malformations represented by cobblestone lissencephaly. Fukutin is related to basement membrane formation via the glycosylation of α-dystoglycan (α-DG), and astrocytes play a crucial role in the pathogenesis of the brain lesion. On the other hand, its precise function in neurons is unknown. In this experiment, the roles of fukutin in mature and immature neurons were examined using brains from control subjects and FCMD patients and cultured neuronal cell lines. In quantitative PCR, the expression level of fukutin looked different depending on the region of the brain examined. A similar tendency in DG expression appears to indicate a relation between fukutin and α-DG in mature neurons. An increase of DG mRNA and core α-DG in the FCMD cerebrum also supports the relation. In immunohistochemistry, dot-like positive reactions for VIA4-1, one of the antibodies detecting the glycosylated α-DG, in Purkinje cells suggest that fukutin is related to at least a post-synaptic function via the glycosylation of α-DG. As for immature neurons, VIA4-1 was predominantly positive in cells before and during migration with expression of fukutin, which suggest a participation of fukutin in neuronal migration via the glycosylation of α-DG. Moreover, fukutin may prevent neuronal differentiation, because its expression was significantly lower in the adult cerebrum and in differentiated cultured cells. A knockdown of fukutin was considered to induce differentiation in cultured cells. Fukutin seems to be necessary to keep migrating neurons immature during migration, and also to support migration via α-DG

The Hem protein mediates neuronal migration by inhibiting WAVE degradation and functions opposite of Abelson tyrosine kinase

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Zhu, Zengrong; Bhat, Krishna Moorthi

2011-01-01

In the nervous system, neurons form in different regions, then they migrate and occupy specific positions. We have previously shown that RP2/sib, a well-studied neuronal pair in the Drosophila ventral nerve cord (VNC), has a complex migration route. Here, we show that the Hem protein, via the WAVE complex, regulates migration of GMC-1 and its progeny RP2 neuron. In Hem or WAVE mutants, RP2 neuron either abnormally migrates, crossing the midline from one hemisegment to the contralateral hemisegment, or does not migrate at al and fail to send out its axon projection. We report that Hem regulates neuronal migration through stabilizing WAVE. Since Hem and WAVE normally form a complex, our data argues that in the absence of Hem, WAVE, which is presumably no longer in a complex, becomes susceptible to degradation. We also find that Abelson Tyrosine kinase affects RP2 migration in a similar manner as Hem and WAVE, and appears to operate via WAVE. However, while Abl negatively regulates the levels of WAVE, it regulates migration via regulating the activity of WAVE. Our results also show that during the degradation of WAVE, Hem function is opposite to that of and downstream of Abl. PMID:21726548

Effects of thyroxine on the migration of hippocampal neurons in newborn rat exposed to HTO

International Nuclear Information System (INIS)

Cai Erpeng; Qiu Jun; Wang Yongsheng; Wu Cuiping; Yao Xiaobo; Wang Mingming

2012-01-01

Objective: To explore the effect of thyroxine (TH) on the migration of hippocampal neurons in newborn rat exposed to tritiated water (HTO). Methods: The hippocampal neurons from neonatal rats were primarily cultured, 7 days later, randomly divided into control group, HTO group, TH group and HTO + TH group (3.7 × 10 5 Bq/ml HTO and 0.3 μg/ml TH were simultaneously added). After 24 h, the distance of neuronal migration was measured with Leica AF 6000, the expressions of BDNF and Reelin mRNA in neurons were analyzed with reverse transcription polymerase chain reaction (RT-PCR), the expression of β-tubulin protein in neurons was assayed with Western blot and immunocytochemical staining. Results: Compared with control group, the expression of Reelin mRNA, BDNF mRNA and β-tubulin in HTO group were significantly reduced (t=5.80, 5.48, 5.47, P<0.01), but those in HTO + TH group and TH group were obviously increased (t=7.75, 12.06, 13.65, P<0.01; t=4.34, 5.47, 5.65, P<0.01) and higher than that in HTO group (t=2.92, 10.32, 8.76, P<0.01; t=18.07, 20.55, 40.13, P<0.01). Accordingly, the neuronal migration distance in HTO group was much shorter than that in control (t=8.62, P<0.01), and in HTO + TH group and TH group was far longer than that in control (t=7.64, 4.93, P<0.01). Moreover, the neuronal migration distance in HTO + TH group was notably elongated in comparison with that in HTO group (t=11.32, 12.31, P<0.01). Conclusions: Thyroxine may promote the migration of hippocampal neurons in newborn rat exposed to HTO. (authors)

Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects.

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Tiziano Pramparo

2011-03-01

Full Text Available Heterozygous LIS1 mutations are the most common cause of human lissencephaly, a human neuronal migration defect, and DCX mutations are the most common cause of X-linked lissencephaly. LIS1 is part of a protein complex including NDEL1 and 14-3-3ε that regulates dynein motor function and microtubule dynamics, while DCX stabilizes microtubules and cooperates with LIS1 during neuronal migration and neurogenesis. Targeted gene mutations of Lis1, Dcx, Ywhae (coding for 14-3-3ε, and Ndel1 lead to neuronal migration defects in mouse and provide models of human lissencephaly, as well as aid the study of related neuro-developmental diseases. Here we investigated the developing brain of these four mutants and wild-type mice using expression microarrays, bioinformatic analyses, and in vivo/in vitro experiments to address whether mutations in different members of the LIS1 neuronal migration complex lead to similar and/or distinct global gene expression alterations. Consistent with the overall successful development of the mutant brains, unsupervised clustering and co-expression analysis suggested that cell cycle and synaptogenesis genes are similarly expressed and co-regulated in WT and mutant brains in a time-dependent fashion. By contrast, focused co-expression analysis in the Lis1 and Ndel1 mutants uncovered substantial differences in the correlation among pathways. Differential expression analysis revealed that cell cycle, cell adhesion, and cytoskeleton organization pathways are commonly altered in all mutants, while synaptogenesis, cell morphology, and inflammation/immune response are specifically altered in one or more mutants. We found several commonly dysregulated genes located within pathogenic deletion/duplication regions, which represent novel candidates of human mental retardation and neurocognitive disabilities. Our analysis suggests that gene expression and pathway analysis in mouse models of a similar disorder or within a common pathway can

Normal and abnormal neuronal migration during brain development

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Rakic, P.

1986-01-01

Conceptual and factual advances in understanding neuronal migration in the past two decades have provided new insight into the pathogenesis of brain malformations at the cellular, molecular, and functional levels. Some of these results may have direct implications in understanding the consequences of ionizing radiation on the fetal central nervous system in utero. (orig.)

Clinical characteristics of the dysfunctions of the neuronal migration

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Espinosa, Eugenia; Dunoyer, Catalina; Acosta, Maria Teresa

1992-01-01

This article describes a group of 22 pediatric patients with neuronal migration anomalies, studied in the department of neuro-pediatrics in the Hospital Militar Central. The clinical findings are emphasized and the value of diagnostic images in the identification and classification of these anomalies is shown

Proneural Transcription Factors Regulate Different Steps of Cortical Neuron Migration through Rnd-Mediated Inhibition of RhoA Signaling

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Pacary, Emilie; Heng, Julian; Azzarelli, Roberta; Riou, Philippe; Castro, Diogo; Lebel-Potter, Mélanie; Parras, Carlos; Bell, Donald M.; Ridley, Anne J.; Parsons, Maddy; Guillemot, François

2011-01-01

Summary Little is known of the intracellular machinery that controls the motility of newborn neurons. We have previously shown that the proneural protein Neurog2 promotes the migration of nascent cortical neurons by inducing the expression of the atypical Rho GTPase Rnd2. Here, we show that another proneural factor, Ascl1, promotes neuronal migration in the cortex through direct regulation of a second Rnd family member, Rnd3. Both Rnd2 and Rnd3 promote neuronal migration by inhibiting RhoA signaling, but they control distinct steps of the migratory process, multipolar to bipolar transition in the intermediate zone and locomotion in the cortical plate, respectively. Interestingly, these divergent functions directly result from the distinct subcellular distributions of the two Rnd proteins. Because Rnd proteins also regulate progenitor divisions and neurite outgrowth, we propose that proneural factors, through spatiotemporal regulation of Rnd proteins, integrate the process of neuronal migration with other events in the neurogenic program. PMID:21435554

The spinal muscular atrophy with pontocerebellar hypoplasia gene VRK1 regulates neuronal migration through an amyloid-β precursor protein-dependent mechanism.

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Vinograd-Byk, Hadar; Sapir, Tamar; Cantarero, Lara; Lazo, Pedro A; Zeligson, Sharon; Lev, Dorit; Lerman-Sagie, Tally; Renbaum, Paul; Reiner, Orly; Levy-Lahad, Ephrat

2015-01-21

Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH) is an infantile SMA variant with additional manifestations, particularly severe microcephaly. We previously identified a nonsense mutation in Vaccinia-related kinase 1 (VRK1), R358X, as a cause of SMA-PCH. VRK1-R358X is a rare founder mutation in Ashkenazi Jews, and additional mutations in patients of different origins have recently been identified. VRK1 is a nuclear serine/threonine protein kinase known to play multiple roles in cellular proliferation, cell cycle regulation, and carcinogenesis. However, VRK1 was not known to have neuronal functions before its identification as a gene mutated in SMA-PCH. Here we show that VRK1-R358X homozygosity results in lack of VRK1 protein, and demonstrate a role for VRK1 in neuronal migration and neuronal stem cell proliferation. Using shRNA in utero electroporation in mice, we show that Vrk1 knockdown significantly impairs cortical neuronal migration, and affects the cell cycle of neuronal progenitors. Expression of wild-type human VRK1 rescues both proliferation and migration phenotypes. However, kinase-dead human VRK1 rescues only the migration impairment, suggesting the role of VRK1 in neuronal migration is partly noncatalytic. Furthermore, we found that VRK1 deficiency in human and mouse leads to downregulation of amyloid-β precursor protein (APP), a known neuronal migration gene. APP overexpression rescues the phenotype caused by Vrk1 knockdown, suggesting that VRK1 affects neuronal migration through an APP-dependent mechanism. Copyright © 2015 the authors 0270-6474/15/350936-08$15.00/0.

Involvement of GSK3 in the formation of the leading process and migration of neurons from the embryonic rat medial ganglionic eminence in vitro.

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Niimura, Yuri; Aminaka, Yuichi; Hayashi, Kensuke

2015-03-04

Migrating neurons have leading processes that direct cell movement in response to guidance cues. We investigated the involvement of glycogen synthase kinase 3 (GSK3) in the formation of leading processes and migration of neurons in vitro. We used embryonic rat medial ganglionic eminence (MGE) neurons, which are precursors of inhibitory neurons that migrate into the cerebral cortex. When MGE neurons were placed on an astrocyte layer, they migrated freely with the highest speed among neurons from other parts of the embryonic forebrain. When they were cultured alone, they showed bipolar morphology and extended leading processes within 20 h. Their leading processes had large growth cones, but did not elongate during 3 days in culture, indicating that leading processes are distinct from short axons. Next, we examined the effect of GSK3 inhibitors on leading processes and the migratory behavior of MGE neurons. MGE neurons treated with GSK3 inhibitors showed multipolar morphology and altered process shapes. Moreover, migration of MGE neurons on the astrocyte layer was significantly decreased in the presence of GSK3 inhibitors. These data suggest that GSK3 is involved in the formation of leading processes and in the migration of MGE neurons.

BAG3 is involved in neuronal differentiation and migration.

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Santoro, Antonietta; Nicolin, Vanessa; Florenzano, Fulvio; Rosati, Alessandra; Capunzo, Mario; Nori, Stefania L

2017-05-01

Bcl2-associated athanogene 3 (BAG3) protein belongs to the family of co-chaperones interacting with several heat shock proteins. It plays a key role in protein quality control and mediates the clearance of misfolded proteins. Little is known about the expression and cellular localization of BAG3 during nervous system development and differentiation. Therefore, we analyze the subcellular distribution and expression of BAG3 in nerve-growth-factor-induced neurite outgrowth in PC12 cells and in developing and adult cortex of mouse brain. In differentiated PC12 cells, BAG3 was localized mainly in the neuritic domain rather than the cell body, whereas in control cells, it appeared to be confined to the cytoplasm near the nuclear membrane. Interestingly, the change of BAG3 localization during neuronal differentiation was associated only with a slight increase in total BAG3 expression. These data were coroborated by transmission electron microscopy showing that BAG3 was confined mainly within large dense-core vesicles of the axon in differentiated PC12 cells. In mouse developing cortex, BAG3 appeared to be intensely expressed in cellular processes of migrating cells, whereas in adult brain, a diffuse expression of low to medium intensity was detected in neuronal cell bodies. These findings suggest that BAG3 expression is required for neuronal differentiation and migration and that its role is linked to a change in its distribution pattern rather than to an increase in its protein expression levels.

The effects of low dose ionizing radiation on the development of rat cerebral cortex, (2); In vitro study with regards to neuronal migration

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Matsushita, Koji [Kyoto Prefectural Univ. of Medicine (Japan)

1993-03-01

In order to study the molecular mechanisms of neuronal migration on developing rat cerebral cortex, we need a tissue culture system in which neuronal migration can be observed. We prepared a tissue culture system of embryonic rat cerebral cortex starting on embryonic day 16 and cultivating it for 48 hours. The autoradiographic study in this system revealed not only the migration of [sup 3]H-thymidine labeled neurons but also neuronal migration delays from low doses of ionizing radiation of more than 10 cGy. In addition, on immunohistochemical study, cell-cell adhesion molecule N-CAM staining was remarkably decreased in the matrix cell layer. In the tissue culture system where monoclonal anti-N-CAM antibodies were added, neuronal migration delay comparable to that of 20 cGy radiation was found. In conclusion, it was speculated that neuronal migration delay might be caused by disturbed N-CAM synthesis in matrix cells after low dose ionizing radiation. (author).

Leading-process actomyosin coordinates organelle positioning and adhesion receptor dynamics in radially migrating cerebellar granule neurons.

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Trivedi, Niraj; Ramahi, Joseph S; Karakaya, Mahmut; Howell, Danielle; Kerekes, Ryan A; Solecki, David J

2014-12-02

During brain development, neurons migrate from germinal zones to their final positions to assemble neural circuits. A unique saltatory cadence involving cyclical organelle movement (e.g., centrosome motility) and leading-process actomyosin enrichment prior to nucleokinesis organizes neuronal migration. While functional evidence suggests that leading-process actomyosin is essential for centrosome motility, the role of the actin-enriched leading process in globally organizing organelle transport or traction forces remains unexplored. We show that myosin ii motors and F-actin dynamics are required for Golgi apparatus positioning before nucleokinesis in cerebellar granule neurons (CGNs) migrating along glial fibers. Moreover, we show that primary cilia are motile organelles, localized to the leading-process F-actin-rich domain and immobilized by pharmacological inhibition of myosin ii and F-actin dynamics. Finally, leading process adhesion dynamics are dependent on myosin ii and F-actin. We propose that actomyosin coordinates the overall polarity of migrating CGNs by controlling asymmetric organelle positioning and cell-cell contacts as these cells move along their glial guides.

The Role of Astrocytes in the Generation, Migration, and Integration of New Neurons in the Adult Olfactory Bulb

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Gengatharan, Archana; Bammann, Rodrigo R.; Saghatelyan, Armen

2016-01-01

In mammals, new neurons in the adult olfactory bulb originate from a pool of neural stem cells in the subventricular zone of the lateral ventricles. Adult-born cells play an important role in odor information processing by adjusting the neuronal network to changing environmental conditions. Olfactory bulb neurogenesis is supported by several non-neuronal cells. In this review, we focus on the role of astroglial cells in the generation, migration, integration, and survival of new neurons in the adult forebrain. In the subventricular zone, neural stem cells with astrocytic properties display regional and temporal specificity when generating different neuronal subtypes. Non-neurogenic astrocytes contribute to the establishment and maintenance of the neurogenic niche. Neuroblast chains migrate through the rostral migratory stream ensheathed by astrocytic processes. Astrocytes play an important regulatory role in neuroblast migration and also assist in the development of a vasculature scaffold in the migratory stream that is essential for neuroblast migration in the postnatal brain. In the olfactory bulb, astrocytes help to modulate the network through a complex release of cytokines, regulate blood flow, and provide metabolic support, which may promote the integration and survival of new neurons. Astrocytes thus play a pivotal role in various processes of adult olfactory bulb neurogenesis, and it is likely that many other functions of these glial cells will emerge in the near future. PMID:27092050

Migration Pathways of Thalamic Neurons and Development of Thalamocortical Connections in Humans Revealed by Diffusion MR Tractography.

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Wilkinson, Molly; Kane, Tara; Wang, Rongpin; Takahashi, Emi

2017-12-01

The thalamus plays an important role in signal relays in the brain, with thalamocortical (TC) neuronal pathways linked to various sensory/cognitive functions. In this study, we aimed to see fetal and postnatal development of the thalamus including neuronal migration to the thalamus and the emergence/maturation of the TC pathways. Pathways from/to the thalami of human postmortem fetuses and in vivo subjects ranging from newborns to adults with no neurological histories were studied using high angular resolution diffusion MR imaging (HARDI) tractography. Pathways likely linked to neuronal migration from the ventricular zone and ganglionic eminence (GE) to the thalami were both successfully detected. Between the ventricular zone and thalami, more tractography pathways were found in anterior compared with posterior regions, which was well in agreement with postnatal observations that the anterior TC segment had more tract count and volume than the posterior segment. Three different pathways likely linked to neuronal migration from the GE to the thalami were detected. No hemispheric asymmetry of the TC pathways was quantitatively observed during development. These results suggest that HARDI tractography is useful to identify multiple differential neuronal migration pathways in human brains, and regional differences in brain development in fetal ages persisted in postnatal development. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Hox paralog group 2 genes control the migration of mouse pontine neurons through slit-robo signaling.

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Marc J Geisen

2008-06-01

Full Text Available The pontine neurons (PN represent a major source of mossy fiber projections to the cerebellum. During mouse hindbrain development, PN migrate tangentially and sequentially along both the anteroposterior (AP and dorsoventral (DV axes. Unlike DV migration, which is controlled by the Netrin-1/Dcc attractive pathway, little is known about the molecular mechanisms guiding PN migration along the AP axis. Here, we show that Hoxa2 and Hoxb2 are required both intrinsically and extrinsically to maintain normal AP migration of subsets of PN, by preventing their premature ventral attraction towards the midline. Moreover, the migration defects observed in Hoxa2 and Hoxb2 mutant mice were phenocopied in compound Robo1;Robo2, Slit1;Slit2, and Robo2;Slit2 knockout animals, indicating that these guidance molecules act downstream of Hox genes to control PN migration. Indeed, using chromatin immunoprecipitation assays, we further demonstrated that Robo2 is a direct target of Hoxa2 in vivo and that maintenance of high Robo and Slit expression levels was impaired in Hoxa2 mutant mice. Lastly, the analysis of Phox2b-deficient mice indicated that the facial motor nucleus is a major Slit signaling source required to prevent premature ventral migration of PN. These findings provide novel insights into the molecular control of neuronal migration from transcription factor to regulation of guidance receptor and ligand expression. Specifically, they address the question of how exposure to multiple guidance cues along the AP and DV axes is regulated at the transcriptional level and in turn translated into stereotyped migratory responses during tangential migration of neurons in the developing mammalian brain.

14-3-3 Proteins in Brain Development: Neurogenesis, Neuronal Migration and Neuromorphogenesis

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Brett Cornell

2017-10-01

Full Text Available The 14-3-3 proteins are a family of highly conserved, multifunctional proteins that are highly expressed in the brain during development. Cumulatively, the seven 14-3-3 isoforms make up approximately 1% of total soluble brain protein. Over the last decade, evidence has accumulated implicating the importance of the 14-3-3 protein family in the development of the nervous system, in particular cortical development, and have more recently been recognized as key regulators in a number of neurodevelopmental processes. In this review we will discuss the known roles of each 14-3-3 isoform in the development of the cortex, their relation to human neurodevelopmental disorders, as well as the challenges and questions that are left to be answered. In particular, we focus on the 14-3-3 isoforms and their involvement in the three key stages of cortical development; neurogenesis and differentiation, neuronal migration and neuromorphogenesis and synaptogenesis.

Neurogenic Radial Glia-like Cells in Meninges Migrate and Differentiate into Functionally Integrated Neurons in the Neonatal Cortex.

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Bifari, Francesco; Decimo, Ilaria; Pino, Annachiara; Llorens-Bobadilla, Enric; Zhao, Sheng; Lange, Christian; Panuccio, Gabriella; Boeckx, Bram; Thienpont, Bernard; Vinckier, Stefan; Wyns, Sabine; Bouché, Ann; Lambrechts, Diether; Giugliano, Michele; Dewerchin, Mieke; Martin-Villalba, Ana; Carmeliet, Peter

2017-03-02

Whether new neurons are added in the postnatal cerebral cortex is still debated. Here, we report that the meninges of perinatal mice contain a population of neurogenic progenitors formed during embryonic development that migrate to the caudal cortex and differentiate into Satb2 + neurons in cortical layers II-IV. The resulting neurons are electrically functional and integrated into local microcircuits. Single-cell RNA sequencing identified meningeal cells with distinct transcriptome signatures characteristic of (1) neurogenic radial glia-like cells (resembling neural stem cells in the SVZ), (2) neuronal cells, and (3) a cell type with an intermediate phenotype, possibly representing radial glia-like meningeal cells differentiating to neuronal cells. Thus, we have identified a pool of embryonically derived radial glia-like cells present in the meninges that migrate and differentiate into functional neurons in the neonatal cerebral cortex. Copyright © 2016 Elsevier Inc. All rights reserved.

Macrophage migration inhibitory factor and autism spectrum disorders

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Grigorenko, Elena L.; Han, Summer S.; Yrigollen, Carolyn M.; Leng, Lin; Mizue, Yuka; Anderson, George M.; Mulder, Erik J.; de Bildt, Annelies; Minderaa, Ruud B.; Volkmar, Fred R.; Chang, Joseph T.; Bucala, Richard

OBJECTIVE. Autistic spectrum disorders are childhood neurodevelopmental disorders characterized by social and communicative impairment and repetitive and stereotypical behavior. Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity that promotes

SFPQ associates to LSD1 and regulates the migration of newborn pyramidal neurons in the developing cerebral cortex.

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Saud, K; Cánovas, J; Lopez, C I; Berndt, F A; López, E; Maass, J C; Barriga, A; Kukuljan, M

2017-04-01

The development of the cerebral cortex requires the coordination of multiple processes ranging from the proliferation of progenitors to the migration and establishment of connectivity of the newborn neurons. Epigenetic regulation carried out by the COREST/LSD1 complex has been identified as a mechanism that regulates the development of pyramidal neurons of the cerebral cortex. We now identify the association of the multifunctional RNA-binding protein SFPQ to LSD1 during the development of the cerebral cortex. In vivo reduction of SFPQ dosage by in utero electroporation of a shRNA results in impaired radial migration of newborn pyramidal neurons, in a similar way to that observed when COREST or LSD1 expressions are decreased. Diminished SFPQ expression also associates to decreased proliferation of progenitor cells, while it does not affect the acquisition of neuronal fate. These results are compatible with the idea that SFPQ, plays an important role regulating proliferation and migration during the development of the cerebral cortex. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

Synapsin III Acts Downstream of Semaphorin 3A/CDK5 Signaling to Regulate Radial Migration and Orientation of Pyramidal Neurons In Vivo

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Laura E. Perlini

2015-04-01

Full Text Available Synapsin III (SynIII is a phosphoprotein that is highly expressed at early stages of neuronal development. Whereas in vitro evidence suggests a role for SynIII in neuronal differentiation, in vivo evidence is lacking. Here, we demonstrate that in vivo downregulation of SynIII expression affects neuronal migration and orientation. By contrast, SynIII overexpression affects neuronal migration, but not orientation. We identify a cyclin-dependent kinase-5 (CDK5 phosphorylation site on SynIII and use phosphomutant rescue experiments to demonstrate its role in SynIII function. Finally, we show that SynIII phosphorylation at the CDK5 site is induced by activation of the semaphorin-3A (Sema3A pathway, which is implicated in migration and orientation of cortical pyramidal neurons (PNs and is known to activate CDK5. Thus, fine-tuning of SynIII expression and phosphorylation by CDK5 activation through Sema3A activity is essential for proper neuronal migration and orientation.

Cadherin 2/4 signaling via PTP1B and catenins is crucial for nucleokinesis during radial neuronal migration in the neocortex.

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Martinez-Garay, Isabel; Gil-Sanz, Cristina; Franco, Santos J; Espinosa, Ana; Molnár, Zoltán; Mueller, Ulrich

2016-06-15

Cadherins are crucial for the radial migration of excitatory projection neurons into the developing neocortical wall. However, the specific cadherins and the signaling pathways that regulate radial migration are not well understood. Here, we show that cadherin 2 (CDH2) and CDH4 cooperate to regulate radial migration in mouse brain via the protein tyrosine phosphatase 1B (PTP1B) and α- and β-catenins. Surprisingly, perturbation of cadherin-mediated signaling does not affect the formation and extension of leading processes of migrating neocortical neurons. Instead, movement of the cell body and nucleus (nucleokinesis) is disrupted. This defect is partially rescued by overexpression of LIS1, a microtubule-associated protein that has previously been shown to regulate nucleokinesis. Taken together, our findings indicate that cadherin-mediated signaling to the cytoskeleton is crucial for nucleokinesis of neocortical projection neurons during their radial migration. © 2016. Published by The Company of Biologists Ltd.

Perinatal Exposure to Glufosinate Ammonium Herbicide Impairs Neurogenesis and Neuroblast Migration through Cytoskeleton Destabilization.

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Herzine, Ameziane; Laugeray, Anthony; Feat, Justyne; Menuet, Arnaud; Quesniaux, Valérie; Richard, Olivier; Pichon, Jacques; Montécot-Dubourg, Céline; Perche, Olivier; Mortaud, Stéphane

2016-01-01

Neurogenesis, a process of generating functional neurons from neural precursors, occurs throughout life in restricted brain regions such as the subventricular zone (SVZ). During this process, newly generated neurons migrate along the rostral migratory stream to the olfactory bulb to replace granule cells and periglomerular neurons. This neuronal migration is pivotal not only for neuronal plasticity but also for adapted olfactory based behaviors. Perturbation of this highly controlled system by exogenous chemicals has been associated with neurodevelopmental disorders. We reported recently that perinatal exposure to low dose herbicide glufosinate ammonium (GLA), leads to long lasting behavioral defects reminiscent of Autism Spectrum Disorder-like phenotype in the offspring (Laugeray et al., 2014). Herein, we demonstrate that perinatal exposure to low dose GLA induces alterations in neuroblast proliferation within the SVZ and abnormal migration from the SVZ to the olfactory bulbs. These disturbances are not only concomitant to changes in cell morphology, proliferation and apoptosis, but are also associated with transcriptomic changes. Therefore, we demonstrate for the first time that perinatal exposure to low dose GLA alters SVZ neurogenesis. Jointly with our previous work, the present results provide new evidence on the link between molecular and cellular consequences of early life exposure to the herbicide GLA and the onset of ASD-like phenotype later in life.

Neuron-microglia interactions in mental health disorders: 'For better, and for worse'

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Eric S Wohleb

2016-11-01

Full Text Available Persistent cognitive and behavioral symptoms that characterize many mental health disorders arise from impaired neuroplasticity in several key corticolimbic brain regions. Recent evidence suggest that reciprocal neuron-microglia interactions shape neuroplasticity during physiological conditions, implicating microglia in the neurobiology of mental health disorders. Neuron-microglia interactions are modulated by several molecular and cellular pathways and dysregulation of these pathways often have neurobiological consequences, including aberrant neuronal responses and microglia activation. The interactions between neurons and microglia have implications for mental health disorders as rodent stress models cause concomitant neuronal dystrophy and alterations in microglia morphology and function. In this context, functional changes in microglia may be indicative of an immune state termed parainflammation in which tissue-resident macrophages (i.e., microglia respond to malfunctioning cells by initiating modest inflammation in an attempt to restore homeostasis. Thus, aberrant neuronal activity and release of damage-associated signals during repeated stress exposure may contribute to functional changes in microglia and resultant parainflammation. Furthermore, accumulating evidence shows that uncoupling neuron-microglia interactions may contribute to altered neuroplasticity and associated anxiety- or depressive-like behaviors. Additional work shows that microglia have varied phenotypes in specific brain regions, which may underlie divergent neuroplasticity observed in corticolimbic structures following stress exposure. These findings indicate that neuron-microglia interactions are critical mediators of the interface between adaptive, homeostatic neuronal function and the neurobiology of mental health disorders.

Congenital malformations of the supratentorial brain. Pt. 1. Disorders of cortical development

International Nuclear Information System (INIS)

Ertl-Wagner, B.; Rummeny, C.; Reiser, M.F.

2003-01-01

Disorders of supratentorial cortical development are usually divided into disorders of neuronal proliferation, neuronal migration and cortical organization. Based upon molecular biologic discoveries, a modified classification has recently been proposed. The category of malformations of abnormal neuronal and glial proliferation and apoptosis now includes microlissencephalies, megalencephalies, hemimegalencephalies and cortical dysplasias with balloon cells. Malformations due to abnormal neuronal migration now subsume the lissencephaly spectrum including the subcortical band heterotopias, the cobblestone complex and the group of heterotopias. Malformations due to abnormal cortical organization include the spectrum of polymicrogyria and schizencephaly as well as cortical dysplasias without balloon cells. High-resolution magnetic resonance imaging (MRI) has led to an increasing awareness of these malformations. This article aims to illustrate the classification, MRI presentation and relevant clinical features of the most commonly encountered disorders of cortical development. (orig.) [de

Mirror neuron dysfunction in autism spectrum disorders.

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Perkins, Tom; Stokes, Mark; McGillivray, Jane; Bittar, Richard

2010-10-01

Autism spectrum disorders (ASDs) are developmental conditions characterized by deficits in social interaction, verbal and nonverbal communication and obsessive/stereotyped patterns of behaviour. Although there is no reliable neurophysiological marker associated with ASDs, dysfunction of the parieto-frontal mirror neuron system has been suggested as a disturbance linked to the disorder. Mirror neurons (MNs) are visuomotor neurons which discharge both when performing and observing a goal directed action. Research suggests MNs may have a role in imitation, empathy, theory of mind and language. Although the research base is small, evidence from functional MRI, transcranial magnetic stimulation, and an electroencephalographic component called the mu rhythm suggests MNs are dysfunctional in subjects with ASD. These deficits are more pronounced when ASD subjects complete tasks with social relevance, or that are emotional in nature. Promising research has identified that interventions targeting MN related functions such as imitation can improve social functioning in ASDs. Boosting the function of MNs may improve the prognosis of ASDs, and contribute to diagnostic clarity. Copyright 2010 Elsevier Ltd. All rights reserved.

Perinatal exposure to glufosinate ammonium herbicide impairs neurogenesis and neuroblast migration through cytoskeleton destabilization

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Ameziane Herzine

2016-08-01

Full Text Available Neurogenesis, a process of generating functional neurons from neural precursors, occurs throughout life in restricted brain regions such as the subventricular zone (SVZ. During this process, newly generated neurons migrate along the rostral migratory stream to the olfactory bulb to replace granule cells and periglomerular neurons. This neuronal migration is pivotal not only for neuronal plasticity but also for adapted olfactory based behaviors. Perturbation of this highly controlled system by exogenous chemicals has been associated with neurodevelopmental disorders. We reported recently that perinatal exposure to low dose herbicide glufosinate ammonium (GLA, leads to long lasting behavioral defects reminiscent of Autism Spectrum Disorder-like phenotype in the offspring (Laugeray, Herzine et al. 2014 . Herein, we demonstrate that perinatal exposure to low dose GLA induces alterations in neuroblast proliferation within the SVZ and abnormal migration from the SVZ to the olfactory bulbs. These disturbances are not only concomitant to changes in cell morphology, proliferation and apoptosis, but are also associated with transcriptomic changes. Therefore, we demonstrate for the first time that perinatal exposure to low dose GLA alters SVZ neurogenesis. Jointly with our previous work, the present results provide new evidence on the link between molecular and cellular consequences of early life exposure to the herbicide GLA and the onset of ASD-like phenotype later in life.

Effects of continuous low-dose prenatal irradiation on neuronal migration in mouse cerebral cortex

International Nuclear Information System (INIS)

Hyodo-Taguchi, Yasuko; Ishikawa, Yuji; Hirobe, Tomohisa; Fushiki, Shinji; Kinoshita, Chikako.

1997-01-01

We investigated the effects of continuous exposure to γ-rays during corticogenesis on the migration of neuronal cells in developing cerebral cortex. Pregnant mice were injected with 0.5 mg of bromodeoxyuridine (BrdU) on day 14 of gestation to label cells in the S phase. The mice were then exposed to 137 Cs γ-rays (dose rates of 0.1, 0.3, and 0.94 Gy/day) continuously for 3 days. Brains from 17-day-old embryos and from offspring at 3 and 8 weeks after birth were processed immunohistochemically to track the movements of BrdU-labeled cells. Comparative analyses of the distribution pattern of BrdU-labeled cells in the cerebral cortex revealed that the migration of neurons was delayed during the embryonic period in mice irradiated at 0.94 Gy/day, in 3-week-old mice, there was a significant difference in the distribution pattern of BrdU-labeled cells in the cerebral cortex between the mice irradiated prenatally and control, and in 8-week-old mice, there were no differences in the distribution pattern of BrdU-labeled cells between control and animals irradiated with 0.1 and 0.3 Gy/day. In contrast, in the animals irradiated with 0.94 Gy/day, the significant difference in the distribution pattern of the labeled cells relative to control was maintained. These results suggest that the migration of neuronal cells in mouse cerebral cortex is disturbed by continuous prenatal irradiation at low-dose and some modificational process occurred during the postnatal period. (author)

Hydroxyl migration disorders the surface structure of hydroxyapatite nanoparticles

Science.gov (United States)

Cheng, Xiajie; Wu, Hong; Zhang, Li; Ma, Xingtao; Zhang, Xingdong; Yang, Mingli

2017-09-01

The surface structure of nano-hydroxyapatite (HAP) was investigated using a combined simulated annealing and molecular dynamics method. The stationary structures of nano-HAP with 4-7 nm in diameter and annealed under different temperatures were analyzed in terms of pair distribution function, structural factor, mean square displacement and atomic coordination number. The particles possess different structures from bulk crystal. A clear radial change in their atomic arrangements was noted. From core to surface the structures change from ordered to disordered. A three-shell model was proposed to describe the structure evolution of nano-HAP. Atoms in the core zone keep their arrangements as in crystal, while atoms in the surface shell are in short-range order and long-range disorder, adopting a typically amorphous structure. Atoms in the middle shell have small displacements and/or deflections but basically retain their original locations as in crystal. The disordered shell is about 1 nm in thickness, in agreement with experimental observations. The disordering mainly stems from hydroxyl migration during which hydroxyls move to the surface and bond with the exposed Ca ions, and their left vacancies bring about a rearrangement of nearby atoms. The disordering is to some extent different for particles unannealed under different temperatures, resulting from fewer number of migrated hydroxyls at lower temperatures. Particles with different sizes have similar surface structures, and their surface energy decreases with increasing size. Moreover, the surface energy is reduced by hydroxyl migration because the exposed Ca ions on the surface are ionically bonded with the migrated hydroxyls. Our calculations proposed a new structure model for nano-HAP, which indicates a surface structure with activities different from those without surface reorganization. This is particularly interesting because most bioactivities of biomaterials are dominated by their surface activity.

The CT and MR evaluation of migrational disorders of the brain. Pt. 1

International Nuclear Information System (INIS)

Byrd, S.E.; Osborn, R.E.; Bohan, T.P.; Texas Univ., Houston; Naidich, T.P.

1989-01-01

The migrational disorders are a rare group of congenital malformations of the brain. They consist of the following entities - lissencephaly (agyria-pachygyria), pachygyria, schizencephaly, heterotopia and polymicrogyria. We studied 40 children with migrational disorders radiologically with CT and MR. This article (part I) deals with our patients with lissencephaly and pachygyria. It emphasizes their characteristic CT and MR findings along with their clinical presentation and course. These patients presented with one or a combination of the following symptoms, hypotonia, seizures, failure to thrive, microcephaly and occasionally hydrocephalus. These two groups of migrational disorders have abnormalities affecting the gyral-sulcal pattern of the cortex and gray-white matter distribution of the brain. MR provided better delineation of these disorders than CT. Because some forms of the migrational disorders can be inherited, it is extremely important for the radiologist to understand the characteristic findings for correct diagnosis which is essential for parental counseling. (orig.)

Colorectal Cancer Cells Adhere to and Migrate Along the Neurons of the Enteric Nervous System

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Emilie Duchalais

2018-01-01

Conclusions: Our data show that the enteric neuronal network guides tumor cell migration, partly via L1CAM and N-cadherin. These results open a new avenue of research on the underlying mechanisms and consequences of perineural invasion in colorectal cancer.

Gender Differences in Stressors Related to Migration and Acculturation in Patients with Psychiatric Disorders and Turkish Migration Background.

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Müller, Matthias Johannes; Koch, Eckhardt

2017-06-01

Migration, acculturation, and psychiatric disorders may cause stress and adaptation processes differently in men and women, but empirical research is scarce. In a retrospective study n = 62 Turkish migrants and n = 62 native German inpatients with depressive or anxiety disorders, matched for age, gender, and diagnoses, were compared using a 10-item instrument for the assessment of migration- and acculturation related stressors (MIGSTR10). Gender differences in the prevalence of stressors and in the total sum of stressors were calculated and compared between migrants and indigenous patients. Results showed a higher global stress level in migrants and in women than in men with migration background. Regarding single stressors, the perceived loss of status was significantly more prevalent and more pronounced in men than in women (P stress should be taken into account in migration and acculturation research.

Movement disorder and neuronal migration disorder due to ARFGEF2 mutation

NARCIS (Netherlands)

M.C.Y. de Wit (Marie Claire); I.F.M. de Coo (René); D. Halley (Dicky); M. Leguin (Maarten); G.M.S. Mancini (Grazia)

2009-01-01

textabstractWe report a child with a severe choreadystonic movement disorder, bilateral periventricular nodular heterotopia (BPNH), and secondary microcephaly based on compound heterozygosity for two new ARFGEF2 mutations (c.2031_2038dup and c.3798_3802del), changing the limited knowledge about the

Structural and temporal requirements of Wnt/PCP protein Vangl2 function for convergence and extension movements and facial branchiomotor neuron migration in zebrafish.

Science.gov (United States)

Pan, Xiufang; Sittaramane, Vinoth; Gurung, Suman; Chandrasekhar, Anand

2014-02-01

Van gogh-like 2 (Vangl2), a core component of the Wnt/planar cell polarity (PCP) signaling pathway, is a four-pass transmembrane protein with N-terminal and C-terminal domains located in the cytosol, and is structurally conserved from flies to mammals. In vertebrates, Vangl2 plays an essential role in convergence and extension (CE) movements during gastrulation and in facial branchiomotor (FBM) neuron migration in the hindbrain. However, the roles of specific Vangl2 domains, of membrane association, and of specific extracellular and intracellular motifs have not been examined, especially in the context of FBM neuron migration. Through heat shock-inducible expression of various Vangl2 transgenes, we found that membrane associated functions of the N-terminal and C-terminal domains of Vangl2 are involved in regulating FBM neuron migration. Importantly, through temperature shift experiments, we found that the critical period for Vangl2 function coincides with the initial stages of FBM neuron migration out of rhombomere 4. Intriguingly, we have also uncovered a putative nuclear localization motif in the C-terminal domain that may play a role in regulating CE movements. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

The CT and MR evaluation of migrational disorders of the brain. Pt. 2

International Nuclear Information System (INIS)

Byrd, S.E.; Osborn, R.E.; Bohan, T.P.; Naidich, T.P.

1989-01-01

The migrational disorders are a rare group of congenital malformations of the brain. They consist of the following entities - lissencephaly (agyria - pachygyria), pachygyria, schizencephaly, heterotopia and polymicrogyria. We studied 40 children with migrational disorders radiologically with CT and MR. This article (Part II) deals with our patients with schizencephaly, heterotopia and polymicrogyria. These patients presented clinically with a variety of symptoms. The most common were seizures, delayed development, failure to thrive and hydrocephalus. CT and MR both demonstrated the characteristic findings in all of our patients except the polymicrogyria group. The gray matter and cleft abnormalities seen in these disorders were demonstrated with CT and MR. However, MR provided better delineation of these disorders than CT. Because some forms of migrational disorders can be inherited, it is extremely important for the radiologist to understand the characteristic findings for correct diagnosis which is essential for parental counseling. (orig.)

Unbroken Mirror Neurons in Autism Spectrum Disorders

Science.gov (United States)

Fan, Yang-Teng; Decety, Jean; Yang, Chia-Yen; Liu, Ji-Lin; Cheng, Yawei

2010-01-01

Background: The "broken mirror" theory of autism, which proposes that a dysfunction of the human mirror neuron system (MNS) is responsible for the core social and cognitive deficits in individuals with autism spectrum disorders (ASD), has received considerable attention despite weak empirical evidence. Methods: In this electroencephalographic…

CT and MR evaluation of migrational disorders of the brain. Pt. 1. Lissencephaly and pachygyria

Energy Technology Data Exchange (ETDEWEB)

Byrd, S E; Osborn, R E; Bohan, T P; Naidich, T P

1989-03-01

The migrational disorders are a rare group of congenital malformations of the brain. They consist of the following entities - lissencephaly (agyria-pachygyria), pachygyria, schizencephaly, heterotopia and polymicrogyria. We studied 40 children with migrational disorders radiologically with CT and MR. This article (part I) deals with our patients with lissencephaly and pachygyria. It emphasizes their characteristic CT and MR findings along with their clinical presentation and course. These patients presented with one or a combination of the following symptoms, hypotonia, seizures, failure to thrive, microcephaly and occasionally hydrocephalus. These two groups of migrational disorders have abnormalities affecting the gyral-sulcal pattern of the cortex and gray-white matter distribution of the brain. MR provided better delineation of these disorders than CT. Because some forms of the migrational disorders can be inherited, it is extremely important for the radiologist to understand the characteristic findings for correct diagnosis which is essential for parental counseling.

Acculturation and other risk factors of depressive disorders in individuals with Turkish migration backgrounds.

Science.gov (United States)

Janssen-Kallenberg, Hanna; Schulz, Holger; Kluge, Ulrike; Strehle, Jens; Wittchen, Hans-Ulrich; Wolfradt, Uwe; Koch-Gromus, Uwe; Heinz, Andreas; Mösko, Mike; Dingoyan, Demet

2017-07-19

Acculturation is a long-term, multi-dimensional process occurring when subjects of different cultures stay in continuous contact. Previous studies have suggested that elevated rates of depression among different migrant groups might be due to patterns of acculturation and migration related risk factors. This paper focused on prevalence rates of depressive disorders and related risk factors among individuals with Turkish migration backgrounds. A population-based sample of 662 individuals with Turkish migration backgrounds were interviewed by bilingual interviewers using a standardised diagnostic interview for DSM-IV-TR and ICD-10 diagnoses (CIDI DIA-X Version 2.8). Associations between 12-month prevalence rates of depressive disorders with potential risk factors were assessed, including gender, age, socioeconomic status, acculturation status and migration status. 12-month prevalence rates of any depressive disorder were 29.0%, 14.4% of major depressive disorder (MDD) and 14.7% of dysthymia. Older age and low socioeconomic status were most consistently related to higher risks of depressive disorders. Acculturation status showed associations with subtypes of depressive disorder. Associations differed between men and women. Symptom severity of MDD was linked to gender, with females being more affected by severe symptoms. The prevalence of depressive disorders is high in individuals with Turkish migration backgrounds, which can be partly explained by older age, low socioeconomic status and acculturation pressures. Only a limited number of risk factors were assessed. Acculturation in particular is a complex process which might not be sufficiently represented by the applied measures. Further risk factors have to be identified in representative samples of this migrant group.

Targeted deletion of Sox10 by Wnt1-cre defects neuronal migration and projection in the mouse inner ear.

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YanYan Mao

Full Text Available Sensory nerves of the brainstem are mostly composed of placode-derived neurons, neural crest-derived neurons and neural crest-derived Schwann cells. This mixed origin of cells has made it difficult to dissect interdependence for fiber guidance. Inner ear-derived neurons are known to connect to the brain after delayed loss of Schwann cells in ErbB2 mutants. However, the ErbB2 mutant related alterations in the ear and the brain compound interpretation of the data. We present here a new model to evaluate exclusively the effect of Schwann cell loss on inner ear innervation. Conditional deletion of the neural crest specific transcription factor, Sox10, using the rhombic lip/neural crest specific Wnt1-cre driver spares Sox10 expression in the ear. We confirm that neural crest-derived cells provide a stop signal for migrating spiral ganglion neurons. In the absence of Schwann cells, spiral ganglion neurons migrate into the center of the cochlea and even out of the ear toward the brain. Spiral ganglion neuron afferent processes reach the organ of Corti, but many afferent fibers bypass the organ of Corti to enter the lateral wall of the cochlea. In contrast to this peripheral disorganization, the central projection to cochlear nuclei is normal. Compared to ErbB2 mutants, conditional Sox10 mutants have limited cell death in spiral ganglion neurons, indicating that the absence of Schwann cells alone contributes little to the embryonic survival of neurons. These data suggest that neural crest-derived cells are dispensable for all central and some peripheral targeting of inner ear neurons. However, Schwann cells provide a stop signal for migratory spiral ganglion neurons and facilitate proper targeting of the organ of Corti by spiral ganglion afferents.

Targeted Deletion of Sox10 by Wnt1-cre Defects Neuronal Migration and Projection in the Mouse Inner Ear

Science.gov (United States)

Mao, YanYan; Reiprich, Simone; Wegner, Michael; Fritzsch, Bernd

2014-01-01

Sensory nerves of the brainstem are mostly composed of placode-derived neurons, neural crest-derived neurons and neural crest-derived Schwann cells. This mixed origin of cells has made it difficult to dissect interdependence for fiber guidance. Inner ear-derived neurons are known to connect to the brain after delayed loss of Schwann cells in ErbB2 mutants. However, the ErbB2 mutant related alterations in the ear and the brain compound interpretation of the data. We present here a new model to evaluate exclusively the effect of Schwann cell loss on inner ear innervation. Conditional deletion of the neural crest specific transcription factor, Sox10, using the rhombic lip/neural crest specific Wnt1-cre driver spares Sox10 expression in the ear. We confirm that neural crest-derived cells provide a stop signal for migrating spiral ganglion neurons. In the absence of Schwann cells, spiral ganglion neurons migrate into the center of the cochlea and even out of the ear toward the brain. Spiral ganglion neuron afferent processes reach the organ of Corti, but many afferent fibers bypass the organ of Corti to enter the lateral wall of the cochlea. In contrast to this peripheral disorganization, the central projection to cochlear nuclei is normal. Compared to ErbB2 mutants, conditional Sox10 mutants have limited cell death in spiral ganglion neurons, indicating that the absence of Schwann cells alone contributes little to the embryonic survival of neurons. These data suggest that neural crest-derived cells are dispensable for all central and some peripheral targeting of inner ear neurons. However, Schwann cells provide a stop signal for migratory spiral ganglion neurons and facilitate proper targeting of the organ of Corti by spiral ganglion afferents. PMID:24718611

Migration Status, Familial Risk for Mental Disorder, and Schizotypal Personality Traits

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Odin van der Stelt

2013-08-01

Full Text Available Markedly raised incidence rates of schizophrenia and other psychotic disorders have been observed in several migrant and ethnic minority groups. To contribute to a better understanding of the elevated risk for psychotic disorders that is conferred by migration status, the present study examined effects associated with migration risk status on schizotypal personality traits, which are thought to reflect an underlying vulnerability to psychotic disorder. Effects of migration status were also compared to effects associated with a family history of psychopathology, which represents a robust nonspecific risk factor. We assessed schizotypal traits, using the Schizotypal Personality Questionnaire (SPQ, in a community-based sample of 62 Moroccan migrants and 41 Dutch nonmigrants, who were classified by the presence or absence of a family history of psychopathology. Overall, Moroccan migrants obtained higher SPQ scores than Dutch nonmigrants. However, migrants who had been classified as having a familial load of psychopathology displayed higher SPQ scores than migrants without such a family history, who in turn did not differ from Dutch nonmigrants. Furthermore, migrants with a familial load, relative to migrants without such a family history, reported higher levels of substance use and feelings of anxiety or depression, and perceived more often ethnic discrimination, which closely paralleled their SPQ scores. These findings indicate that primarily those migrants who are both intrinsically vulnerable and chronically exposed to social adversity, particularly ethnic discrimination, are at elevated risk for psychotic and other disorders. The results add to the evidence that migration status and perceived discrimination are associated with mental health.

Neuronal migration is regulated by endogenous RNAi and chromatin-binding factor ZFP-1/AF10 in Caenorhabditis elegans.

Science.gov (United States)

Kennedy, Lisa M; Grishok, Alla

2014-05-01

Endogenous short RNAs and the conserved plant homeodomain (PHD) zinc-finger protein ZFP-1/AF10 regulate overlapping sets of genes in Caenorhabditis elegans, which suggests that they control common biological pathways. We have shown recently that the RNAi factor RDE-4 and ZFP-1 negatively modulate transcription of the insulin/PI3 signaling-dependent kinase PDK-1 to promote C. elegans fitness. Moreover, we have demonstrated that the insulin/IGF-1-PI3K-signaling pathway regulates the activity of the DAF-16/FOXO transcription factor in the hypodermis to nonautonomously promote the anterior migrations of the hermaphrodite-specific neurons (HSNs) during embryogenesis of C. elegans. In this study, we implicate the PHD-containing isoform of ZFP-1 and endogenous RNAi in the regulation of HSN migration. ZFP-1 affects HSN migration in part through its negative effect on pdk-1 transcription and modulation of downstream DAF-16 activity. We also identify a novel role for ZFP-1 and RNAi pathway components, including RDE-4, in the regulation of HSN migration in parallel with DAF-16. Therefore, the coordinated activities of DAF-16, ZFP-1, and endogenous RNAi contribute to gene regulation during development to ensure proper neuronal positioning.

Mirror neuron activity associated with social impairments but not age in autism spectrum disorder.

Science.gov (United States)

Enticott, Peter G; Kennedy, Hayley A; Rinehart, Nicole J; Tonge, Bruce J; Bradshaw, John L; Taffe, John R; Daskalakis, Zafiris J; Fitzgerald, Paul B

2012-03-01

The neurobiology of autism spectrum disorder (ASD) is not particularly well understood, and biomedical treatment approaches are therefore extremely limited. A prominent explanatory model suggests that social-relating symptoms may arise from dysfunction within the mirror neuron system, while a recent neuroimaging study suggests that these impairments in ASD might reduce with age. Participants with autism spectrum disorder (i.e., DSM-IV autistic disorder or Asperger's disorder) (n = 34) and matched control subjects (n = 36) completed a transcranial magnetic stimulation study in which corticospinal excitability was assessed during the observation of hand gestures. Regression analyses revealed that the ASD group presented with significantly reduced corticospinal excitability during the observation of a transitive hand gesture (relative to observation of a static hand) (p mirror neuron system activity within ventral premotor cortex/inferior frontal gyrus. Among the ASD group, there was also a negative association between putative mirror neuron activity and self-reported social-relating impairments, but there was no indication that mirror neuron impairments in ASD decrease with age. These data provide general support for the mirror neuron hypothesis of autism; researchers now must clarify the precise functional significance of mirror neurons to truly understand their role in the neuropathophysiology of ASD and to determine whether they should be used as targets for the treatment of ASD.

Cat-Scan and nuclear magnetic resonance imaging in abnormalities of neuronal migration

International Nuclear Information System (INIS)

Wilms, G.; Marchal, G.; Decrop, E.; Van Hecke, P.; Baert, A.L.; Casaer, P.

1989-01-01

This is a report of the CAT-scan and MRI characteristics in 14 patients with anomalies of neuronal migration. There were 3 cases of heterotopia of the gray matter, 2 cases of agyria, 3 cases of pachygyria, 2 cases of schizencephaly and 4 cases of hemimegalencephaly. The primary advantages of MRI in comparison with CAT-scanning, are better contrast between the white and gray matter; better delineation of the cerebral cortex and the possibility of direct mutiplanar imaging. NMRI will become the investigation of choice in children with epilepsy or psychomotor retardation [fr

Characterization of Induced Pluripotent Stem Cell-derived Human Serotonergic Neurons

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Lining Cao

2017-05-01

Full Text Available In the brain, the serotonergic neurons located in the raphe nucleus are the unique resource of the neurotransmitter serotonin, which plays a pivotal role in the regulation of brain development and functions. Dysfunction of the serotonin system is present in many psychiatric disorders. Lack of in vitro functional human model limits the understanding of human central serotonergic system and its related diseases and clinical applications. Previously, we have developed a method generating human serotonergic neurons from induced pluripotent stem cells (iPSCs. In this study, we analyzed the features of these human iPSCs-derived serotonergic neurons both in vitro and in vivo. We found that these human serotonergic neurons are sensitive to the selective neurotoxin 5, 7-Dihydroxytryptamine (5,7-DHT in vitro. After being transplanted into newborn mice, the cells not only expressed their typical molecular markers, but also showed the migration and projection to the host’s cerebellum, hindbrain and spinal cord. The data demonstrate that these human iPSCs-derived neurons exhibit the typical features as the serotonergic neurons in the brain, which provides a solid foundation for studying on human serotonin system and its related disorders.

Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium.

Science.gov (United States)

Stern, S; Santos, R; Marchetto, M C; Mendes, A P D; Rouleau, G A; Biesmans, S; Wang, Q-W; Yao, J; Charnay, P; Bang, A G; Alda, M; Gage, F H

2017-02-28

Bipolar disorder (BD) is a progressive psychiatric disorder with more than 3% prevalence worldwide. Affected individuals experience recurrent episodes of depression and mania, disrupting normal life and increasing the risk of suicide greatly. The complexity and genetic heterogeneity of psychiatric disorders have challenged the development of animal and cellular models. We recently reported that hippocampal dentate gyrus (DG) neurons differentiated from induced pluripotent stem cell (iPSC)-derived fibroblasts of BD patients are electrophysiologically hyperexcitable. Here we used iPSCs derived from Epstein-Barr virus-immortalized B-lymphocytes to verify that the hyperexcitability of DG-like neurons is reproduced in this different cohort of patients and cells. Lymphocytes are readily available for research with a large number of banked lines with associated patient clinical description. We used whole-cell patch-clamp recordings of over 460 neurons to characterize neurons derived from control individuals and BD patients. Extensive functional analysis showed that intrinsic cell parameters are very different between the two groups of BD neurons, those derived from lithium (Li)-responsive (LR) patients and those derived from Li-non-responsive (NR) patients, which led us to partition our BD neurons into two sub-populations of cells and suggested two different subdisorders. Training a Naïve Bayes classifier with the electrophysiological features of patients whose responses to Li are known allows for accurate classification with more than 92% success rate for a new patient whose response to Li is unknown. Despite their very different functional profiles, both populations of neurons share a large, fast after-hyperpolarization (AHP). We therefore suggest that the large, fast AHP is a key feature of BD and a main contributor to the fast, sustained spiking abilities of BD neurons. Confirming our previous report with fibroblast-derived DG neurons, chronic Li treatment reduced

Rp58 and p27kip1 coordinate cell cycle exit and neuronal migration within the embryonic mouse cerebral cortex.

Science.gov (United States)

Clément, Olivier; Hemming, Isabel Anne; Gladwyn-Ng, Ivan Enghian; Qu, Zhengdong; Li, Shan Shan; Piper, Michael; Heng, Julian Ik-Tsen

2017-05-15

During the development of the mammalian cerebral cortex, newborn postmitotic projection neurons are born from local neural stem cells and must undergo radial migration so as to position themselves appropriately to form functional neural circuits. The zinc finger transcriptional repressor Rp58 (also known as Znf238 or Zbtb18) is critical for coordinating corticogenesis, but its underlying molecular mechanism remains to be better characterised. Here, we demonstrate that the co-expression of Rp58 and the cyclin dependent kinase inhibitor (CDKI) p27 kip1 is important for E14.5-born cortical neurons to coordinate cell cycle exit and initiate their radial migration. Notably, we find that the impaired radial positioning of Rp58-deficient cortical neurons within the embryonic (E17.5) mouse cortex, as well as their multipolar to bipolar transition from the intermediate zone to the cortical plate can be restored by forced expression of p27 kip1 in concert with suppression of Rnd2, a downstream target gene of Rp58. Furthermore, the restorative effects of p27 kip1 and Rnd2 abrogation are reminiscent of suppressing RhoA signalling in Rp58-deficient cells. Our findings demonstrate functional interplay between a transcriptional regulator and a CDKI to mediate neuroprogenitor cell cycle exit, as well as to promote radial migration through a molecular mechanism consistent with suppression of RhoA signalling.

An epidermal microRNA regulates neuronal migration through control of the cellular glycosylation state

DEFF Research Database (Denmark)

Pedersen, Mikael Egebjerg; Snieckute, Goda; Kagias, Konstantinos

2013-01-01

An appropriate balance in glycosylation of proteoglycans is crucial for their ability to regulate animal development. Here, we report that the Caenorhabditis elegans microRNA mir-79, an ortholog of mammalian miR-9, controls sugar-chain homeostasis by targeting two proteins in the proteoglycan bio...... that impinges on a LON-2/glypican pathway and disrupts neuronal migration. Our results identify a regulatory axis controlled by a conserved microRNA that maintains proteoglycan homeostasis in cells....

Neuronal glucose transporter isoform 3 deficient mice demonstrate features of autism spectrum disorders.

Science.gov (United States)

Zhao, Y; Fung, C; Shin, D; Shin, B-C; Thamotharan, S; Sankar, R; Ehninger, D; Silva, A; Devaskar, S U

2010-03-01

Neuronal glucose transporter (GLUT) isoform 3 deficiency in null heterozygous mice led to abnormal spatial learning and working memory but normal acquisition and retrieval during contextual conditioning, abnormal cognitive flexibility with intact gross motor ability, electroencephalographic seizures, perturbed social behavior with reduced vocalization and stereotypies at low frequency. This phenotypic expression is unique as it combines the neurobehavioral with the epileptiform characteristics of autism spectrum disorders. This clinical presentation occurred despite metabolic adaptations consisting of an increase in microvascular/glial GLUT1, neuronal GLUT8 and monocarboxylate transporter isoform 2 concentrations, with minimal to no change in brain glucose uptake but an increase in lactate uptake. Neuron-specific glucose deficiency has a negative impact on neurodevelopment interfering with functional competence. This is the first description of GLUT3 deficiency that forms a possible novel genetic mechanism for pervasive developmental disorders, such as the neuropsychiatric autism spectrum disorders, requiring further investigation in humans.

CT and MR evaluation of migrational disorders of the brain. Pt. 2. Schizencephaly, heterotopia and polymicrogyria

Energy Technology Data Exchange (ETDEWEB)

Byrd, S E; Osborn, R E; Bohan, T P; Naidich, T P

1989-05-01

The migrational disorders are a rare group of congenital malformations of the brain. They consist of the following entities - lissencephaly (agyria - pachygyria), pachygyria, schizencephaly, heterotopia and polymicrogyria. We studied 40 children with migrational disorders radiologically with CT and MR. This article (Part II) deals with our patients with schizencephaly, heterotopia and polymicrogyria. These patients presented clinically with a variety of symptoms. The most common were seizures, delayed development, failure to thrive and hydrocephalus. CT and MR both demonstrated the characteristic findings in all of our patients except the polymicrogyria group. The gray matter and cleft abnormalities seen in these disorders were demonstrated with CT and MR. However, MR provided better delineation of these disorders than CT. Because some forms of migrational disorders can be inherited, it is extremely important for the radiologist to understand the characteristic findings for correct diagnosis which is essential for parental counseling.

Histogenetic disorders of cerebral cortex induced by in utero exposure to low-doses of ionizing radiation

International Nuclear Information System (INIS)

Fushiki, Shinji; Kinoshita, Chikako; Hyodo-Taguchi, Yasuko; Ishikawa, Yuji; Hirobe, Tomohisa

1999-01-01

To elucidate the short- and long-term effects of low-level ionizing radiation on cell migration in the developing cerebral cortex of mice and rats, we irradiated them at the middle of cortical histogenesis with either γ-rays or X-rays. We have demonstrated an effect of ionizing radiation on neuronal migration at doses as low as 0.15 Gy together with a changing pattern of expression of the neural cell adhesion molecule N-CAM. Our findings suggest a possible role of N-CAM in neuronal migration and suggest the presence of a threshold in terms of the effects of small radiation doses on the developing cerebral cortex. In addition, the effects of radiation on neuronal migration during the embryonic stage remained even after birth in that aberrantly placed neurons were noted in the cerebral cortex. However, such derangement was less pronounced in mature animals compared to younger ones. These observations suggest that some modification process including apoptosis might have occurred during the postnatal period. In this review, molecular pathogenesis of neuronal migration disorders will also be discussed, based upon recent experimental as well as molecular genetic studies. (author)

Migration background and juvenile mental health: a descriptive retrospective analysis of diagnostic rates of psychiatric disorders in young people

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Tilman Jakob Gaber

2013-06-01

Full Text Available Introduction: This article presents diagnostic rates for specific mental disorders in a German pediatric inpatient population over a period of 20 years with respect to migration background and socioeconomic status (SES. Methods: Diagnostic data were obtained over a period of 20 years from 8,904 patients who visited a child and adolescent psychiatry mental health service in Germany. Data from 5,985 diagnosed patients (ICD-9 and ICD-10 criteria were included with respect to gender, migration background, and SES. Results:Migration- and gender-specific effects were found for both periods of assessment. The group of boys with a migration background showed significantly higher rates of reactions to severe stress, adjustment disorders, and posttraumatic stress disorder compared to their male, non-migrant counterparts. Conversely, boys without a migration background showed a significantly higher percentage rate of hyperkinetic disorders than male migrants. Similar results were found for female migrants in the latter assessment period (ICD-10. In addition, female migrants showed lower rates of emotional disorders whose onset occurs in childhood compared to their non-migrant counterparts. Conclusions: Data from this investigation provide preliminary evidence that the prevalence of various psychiatric disorders in children and adolescents is influenced by migration background and SES.

Roles of taurine-mediated tonic GABAA receptor activation in the radial migration of neurons in the fetal mouse cerebral cortex

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Tomonori eFurukawa

2014-03-01

Full Text Available γ-Aminobutyric acid (GABA depolarizes embryonic cerebrocortical neurons and continuous activation of the GABAA receptor (GABAAR contributes to their tonic depolarization. Although multiple reports have demonstrated a role of GABAAR activation in neocortical development, including in migration, most of these studies have used pharmacological blockers. Herein, we performed in utero electroporation in GABA synthesis-lacking homozygous GAD67-GFP knock-in mice (GAD67GFP/GFP to label neurons born in the ventricular zone. Three days after electroporation, there were no differences in the distribution of labeled cells between the genotypes. The dose-response properties of cells labeled to detect GABA were equivalent among genotypes. However, continuous blockade of GABAAR with the GABAAR antagonist SR95531 accelerated radial migration. This effect of GABAAR blockade in GAD67GFP/GFP mice suggested a role for alternative endogenous GABAAR agonists. Thus, we tested the role of taurine, which is derived from maternal blood but is abundant in the fetal brain. The taurine-evoked currents in labeled cells were mediated by GABAAR. Taurine uptake was blocked by a taurine transporter inhibitor, 2-(guanidinoethanesulfonic acid (GES, and taurine release was blocked by a volume-sensitive anion channel blocker, 4-(2-butyl-6,7-dichlor-2-cyclopentylindan-1-on-5-yl oxobutyric acid (DCPIB, as examined through high-performance liquid chromatography (HPLC. GES increased the extracellular taurine concentration and induced an inward shift of the holding current, which was reversed by SR95531. In a taurine-deficient mouse model, the GABAAR-mediated tonic currents were greatly reduced, and radial migration was accelerated. As the tonic currents were equivalent among the genotypes of GAD67-GFP knock-in mice, taurine, rather than GABA, might play a major role as an endogenous agonist of embryonic tonic GABAAR conductance, regulating the radial migration of neurons in the

Specific Intensity Direct Current (DC) Electric Field Improves Neural Stem Cell Migration and Enhances Differentiation towards βIII-Tubulin+ Neurons

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Zhao, Huiping; Steiger, Amanda; Nohner, Mitch; Ye, Hui

2015-01-01

Control of stem cell migration and differentiation is vital for efficient stem cell therapy. Literature reporting electric field–guided migration and differentiation is emerging. However, it is unknown if a field that causes cell migration is also capable of guiding cell differentiation—and the mechanisms for these processes remain unclear. Here, we report that a 115 V/m direct current (DC) electric field can induce directional migration of neural precursor cells (NPCs). Whole cell patching revealed that the cell membrane depolarized in the electric field, and buffering of extracellular calcium via EGTA prevented cell migration under these conditions. Immunocytochemical staining indicated that the same electric intensity could also be used to enhance differentiation and increase the percentage of cell differentiation into neurons, but not astrocytes and oligodendrocytes. The results indicate that DC electric field of this specific intensity is capable of promoting cell directional migration and orchestrating functional differentiation, suggestively mediated by calcium influx during DC field exposure. PMID:26068466

Neuronal Surface Autoantibodies in Neuropsychiatric Disorders: Are There Implications for Depression?

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Shenghua Zong

2017-07-01

Full Text Available Autoimmune diseases are affecting around 7.6–9.4% of the general population. A number of central nervous system disorders, including encephalitis and severe psychiatric disorders, have been demonstrated to associate with specific neuronal surface autoantibodies (NSAbs. It has become clear that specific autoantibodies targeting neuronal surface antigens and ion channels could cause severe mental disturbances. A number of studies have focused or are currently investigating the presence of autoantibodies in specific mental conditions such as schizophrenia and bipolar disorders. However, less is known about other conditions such as depression. Depression is a psychiatric disorder with complex etiology and pathogenesis. The diagnosis criteria of depression are largely based on symptoms but not on the origin of the disease. The question which arises is whether in a subgroup of patients with depression, the symptoms might be caused by autoantibodies targeting membrane-associated antigens. Here, we describe how autoantibodies targeting membrane proteins and ion channels cause pathological effects. We discuss the physiology of these antigens and their role in relation to depression. Finally, we summarize a number of studies detecting NSAbs with a special focus on cohorts that include depression diagnosis and/or show depressive symptoms.

Developmental origins of brain disorders: roles for dopamine

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Kelli M Money

2013-12-01

Full Text Available Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain, including movement, cognition, and reward. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse. Pharmacologic and genetic disruptions demonstrate that these effects are brain region- and receptor subtype-specific. For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling. Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders.

Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain

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Andrea Forero

2017-09-01

density of the developing DR and the posterior innervation of the prefrontal cortex (PFC, and therefore might be involved in the migration, axonal outgrowth and terminal target finding of DR 5-HT neurons. Dysregulation of CDH13 expression may thus contribute to alterations in this system of neurotransmission, impacting cognitive function, which is frequently impaired in neurodevelopmental disorders including attention-deficit/hyperactivity and autism spectrum disorders.

The Relationship Between Post-Migration Stress and Psychological Disorders in Refugees and Asylum Seekers.

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Li, Susan S Y; Liddell, Belinda J; Nickerson, Angela

2016-09-01

Refugees demonstrate high rates of post-traumatic stress disorder (PTSD) and other psychological disorders. The recent increase in forcible displacement internationally necessitates the understanding of factors associated with refugee mental health. While pre-migration trauma is recognized as a key predictor of mental health outcomes in refugees and asylum seekers, research has increasingly focused on the psychological effects of post-migration stressors in the settlement environment. This article reviews the research evidence linking post-migration factors and mental health outcomes in refugees and asylum seekers. Findings indicate that socioeconomic, social, and interpersonal factors, as well as factors relating to the asylum process and immigration policy affect the psychological functioning of refugees. Limitations of the existing literature and future directions for research are discussed, along with implications for treatment and policy.

Role of Class III phosphoinositide 3-kinase in the brain development: possible involvement in specific learning disorders.

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Inaguma, Yutaka; Matsumoto, Ayumi; Noda, Mariko; Tabata, Hidenori; Maeda, Akihiko; Goto, Masahide; Usui, Daisuke; Jimbo, Eriko F; Kikkawa, Kiyoshi; Ohtsuki, Mamitaro; Momoi, Mariko Y; Osaka, Hitoshi; Yamagata, Takanori; Nagata, Koh-Ichi

2016-10-01

Class III phosphoinositide 3-kinase (PIK3C3 or mammalian vacuolar protein sorting 34 homolog, Vps34) regulates vesicular trafficking, autophagy, and nutrient sensing. Recently, we reported that PIK3C3 is expressed in mouse cerebral cortex throughout the developmental process, especially at early embryonic stage. We thus examined the role of PIK3C3 in the development of the mouse cerebral cortex. Acute silencing of PIK3C3 with in utero electroporation method caused positional defects of excitatory neurons during corticogenesis. Time-lapse imaging revealed that the abnormal positioning was at least partially because of the reduced migration velocity. When PIK3C3 was silenced in cortical neurons in one hemisphere, axon extension to the contralateral hemisphere was also delayed. These aberrant phenotypes were rescued by RNAi-resistant PIK3C3. Notably, knockdown of PIK3C3 did not affect the cell cycle of neuronal progenitors and stem cells at the ventricular zone. Taken together, PIK3C3 was thought to play a crucial role in corticogenesis through the regulation of excitatory neuron migration and axon extension. Meanwhile, when we performed comparative genomic hybridization on a patient with specific learning disorders, a 107 Kb-deletion was identified on 18q12.3 (nt. 39554147-39661206) that encompasses exons 5-23 of PIK3C3. Notably, the above aberrant migration and axon growth phenotypes were not rescued by the disease-related truncation mutant (172 amino acids) lacking the C-terminal kinase domain. Thus, functional defects of PIK3C3 might impair corticogenesis and relate to the pathophysiology of specific learning disorders and other neurodevelopmental disorders. Acute knockdown of Class III phosphoinositide 3-kinase (PIK3C3) evokes migration defects of excitatory neurons during corticogenesis. PIK3C3-knockdown also disrupts axon outgrowth, but not progenitor proliferation in vivo. Involvement of PIK3C3 in neurodevelopmental disorders might be an interesting future

Identification of Arx targets unveils new candidates for controlling cortical interneuron migration and differentiation

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Gaelle M Friocourt

2011-12-01

Full Text Available Mutations in the homeobox transcription factor ARX have been found to be responsible for a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of intellectual disabilities without apparent brain abnormalities, but with associated features of dystonia and epilepsy. Arx expression is mainly restricted to populations of GABA-containing neurons. Studies of the effects of ARX loss of function, either in humans or mutant mice, revealed varying defects, suggesting multiple roles of this gene in brain patterning, neuronal proliferation and migration, cell maturation and differentiation, as well as axonal outgrowth and connectivity. However, to date, little is known about how Arx functions as a transcription factor or which genes it binds and regulates. Recently, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified approximately 1000 gene promoters bound by Arx in transfected neuroblastoma N2a cells and mouse embryonic brain. To narrow the analysis of Arx targets to those most likely to control cortical interneuron migration and/or differentiation, we compare here our data to previously published studies searching for genes enriched or down-regulated in cortical interneurons between E13.5 and E15.5. We thus identified 14 Arx-target genes enriched (Cxcr7, Meis1, Ppap2a, Slc12a5, Ets2, Phlda1, Zif268, Igf1, Lmo3, Sema6, Lgi1, Alk, Tgfb3, Napb and 5 genes specifically down-regulated (Hmgn3, Lmo1, Ebf3, Rasgef1b and Slit2 in cortical migrating neurons. In this review, we present these genes and discuss how their possible regulation by Arx may lead to the dysfunction of GABAergic neurons, resulting in mental retardation and epilepsy.

Novel transcriptional networks regulated by CLOCK in human neurons.

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Fontenot, Miles R; Berto, Stefano; Liu, Yuxiang; Werthmann, Gordon; Douglas, Connor; Usui, Noriyoshi; Gleason, Kelly; Tamminga, Carol A; Takahashi, Joseph S; Konopka, Genevieve

2017-11-01

The molecular mechanisms underlying human brain evolution are not fully understood; however, previous work suggested that expression of the transcription factor CLOCK in the human cortex might be relevant to human cognition and disease. In this study, we investigated this novel transcriptional role for CLOCK in human neurons by performing chromatin immunoprecipitation sequencing for endogenous CLOCK in adult neocortices and RNA sequencing following CLOCK knockdown in differentiated human neurons in vitro. These data suggested that CLOCK regulates the expression of genes involved in neuronal migration, and a functional assay showed that CLOCK knockdown increased neuronal migratory distance. Furthermore, dysregulation of CLOCK disrupts coexpressed networks of genes implicated in neuropsychiatric disorders, and the expression of these networks is driven by hub genes with human-specific patterns of expression. These data support a role for CLOCK-regulated transcriptional cascades involved in human brain evolution and function. © 2017 Fontenot et al.; Published by Cold Spring Harbor Laboratory Press.

Catenin-dependent cadherin function drives divisional segregation of spinal motor neurons.

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Bello, Sanusi M; Millo, Hadas; Rajebhosale, Manisha; Price, Stephen R

2012-01-11

Motor neurons that control limb movements are organized as a neuronal nucleus in the developing ventral horn of the spinal cord called the lateral motor column. Neuronal migration segregates motor neurons into distinct lateral and medial divisions within the lateral motor column that project axons to dorsal or ventral limb targets, respectively. This migratory phase is followed by an aggregation phase whereby motor neurons within a division that project to the same muscle cluster together. These later phases of motor neuron organization depend on limb-regulated differential cadherin expression within motor neurons. Initially, all motor neurons display the same cadherin expression profile, which coincides with the migratory phase of motor neuron segregation. Here, we show that this early, pan-motor neuron cadherin function drives the divisional segregation of spinal motor neurons in the chicken embryo by controlling motor neuron migration. We manipulated pan-motor neuron cadherin function through dissociation of cadherin binding to their intracellular partners. We found that of the major intracellular transducers of cadherin signaling, γ-catenin and α-catenin predominate in the lateral motor column. In vivo manipulations that uncouple cadherin-catenin binding disrupt divisional segregation via deficits in motor neuron migration. Additionally, reduction of the expression of cadherin-7, a cadherin predominantly expressed in motor neurons only during their migration, also perturbs divisional segregation. Our results show that γ-catenin-dependent cadherin function is required for spinal motor neuron migration and divisional segregation and suggest a prolonged role for cadherin expression in all phases of motor neuron organization.

The terminal nerve plays a prominent role in GnRH-1 neuronal migration independent from proper olfactory and vomeronasal connections to the olfactory bulbs

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Ed Zandro M. Taroc

2017-10-01

Yoshihara et al., 2005. Our data prove that correct development of the OBs and axonal connection of the olfactory/vomeronasal sensory neurons to the forebrain are not required for GnRH-1 ns migration, and suggest that the terminal nerve, which forms the GnRH-1 migratory scaffold, follows different guidance cues and differs in gene expression from olfactory/vomeronasal sensory neurons.

The MR spectrum of peroxisomal disorders

International Nuclear Information System (INIS)

Knaap, M.S. van der; Valk, J.; Vrije Univ., Amsterdam

1991-01-01

In the last decade an increasing number of peroxisomal disorders has been recognized. Almost all peroxisomal disorders affect the central nervous system. Many of them lead to demyelination, some of them lead to migrational disturbances. The MR pattern of X-linked adrenoleukodystrophy is well known, but the pattern of the other peroxisomal disorders is less well known. We evaluated the gray and white matter abnormalities of 20 patients on 32 occasions. We compared the results with histological data and in this way came to the description of a number of characteristic MR patterns occurring in peroxisomal disorders: (1) Neuronal migrational disturbances in combination with hypomyelination, dysmyelination or demyelination. (2) Symmetrical demyelination of posterior limb of the internal capsule, cerebellar white matter and brain stem tracts with a variable affection of cerebral hemispheres. (3) Symmetrical demyelination, exhibiting two zones, starting in the occipital area and spreading outwards and forwards; affection of brain stem tracts. (4) Less characteristic patterns of demyelination. The patterns are illustrated and differentiation from other disorders is discussed. (orig.)

Direct reprogramming of somatic cells into neural stem cells or neurons for neurological disorders.

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Hou, Shaoping; Lu, Paul

2016-01-01

Direct reprogramming of somatic cells into neurons or neural stem cells is one of the most important frontier fields in current neuroscience research. Without undergoing the pluripotency stage, induced neurons or induced neural stem cells are a safer and timelier manner resource in comparison to those derived from induced pluripotent stem cells. In this prospective, we review the recent advances in generation of induced neurons and induced neural stem cells in vitro and in vivo and their potential treatments of neurological disorders.

Unraveling the biology of bipolar disorder using induced pluripotent stem-derived neurons.

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Miller, Nathaniel D; Kelsoe, John R

2017-11-01

Bipolar disorder has been studied from numerous angles, from pathological studies to large-scale genomic studies, overall making moderate gains toward an understanding of the disorder. With the advancement of induced pluripotent stem (iPS) cell technology, in vitro models based on patient samples are now available that inherently incorporate the complex genetic variants that largely are the basis for this disorder. A number of groups are starting to apply iPS technology to the study of bipolar disorder. We selectively reviewed the literature related to understanding bipolar disorder based on using neurons derived from iPS cells. So far, most work has used the prototypical iPS cells. However, others have been able to transdifferentiate fibroblasts directly to neurons. Others still have utilized olfactory epithelium tissue as a source of neural-like cells that do not need reprogramming. In general, iPS and related cells can be used for studies of disease pathology, drug discovery, or stem cell therapy. Published studies have primarily focused on understanding bipolar disorder pathology, but initial work is also being done to use iPS technology for drug discovery. In terms of disease pathology, some evidence is pointing toward a differentiation defect with more ventral cell types being prominent. Additionally, there is evidence for a calcium signaling defect, a finding that builds on the genome-wide association study results. Continued work with iPS cells will certainly help us understand bipolar disorder and provide a way forward for improved treatments. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Thyroid Hormone in the CNS: Contribution of Neuron-Glia Interaction.

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Noda, Mami

2018-01-01

The endocrine system and the central nervous system (CNS) are intimately linked. Among hormones closely related to the nervous system, thyroid hormones (THs) are critical for the regulation of development and differentiation of neurons and neuroglia and hence for development and function of the CNS. T3 (3,3',5-triiodothyronine), an active form of TH, is important not only for neuronal development but also for differentiation of astrocytes and oligodendrocytes, and for microglial development. In adult brain, T3 affects glial morphology with sex- and age-dependent manner and therefore may affect their function, leading to influence on neuron-glia interaction. T3 is an important signaling factor that affects microglial functions such as migration and phagocytosis via complex mechanisms. Therefore, dysfunction of THs may impair glial function as well as neuronal function and thus disturb the brain, which may cause mental disorders. Investigations on molecular and cellular basis of hyperthyroidism and hypothyroidism will help us to understand changes in neuron-glia interaction and therefore consequent psychiatric symptoms. © 2018 Elsevier Inc. All rights reserved.

Increased seroreactivity in tic disorder patients to a 60 kDa protein band from a neuronal cell line

NARCIS (Netherlands)

Hoekstra, P.J.; Limburg, Piet; Troost, P.W.; van Lang, N.; De Bildt, A.; Korf, J; Kallenberg, Cees; Minderaa, R.B.; Horst, G.

In tic disorders, increased seroreactivity against neuronal antigens has been demonstrated, without performing molecular characterization of antigens. Here, unselected patients with a tic disorder were compared with healthy controls, autistic disorder (AD), and obsessive-compulsive disorder (OCD)

Neurogenesis in the vomeronasal epithelium of adult garter snakes: 3. Use of 3H-thymidine autoradiography to trace the genesis and migration of bipolar neurons

International Nuclear Information System (INIS)

Wang, R.T.; Halpern, M.

1988-01-01

Use of 3H-thymidine autoradiography and unilateral vomeronasal (VN) axotomy has permitted us to demonstrate directly the existence of VN stem cells in the adult garter snake and to trace continuous bipolar neuron development and migration in the normal VN and deafferentated VN epithelium in the same animal. The vomeronasal epithelium and olfactory epithelium of adult garter snakes are both capable of incorporating 3H-thymidine. In the sensory epithelium of the vomeronasal organ, 3H-thymidine-labeled cells were initially restricted to the base of the undifferentiated cell layer in animals surviving 1 day following 3H-thymidine injection. With increasing survival time, labeled cells progressively migrated vertically within the receptor cell column toward the apex of the bipolar neuron layer. In both the normal and denervated VN epithelium, labeled cells were observed through the 56 days of postoperative survival. In the normal epithelium, labeled cells were always located within the matrix of the intact receptor cell columns. However, labeled cells of the denervated epithelium were always located at the apical front of the newly formed cell mass following depletion of the original neuronal cell population. In addition, at postoperative days 28 and 56, labeled cells of the denervated VN epithelium achieved neuronal differentiation and maturation by migrating much farther away from the base of the receptor cell column than the labeled cells on the normal, unoperated contralateral side. This study directly demonstrates that basal cells initially incorporating 3H-thymidine are indeed stem cells of the VN epithelium in adult garter snakes

Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder.

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Jukic, Marin M; Carrillo-Roa, Tania; Bar, Michal; Becker, Gal; Jovanovic, Vukasin M; Zega, Ksenija; Binder, Elisabeth B; Brodski, Claude

2015-03-01

Subtle mood fluctuations are normal emotional experiences, whereas drastic mood swings can be a manifestation of bipolar disorder (BPD). Despite their importance for normal and pathological behavior, the mechanisms underlying endogenous mood instability are largely unknown. During embryogenesis, the transcription factor Otx2 orchestrates the genetic networks directing the specification of dopaminergic (DA) and serotonergic (5-HT) neurons. Here we behaviorally phenotyped mouse mutants overexpressing Otx2 in the hindbrain, resulting in an increased number of DA neurons and a decreased number of 5-HT neurons in both developing and mature animals. Over the course of 1 month, control animals exhibited stable locomotor activity in their home cages, whereas mutants showed extended periods of elevated or decreased activity relative to their individual average. Additional behavioral paradigms, testing for manic- and depressive-like behavior, demonstrated that mutants showed an increase in intra-individual fluctuations in locomotor activity, habituation, risk-taking behavioral parameters, social interaction, and hedonic-like behavior. Olanzapine, lithium, and carbamazepine ameliorated the behavioral alterations of the mutants, as did the mixed serotonin receptor agonist quipazine and the specific 5-HT2C receptor agonist CP-809101. Testing the relevance of the genetic networks specifying monoaminergic neurons for BPD in humans, we applied an interval-based enrichment analysis tool for genome-wide association studies. We observed that the genes specifying DA and 5-HT neurons exhibit a significant level of aggregated association with BPD but not with schizophrenia or major depressive disorder. The results of our translational study suggest that aberrant development of monoaminergic neurons leads to mood fluctuations and may be associated with BPD.

PRENATAL HYPOXIA IN DIFFERENT PERIODS OF EMBRYOGENESIS DIFFERENTIALLY AFFECTS CELL MIGRATION, NEURONAL PLASTICITY AND RAT BEHAVIOR IN POSTNATAL ONTOGENESIS

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Dmitrii S Vasilev

2016-03-01

Full Text Available Long-term effects of prenatal hypoxia on embryonic days E14 or E18 on the number, type and localization of cortical neurons, density of labile synaptopodin-positive dendritic spines and parietal cortex-dependent behavioral tasks were examined in the postnatal ontogenesis of rats. An injection of 5’ethynyl-2’deoxyuridine to pregnant rats was used to label neurons generated on E14 or E18 in the fetuses. In control rat pups a majority of cells labeled on E14 were localized in the lower cortical layers V-VI while the cells labeled on E18 were mainly found in the superficial cortical layers II-III. It was shown that hypoxia both on E14 and E18 results in disruption of neuroblast generation and migration but affects different cell populations. In rat pups subjected to hypoxia on E14, the total number of labeled cells in the parietal cortex was decreased while the number of labeled neurons scattered within the superficial cortical layers was increased. In rat pups subjected to hypoxia on E18, the total number of labeled cells in the parietal cortex was also decreased but the number of scattered labeled neurons was higher in the lower cortical layers. It can be suggested that prenatal hypoxia both on E14 and E18 causes a disruption in neuroblast migration but with a different outcome. Only in rats subjected to hypoxia on E14 did we observe a reduction in the total number of pyramidal cortical neurons and the density of labile synaptopodin-positive dendritic spines in the molecular cortical layer during the first month after birth which affected development of the cortical functions. As a result, rats subjected to hypoxia on E14, but not on E18, had impaired development of the whisker-placing reaction and reduced ability to learn reaching by a forepaw. The data obtained suggest that hypoxia on E14 in the period of generation of the cells, which later differentiate into the pyramidal cortical neurons of the V-VI layers and form cortical minicolumns

Neuronal migration disorders in microcephalic osteodysplastic primordial dwarfism type I/III.

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Juric-Sekhar, Gordana; Kapur, Raj P; Glass, Ian A; Murray, Mitzi L; Parnell, Shawn E; Hevner, Robert F

2011-04-01

Microcephalic osteodysplastic primordial dwarfism (MOPD) is a rare microlissencephaly syndrome, with at least two distinct phenotypic and genetic types. MOPD type II is caused by pericentrin mutations, while types I and III appear to represent a distinct entity (MOPD I/III) with variably penetrant phenotypes and unknown genetic basis. The neuropathology of MOPD I/III is little understood, especially in comparison to other forms of lissencephaly. Here, we report postmortem brain findings in an 11-month-old female infant with MOPD I/III. The cerebral cortex was diffusely pachygyric, with a right parietal porencephalic lesion. Histologically, the cortex was abnormally thick and disorganized. Distinct malformations were observed in different cerebral lobes, as characterized using layer-specific neuronal markers. Frontal cortex was severely disorganized and coated with extensive leptomeningeal glioneuronal heterotopia. Temporal cortex had a relatively normal 6-layered pattern, despite cortical thickening. Occipital cortex was variably affected. The corpus callosum was extremely hypoplastic. Brainstem and cerebellar malformations were also present, as well as old necrotic foci. Findings in this case suggest that the cortical malformation in MOPD I/III is distinct from other forms of pachygyria-lissencephaly.

Migration from Mexico to the United States and subsequent risk for depressive and anxiety disorders: a cross-national study.

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Breslau, Joshua; Borges, Guilherme; Tancredi, Daniel; Saito, Naomi; Kravitz, Richard; Hinton, Ladson; Vega, William; Medina-Mora, Maria Elena; Aguilar-Gaxiola, Sergio

2011-04-01

Migration is suspected to increase risk for depressive and anxiety disorders. To test the hypothesized increase in risk for depressive and anxiety disorders after arrival in the United States among Mexican migrants. We combined data from surveys conducted separately in Mexico and the United States that used the same diagnostic interview. Discrete time survival models were specified to estimate the relative odds of first onset of depressive disorders (major depressive episode and dysthymia) and anxiety disorders (generalized anxiety disorder, social phobia, panic disorder, and posttraumatic stress disorder) among migrants after their arrival in the United States compared with nonmigrant Mexicans who have a migrant in their immediate family. Population surveys in the United States and Mexico. Two thousand five hundred nineteen nonmigrant family members of migrants in Mexico and 554 Mexican migrants in the United States. First onset of any depressive or anxiety disorder. After arrival in the United States, migrants had a significantly higher risk for first onset of any depressive or anxiety disorder than did nonmigrant family members of migrants in Mexico (odds ratio, 1.42; 95% confidence interval, 1.04-1.94). Associations between migration and disorder varied across birth cohorts. Elevated risk among migrants relative to nonmigrants was restricted to the 2 younger cohorts (those aged 18-25 or 26-35 years at interview). In the most recent birth cohort, the association between migration and first onset of any depressive or anxiety disorder was particularly strong (odds ratio, 3.89; 95% confidence interval, 2.74-5.53). This is, to our knowledge, the first study to compare risk for first onset of psychiatric disorder between representative samples of migrants in the United States and nonmigrants in Mexico. The findings are consistent with the hypothesized adverse effect of migration from Mexico to the United States on the mental health of migrants, but only among

Walk like me, talk like me. The connection between mirror neurons and autism spectrum disorder.

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Saffin, Jillian M; Tohid, Hassaan

2016-04-01

Understanding social cognition has become a hallmark in deciphering autism spectrum disorder. Neurobiological theories are taking precedence in causation studies as researchers look to abnormalities in brain development as the cause of deficits in social behavior, cognitive processes, and language. Following their discovery in the 1990s, mirror neurons have become a dominant theory for that the mirror neuron system may play a critical role in the pathophysiology of various symptoms of autism. Over the decades, the theory has evolved from the suggestion of a broken mirror neuron system to impairments in mirror neuron circuitry. The mirror neuron system has not gained total support due to inconsistent findings; a comprehensive analysis of the growing body of research could shed light on the benefits, or the disadvantage of continuing to study mirror neurons and their connection to autism.

Mirror neuron system based therapy for emotional disorders.

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Yuan, Ti-Fei; Hoff, Robert

2008-11-01

Mirror neuron system (MNS) represents one of the most important discoveries in the area of neuropsychology of past decades. More than 500 papers have been published in this area (PubMed), and the major functions of MNS include action understanding, imitation, empathy, all of which are critical for an individual to be social. Recent studies suggested that MNS can modulate emotion states possibly through the empathy mechanism. Here we propose that MNS-based therapies provide a non-invasive approach in treatments to emotional disorders that were observed in autism patients, post-stroke patients with depression as well as other mood dysregulation conditions.

Inhibition of the proliferation and acceleration of migration of vascular endothelial cells by increased cysteine-rich motor neuron 1

International Nuclear Information System (INIS)

Nakashima, Yukiko; Morimoto, Mayuka; Toda, Ken-ichi; Shinya, Tomohiro; Sato, Keizo; Takahashi, Satoru

2015-01-01

Cysteine-rich motor neuron 1 (CRIM1) is upregulated only in extracellular matrix gels by angiogenic factors such as vascular endothelial growth factor (VEGF). It then plays a critical role in the tube formation of endothelial cells. In the present study, we investigated the effects of increased CRIM1 on other endothelial functions such as proliferation and migration. Knock down of CRIM1 had no effect on VEGF-induced proliferation or migration of human umbilical vein endothelial cells (HUVECs), indicating that basal CRIM1 is not involved in the proliferation or migration of endothelial cells. Stable CRIM1-overexpressing endothelial F-2 cells, termed CR1 and CR2, were constructed, because it was difficult to prepare monolayer HUVECs that expressed high levels of CRIM1. Proliferation was reduced and migration was accelerated in both CR1 and CR2 cells, compared with normal F-2 cells. Furthermore, the transient overexpression of CRIM1 resulted in decreased proliferation and increased migration of bovine aortic endothelial cells. In contrast, neither proliferation nor migration of COS-7 cells were changed by the overexpression of CRIM1. These results demonstrate that increased CRIM1 reduces the proliferation and accelerates the migration of endothelial cells. These CRIM1 effects might contribute to tube formation of endothelial cells. CRIM1 induced by angiogenic factors may serve as a regulator in endothelial cells to switch from proliferating cells to morphological differentiation. - Highlights: • CRIM1 was upregulated only in tubular endothelial cells, but not in monolayers. • Increased CRIM1 reduced the proliferation of endothelial cells. • Increased CRIM1 accelerated the migration of endothelial cells. • Increased CRIM1 had no effect on the proliferation or migration of COS-7 cells

Inhibition of the proliferation and acceleration of migration of vascular endothelial cells by increased cysteine-rich motor neuron 1

Energy Technology Data Exchange (ETDEWEB)

Nakashima, Yukiko; Morimoto, Mayuka [Department of Immunobiology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women' s University, 11-68 Koshien Kyuban-cho, Nishinomiya, Hyogo 663-8179 (Japan); Toda, Ken-ichi [Department of Dermatology, Kitano Hospital, The Tazuke Kofukai Nedical Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480 (Japan); Shinya, Tomohiro; Sato, Keizo [Department of Clinical Biochemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, Nobeoka, Miyazaki 882-8508 (Japan); Takahashi, Satoru, E-mail: imwalrus@mukogawa-u.ac.jp [Department of Immunobiology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women' s University, 11-68 Koshien Kyuban-cho, Nishinomiya, Hyogo 663-8179 (Japan); Institute for Biosciences, Mukogawa Women' s University, 11-68 Koshien Kyuban-cho, Nishinomiya, Hyogo 663-8179 (Japan)

2015-07-03

Cysteine-rich motor neuron 1 (CRIM1) is upregulated only in extracellular matrix gels by angiogenic factors such as vascular endothelial growth factor (VEGF). It then plays a critical role in the tube formation of endothelial cells. In the present study, we investigated the effects of increased CRIM1 on other endothelial functions such as proliferation and migration. Knock down of CRIM1 had no effect on VEGF-induced proliferation or migration of human umbilical vein endothelial cells (HUVECs), indicating that basal CRIM1 is not involved in the proliferation or migration of endothelial cells. Stable CRIM1-overexpressing endothelial F-2 cells, termed CR1 and CR2, were constructed, because it was difficult to prepare monolayer HUVECs that expressed high levels of CRIM1. Proliferation was reduced and migration was accelerated in both CR1 and CR2 cells, compared with normal F-2 cells. Furthermore, the transient overexpression of CRIM1 resulted in decreased proliferation and increased migration of bovine aortic endothelial cells. In contrast, neither proliferation nor migration of COS-7 cells were changed by the overexpression of CRIM1. These results demonstrate that increased CRIM1 reduces the proliferation and accelerates the migration of endothelial cells. These CRIM1 effects might contribute to tube formation of endothelial cells. CRIM1 induced by angiogenic factors may serve as a regulator in endothelial cells to switch from proliferating cells to morphological differentiation. - Highlights: • CRIM1 was upregulated only in tubular endothelial cells, but not in monolayers. • Increased CRIM1 reduced the proliferation of endothelial cells. • Increased CRIM1 accelerated the migration of endothelial cells. • Increased CRIM1 had no effect on the proliferation or migration of COS-7 cells.

Gonadotropin Releasing Hormone (GnRH) Neuron Migration: Initiation, Maintenance and Cessation as Critical Steps to Ensure Normal Reproductive Function

OpenAIRE

Wierman, Margaret E.; Kiseljak-Vassiliades, Katja; Tobet, Stuart

2010-01-01

GnRH neurons follow a carefully orchestrated journey from their birth in the olfactory placode area. Initially, they migrate along with the vomeronasal nerve into the brain at the cribriform plate, then progress caudally to sites within the hypothalamus where they halt and send projections to the median eminence to activate pituitary gonadotropes. Many factors controlling this precise journey have been elucidated by the silencing or over expression of candidate genes in mouse models. Importan...

Microendophenotypes of psychiatric disorders: phenotypes of psychiatric disorders at the level of molecular dynamics, synapses, neurons, and neural circuits.

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Kida, S; Kato, T

2015-01-01

Psychiatric disorders are caused not only by genetic factors but also by complicated factors such as environmental ones. Moreover, environmental factors are rarely quantitated as biological and biochemical indicators, making it extremely difficult to understand the pathological conditions of psychiatric disorders as well as their underlying pathogenic mechanisms. Additionally, we have actually no other option but to perform biological studies on postmortem human brains that display features of psychiatric disorders, thereby resulting in a lack of experimental materials to characterize the basic biology of these disorders. From these backgrounds, animal, tissue, or cell models that can be used in basic research are indispensable to understand biologically the pathogenic mechanisms of psychiatric disorders. In this review, we discuss the importance of microendophenotypes of psychiatric disorders, i.e., phenotypes at the level of molecular dynamics, neurons, synapses, and neural circuits, as targets of basic research on these disorders.

Study on cognition disorder and morphologic change of neurons in hippocampus area following traumatic brain injury in rats

Institute of Scientific and Technical Information of China (English)

洪军; 崔建忠; 周云涛; 高俊玲

2002-01-01

Objective:　To explore the correlation between cognition disorder and morphologic change of hippocampal neurons after traumatic brain injury (TBI). 　　Methods:　Wistar rat models with severe TBI were made by Marmarous method. The histopathological change of the neurons in the hippocampus area were studied with hematoxylin-eosin (HE) staining and terminal deoxynucleotidyl transferase-mediated X-dUPT nick end labeling (TUNEL), respectively. The cognitive function was evaluated with the Morris water maze test. 　　Results:　The comprehensive neuronal degeneration and necrosis could be observed in CA2-3 regions of hippocampus at 3 days after injury. Apoptotic positive neurons in CA2-4 regions of hippocampus and dentate gyrus increased in the injured group at 24 hours following TBI. They peaked at 7 days and then declined. Significant impairment of spatial learning and memory was observed after injury in the rats. 　　Conclusions:　The rats have obvious disorders in spatial learning and memory after severe TBI. Meanwhile, delayed neuronal necrosis and apoptosis can be observed in the neurons in the hippocampus area. It suggests that delayed hippocampal cell death may contribute to the functional deficit.

Migration from Mexico to the US and Subsequent Risk for Depressive and Anxiety Disorders: A Cross-National Study

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Breslau, Joshua; Borges, Guilherme; Tancredi, Daniel; Saito, Naomi; Kravitz, Richard; Hinton, Ladson; Vega, William; Medina-Mora, Maria Elena; Aguilar-Gaxiola, Sergio

2013-01-01

Objective To test the hypothesized increase in risk for depressive and anxiety disorders following arrival in the US among Mexican-origin migrants. Method Data from surveys conducted in Mexico and the US were combined. The surveys were conducted separately, but used the same structured diagnostic interview. Discrete time survival models were specified to estimate the relative odds of first onset of depressive (major depressive episode, dysthymia) and anxiety (generalized anxiety disorder, social phobia, panic disorder, posttraumatic stress disorder) disorders among migrants after their arrival in the US compared with non-migrant Mexicans who have a migrant in their immediate family. Results After arrival in the US, migrants had signficantly higher risk for first onset of any depressive or anxiety disorder than non-migrant family members of migrants in Mexico (OR=1.4, 95% CI =1.04–1.94). Associations between migration and disorder varied across birth cohorts. Elevated risk among migrants relative to non-migrants was restricted to the two younger cohorts, those 18–25 or 26–35 years old at interview. In the most recent cohort, the association between migration and first onset of any depressive or anxiety disorder was particularly strong (OR=3.89, 95% CI=2.74–5.53). Conclusions This is the first study to compare risk for first onset of psychaitric disorder between representative samples of migrants in the US and non-migrants in Mexico. The findings are consistent with the hypothesized adverse effect of migration from Mexico to the US on the mental health of migrants, but only among migrants in recent birth cohorts. PMID:21464367

Mirror Neurons Modeled Through Spike-Timing-Dependent Plasticity are Affected by Channelopathies Associated with Autism Spectrum Disorder.

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Antunes, Gabriela; Faria da Silva, Samuel F; Simoes de Souza, Fabio M

2018-06-01

Mirror neurons fire action potentials both when the agent performs a certain behavior and watches someone performing a similar action. Here, we present an original mirror neuron model based on the spike-timing-dependent plasticity (STDP) between two morpho-electrical models of neocortical pyramidal neurons. Both neurons fired spontaneously with basal firing rate that follows a Poisson distribution, and the STDP between them was modeled by the triplet algorithm. Our simulation results demonstrated that STDP is sufficient for the rise of mirror neuron function between the pairs of neocortical neurons. This is a proof of concept that pairs of neocortical neurons associating sensory inputs to motor outputs could operate like mirror neurons. In addition, we used the mirror neuron model to investigate whether channelopathies associated with autism spectrum disorder could impair the modeled mirror function. Our simulation results showed that impaired hyperpolarization-activated cationic currents (Ih) affected the mirror function between the pairs of neocortical neurons coupled by STDP.

No neuronal autoantibodies detected in plasma of patients with a bipolar I disorder

NARCIS (Netherlands)

Snijders, Gijsje; Titulaer, Maarten J.; Bergink, Veerle; Bastiaansen, Anna E.; Schreurs, Marco W.J.; Ophoff, Roel A.; Boks, Marco P.; Kahn, René S.; de Witte, Lot D.

2018-01-01

A subpopulation of patients with bipolar disorder type I (BD-I) might suffer from undiagnosed autoimmune encephalitis. We tested plasma of 104 BD-I patients with a current or recent manic episode in the past 2 years for the presence of neuronal autoantibodies using immunohistochemistry,

Accumulation of GABAergic neurons, causing a focal ambient GABA gradient, and downregulation of KCC2 are induced during microgyrus formation in a mouse model of polymicrogyria.

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Wang, Tianying; Kumada, Tatsuro; Morishima, Toshitaka; Iwata, Satomi; Kaneko, Takeshi; Yanagawa, Yuchio; Yoshida, Sachiko; Fukuda, Atsuo

2014-04-01

Although focal cortical malformations are considered neuronal migration disorders, their formation mechanisms remain unknown. We addressed how the γ-aminobutyric acid (GABA)ergic system affects the GABAergic and glutamatergic neuronal migration underlying such malformations. A focal freeze-lesion (FFL) of the postnatal day zero (P0) glutamic acid decarboxylase-green fluorescent protein knock-in mouse neocortex produced a 3- or 4-layered microgyrus at P7. GABAergic interneurons accumulated around the necrosis including the superficial region during microgyrus formation at P4, whereas E17.5-born, Cux1-positive pyramidal neurons outlined the GABAergic neurons and were absent from the superficial layer, forming cell-dense areas in layer 2 of the P7 microgyrus. GABA imaging showed that an extracellular GABA level temporally increased in the GABAergic neuron-positive area, including the necrotic center, at P4. The expression of the Cl(-) transporter KCC2 was downregulated in the microgyrus-forming GABAergic and E17.5-born glutamatergic neurons at P4; these cells may need a high intracellular Cl(-) concentration to induce depolarizing GABA effects. Bicuculline decreased the frequency of spontaneous Ca(2+) oscillations in these microgyrus-forming cells. Thus, neonatal FFL causes specific neuronal accumulation, preceded by an increase in ambient GABA during microgyrus formation. This GABA increase induces GABAA receptor-mediated Ca(2+) oscillation in KCC2-downregulated microgyrus-forming cells, as seen in migrating cells during early neocortical development.

Markers of neuroinflammation and neuronal injury in bipolar disorder: Relation to prospective clinical outcomes.

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Isgren, Anniella; Sellgren, Carl; Ekman, Carl-Johan; Holmén-Larsson, Jessica; Blennow, Kaj; Zetterberg, Henrik; Jakobsson, Joel; Landén, Mikael

2017-10-01

Neuroimmune mechanisms have been linked to the pathophysiology of bipolar disorder based on studies of biomarkers in plasma, cerebrospinal fluid (CSF), and postmortem brain tissue. There are, however, no longitudinal studies investigating if CSF markers of neuroinflammation and neuronal injury predict clinical outcomes in patients with bipolar disorder. We have in previous studies found higher CSF concentrations of interleukin-8 (IL-8), monocyte chemoattractant protein 1 (MCP-1/CCL-2), chitinase-3-like protein 1 (CHI3L1/YKL-40), and neurofilament light chain (NF-L) in euthymic patients with bipolar disorder compared with controls. Here, we investigated the relationship of these CSF markers of neuroinflammation and neuronal injury with clinical outcomes in a prospective study. 77 patients with CSF analyzed at baseline were followed for 6-7years. Associations of baseline biomarkers with clinical outcomes (manic/hypomanic and depressive episodes, suicide attempts, psychotic symptoms, inpatient care, GAF score change) were investigated. Baseline MCP-1 concentrations were positively associated with manic/hypomanic episodes and inpatient care during follow-up. YKL-40 concentrations were negatively associated with manic/hypomanic episodes and with occurrence of psychotic symptoms. The prospective negative association between YKL-40 and manic/hypomanic episodes survived multiple testing correction. Concentrations of IL-8 and NF-L were not associated with clinical outcomes. High concentrations of these selected CSF markers of neuroinflammation and neuronal injury at baseline were not consistently associated with poor clinical outcomes in this prospective study. The assessed proteins may be involved in adaptive immune processes or reflect a state of vulnerability for bipolar disorder rather than being of predictive value for disease progression. Copyright © 2017 Elsevier Inc. All rights reserved.

Lesion-induced increase in survival and migration of human neural progenitor cells releasing GDNF

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Behrstock, Soshana; Ebert, Allison D.; Klein, Sandra; Schmitt, Melanie; Moore, Jeannette M.; Svendsen, Clive N.

2009-01-01

The use of human neural progenitor cells (hNPC) has been proposed to provide neuronal replacement or astrocytes delivering growth factors for brain disorders such as Parkinson’s and Huntington’s disease. Success in such studies likely requires migration from the site of transplantation and integration into host tissue in the face of ongoing damage. In the current study, hNPC modified to release glial cell line derived neurotrophic factor (hNPCGDNF) were transplanted into either intact or lesioned animals. GDNF release itself had no effect on the survival, migration or differentiation of the cells. The most robust migration and survival was found using a direct lesion of striatum (Huntington’s model) with indirect lesions of the dopamine system (Parkinson’s model) or intact animals showing successively less migration and survival. No lesion affected differentiation patterns. We conclude that the type of brain injury dictates migration and integration of hNPC which has important consequences when considering transplantation of these cells as a therapy for neurodegenerative diseases. PMID:19044202

Trajectory Analysis Unveils Reelin's Role in the Directed Migration of Granule Cells in the Dentate Gyrus.

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Wang, Shaobo; Brunne, Bianka; Zhao, Shanting; Chai, Xuejun; Li, Jiawei; Lau, Jeremie; Failla, Antonio Virgilio; Zobiak, Bernd; Sibbe, Mirjam; Westbrook, Gary L; Lutz, David; Frotscher, Michael

2018-01-03

Reelin controls neuronal migration and layer formation. Previous studies in reeler mice deficient in Reelin focused on the result of the developmental process in fixed tissue sections. It has remained unclear whether Reelin affects the migratory process, migration directionality, or migrating neurons guided by the radial glial scaffold. Moreover, Reelin has been regarded as an attractive signal because newly generated neurons migrate toward the Reelin-containing marginal zone. Conversely, Reelin might be a stop signal because migrating neurons in reeler , but not in wild-type mice, invade the marginal zone. Here, we monitored the migration of newly generated proopiomelanocortin-EGFP -expressing dentate granule cells in slice cultures from reeler , reeler -like mutants and wild-type mice of either sex using real-time microscopy. We discovered that not the actual migratory process and migratory speed, but migration directionality of the granule cells is controlled by Reelin. While wild-type granule cells migrated toward the marginal zone of the dentate gyrus, neurons in cultures from reeler and reeler -like mutants migrated randomly in all directions as revealed by vector analyses of migratory trajectories. Moreover, live imaging of granule cells in reeler slices cocultured to wild-type dentate gyrus showed that the reeler neurons changed their directions and migrated toward the Reelin-containing marginal zone of the wild-type culture, thus forming a compact granule cell layer. In contrast, directed migration was not observed when Reelin was ubiquitously present in the medium of reeler slices. These results indicate that topographically administered Reelin controls the formation of a granule cell layer. SIGNIFICANCE STATEMENT Neuronal migration and the various factors controlling its onset, speed, directionality, and arrest are poorly understood. Slice cultures offer a unique model to study the migration of individual neurons in an almost natural environment. In the

Migration and common mental disorder: an improvement in mental health over time?

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Butler, Margaret; Warfa, Nasir; Khatib, Yasmin; Bhui, Kamaldeep

2015-02-01

Global migration is reaching record high levels and UK migrant groups comprise an increasing proportion of the total population. The migratory process causes stress that can affect mental health. There is limited consistent empirical evidence of a longitudinal nature to explain the association between migration and mental health. This review aims to examine the evidence of a relationship between migration and common mental disorder (CMD) amongst migrants over time. A comprehensive search of medical and psychiatric databases for global quantitative empirical studies investigating incidence of CMD amongst adult migrants from 1975 to July 2012 was conducted. Declines in rates of CMD amongst migrants over time were reported by two thirds of the 18 studies reviewed, less than one third of which were statistically significant. On the contrary, three studies showed an increased rate of CMD, one statistically significant. Individual psychological resources, social support, the acculturation process, cultural variations and time since relocation are identified as statistically significant protective factors against the development of CMD amongst migrants. New enlightening points include the significant impact of varying patterns of psychological distress, of which negative is the most adverse for CMD. Migration is an extremely complex process. Further clarification is needed to gain deeper understanding of the relationship between migration and CMD to address contradictions in the literature and health inequalities amongst migrants.

Netrin-1 Confines Rhombic Lip-Derived Neurons to the CNS

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Andrea R. Yung

2018-02-01

Full Text Available During brainstem development, newborn neurons originating from the rhombic lip embark on exceptionally long migrations to generate nuclei important for audition, movement, and respiration. Along the way, this highly motile population passes several cranial nerves yet remains confined to the CNS. We found that Ntn1 accumulates beneath the pial surface separating the CNS from the PNS, with gaps at nerve entry sites. In mice null for Ntn1 or its receptor DCC, hindbrain neurons enter cranial nerves and migrate into the periphery. CNS neurons also escape when Ntn1 is selectively lost from the sub-pial region (SPR, and conversely, expression of Ntn1 throughout the mutant hindbrain can prevent their departure. These findings identify a permissive role for Ntn1 in maintaining the CNS-PNS boundary. We propose that Ntn1 confines rhombic lip-derived neurons by providing a preferred substrate for tangentially migrating neurons in the SPR, preventing their entry into nerve roots.

Neurons other than motor neurons in motor neuron disease.

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Ruffoli, Riccardo; Biagioni, Francesca; Busceti, Carla L; Gaglione, Anderson; Ryskalin, Larisa; Gambardella, Stefano; Frati, Alessandro; Fornai, Francesco

2017-11-01

Amyotrophic lateral sclerosis (ALS) is typically defined by a loss of motor neurons in the central nervous system. Accordingly, morphological analysis for decades considered motor neurons (in the cortex, brainstem and spinal cord) as the neuronal population selectively involved in ALS. Similarly, this was considered the pathological marker to score disease severity ex vivo both in patients and experimental models. However, the concept of non-autonomous motor neuron death was used recently to indicate the need for additional cell types to produce motor neuron death in ALS. This means that motor neuron loss occurs only when they are connected with other cell types. This concept originally emphasized the need for resident glia as well as non-resident inflammatory cells. Nowadays, the additional role of neurons other than motor neurons emerged in the scenario to induce non-autonomous motor neuron death. In fact, in ALS neurons diverse from motor neurons are involved. These cells play multiple roles in ALS: (i) they participate in the chain of events to produce motor neuron loss; (ii) they may even degenerate more than and before motor neurons. In the present manuscript evidence about multi-neuronal involvement in ALS patients and experimental models is discussed. Specific sub-classes of neurons in the whole spinal cord are reported either to degenerate or to trigger neuronal degeneration, thus portraying ALS as a whole spinal cord disorder rather than a disease affecting motor neurons solely. This is associated with a novel concept in motor neuron disease which recruits abnormal mechanisms of cell to cell communication.

Paracrine Maturation and Migration of SH-SY5Y Cells by Dental Pulp Stem Cells

OpenAIRE

Gervois, Pascal; Wolfs, Esther; Dillen, Yörg; Hilkens, Petra; Ratajczak, Jessica; Driesen, Ronald; Vangansewinkel, Tim; Bronckaers, Annelies; Brône, Bert; Struys, Tom; Lambrichts, Ivo

2017-01-01

Neurological disorders are characterized by neurodegeneration and/or loss of neuronal function, which cannot be adequately repaired by the host. Therefore, there is need for novel treatment options such as cell-based therapies that aim to salvage or reconstitute the lost tissue or that stimulate host repair. The present study aimed to evaluate the paracrine effects of human dental pulp stem cells (hDPSCs) on the migration and neural maturation of human SH-SY5Y neuroblastoma cells. The hDPSC s...

Brain-specific transcriptional regulator T-brain-1 controls brain wiring and neuronal activity in autism spectrum disorders

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Tzyy-Nan eHuang

2015-11-01

Full Text Available T-brain-1 (TBR1 is a brain-specific T-box transcription factor. In 1995, Tbr1 was first identified from a subtractive hybridization that compared mouse embryonic and adult telencephalons. Previous studies of Tbr1–/– mice have indicated critical roles for TBR1 in the development of the cerebral cortex, amygdala and olfactory bulb. Neuronal migration and axonal projection are two important developmental features controlled by TBR1. Recently, recurrent de novo disruptive mutations in the TBR1 gene have been found in patients with autism spectrum disorders (ASDs. Human genetic studies have identified TBR1 as a high-confidence risk factor for ASDs. Because only one allele of the TBR1 gene is mutated in these patients, Tbr1+/– mice serve as a good genetic mouse model to explore the mechanism by which de novo TBR1 mutation leads to ASDs. Although neuronal migration and axonal projection defects of cerebral cortex are the most prominent phenotypes in Tbr1–/– mice, these features are not found in Tbr1+/– mice. Instead, inter- and intra-amygdalar axonal projections and NMDAR expression and activity in amygdala are particularly susceptible to Tbr1 haploinsufficiency. The studies indicated that both abnormal brain wiring (abnormal amygdalar connections and excitation/inhibition imbalance (NMDAR hypoactivity, two prominent models for ASD etiology, are present in Tbr1+/– mice. Moreover, calcium/calmodulin-dependent serine protein kinase (CASK was found to interact with TBR1. The CASK-TBR1 complex had been shown to directly bind the promoter of the Grin2b gene, which is also known as Nmdar2b, and upregulate Grin2b expression. This molecular function of TBR1 provides an explanation for NMDAR hypoactivity in Tbr1+/– mice. In addition to Grin2b, cell adhesion molecules－including Ntng1, Cdh8 and Cntn2－are also regulated by TBR1 to control axonal projections of amygdala. Taken together, the studies of Tbr1 provide an integrated picture of ASD

Bacurd2 is a novel interacting partner to Rnd2 which controls radial migration within the developing mammalian cerebral cortex.

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Gladwyn-Ng, Ivan Enghian; Li, Shan Shan; Qu, Zhengdong; Davis, John Michael; Ngo, Linh; Haas, Matilda; Singer, Jeffrey; Heng, Julian Ik-Tsen

2015-03-31

During fetal brain development in mammals, newborn neurons undergo cell migration to reach their appropriate positions and form functional circuits. We previously reported that the atypical RhoA GTPase Rnd2 promotes the radial migration of mouse cerebral cortical neurons (Nature 455(7209):114-8, 2008; Neuron 69(6):1069-84, 2011), but its downstream signalling pathway is not well understood. We have identified BTB-domain containing adaptor for Cul3-mediated RhoA degradation 2 (Bacurd2) as a novel interacting partner to Rnd2, which promotes radial migration within the developing cerebral cortex. We find that Bacurd2 binds Rnd2 at its C-terminus, and this interaction is critical to its cell migration function. We show that forced expression or knockdown of Bacurd2 impairs neuronal migration within the embryonic cortex and alters the morphology of immature neurons. Our in vivo cellular analysis reveals that Bacurd2 influences the multipolar-to-bipolar transition of radially migrating neurons in a cell autonomous fashion. When we addressed the potential signalling relationship between Bacurd2 and Rnd2 using a Bacurd2-Rnd2 chimeric construct, our results suggest that Bacurd2 and Rnd2 could interact to promote radial migration within the embryonic cortex. Our studies demonstrate that Bacurd2 is a novel player in neuronal development and influences radial migration within the embryonic cerebral cortex.

Human iPSC-derived neurons and lymphoblastoid cells for personalized medicine research in neuropsychiatric disorders.

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Gurwitz, David

2016-09-01

The development and clinical implementation of personalized medicine crucially depends on the availability of high-quality human biosamples; animal models, although capable of modeling complex human diseases, cannot reflect the large variation in the human genome, epigenome, transcriptome, proteome, and metabolome. Although the biosamples available from public biobanks that store human tissues and cells may represent the large human diversity for most diseases, these samples are not always sufficient for developing biomarkers for patient-tailored therapies for neuropsychiatric disorders. Postmortem human tissues are available from many biobanks; nevertheless, collections of neuronal human cells from large patient cohorts representing the human diversity remain scarce. Two tools are gaining popularity for personalized medicine research on neuropsychiatric disorders: human induced pluripotent stem cell-derived neurons and human lymphoblastoid cell lines. This review examines and contrasts the advantages and limitations of each tool for personalized medicine research.

Developmental Patterns of Doublecortin Expression and White Matter Neuron Density in the Postnatal Primate Prefrontal Cortex and Schizophrenia

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Fung, Samantha J.; Joshi, Dipesh; Allen, Katherine M.; Sivagnanasundaram, Sinthuja; Rothmond, Debora A.; Saunders, Richard; Noble, Pamela L.; Webster, Maree J.; Shannon Weickert, Cynthia

2011-01-01

Postnatal neurogenesis occurs in the subventricular zone and dentate gyrus, and evidence suggests that new neurons may be present in additional regions of the mature primate brain, including the prefrontal cortex (PFC). Addition of new neurons to the PFC implies local generation of neurons or migration from areas such as the subventricular zone. We examined the putative contribution of new, migrating neurons to postnatal cortical development by determining the density of neurons in white matter subjacent to the cortex and measuring expression of doublecortin (DCX), a microtubule-associated protein involved in neuronal migration, in humans and rhesus macaques. We found a striking decline in DCX expression (human and macaque) and density of white matter neurons (humans) during infancy, consistent with the arrival of new neurons in the early postnatal cortex. Considering the expansion of the brain during this time, the decline in white matter neuron density does not necessarily indicate reduced total numbers of white matter neurons in early postnatal life. Furthermore, numerous cells in the white matter and deep grey matter were positive for the migration-associated glycoprotein polysialiated-neuronal cell adhesion molecule and GAD65/67, suggesting that immature migrating neurons in the adult may be GABAergic. We also examined DCX mRNA in the PFC of adult schizophrenia patients (n = 37) and matched controls (n = 37) and did not find any difference in DCX mRNA expression. However, we report a negative correlation between DCX mRNA expression and white matter neuron density in adult schizophrenia patients, in contrast to a positive correlation in human development where DCX mRNA and white matter neuron density are higher earlier in life. Accumulation of neurons in the white matter in schizophrenia would be congruent with a negative correlation between DCX mRNA and white matter neuron density and support the hypothesis of a migration deficit in schizophrenia. PMID

Developmental patterns of doublecortin expression and white matter neuron density in the postnatal primate prefrontal cortex and schizophrenia.

Directory of Open Access Journals (Sweden)

Samantha J Fung

Full Text Available Postnatal neurogenesis occurs in the subventricular zone and dentate gyrus, and evidence suggests that new neurons may be present in additional regions of the mature primate brain, including the prefrontal cortex (PFC. Addition of new neurons to the PFC implies local generation of neurons or migration from areas such as the subventricular zone. We examined the putative contribution of new, migrating neurons to postnatal cortical development by determining the density of neurons in white matter subjacent to the cortex and measuring expression of doublecortin (DCX, a microtubule-associated protein involved in neuronal migration, in humans and rhesus macaques. We found a striking decline in DCX expression (human and macaque and density of white matter neurons (humans during infancy, consistent with the arrival of new neurons in the early postnatal cortex. Considering the expansion of the brain during this time, the decline in white matter neuron density does not necessarily indicate reduced total numbers of white matter neurons in early postnatal life. Furthermore, numerous cells in the white matter and deep grey matter were positive for the migration-associated glycoprotein polysialiated-neuronal cell adhesion molecule and GAD65/67, suggesting that immature migrating neurons in the adult may be GABAergic. We also examined DCX mRNA in the PFC of adult schizophrenia patients (n = 37 and matched controls (n = 37 and did not find any difference in DCX mRNA expression. However, we report a negative correlation between DCX mRNA expression and white matter neuron density in adult schizophrenia patients, in contrast to a positive correlation in human development where DCX mRNA and white matter neuron density are higher earlier in life. Accumulation of neurons in the white matter in schizophrenia would be congruent with a negative correlation between DCX mRNA and white matter neuron density and support the hypothesis of a migration deficit in

[Neurotransmission in developmental disorders].

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Takeuchi, Yoshihiro

2008-11-01

Attention deficit/hyperactivity disorder (AD/HD) is a heterogeneous developmental disorder with an etiology that is not fully understood. AD/HD has been considered to occur due to a disturbance in cathecholaminergic neurotransmission, with particular emphasis on dopamine. The neurotransmission of dopamine in subcortical regions such as the basal ganglia and limbic areas is synaptic; on the other hand, dopamine neurotransmission in the frontal cortex is quite different, because there are very few dopamine transporters (DAT) in the frontal cortex that allow dopamine to diffuse away from the dopamine synapse ("volume transmission"). It is now clear that noradrenergic neurons play a key regulatory role in dopaminergic function in the frontal cortex. Furthermore, serotonergic neurons exert an inhibitory effect on midbrain dopamine cell bodies, and they have an influence on dopamine release in terminal regions. There is accumulating neurobiological evidence pointing toward a role of the serotonin system in AD/HD. The etiology of autism spectrum disorders (ASD) is still unclear, but information from genetics, neuropathology, brain imaging, and basic neuroscience has provided insights into the understanding of this developmental disorder. In addition to abnormal circuitry in specific limbic and neocortical areas of the cerebral cortex, impairments in brainstem, cerebellar, thalamic, and basal ganglia connections have been reported. Numerous studies have pointed to abnormalities in serotonin and glutamate neurotransmission. Three important aspects involved in the pathophysiology of ASD have been proposed. The first is cell migration, the second is unbalanced excitatory-inhibitory networks, and the third is synapse formation and pruning, the key factors being reelin, neurexin, and neuroligin. Serotonin is considered to play an important role in all of these aspects of the pathophysiology of ASD. Finally, I would like to emphasize that it is crucial in the field of child

Sugar Antennae for Guidance Signals: Syndecans and Glypicans Integrate Directional Cues for Navigating Neurons

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Christa Rhiner

2006-01-01

Full Text Available Attractive and repulsive signals guide migrating nerve cells in all directions when the nervous system starts to form. The neurons extend thin processes, axons, that connect over wide distances with other brain cells to form a complicated neuronal network. One of the most fascinating questions in neuroscience is how the correct wiring of billions of nerve cells in our brain is controlled. Several protein families are known to serve as guidance cues for navigating neurons and axons. Nevertheless, the combinatorial potential of these proteins seems to be insufficient to sculpt the entire neuronal network and the appropriate formation of connections. Recently, heparan sulfate proteoglycans (HSPGs, which are present on the cell surface of neurons and in the extracellular matrix through which neurons and axons migrate, have been found to play a role in regulating cell migration and axon guidance. Intriguingly, the large number of distinct modifications that can be put onto the sugar side chains of these PGs would in principle allow for an enormous diversity of HSPGs, which could help in regulating the vast number of guidance choices taken by individual neurons. In this review, we will focus on the role of the cell surface HSPGs syndecan and glypican and specific HS modifications in promoting neuronal migration, axon guidance, and synapse formation.

Assessment of Perceived Stress Related to Migration and Acculturation in Patients with Psychiatric Disorders (MIGSTR10)-Development, Reliability, and Dimensionality of a Brief Instrument.

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Müller, Matthias J; Zink, Sabrina; Koch, Eckhardt

2017-09-01

Assessment of stressors related to migration and acculturation in patients with psychiatric disorder and migration background could help improve culturally sensitive concepts of psychiatry and psychotherapy for diagnosis and treatment. The present overview delineates development and psychometric properties of an instrument (MIGSTR10) for assessment of stressors related to migration and acculturation, particularly for application in patients with psychiatric disorders. Ten migration-related stressors were derived from a qualitative content analysis of case histories of patients with psychiatric disorder and migration background and put into a suitable interview and questionnaire format (MIGSTR10; 10 questions, answer format: categorical yes/no, and dimensional 0-10) for self-assessment and observer ratings in several languages. Reliability (interrater agreement, internal consistency) and dimensionality (multi-dimensional scaling, MDS) were investigated in n = 235 patients with migration background and n = 612 indigenous German patients. Interrater agreement (ICC) for MIGSTR10 single items and sum scores (categorical and dimensional) was sufficiently high (≥.58); internal consistency (Cronbach's α) reached medium to high values (.56-.73). MDS revealed a two-dimensional solution with two item clusters (A: communication, migration history, forced marriage, homesickness, discrimination, other stressors; B: family conflicts, loss of status, feelings of shame, guilt feelings). The MIGSTR10 is a rationally developed, straightforward 10-item screening instrument with satisfactory psychometric properties for the assessment of individual and specific stressors related to migration and acculturation.

Mirror neurons and the understanding of behavioural symptoms in psychiatric disorders.

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Buccino, Giovanni; Amore, Mario

2008-05-01

Recent findings show that we can understand other people's actions, intentions and emotions through a mirror mechanism as if we performed the same actions and felt the same intentions or emotions (embodied simulation). The present paper reviews experimental evidence that this mechanism may be broken in some psychiatric disorders. A mirror neuron system has been described in both monkeys and humans that allows one to map an observed action on a correspondent motor representation in the observer's brain. This mechanism has been involved in many higher motor functions ranging from action understanding to imitation and intention coding. A mirror mechanism has also been invoked in empathy, through an embodied simulation. A dysfunction of the mirror neuron system may be at the root of the inability to empathize in patients with autism and may play a role in some negative and positive symptoms found in patients with schizophrenia. This opens up new perspectives in the interpretation of psychotic symptoms and possibly in developing therapeutic strategies.

CT and MR imaging evaluation of the inherited and prenatally acquired migrational disorders of the brain

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Byrd, S.E.; Osborn, R.E.; Naidich, T.P.; Bohan, T.P.

1987-01-01

The migrational disorders are a rare group of congenital malformations of the brain seen in children. They are primarily cortical and gray matter abnormalities. Forty patients, divided into two groups, were studied. In one group were patients with the classic migrational lesions of lissencephaly, pachygyria, schizencephaly, heterotopia, and polymicrogyria in which the underlying cause is genetic, chromosomal, or unknown. In the second group were patients with lesions caused by a prenatally acquired infection (toxoplasmosis or cytomegalic virus) or a metabolic abnormality. The CT and MR imaging findings in these two groups are discussed

EEG evidence for mirror neuron dysfunction in autism spectrum disorders.

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Oberman, Lindsay M; Hubbard, Edward M; McCleery, Joseph P; Altschuler, Eric L; Ramachandran, Vilayanur S; Pineda, Jaime A

2005-07-01

Autism spectrum disorders (ASD) are largely characterized by deficits in imitation, pragmatic language, theory of mind, and empathy. Previous research has suggested that a dysfunctional mirror neuron system may explain the pathology observed in ASD. Because EEG oscillations in the mu frequency (8-13 Hz) over sensorimotor cortex are thought to reflect mirror neuron activity, one method for testing the integrity of this system is to measure mu responsiveness to actual and observed movement. It has been established that mu power is reduced (mu suppression) in typically developing individuals both when they perform actions and when they observe others performing actions, reflecting an observation/execution system which may play a critical role in the ability to understand and imitate others' behaviors. This study investigated whether individuals with ASD show a dysfunction in this system, given their behavioral impairments in understanding and responding appropriately to others' behaviors. Mu wave suppression was measured in ten high-functioning individuals with ASD and ten age- and gender-matched control subjects while watching videos of (1) a moving hand, (2) a bouncing ball, and (3) visual noise, or (4) moving their own hand. Control subjects showed significant mu suppression to both self and observed hand movement. The ASD group showed significant mu suppression to self-performed hand movements but not to observed hand movements. These results support the hypothesis of a dysfunctional mirror neuron system in high-functioning individuals with ASD.

Fishing for causes and cures of motor neuron disorders.

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Patten, Shunmoogum A; Armstrong, Gary A B; Lissouba, Alexandra; Kabashi, Edor; Parker, J Alex; Drapeau, Pierre

2014-07-01

Motor neuron disorders (MNDs) are a clinically heterogeneous group of neurological diseases characterized by progressive degeneration of motor neurons, and share some common pathological pathways. Despite remarkable advances in our understanding of these diseases, no curative treatment for MNDs exists. To better understand the pathogenesis of MNDs and to help develop new treatments, the establishment of animal models that can be studied efficiently and thoroughly is paramount. The zebrafish (Danio rerio) is increasingly becoming a valuable model for studying human diseases and in screening for potential therapeutics. In this Review, we highlight recent progress in using zebrafish to study the pathology of the most common MNDs: spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). These studies indicate the power of zebrafish as a model to study the consequences of disease-related genes, because zebrafish homologues of human genes have conserved functions with respect to the aetiology of MNDs. Zebrafish also complement other animal models for the study of pathological mechanisms of MNDs and are particularly advantageous for the screening of compounds with therapeutic potential. We present an overview of their potential usefulness in MND drug discovery, which is just beginning and holds much promise for future therapeutic development. © 2014. Published by The Company of Biologists Ltd.

Fishing for causes and cures of motor neuron disorders

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Shunmoogum A. Patten

2014-07-01

Full Text Available Motor neuron disorders (MNDs are a clinically heterogeneous group of neurological diseases characterized by progressive degeneration of motor neurons, and share some common pathological pathways. Despite remarkable advances in our understanding of these diseases, no curative treatment for MNDs exists. To better understand the pathogenesis of MNDs and to help develop new treatments, the establishment of animal models that can be studied efficiently and thoroughly is paramount. The zebrafish (Danio rerio is increasingly becoming a valuable model for studying human diseases and in screening for potential therapeutics. In this Review, we highlight recent progress in using zebrafish to study the pathology of the most common MNDs: spinal muscular atrophy (SMA, amyotrophic lateral sclerosis (ALS and hereditary spastic paraplegia (HSP. These studies indicate the power of zebrafish as a model to study the consequences of disease-related genes, because zebrafish homologues of human genes have conserved functions with respect to the aetiology of MNDs. Zebrafish also complement other animal models for the study of pathological mechanisms of MNDs and are particularly advantageous for the screening of compounds with therapeutic potential. We present an overview of their potential usefulness in MND drug discovery, which is just beginning and holds much promise for future therapeutic development.

RP58 Regulates the Multipolar-Bipolar Transition of Newborn Neurons in the Developing Cerebral Cortex

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Chiaki Ohtaka-Maruyama

2013-02-01

Full Text Available Accumulating evidence suggests that many brain diseases are associated with defects in neuronal migration, suggesting that this step of neurogenesis is critical for brain organization. However, the molecular mechanisms underlying neuronal migration remain largely unknown. Here, we identified the zinc-finger transcriptional repressor RP58 as a key regulator of neuronal migration via multipolar-to-bipolar transition. RP58−/− neurons exhibited severe defects in the formation of leading processes and never shifted to the locomotion mode. Cre-mediated deletion of RP58 using in utero electroporation in RP58flox/flox mice revealed that RP58 functions in cell-autonomous multipolar-to-bipolar transition, independent of cell-cycle exit. Finally, we found that RP58 represses Ngn2 transcription to regulate the Ngn2-Rnd2 pathway; Ngn2 knockdown rescued migration defects of the RP58−/− neurons. Our findings highlight the critical role of RP58 in multipolar-to-bipolar transition via suppression of the Ngn2-Rnd2 pathway in the developing cerebral cortex.

Fate of Cajal-Retzius neurons in the postnatal mouse neocortex

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Tara G Chowdhury

2010-03-01

Full Text Available Cajal-Retzius (CR neurons play a critical role in cortical neuronal migration, but their exact fate after the completion of neocortical lamination remains a mystery. Histological evidence has been unable to unequivocally determine whether these cells die or undergo a phenotypic transformation to become resident interneurons of Layer 1 in the adult neocortex. To determine their ultimate fate, we performed chronic in vivo two-photon imaging of identified CR neurons during postnatal development in mice that express the green fluorescent protein (GFP under the control of the early B-cell factor 2 (Ebf2 promoter. We find that, after birth, virtually all CR neurons in mouse neocortex express Ebf2. Although postnatal CR neurons undergo dramatic morphological transformations, they do not migrate to deeper layers. Instead, their gradual disappearance from the cortex is due to apoptotic death during the second postnatal week. A small fraction of CR neurons present at birth survive into adulthood. We conclude that, in addition to orchestrating cortical layering, a subset of CR neurons must play other roles beyond the third postnatal week.

In Vivo Profiling Reveals a Competent Heat Shock Response in Adult Neurons: Implications for Neurodegenerative Disorders.

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Alisia Carnemolla

Full Text Available The heat shock response (HSR is the main pathway used by cells to counteract proteotoxicity. The inability of differentiated neurons to induce an HSR has been documented in primary neuronal cultures and has been proposed to play a critical role in ageing and neurodegeneration. However, this accepted dogma has not been demonstrated in vivo. We used BAC transgenic mice generated by the Gene Expression Nervous System Atlas project to investigate the capacity of striatal medium sized spiny neurons to induce an HSR as compared to that of astrocytes and oligodendrocytes. We found that all cell populations were competent to induce an HSR upon HSP90 inhibition. We also show the presence and relative abundance of heat shock-related genes and proteins in these striatal cell populations. The identification of a competent HSR in adult neurons supports the development of therapeutics that target the HSR pathway as treatments for neurodegenerative disorders.

The Caenorhabditis elegans NF2/Merlin Molecule NFM-1 Nonautonomously Regulates Neuroblast Migration and Interacts Genetically with the Guidance Cue SLT-1/Slit

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Josephson, Matthew P.; Aliani, Rana; Norris, Megan L.; Ochs, Matthew E.; Gujar, Mahekta; Lundquist, Erik A.

2016-01-01

During nervous system development, neurons and their progenitors migrate to their final destinations. In Caenorhabditis elegans, the bilateral Q neuroblasts and their descendants migrate long distances in opposite directions, despite being born in the same posterior region. QR on the right migrates anteriorly and generates the AQR neuron positioned near the head, and QL on the left migrates posteriorly, giving rise to the PQR neuron positioned near the tail. In a screen for genes required for...

Motor-auditory-visual integration: The role of the human mirror neuron system in communication and communication disorders.

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Le Bel, Ronald M; Pineda, Jaime A; Sharma, Anu

2009-01-01

The mirror neuron system (MNS) is a trimodal system composed of neuronal populations that respond to motor, visual, and auditory stimulation, such as when an action is performed, observed, heard or read about. In humans, the MNS has been identified using neuroimaging techniques (such as fMRI and mu suppression in the EEG). It reflects an integration of motor-auditory-visual information processing related to aspects of language learning including action understanding and recognition. Such integration may also form the basis for language-related constructs such as theory of mind. In this article, we review the MNS system as it relates to the cognitive development of language in typically developing children and in children at-risk for communication disorders, such as children with autism spectrum disorder (ASD) or hearing impairment. Studying MNS development in these children may help illuminate an important role of the MNS in children with communication disorders. Studies with deaf children are especially important because they offer potential insights into how the MNS is reorganized when one modality, such as audition, is deprived during early cognitive development, and this may have long-term consequences on language maturation and theory of mind abilities. Readers will be able to (1) understand the concept of mirror neurons, (2) identify cortical areas associated with the MNS in animal and human studies, (3) discuss the use of mu suppression in the EEG for measuring the MNS in humans, and (4) discuss MNS dysfunction in children with (ASD).

Direct Neuronal Reprogramming for Disease Modeling Studies Using Patient-Derived Neurons: What Have We Learned?

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Janelle Drouin-Ouellet

2017-09-01

Full Text Available Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows for the possibility of generating patient-derived neurons. A unique feature of these so-called induced neurons (iNs is the potential to maintain aging and epigenetic signatures of the donor, which is critical given that many diseases of the CNS are age related. Here, we review the published literature on the work that has been undertaken using iNs to model human brain disorders. Furthermore, as disease-modeling studies using this direct neuronal reprogramming approach are becoming more widely adopted, it is important to assess the criteria that are used to characterize the iNs, especially in relation to the extent to which they are mature adult neurons. In particular: i what constitutes an iN cell, ii which stages of conversion offer the earliest/optimal time to assess features that are specific to neurons and/or a disorder and iii whether generating subtype-specific iNs is critical to the disease-related features that iNs express. Finally, we discuss the range of potential biomedical applications that can be explored using patient-specific models of neurological disorders with iNs, and the challenges that will need to be overcome in order to realize these applications.

APLP2 regulates neuronal stem cell differentiation during cortical development.

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Shariati, S Ali M; Lau, Pierre; Hassan, Bassem A; Müller, Ulrike; Dotti, Carlos G; De Strooper, Bart; Gärtner, Annette

2013-03-01

Expression of amyloid precursor protein (APP) and its two paralogues, APLP1 and APLP2 during brain development coincides with key cellular events such as neuronal differentiation and migration. However, genetic knockout and shRNA studies have led to contradictory conclusions about their role during embryonic brain development. To address this issue, we analysed in depth the role of APLP2 during neurogenesis by silencing APLP2 in vivo in an APP/APLP1 double knockout mouse background. We find that under these conditions cortical progenitors remain in their undifferentiated state much longer, displaying a higher number of mitotic cells. In addition, we show that neuron-specific APLP2 downregulation does not impact the speed or position of migrating excitatory cortical neurons. In summary, our data reveal that APLP2 is specifically required for proper cell cycle exit of neuronal progenitors, and thus has a distinct role in priming cortical progenitors for neuronal differentiation.

Neuron-specific chromatin remodeling: a missing link in epigenetic mechanisms underlying synaptic plasticity, memory, and intellectual disability disorders.

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Vogel-Ciernia, Annie; Wood, Marcelo A

2014-05-01

Long-term memory formation requires the coordinated regulation of gene expression. Until recently nucleosome remodeling, one of the major epigenetic mechanisms for controlling gene expression, had been largely unexplored in the field of neuroscience. Nucleosome remodeling is carried out by chromatin remodeling complexes (CRCs) that interact with DNA and histones to physically alter chromatin structure and ultimately regulate gene expression. Human exome sequencing and gene wide association studies have linked mutations in CRC subunits to intellectual disability disorders, autism spectrum disorder and schizophrenia. However, how mutations in CRC subunits were related to human cognitive disorders was unknown. There appears to be both developmental and adult specific roles for the neuron specific CRC nBAF (neuronal Brg1/hBrm Associated Factor). nBAF regulates gene expression required for dendritic arborization during development, and in the adult, contributes to long-term potentiation, a form of synaptic plasticity, and long-term memory. We propose that the nBAF complex is a novel epigenetic mechanism for regulating transcription required for long-lasting forms of synaptic plasticity and memory processes and that impaired nBAF function may result in human cognitive disorders. Copyright © 2013 Elsevier Ltd. All rights reserved.

An in silico agent-based model demonstrates Reelin function in directing lamination of neurons during cortical development.

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Caffrey, James R; Hughes, Barry D; Britto, Joanne M; Landman, Kerry A

2014-01-01

The characteristic six-layered appearance of the neocortex arises from the correct positioning of pyramidal neurons during development and alterations in this process can cause intellectual disabilities and developmental delay. Malformations in cortical development arise when neurons either fail to migrate properly from the germinal zones or fail to cease migration in the correct laminar position within the cortical plate. The Reelin signalling pathway is vital for correct neuronal positioning as loss of Reelin leads to a partially inverted cortex. The precise biological function of Reelin remains controversial and debate surrounds its role as a chemoattractant or stop signal for migrating neurons. To investigate this further we developed an in silico agent-based model of cortical layer formation. Using this model we tested four biologically plausible hypotheses for neuron motility and four biologically plausible hypotheses for the loss of neuron motility (conversion from migration). A matrix of 16 combinations of motility and conversion rules was applied against the known structure of mouse cortical layers in the wild-type cortex, the Reelin-null mutant, the Dab1-null mutant and a conditional Dab1 mutant. Using this approach, many combinations of motility and conversion mechanisms can be rejected. For example, the model does not support Reelin acting as a repelling or as a stopping signal. In contrast, the study lends very strong support to the notion that the glycoprotein Reelin acts as a chemoattractant for neurons. Furthermore, the most viable proposition for the conversion mechanism is one in which conversion is affected by a motile neuron sensing in the near vicinity neurons that have already converted. Therefore, this model helps elucidate the function of Reelin during neuronal migration and cortical development.

An in silico agent-based model demonstrates Reelin function in directing lamination of neurons during cortical development.

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James R Caffrey

Full Text Available The characteristic six-layered appearance of the neocortex arises from the correct positioning of pyramidal neurons during development and alterations in this process can cause intellectual disabilities and developmental delay. Malformations in cortical development arise when neurons either fail to migrate properly from the germinal zones or fail to cease migration in the correct laminar position within the cortical plate. The Reelin signalling pathway is vital for correct neuronal positioning as loss of Reelin leads to a partially inverted cortex. The precise biological function of Reelin remains controversial and debate surrounds its role as a chemoattractant or stop signal for migrating neurons. To investigate this further we developed an in silico agent-based model of cortical layer formation. Using this model we tested four biologically plausible hypotheses for neuron motility and four biologically plausible hypotheses for the loss of neuron motility (conversion from migration. A matrix of 16 combinations of motility and conversion rules was applied against the known structure of mouse cortical layers in the wild-type cortex, the Reelin-null mutant, the Dab1-null mutant and a conditional Dab1 mutant. Using this approach, many combinations of motility and conversion mechanisms can be rejected. For example, the model does not support Reelin acting as a repelling or as a stopping signal. In contrast, the study lends very strong support to the notion that the glycoprotein Reelin acts as a chemoattractant for neurons. Furthermore, the most viable proposition for the conversion mechanism is one in which conversion is affected by a motile neuron sensing in the near vicinity neurons that have already converted. Therefore, this model helps elucidate the function of Reelin during neuronal migration and cortical development.

Epigenetic Basis of Neuronal and Synaptic Plasticity.

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Karpova, Nina N; Sales, Amanda J; Joca, Samia R

2017-01-01

Neuronal network and plasticity change as a function of experience. Altered neural connectivity leads to distinct transcriptional programs of neuronal plasticity-related genes. The environmental challenges throughout life may promote long-lasting reprogramming of gene expression and the development of brain disorders. The modifications in neuronal epigenome mediate gene-environmental interactions and are required for activity-dependent regulation of neuronal differentiation, maturation and plasticity. Here, we highlight the latest advances in understanding the role of the main players of epigenetic machinery (DNA methylation and demethylation, histone modifications, chromatin-remodeling enzymes, transposons, and non-coding RNAs) in activity-dependent and long- term neural and synaptic plasticity. The review focuses on both the transcriptional and post-transcriptional regulation of gene expression levels, including the processes of promoter activation, alternative splicing, regulation of stability of gene transcripts by natural antisense RNAs, and alternative polyadenylation. Further, we discuss the epigenetic aspects of impaired neuronal plasticity and the pathogenesis of neurodevelopmental (Rett syndrome, Fragile X Syndrome, genomic imprinting disorders, schizophrenia, and others), stressrelated (mood disorders) and neurodegenerative Alzheimer's, Parkinson's and Huntington's disorders. The review also highlights the pharmacological compounds that modulate epigenetic programming of gene expression, the potential treatment strategies of discussed brain disorders, and the questions that should be addressed during the development of effective and safe approaches for the treatment of brain disorders.

Imitation and Action Understanding in Autistic Spectrum Disorders: How Valid Is the Hypothesis of a Deficit in the Mirror Neuron System?

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Hamilton, Antonia F. de C.; Brindley, Rachel M.; Frith, Uta

2007-01-01

The motor mirror neuron system supports imitation and goal understanding in typical adults. Recently, it has been proposed that a deficit in this mirror neuron system might contribute to poor imitation performance in children with autistic spectrum disorders (ASD) and might be a cause of poor social abilities in these children. We aimed to test…

RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders.

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Mingyan Lin

Full Text Available Genome-wide expression analysis using next generation sequencing (RNA-Seq provides an opportunity for in-depth molecular profiling of fundamental biological processes, such as cellular differentiation and malignant transformation. Differentiating human neurons derived from induced pluripotent stem cells (iPSCs provide an ideal system for RNA-Seq since defective neurogenesis caused by abnormalities in transcription factors, DNA methylation, and chromatin modifiers lie at the heart of some neuropsychiatric disorders. As a preliminary step towards applying next generation sequencing using neurons derived from patient-specific iPSCs, we have carried out an RNA-Seq analysis on control human neurons. Dramatic changes in the expression of coding genes, long non-coding RNAs (lncRNAs, pseudogenes, and splice isoforms were seen during the transition from pluripotent stem cells to early differentiating neurons. A number of genes that undergo radical changes in expression during this transition include candidates for schizophrenia (SZ, bipolar disorder (BD and autism spectrum disorders (ASD that function as transcription factors and chromatin modifiers, such as POU3F2 and ZNF804A, and genes coding for cell adhesion proteins implicated in these conditions including NRXN1 and NLGN1. In addition, a number of novel lncRNAs were found to undergo dramatic changes in expression, one of which is HOTAIRM1, a regulator of several HOXA genes during myelopoiesis. The increase we observed in differentiating neurons suggests a role in neurogenesis as well. Finally, several lncRNAs that map near SNPs associated with SZ in genome wide association studies also increase during neuronal differentiation, suggesting that these novel transcripts may be abnormally regulated in a subgroup of patients.

Migrational disorders: a review of 13 cases. Computed tomography and Magnetic resonance imaging

International Nuclear Information System (INIS)

Machado Junior, M.A.; Barbosa, V.A.; Puglio, N.; Bastos, C.A.

1994-01-01

The authors reviewed 13 cases of migrational disorders using Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). They found a large advantage of MRI in relation to CT, mainly, to study Schizencephaly, because MRI is more efficient way to demonstrate that the margins of the clefts are lined by cortical and make reliable differentiation with Porencephalic cysts. The relationship of the pathological anatomy to theories of pathogenesis is emphasized. No abnormal findings was detected in the process of Myelinization. (author)

Peroxiredoxin distribution in the mouse brain with emphasis on neuronal populations affected in neurodegenerative disorders.

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Goemaere, Julie; Knoops, Bernard

2012-02-01

Redox changes are observed in neurodegenerative diseases, ranging from increased levels of reactive oxygen/nitrogen species and disturbance of antioxidant systems, to nitro-oxidative damage. By reducing hydrogen peroxide, peroxynitrite, and organic hydroperoxides, peroxiredoxins (Prdxs) represent a major potential protective barrier against nitro-oxidative insults in the brain. While recent works have investigated the putative role of Prdxs in neurodegenerative disorders, less is known about their expression in the healthy brain. Here we used immunohistochemistry to map basal expression of Prdxs throughout C57BL/6 mouse brain. We first confirmed the neuronal localization of Prdx2-5 and the glial expression of Prdx1, Prdx4, and Prdx6. Then we performed an in-depth analysis of neuronal Prdx distribution in the brain. Our results show that Prdx2-5 are widely detected in the different neuronal populations, and especially well expressed in the olfactory bulb, in the cerebral cortex, in pons nuclei, in the red nucleus, in all cranial nerve nuclei, in the cerebellum, and in motor neurons of the spinal cord. In contrast, Prdx expression is very low in the dopaminergic neurons of substantia nigra pars compacta and in the CA1/2 pyramidal cells of hippocampus. This low basal expression may contribute to the vulnerability of these neurons to nitro-oxidative attacks occurring in Parkinson's disease and Alzheimer's disease. In addition, we found that Prdx expression levels are unevenly distributed among neurons of a determined region and that distinct regional patterns of expression are observed between isoforms, reinforcing the hypothesis of the nonredundant function of Prdxs. Copyright © 2011 Wiley-Liss, Inc.

Neuron-specific regulation of class I PI3K catalytic subunits and their dysfunction in brain disorders

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Christina eGross

2014-02-01

Full Text Available The PI3K complex plays important roles in virtually all cells of the body. The enzymatic activity of PI3K to phosphorylate phosphoinositides in the membrane is mediated by a group of catalytic and regulatory subunits. Among those, the class I catalytic subunits, p110α, p110β, p110γ and p110δ, have recently drawn attention in the neuroscience field due to their specific dysregulation in diverse brain disorders. While in non-neuronal cells these catalytic subunits may have partially redundant functions, there is increasing evidence that in neurons their roles are more specialized, and confined to distinct receptor-dependent pathways. This review will summarize the emerging role of class I PI3K catalytic subunits in neurotransmitter-regulated neuronal signaling, and their dysfunction in a variety of neurological diseases, including fragile X syndrome, schizophrenia and epilepsy. We will discuss recent literature describing the use of PI3K subunit-selective inhibitors to rescue brain disease-associated phenotypes in in vitro and animal models. These studies give rise to the exciting prospect that these drugs, originally designed for cancer treatment, may be repurposed as therapeutic drugs for brain disorders in the future.

BACE1 Deficiency Causes Abnormal Neuronal Clustering in the Dentate Gyrus

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Hailong Hou

2017-07-01

Full Text Available BACE1 is validated as Alzheimer's β-secretase and a therapeutic target for Alzheimer's disease. In examining BACE1-null mice, we discovered that BACE1 deficiency develops abnormal clusters of immature neurons, forming doublecortin-positive neuroblasts, in the developing dentate gyrus, mainly in the subpial zone (SPZ. Such clusters were rarely observed in wild-type SPZ and not reported in other mouse models. To understand their origins and fates, we examined how neuroblasts in BACE1-null SPZ mature and migrate during early postnatal development. We show that such neuroblasts are destined to form Prox1-positive granule cells in the dentate granule cell layer, and mainly mature to form excitatory neurons, but not inhibitory neurons. Mechanistically, higher levels of reelin potentially contribute to abnormal neurogenesis and timely migration in BACE1-null SPZ. Altogether, we demonstrate that BACE1 is a critical regulator in forming the dentate granule cell layer through timely maturation and migration of SPZ neuroblasts.

Neuronal and epithelial cell rescue resolves chronic systemic inflammation in the lipid storage disorder Niemann-Pick C.

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Lopez, Manuel E; Klein, Andrés D; Hong, Jennifer; Dimbil, Ubah J; Scott, Matthew P

2012-07-01

Chronic systemic inflammation is thought to be a major contributor to metabolic and neurodegenerative diseases. Since inflammatory components are shared among different disorders, targeting inflammation is an attractive option for mitigating disease. To test the significance of inflammation in the lipid storage disorder (LSD) Niemann-Pick C (NPC), we deleted the macrophage inflammatory gene Mip1a/Ccl3 from NPC diseased mice. Deletion of Ccl3 had been reported to delay neuronal loss in Sandhoff LSD mice by inhibiting macrophage infiltration. For NPC mice, in contrast, deleting Ccl3 did not retard neurodegeneration and worsened the clinical outcome. Depletion of visceral tissue macrophages also did not alter central nervous system (CNS) pathology and instead increased liver injury, suggesting a limited macrophage infiltration response into the CNS and a beneficial role of macrophage activity in visceral tissue. Prevention of neuron loss or liver injury, even at late stages in the disease, was achieved through specific rescue of NPC disease in neurons or in liver epithelial cells, respectively. Local epithelial cell correction was also sufficient to reduce the macrophage-associated pathology in lung tissue. These results demonstrate that elevated inflammation and macrophage activity does not necessarily contribute to neurodegeneration and tissue injury, and LSD defects in immune cells may not preclude an appropriate inflammatory response. We conclude that inflammation remains secondary to neuronal and epithelial cell dysfunction and does not irreversibly contribute to the pathogenic cascade in NPC disease. Without further exploration of possible beneficial roles of inflammatory mediators, targeting inflammation may not be therapeutically effective at ameliorating disease severity.

Metabolic reprogramming during neuronal differentiation.

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Agostini, M; Romeo, F; Inoue, S; Niklison-Chirou, M V; Elia, A J; Dinsdale, D; Morone, N; Knight, R A; Mak, T W; Melino, G

2016-09-01

Newly generated neurons pass through a series of well-defined developmental stages, which allow them to integrate into existing neuronal circuits. After exit from the cell cycle, postmitotic neurons undergo neuronal migration, axonal elongation, axon pruning, dendrite morphogenesis and synaptic maturation and plasticity. Lack of a global metabolic analysis during early cortical neuronal development led us to explore the role of cellular metabolism and mitochondrial biology during ex vivo differentiation of primary cortical neurons. Unexpectedly, we observed a huge increase in mitochondrial biogenesis. Changes in mitochondrial mass, morphology and function were correlated with the upregulation of the master regulators of mitochondrial biogenesis, TFAM and PGC-1α. Concomitant with mitochondrial biogenesis, we observed an increase in glucose metabolism during neuronal differentiation, which was linked to an increase in glucose uptake and enhanced GLUT3 mRNA expression and platelet isoform of phosphofructokinase 1 (PFKp) protein expression. In addition, glutamate-glutamine metabolism was also increased during the differentiation of cortical neurons. We identified PI3K-Akt-mTOR signalling as a critical regulator role of energy metabolism in neurons. Selective pharmacological inhibition of these metabolic pathways indicate existence of metabolic checkpoint that need to be satisfied in order to allow neuronal differentiation.

THYROID HORMONE TREATED ASTROCYTES INDUCE MATURATION OF CEREBRAL CORTICAL NEURONS THROUGH MODULATION OF PROTEOGLYCAN LEVELS

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Romulo Sperduto Dezonne

2013-08-01

Full Text Available Proper brain neuronal circuitry formation and synapse development is dependent on specific cues, either genetic or epigenetic, provided by the surrounding neural environment. Within these signals, thyroid hormones (T3 and T4 play crucial role in several steps of brain morphogenesis including proliferation of progenitor cells, neuronal differentiation, maturation, migration, and synapse formation. The lack of thyroid hormones during childhood is associated with several impair neuronal connections, cognitive deficits, and mental disorders. Many of the thyroid hormones effects are mediated by astrocytes, although the mechanisms underlying these events are still unknown. In this work, we investigated the effect of 3, 5, 3’-triiodothyronine-treated (T3-treated astrocytes on cerebral cortex neuronal differentiation. Culture of neural progenitors from embryonic cerebral cortex mice onto T3-treated astrocyte monolayers yielded an increment in neuronal population, followed by enhancement of neuronal maturation, arborization and neurite outgrowth. In addition, real time PCR assays revealed an increase in the levels of the heparan sulfate proteoglycans, Glypican 1 (GPC-1 and Syndecans 3 e 4 (SDC-3 e SDC-4, followed by a decrease in the levels of the chondroitin sulfate proteoglycan, Versican. Disruption of glycosaminoglycan chains by chondroitinase AC or heparanase III completely abolished the effects of T3-treated astrocytes on neuronal morphogenesis. Our work provides evidence that astrocytes are key mediators of T3 actions on cerebral cortex neuronal development and identified potential molecules and pathways involved in neurite extension; which might eventually contribute to a better understanding of axonal regeneration, synapse formation and neuronal circuitry recover.

Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro

NARCIS (Netherlands)

Bardy, C.; Hurk, M. van den; Eames, T.; Marchand, C.; Hernandez, R.V.; Kellogg, M.; Gorris, M.A.J.; Galet, B.; Palomares, V.; Brown, J.; Bang, A.G.; Mertens, J.; Bohnke, L.; Boyer, L.; Simon, S.; Gage, F.H.

2015-01-01

Human cell reprogramming technologies offer access to live human neurons from patients and provide a new alternative for modeling neurological disorders in vitro. Neural electrical activity is the essence of nervous system function in vivo. Therefore, we examined neuronal activity in media widely

Neural regeneration protein is a novel chemoattractive and neuronal survival-promoting factor

International Nuclear Information System (INIS)

Gorba, Thorsten; Bradoo, Privahini; Antonic, Ana; Marvin, Keith; Liu, Dong-Xu; Lobie, Peter E.; Reymann, Klaus G.; Gluckman, Peter D.; Sieg, Frank

2006-01-01

Neurogenesis and neuronal migration are the prerequisites for the development of the central nervous system. We have identified a novel rodent gene encoding for a neural regeneration protein (NRP) with an activity spectrum similar to the chemokine stromal-derived factor (SDF)-1, but with much greater potency. The Nrp gene is encoded as a forward frameshift to the hypothetical alkylated DNA repair protein AlkB. The predicted protein sequence of NRP contains domains with homology to survival-promoting peptide (SPP) and the trefoil protein TFF-1. The Nrp gene is first expressed in neural stem cells and expression continues in glial lineages. Recombinant NRP and NRP-derived peptides possess biological activities including induction of neural migration and proliferation, promotion of neuronal survival, enhancement of neurite outgrowth and promotion of neuronal differentiation from neural stem cells. NRP exerts its effect on neuronal survival by phosphorylation of the ERK1/2 and Akt kinases, whereas NRP stimulation of neural migration depends solely on p44/42 MAP kinase activity. Taken together, the expression profile of Nrp, the existence in its predicted protein structure of domains with similarities to known neuroprotective and migration-inducing factors and the high potency of NRP-derived synthetic peptides acting in femtomolar concentrations suggest it to be a novel gene of relevance in cellular and developmental neurobiology

Distinctive transcriptome alterations of prefrontal pyramidal neurons in schizophrenia and schizoaffective disorder.

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Arion, D; Corradi, J P; Tang, S; Datta, D; Boothe, F; He, A; Cacace, A M; Zaczek, R; Albright, C F; Tseng, G; Lewis, D A

2015-11-01

Schizophrenia is associated with alterations in working memory that reflect dysfunction of dorsolateral prefrontal cortex (DLPFC) circuitry. Working memory depends on the activity of excitatory pyramidal cells in DLPFC layer 3 and, to a lesser extent, in layer 5. Although many studies have profiled gene expression in DLPFC gray matter in schizophrenia, little is known about cell-type-specific transcript expression in these two populations of pyramidal cells. We hypothesized that interrogating gene expression, specifically in DLPFC layer 3 or 5 pyramidal cells, would reveal new and/or more robust schizophrenia-associated differences that would provide new insights into the nature of pyramidal cell dysfunction in the illness. We also sought to determine the impact of other variables, such as a diagnosis of schizoaffective disorder or medication use at the time of death, on the patterns of gene expression in pyramidal neurons. Individual pyramidal cells in DLPFC layers 3 or 5 were captured by laser microdissection from 36 subjects with schizophrenia or schizoaffective disorder and matched normal comparison subjects. The mRNA from cell collections was subjected to transcriptome profiling by microarray followed by quantitative PCR validation. Expression of genes involved in mitochondrial (MT) or ubiquitin-proteasome system (UPS) functions were markedly downregulated in the patient group (P-values for MT-related and UPS-related pathways were schizoaffective disorder subjects (diagnosis of schizoaffective disorder was the most significant covariate, Pschizoaffective disorder, providing a potential molecular-cellular basis of differences in clinical phenotypes.

Hepatocyte growth factor/c-MET axis-mediated tropism of cord blood-derived unrestricted somatic stem cells for neuronal injury.

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Trapp, Thorsten; Kögler, Gesine; El-Khattouti, Abdelouahid; Sorg, Rüdiger V; Besselmann, Michael; Föcking, Melanie; Bührle, Christian P; Trompeter, Ingo; Fischer, Johannes C; Wernet, Peter

2008-11-21

An under-agarose chemotaxis assay was used to investigate whether unrestricted somatic stem cells (USSC) that were recently characterized in human cord blood are attracted by neuronal injury in vitro. USSC migrated toward extracts of post-ischemic brain tissue of mice in which stroke had been induced. Moreover, apoptotic neurons secrete factors that strongly attracted USSC, whereas necrotic and healthy neurons did not. Investigating the expression of growth factors and chemokines in lesioned brain tissue and neurons and of their respective receptors in USSC revealed expression of hepatocyte growth factor (HGF) in post-ischemic brain and in apoptotic but not in necrotic neurons and of the HGF receptor c-MET in USSC. Neuronal lesion-triggered migration was observed in vitro and in vivo only when c-MET was expressed at a high level in USSC. Neutralization of the bioactivity of HGF with an antibody inhibited migration of USSC toward neuronal injury. This, together with the finding that human recombinant HGF attracts USSC, document that HGF signaling is necessary for the tropism of USSC for neuronal injury. Our data demonstrate that USSC have the capacity to migrate toward apoptotic neurons and injured brain. Together with their neural differentiation potential, this suggests a neuroregenerative potential of USSC. Moreover, we provide evidence for a hitherto unrecognized pivotal role of the HGF/c-MET axis in guiding stem cells toward brain injury, which may partly account for the capability of HGF to improve function in the diseased central nervous system.

GABA regulates the multidirectional tangential migration of GABAergic interneurons in living neonatal mice.

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Hiroyuki Inada

Full Text Available Cortical GABAergic interneurons originate from ganglionic eminences and tangentially migrate into the cortical plate at early developmental stages. To elucidate the characteristics of this migration of GABAergic interneurons in living animals, we established an experimental design specialized for in vivo time-lapse imaging of the neocortex of neonate mice with two-photon laser-scanning microscopy. In vesicular GABA/glycine transporter (VGAT-Venus transgenic mice from birth (P0 through P3, we observed multidirectional tangential migration of genetically-defined GABAergic interneurons in the neocortical marginal zone. The properties of this migration, such as the motility rate (distance/hr, the direction moved, and the proportion of migrating neurons to stationary neurons, did not change through P0 to P3, although the density of GABAergic neurons at the marginal zone decreased with age. Thus, the characteristics of the tangential motility of individual GABAergic neurons remained constant in development. Pharmacological block of GABA(A receptors and of the Na⁺-K⁺-Cl⁻ cotransporters, and chelating intracellular Ca²⁺, all significantly reduced the motility rate in vivo. The motility rate and GABA content within the cortex of neonatal VGAT-Venus transgenic mice were significantly greater than those of GAD67-GFP knock-in mice, suggesting that extracellular GABA concentration could facilitate the multidirectional tangential migration. Indeed, diazepam applied to GAD67-GFP mice increased the motility rate substantially. In an in vitro neocortical slice preparation, we confirmed that GABA induced a NKCC sensitive depolarization of GABAergic interneurons in VGAT-Venus mice at P0-P3. Thus, activation of GABA(AR by ambient GABA depolarizes GABAergic interneurons, leading to an acceleration of their multidirectional motility in vivo.

Like father, like son: periventricular nodular heterotopia and nonverbal learning disorder.

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McCann, Marcia V; Pongonis, Stephen J; Golomb, Meredith R; Edwards-Brown, Mary; Christensen, Celanie K; Sokol, Deborah K

2008-08-01

Periventricular nodular heterotopia is a common malformation of cortical development in which the migration of developing neurons destined for the cerebral cortex is abbreviated. Bilateral periventricular nodular heterotopia is most commonly an X-linked disorder that involves mutations in the filamin A (FLNA) gene, but an autosomal recessive form and sporadic forms have been identified. To our knowledge, autosomal dominant transmission of isolated periventricular nodular heterotopia has not been reported. Periventricular nodular heterotopia has a heterogeneous phenotype, associated commonly with seizure disorder, and more recently with reading deficits and visual-spatial deficits in some patients. We present a father and son with bilateral periventricular nodular heterotopia and similar visual-spatial learning deficits, consistent with nonverbal learning disability.

[Eating Disorders in Female High School Students: Educational and Migration Background, School-Related Stress and Performance-Orientated Classes].

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Grüttner, M

2018-02-01

Many adolescents and young adults, especially young females, suffer from eating disorders or problematic nutrition behavior. Children and adolescents with migration background as well as from a lower social class are more likely to have eating disorders 1. Although schools are an important context in these age groups, there is a lack of scientific inquiry concerning the relationship between schooling and eating disorders. The present study investigates the relationship between performance-related stress at school and eating disorders while controlling for personnel and familial resources. Interview data on the 7 th grade high school students from the National Educational Panel Study (NEPS)* starting cohort 3 are used. The dependent variable is based on the SCOFF questionnaire. Logistic regressions are calculated using information from students and parents. Performance-related stress at school is operationalized by the negative deviation of realistic from idealistic educational aspirations (EA) and unfulfilled social expectations (SE), performance-oriented class climate is operationalized by students' perception of the performance-orientation of the teacher (PT) and the expectations of classmates (EC). The results point towards an increased risk of suffering from an eating disorder due to performance-related school stress (EA: AME: 0.18; p<0.001; SE: AME: 0.12; p<0.05) and performance-oriented class climate (PT: AME: 0.05; p<0.1; EC: AME: 0.15, p<0.01). They partly explain the relation between both migration background and educational background and eating disorders. In order to prevent eating disorders in female high school students, attention should be paid to performance-orientation experienced at school and in the social background, and improved individual support for disadvantaged students should be made available. © Georg Thieme Verlag KG Stuttgart · New York.

Ventromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder.

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Valencia Garcia, Sara; Brischoux, Frédéric; Clément, Olivier; Libourel, Paul-Antoine; Arthaud, Sébastien; Lazarus, Michael; Luppi, Pierre-Hervé; Fort, Patrice

2018-02-05

Despite decades of research, there is a persistent debate regarding the localization of GABA/glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical (or REM) sleep (PS), resulting in the loss of muscle tone during this sleep state. Combining complementary neuroanatomical approaches in rats, we first show that these inhibitory neurons are localized within the ventromedial medulla (vmM) rather than within the spinal cord. We then demonstrate their functional role in PS expression through local injections of adeno-associated virus carrying specific short-hairpin RNA in order to chronically impair inhibitory neurotransmission from vmM. After such selective genetic inactivation, rats display PS without atonia associated with abnormal and violent motor activity, concomitant with a small reduction of daily PS quantity. These symptoms closely mimic human REM sleep behavior disorder (RBD), a prodromal parasomnia of synucleinopathies. Our findings demonstrate the crucial role of GABA/glycine inhibitory vmM neurons in muscle atonia during PS and highlight a candidate brain region that can be susceptible to α-synuclein-dependent degeneration in RBD patients.

Effect of Transcranial Magnetic Stimulation on Neuronal Networks

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Unsal, Ahmet; Hadimani, Ravi; Jiles, David

2013-03-01

The human brain contains around 100 billion nerve cells controlling our day to day activities. Consequently, brain disorders often result in impairments such as paralysis, loss of coordination and seizure. It has been said that 1 in 5 Americans suffer some diagnosable mental disorder. There is an urgent need to understand the disorders, prevent them and if possible, develop permanent cure for them. As a result, a significant amount of research activities is being directed towards brain research. Transcranial Magnetic Stimulation (TMS) is a promising tool for diagnosing and treating brain disorders. It is a non-invasive treatment method that produces a current flow in the brain which excites the neurons. Even though TMS has been verified to have advantageous effects on various brain related disorders, there have not been enough studies on the impact of TMS on cells. In this study, we are investigating the electrophysiological effects of TMS on one dimensional neuronal culture grown in a circular pathway. Electrical currents are produced on the neuronal networks depending on the directionality of the applied field. This aids in understanding how neuronal networks react under TMS treatment.

Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures

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Stödberg, Tommy; McTague, Amy; Ruiz, Arnaud J.; Hirata, Hiromi; Zhen, Juan; Long, Philip; Farabella, Irene; Meyer, Esther; Kawahara, Atsuo; Vassallo, Grace; Stivaros, Stavros M.; Bjursell, Magnus K.; Stranneheim, Henrik; Tigerschiöld, Stephanie; Persson, Bengt; Bangash, Iftikhar; Das, Krishna; Hughes, Deborah; Lesko, Nicole; Lundeberg, Joakim; Scott, Rod C.; Poduri, Annapurna; Scheffer, Ingrid E.; Smith, Holly; Gissen, Paul; Schorge, Stephanie; Reith, Maarten E. A.; Topf, Maya; Kullmann, Dimitri M.; Harvey, Robert J.; Wedell, Anna; Kurian, Manju A.

2015-01-01

The potassium-chloride co-transporter KCC2, encoded by SLC12A5, plays a fundamental role in fast synaptic inhibition by maintaining a hyperpolarizing gradient for chloride ions. KCC2 dysfunction has been implicated in human epilepsy, but to date, no monogenic KCC2-related epilepsy disorders have been described. Here we show recessive loss-of-function SLC12A5 mutations in patients with a severe infantile-onset pharmacoresistant epilepsy syndrome, epilepsy of infancy with migrating focal seizures (EIMFS). Decreased KCC2 surface expression, reduced protein glycosylation and impaired chloride extrusion contribute to loss of KCC2 activity, thereby impairing normal synaptic inhibition and promoting neuronal excitability in this early-onset epileptic encephalopathy. PMID:26333769

Computed tomography in the evaluation of migrational disorders of the brain. 1

International Nuclear Information System (INIS)

Byrd, S.E.; Bohan, T.P.; Osborn, R.E.

1988-01-01

The migrational disorders are a rare group of congenital malformations of the brain which are almost exclusively seen in children. They are comprised of four types, lissencephaly, schizencephaly, heterotopia and polymicrogyria. They have received little attention in the radiology literature because until recently the radiographic modalities to evaluate these disorders (which are primarily abnormalities of the cortex of the brain (gyri and sulci) and gray matter) were not available. Advanced CT scanners have allowed better resolution of the pediatric brain, and in turn better delineation of this group of congenital malformations. The development of the neocortex of the brain is reviewed and the entity of lissencephaly is emphasized. The characteristic CT appearance of lissencephaly is discussed with a delineation of the major findings of (1) agyric-pachygyric cortex (2) shallow sylvian grooves producing a 'figure of eight' appearance and (3) thickened cortical gray matter with loss of the gray-white matter interdigitations. A classification of lissencephaly is proposed, based on the 13 patients of this study and the patients' reviews in the medical literature. 24 refs.; 8 figs.; 3 tabs

Beyond Neuronal Activity Markers: Select Immediate Early Genes in Striatal Neuron Subtypes Functionally Mediate Psychostimulant Addiction

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Ramesh Chandra

2017-06-01

Full Text Available Immediate early genes (IEGs were traditionally used as markers of neuronal activity in striatum in response to stimuli including drugs of abuse such as psychostimulants. Early studies using these neuronal activity markers led to important insights in striatal neuron subtype responsiveness to psychostimulants. Such studies have helped identify striatum as a critical brain center for motivational, reinforcement and habitual behaviors in psychostimulant addiction. While the use of IEGs as neuronal activity markers in response to psychostimulants and other stimuli persists today, the functional role and implications of these IEGs has often been neglected. Nonetheless, there is a subset of research that investigates the functional role of IEGs in molecular, cellular and behavioral alterations by psychostimulants through striatal medium spiny neuron (MSN subtypes, the two projection neuron subtypes in striatum. This review article will address and highlight the studies that provide a functional mechanism by which IEGs mediate psychostimulant molecular, cellular and behavioral plasticity through MSN subtypes. Insight into the functional role of IEGs in striatal MSN subtypes could provide improved understanding into addiction and neuropsychiatric diseases affecting striatum, such as affective disorders and compulsive disorders characterized by dysfunctional motivation and habitual behavior.

CDKL5, a protein associated with rett syndrome, regulates neuronal morphogenesis via Rac1 signaling.

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Chen, Qian; Zhu, Yong-Chuan; Yu, Jing; Miao, Sheng; Zheng, Jing; Xu, Li; Zhou, Yang; Li, Dan; Zhang, Chi; Tao, Jiong; Xiong, Zhi-Qi

2010-09-22

Mutations in cyclin-dependent kinase-like 5 (CDKL5), also known as serine/threonine kinase 9 (STK9), have been identified in patients with Rett syndrome (RTT) and X-linked infantile spasm. However, the function of CDKL5 in the brain remains unknown. Here, we report that CDKL5 is a critical regulator of neuronal morphogenesis. We identified a neuron-specific splicing variant of CDKL5 whose expression was markedly induced during postnatal development of the rat brain. Downregulating CDKL5 by RNA interference (RNAi) in cultured cortical neurons inhibited neurite growth and dendritic arborization, whereas overexpressing CDKL5 had opposite effects. Furthermore, knocking down CDKL5 in the rat brain by in utero electroporation resulted in delayed neuronal migration, and severely impaired dendritic arborization. In contrast to its proposed function in the nucleus, we found that CDKL5 regulated dendrite development through a cytoplasmic mechanism. In fibroblasts and in neurons, CDKL5 colocalized and formed a protein complex with Rac1, a critical regulator of actin remodeling and neuronal morphogenesis. Overexpression of Rac1 prevented the inhibition of dendrite growth caused by CDKL5 knockdown, and the growth-promoting effect of ectopically expressed CDKL5 on dendrites was abolished by coexpressing a dominant-negative form of Rac1. Moreover, CDKL5 was required for brain-derived neurotrophic factor (BDNF)-induced activation of Rac1. Together, these results demonstrate a critical role of CDKL5 in neuronal morphogenesis and identify a Rho GTPase signaling pathway which may contribute to CDKL5-related disorders.

Stability and migration across femoral varus derotation osteotomies in children with neuromuscular disorders

DEFF Research Database (Denmark)

Buxbom, Peter; Sonne-Holm, Stig; Ellitsgaard, Niels

2017-01-01

), and acetabuloplasty. Relapse is observed in one-fifth of cases during adolescence. In this prospective cohort study, we performed a descriptive evaluation of translation and rotation across VDROs in children with neuromuscular disorders and syndromes by radiostereometric analysis (RSA). We assessed "RSA stability......" and migration across the VDROs. Patients and methods - Children with a neuromuscular disorder were set up for skeletal corrective surgery of the hip. RSA follow-ups were performed postoperatively, at 5 weeks, and 3, 6, and 12 months after surgery. Results - 27 femoral VDROs were included; 2 patients were...... excluded during the study period. RSA data showed stability across the VDRO in the majority of cases within the first 5 weeks. At the 1-year follow-up, the mean translations (SD) of the femoral shaft distal to the VDRO were 0.51 (1.12) mm medial, 0.69 (1.61) mm superior, and 0.21 (1.28) mm posterior...

Mental health of newly arrived Burmese refugees in Australia: contributions of pre-migration and post-migration experience.

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Schweitzer, Robert D; Brough, Mark; Vromans, Lyn; Asic-Kobe, Mary

2011-04-01

This study documents the mental health status of people from Burmese refugee backgrounds recently arrived in Australia, then examines the contributions of gender, pre-migration and post-migration factors in predicting mental health. Structured interviews, including a demographic questionnaire, the Harvard Trauma Questionnaire, the Post-migration Living Difficulties Checklist and Hopkins Symptom Checklist assessed pre-migration trauma, post-migration living difficulties, depression, anxiety, somatization and traumatization symptoms in a sample of 70 adults across five Burmese ethnic groups. Substantial proportions of participants reported psychological distress in symptomatic ranges including: post-traumatic stress disorder (9%), anxiety (20%) and depression (36%), as well as significant symptoms of somatization (37%). Participants reported multiple and severe pre-migration traumas. Post-migration living difficulties of greatest concern included communication problems and worry about family not in Australia. Gender did not predict mental health. Level of exposure to traumatic events and post-migration living difficulties each made unique and relatively equal contributions to traumatization symptoms. Post-migration living difficulties made unique contributions to depression, anxiety and somatization symptoms. While exposure to traumatic events impacted on participants' mental well-being, post-migration living difficulties had greater salience in predicting mental health outcomes of people from Burmese refugee backgrounds. Reported rates of post-traumatic stress disorder symptoms were consistent with a large review of adults across seven western countries. High levels of somatization point to a nuanced expression of distress. Findings have implications for service provision in terms of implementing appropriate interventions to effectively meet the needs of this newly arrived group in Australia.

Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders

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Yamasaki Nobuyuki

2008-09-01

Full Text Available Abstract Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/- have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG. The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and

Inhibition of neuronal cell–cell adhesion measured by the microscopic aggregation assay and impedance sensing

NARCIS (Netherlands)

Wiertz, Remy; Marani, Enrico; Rutten, Wim

2010-01-01

Microscopic aggregation assay and impedance sensing (IS) were used to monitor a change in in vitro neuron–neuron adhesion in response to blocking of cell adhesion molecules. By blocking neuron–neuron adhesion, migration and aggregation of neuronal cells can be inhibited. This leads to better control

Chondroitin sulfate proteoglycans regulate the growth, differentiation and migration of multipotent neural precursor cells through the integrin signaling pathway

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Lü He-Zuo

2009-10-01

Full Text Available Abstract Background Neural precursor cells (NPCs are defined by their ability to proliferate, self-renew, and retain the potential to differentiate into neurons and glia. Deciphering the factors that regulate their behaviors will greatly aid in their use as potential therapeutic agents or targets. Chondroitin sulfate proteoglycans (CSPGs are prominent components of the extracellular matrix (ECM in the central nervous system (CNS and are assumed to play important roles in controlling neuronal differentiation and development. Results In the present study, we demonstrated that CSPGs were constitutively expressed on the NPCs isolated from the E16 rat embryonic brain. When chondroitinase ABC was used to abolish the function of endogenous CSPGs on NPCs, it induced a series of biological responses including the proliferation, differentiation and migration of NPCs, indicating that CSPGs may play a critical role in NPC development and differentiation. Finally, we provided evidence suggesting that integrin signaling pathway may be involved in the effects of CSPGs on NPCs. Conclusion The present study investigating the influence and mechanisms of CSPGs on the differentiation and migration of NPCs should help us to understand the basic biology of NPCs during CNS development and provide new insights into developing new strategies for the treatment of the neurological disorders in the CNS.

Age at migration and future risk of psychotic disorders among immigrants in the Netherlands : a 7-year incidence study

NARCIS (Netherlands)

Veling, Wim; Hoek, Hans W; Selten, Jean-Paul; Susser, Ezra

2011-01-01

Objective: The purpose of this study was to examine whether the increased risk for developing a psychotic disorder among immigrants is related to their age at the time of migration. Method: In a 7-year first-contact incidence study, immigrants to the Netherlands and Dutch citizens, ages 15-54 years,

Psychiatric symptoms and disorders among Yazidi children and adolescents immediately after forced migration following ISIS attacks.

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Ceri, Veysi; Özlü-Erkilic, Zeliha; Özer, Ürün; Yalcin, Murat; Popow, Christian; Akkaya-Kalayci, Türkan

2016-09-01

The aim of the present study was to evaluate psychiatric problems and disorders among Yazidi Kurd refugee children and adolescents, who were assessed immediately after their forced migration following life-threatening attacks by ISIS terrorists. We retrospectively analyzed the psychiatric assessments of 38 Yazidi children and adolescents (age 2-18, mean 12 years, m:f = 16:22), which were performed upon their arrival at the refugee camp. All children and adolescents exhibited psychiatric problems and disorders, 50 % had one, and 50 % had more than one. The most relevant problems were disturbed sleeping (71 % of children), followed by depression (36.8 %), conversion disorders (28.9 %), adjustment (21.8 %), acute (18.4 %) and posttraumatic stress (PTSD, 10.5 %) disorders, and non-organic enuresis (18.4 %). Our study confirms the results of previous studies, asserting that refugee children and adolescents do not just suffer from PTSD but from various other problems that are already present in the first days of resettlement. Children and adolescents living in refugee camps urgently need psychosocial support.

Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro.

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Bardy, Cedric; van den Hurk, Mark; Eames, Tameji; Marchand, Cynthia; Hernandez, Ruben V; Kellogg, Mariko; Gorris, Mark; Galet, Ben; Palomares, Vanessa; Brown, Joshua; Bang, Anne G; Mertens, Jerome; Böhnke, Lena; Boyer, Leah; Simon, Suzanne; Gage, Fred H

2015-05-19

Human cell reprogramming technologies offer access to live human neurons from patients and provide a new alternative for modeling neurological disorders in vitro. Neural electrical activity is the essence of nervous system function in vivo. Therefore, we examined neuronal activity in media widely used to culture neurons. We found that classic basal media, as well as serum, impair action potential generation and synaptic communication. To overcome this problem, we designed a new neuronal medium (BrainPhys basal + serum-free supplements) in which we adjusted the concentrations of inorganic salts, neuroactive amino acids, and energetic substrates. We then tested that this medium adequately supports neuronal activity and survival of human neurons in culture. Long-term exposure to this physiological medium also improved the proportion of neurons that were synaptically active. The medium was designed to culture human neurons but also proved adequate for rodent neurons. The improvement in BrainPhys basal medium to support neurophysiological activity is an important step toward reducing the gap between brain physiological conditions in vivo and neuronal models in vitro.

L1cam is crucial for cell locomotion and terminal translocation of the Soma in radial migration during murine corticogenesis.

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Madoka Tonosaki

Full Text Available L1cam (L1 is a cell adhesion molecule associated with a spectrum of human neurological diseases, the most well-known being X-linked hydrocephalus. Although we recently demonstrated that L1 plays an important role in neuronal migration during cortical histogenesis, the mechanisms of delayed migration have still not been clarified. In this study, we found that cell locomotion in the intermediate zone and terminal translocation in the primitive cortical zone (PCZ were affected by L1-knockdown (L1-KD. Time-lapse analyses revealed that L1-KD neurons produced by in utero electroporation of shRNA targeting L1 (L1-shRNAs molecules showed decreased locomotion velocity in the intermediate zone, compared with control neurons. Furthermore, L1-KD neurons showed longer and more undulated leading processes during translocation through the primitive cortical zone. The curvature index, a quantitative index for curvilinearity, as well as the length of the leading process, were increased, whereas the somal movement was decreased in L1-KD neurons during terminal translocation in the PCZ. These results suggest that L1 has a role in radial migration of cortical neurons.

Pre-migration trauma and HIV-risk behavior.

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Steel, Jennifer; Herlitz, Claes; Matthews, Jesse; Snyder, Wendy; Mazzaferro, Kathryn; Baum, Andy; Theorell, Töres

2003-03-01

This study examined the relationship between pre-migration trauma and HIV-risk behavior in refugees from sub-Saharan Africa. The sample comprised 122 persons who had emigrated from sub-Saharan Africa and were currently residing in Sweden. Qualitative methods including individual interviews, focus groups, and interviews with key informants addressed questions regarding trauma experience and HIV-risk behavior. A history of pre-migration trauma was found to be associated with HIV-risk behavior. According to the participants, symptoms associated with post-traumatic stress disorder, depression, adjustment disorder, and substance use mediated the relationship between pre-migration trauma and sexual risk behavior. In contrast, a minority of the participants who reported pre-migration trauma but not psychological sequelae, or experienced post-traumatic growth, reported safer sexual practices. It appears that for some individuals, pre-migration trauma resulted in psychiatric sequelae, which may increase an individual's risk to be infected with HIV. Interventions targeted at individuals at increased risk (i.e. pre-migration trauma with unresolved psychiatric symptomatology) may facilitate the prevention of HIV and other sexually transmitted diseases in this population. Integration of multiple psychosocial and health issues is recommended for comprehensive treatment and prevention programs.

C. elegans model of neuronal aging

OpenAIRE

Peng, Chiu-Ying; Chen, Chun-Hao; Hsu, Jiun-Min; Pan, Chun-Liang

2011-01-01

Aging of the nervous system underlies the behavioral and cognitive decline associated with senescence. Understanding the molecular and cellular basis of neuronal aging will therefore contribute to the development of effective treatments for aging and age-associated neurodegenerative disorders. Despite this pressing need, there are surprisingly few animal models that aim at recapitulating neuronal aging in a physiological context. We recently developed a C. elegans model of neuronal aging, and...

Area-specific migration and recruitment of new neurons in the adult songbird brain

DEFF Research Database (Denmark)

Vellema, Michiel; Van der Linden, Annemie; Gahr, Manfred

2010-01-01

sensitive to plastic changes, such as nucleus higher vocal center (HVC) and area X, recruited similar numbers of new neurons as their surrounding brain tissues, employing no specific directional mechanisms. The distribution pattern in and around HVC could best be described by a random displacement model......Neuron recruitment has been implicated in morphological and functional plasticity in the adult brain. Whereas mammals restrict neuron recruitment specifically to two regions of known plasticity, the hippocampus and olfactory bulb, newborn neurons are found throughout the forebrain of adult...... songbirds. In order to study the area-specificity of the widespread proliferation and recruitment in the songbird brain, six adult male canaries received repetitive intraperitoneal injections of the mitotic marker BrdU (5-bromo-2-deoxyuridine) and were sacrificed after 24 hours to study proliferation...

Connective tissue growth factor (CTGF/CCN2 is negatively regulated during neuron-glioblastoma interaction.

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Luciana F Romão

Full Text Available Connective-tissue growth factor (CTGF/CCN2 is a matricellular-secreted protein involved in complex processes such as wound healing, angiogenesis, fibrosis and metastasis, in the regulation of cell proliferation, migration and extracellular matrix remodeling. Glioblastoma (GBM is the major malignant primary brain tumor and its adaptation to the central nervous system microenvironment requires the production and remodeling of the extracellular matrix. Previously, we published an in vitro approach to test if neurons can influence the expression of the GBM extracellular matrix. We demonstrated that neurons remodeled glioma cell laminin. The present study shows that neurons are also able to modulate CTGF expression in GBM. CTGF immnoreactivity and mRNA levels in GBM cells are dramatically decreased when these cells are co-cultured with neonatal neurons. As proof of particular neuron effects, neonatal neurons co-cultured onto GBM cells also inhibit the reporter luciferase activity under control of the CTGF promoter, suggesting inhibition at the transcription level. This inhibition seems to be contact-mediated, since conditioned media from embryonic or neonatal neurons do not affect CTGF expression in GBM cells. Furthermore, the inhibition of CTGF expression in GBM/neuronal co-cultures seems to affect the two main signaling pathways related to CTGF. We observed inhibition of TGFβ luciferase reporter assay; however phopho-SMAD2 levels did not change in these co-cultures. In addition levels of phospho-p44/42 MAPK were decreased in co-cultured GBM cells. Finally, in transwell migration assay, CTGF siRNA transfected GBM cells or GBM cells co-cultured with neurons showed a decrease in the migration rate compared to controls. Previous data regarding laminin and these results demonstrating that CTGF is down-regulated in GBM cells co-cultured with neonatal neurons points out an interesting view in the understanding of the tumor and cerebral microenvironment

Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus.

Science.gov (United States)

Hernández, Vivian M; Hegeman, Daniel J; Cui, Qiaoling; Kelver, Daniel A; Fiske, Michael P; Glajch, Kelly E; Pitt, Jason E; Huang, Tina Y; Justice, Nicholas J; Chan, C Savio

2015-08-26

Compelling evidence suggests that pathological activity of the external globus pallidus (GPe), a nucleus in the basal ganglia, contributes to the motor symptoms of a variety of movement disorders such as Parkinson's disease. Recent studies have challenged the idea that the GPe comprises a single, homogenous population of neurons that serves as a simple relay in the indirect pathway. However, we still lack a full understanding of the diversity of the neurons that make up the GPe. Specifically, a more precise classification scheme is needed to better describe the fundamental biology and function of different GPe neuron classes. To this end, we generated a novel multicistronic BAC (bacterial artificial chromosome) transgenic mouse line under the regulatory elements of the Npas1 gene. Using a combinatorial transgenic and immunohistochemical approach, we discovered that parvalbumin-expressing neurons and Npas1-expressing neurons in the GPe represent two nonoverlapping cell classes, amounting to 55% and 27% of the total GPe neuron population, respectively. These two genetically identified cell classes projected primarily to the subthalamic nucleus and to the striatum, respectively. Additionally, parvalbumin-expressing neurons and Npas1-expressing neurons were distinct in their autonomous and driven firing characteristics, their expression of intrinsic ion conductances, and their responsiveness to chronic 6-hydroxydopamine lesion. In summary, our data argue that parvalbumin-expressing neurons and Npas1-expressing neurons are two distinct functional classes of GPe neurons. This work revises our understanding of the GPe, and provides the foundation for future studies of its function and dysfunction. Until recently, the heterogeneity of the constituent neurons within the external globus pallidus (GPe) was not fully appreciated. We addressed this knowledge gap by discovering two principal GPe neuron classes, which were identified by their nonoverlapping expression of the

Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus

Science.gov (United States)

Hernández, Vivian M.; Hegeman, Daniel J.; Cui, Qiaoling; Kelver, Daniel A.; Fiske, Michael P.; Glajch, Kelly E.; Pitt, Jason E.; Huang, Tina Y.; Justice, Nicholas J.

2015-01-01

Compelling evidence suggests that pathological activity of the external globus pallidus (GPe), a nucleus in the basal ganglia, contributes to the motor symptoms of a variety of movement disorders such as Parkinson's disease. Recent studies have challenged the idea that the GPe comprises a single, homogenous population of neurons that serves as a simple relay in the indirect pathway. However, we still lack a full understanding of the diversity of the neurons that make up the GPe. Specifically, a more precise classification scheme is needed to better describe the fundamental biology and function of different GPe neuron classes. To this end, we generated a novel multicistronic BAC (bacterial artificial chromosome) transgenic mouse line under the regulatory elements of the Npas1 gene. Using a combinatorial transgenic and immunohistochemical approach, we discovered that parvalbumin-expressing neurons and Npas1-expressing neurons in the GPe represent two nonoverlapping cell classes, amounting to 55% and 27% of the total GPe neuron population, respectively. These two genetically identified cell classes projected primarily to the subthalamic nucleus and to the striatum, respectively. Additionally, parvalbumin-expressing neurons and Npas1-expressing neurons were distinct in their autonomous and driven firing characteristics, their expression of intrinsic ion conductances, and their responsiveness to chronic 6-hydroxydopamine lesion. In summary, our data argue that parvalbumin-expressing neurons and Npas1-expressing neurons are two distinct functional classes of GPe neurons. This work revises our understanding of the GPe, and provides the foundation for future studies of its function and dysfunction. SIGNIFICANCE STATEMENT Until recently, the heterogeneity of the constituent neurons within the external globus pallidus (GPe) was not fully appreciated. We addressed this knowledge gap by discovering two principal GPe neuron classes, which were identified by their nonoverlapping

Entropy measures of collective cell migration

Science.gov (United States)

Whitby, Ariadne; Parrinello, Simona; Faisal, Aldo

2015-03-01

Collective cell migration is a critical process during tissue formation and repair. To this end there is a need to develop tools to quantitatively measure the dynamics of collective cell migration obtained from microscopy data. Drawing on statistical physics we use entropy of velocity fields derived from dense optic flow to quantitatively measure collective migration. Using peripheral nerve repair after injury as experimental system, we study how Schwann cells, guided by fibroblasts, migrate in cord-like structures across the cut, paving a highway for neurons. This process of emergence of organised behaviour is key for successful repair, yet the emergence of leader cells and transition from a random to ordered state is not understood. We find fibroblasts induce correlated directionality in migrating Schwann cells as measured by a decrease in the entropy of motion vector. We show our method is robust with respect to image resolution in time and space, giving a principled assessment of how various molecular mechanisms affect macroscopic features of collective cell migration. Finally, the generality of our method allows us to process both simulated cell movement and microscopic data, enabling principled fitting and comparison of in silico to in vitro. ICCS, Imperial College London & MRC Clinical Sciences Centre.

Essential roles of mitochondrial depolarization in neuron loss through microglial activation and attraction toward neurons.

Science.gov (United States)

Nam, Min-Kyung; Shin, Hyun-Ah; Han, Ji-Hye; Park, Dae-Wook; Rhim, Hyangshuk

2013-04-10

As life spans increased, neurodegenerative disorders that affect aging populations have also increased. Progressive neuronal loss in specific brain regions is the most common cause of neurodegenerative disease; however, key determinants mediating neuron loss are not fully understood. Using a model of mitochondrial membrane potential (ΔΨm) loss, we found only 25% cell loss in SH-SY5Y (SH) neuronal mono-cultures, but interestingly, 85% neuronal loss occurred when neurons were co-cultured with BV2 microglia. SH neurons overexpressing uncoupling protein 2 exhibited an increase in neuron-microglia interactions, which represent an early step in microglial phagocytosis of neurons. This result indicates that ΔΨm loss in SH neurons is an important contributor to recruitment of BV2 microglia. Notably, we show that ΔΨm loss in BV2 microglia plays a crucial role in microglial activation and phagocytosis of damaged SH neurons. Thus, our study demonstrates that ΔΨm loss in both neurons and microglia is a critical determinant of neuron loss. These findings also offer new insights into neuroimmunological and bioenergetical aspects of neurodegenerative disease. Copyright © 2013 Elsevier B.V. All rights reserved.

Migration from Mexico to the US and Conduct Disorder: A Cross-National Study

Science.gov (United States)

Breslau, Joshua; Borges, Guilherme; Saito, Naomi; Tancredi, Daniel J.; Benjet, Corina; Hinton, Ladson; Kendler, Kenneth S.; Kravitz, Richard; Vega, William; Aguilar-Gaxiola, Sergio; Medina-Mora, Maria Elena

2013-01-01

Context Twin studies suggest that Conduct Disorder (CD) is under substantial genetic influence, which is stronger for aggressive than for non-aggressive symptoms. Studies of migrating populations offer an alternative strategy for separating environmental and genetic influences on psychopathology. Objective To examine variation in the prevalence of CD associated with migration from Mexico to the US and whether this variation is similar for aggressive and non-aggressive CD symptoms and symptom profiles. Design The prevalence of CD, different types of CD symptoms and CD symptom profiles were compared across three generations of people of Mexican origin with increasing levels of exposure to American culture: families of origin of migrants (in Mexico), children of Mexican migrants raised in the US and Mexican-American children of US-born parents. Setting General population surveys conducted in Mexico and the US using the same diagnostic interview. Participants Adults age 18–44 in the household population of Mexico and the household population of people of Mexican descent in the US. Main Outcome Measures CD criteria assessed using the World Mental Health version of the Composite International Diagnostic Instrument (WMH-CIDI). Results Compared with families of origin of migrants, risk of CD is lower in the general population of Mexico (OR=0.54, 95% CI 0.19–1.51), higher in children of Mexican-born immigrants who are raised in the US (OR=4.12, 95% CI 1.47–11.52) and higher still in Mexican-American children of US-born parents (OR=7.64, 95% CI 3.20–18.27). The association with migration is markedly weaker for aggressive than for non-aggressive symptoms. Conclusions The prevalence of CD increases dramatically across generations of the Mexican-origin population following migration to the US. This increase is of larger magnitude for non-aggressive than for aggressive symptoms, consistent with the suggestion that non-aggressive symptoms are more strongly influenced by

Parental migration patterns and risk of depression and anxiety disorder among rural children aged 10-18 years in China: a cross-sectional study.

Science.gov (United States)

Shen, Min; Gao, Jing; Liang, Zenzen; Wang, Youjie; Du, Yukai; Stallones, Lorann

2015-12-29

This study aims to explore the prevalence of depression and anxiety in left-behind children, and to identify patterns of parents' migration and relative factors associated with depression and anxiety risk in this population. A cross-sectional survey using a school-based sample was conducted in Puyang, Hebei, North China in December 2012. 2283 students aged 10-18 years. Parental migration status, depression and anxiety disorder. 61.2% of participants were left-behind children. The prevalence rate of depression among left-behind children with both parents migrating (14.2%) was higher than that of children with one parent migrating (11.7%) and no parent migrating (12.6%). The prevalence rate of anxiety disorder for children with no parent migrating (25.1%) was higher than that for children living with one or neither parent (22.2% and 22.0%). The risk factors for depression were low-level social support (OR=3.46, 95% CI 2.00 to 6.01), average academic performance (OR=2.37, 95% CI 1.7 to 3.3) and low academic performance (OR=3.01, 95% CI 1.92 to 4.72), staying up late (OR=1.67, 95% CI 1.17 to 2.39), having difficulty falling asleep (OR=2.04, 95% CI 1.48 to 2.82) and being an only child (OR=1.73, 95% CI 1.04 to 2.89). The factors associated with anxiety disorder were being female (OR=2.09, 95% CI 1.64 to 2.66), being in high school (OR=1.8, 95% CI 1.38 to 2.36), physical abuse (OR=1.5, 95% CI 1.04 to 2.15), having difficulty falling asleep (OR=1.67, 95% CI 1.33 to 2.10) and low-level social support (OR=2.17, 95% CI 1.44 to 3.28) and middle-level social support (OR=1.82, 95% CI 1.3 to 2.56). Parents' migration was not associated with depression and anxiety in rural children aged 10-18 years, but academic performance at school, sleep problems and lack of social support were associated with depression and anxiety. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Iron-induced neuronal damage in a rat model of post-traumatic stress disorder.

Science.gov (United States)

Zhao, Ming; Yu, Zhibo; Zhang, Yang; Huang, Xueling; Hou, Jingming; Zhao, YanGang; Luo, Wei; Chen, Lin; Ou, Lan; Li, Haitao; Zhang, Jiqiang

2016-08-25

Previous studies have shown that iron redistribution and deposition in the brain occurs in some neurodegenerative diseases, and oxidative damage due to abnormal iron level is a primary cause of neuronal death. In the present study, we used the single prolonged stress (SPS) model to mimic post-traumatic stress disorder (PTSD), and examined whether iron was involved in the progression of PTSD. The anxiety-like behaviors of the SPS group were assessed by the elevated plus maze (EPM) and open field tests, and iron levels were measured by inductively coupled plasma optical emission spectrometer (ICP-OES). Expression of glucocorticoid receptors and transferrin receptor 1 (TfR1) and ferritin (Fn) was detected by Western blot and immunohistochemistry in selected brain areas; TfR1 and Fn mRNA expression were detected by quantitative-polymerase chain reaction (Q-PCR). Ultrastructures of the hippocampus were observed under a transmission electron microscope. Our results showed that SPS exposure induced anxiety-like symptoms and increased the level of serum cortisol and the concentration of iron in key brain areas such as the hippocampus, prefrontal cortex, and striatum. The stress induced region-specific changes in both protein and mRNA levels of TfR1 and Fn. Moreover, swelling mitochondria and cell apoptosis were observed in neurons in brain regions with iron accumulation. We concluded that SPS stress increased iron in some cognition-related brain regions and subsequently cause neuronal injury, indicating that the iron may function in the pathology of PTSD. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Diffusion Tensor Imaging of Heterotopia: Changes of Fractional Anisotropy during Radial Migration of Neurons

Science.gov (United States)

Kim, Jinna

2010-01-01

Purpose Diffusion tensor imaging provides better understanding of pathophysiology of congenital anomalies, involving central nervous system. This study was aimed to specify the pathogenetic mechanism of heterotopia, proved by diffusion tensor imaging, and establish new findings of heterotopia on fractional anisotropy maps. Materials and Methods Diffusion-weighted imaging data from 11 patients (M : F = 7 : 4, aged from 1 to 22 years, mean = 12.3 years) who visited the epilepsy clinic and received a routine seizure protocol MRI exam were retrospectively analyzed. Fractional anisotropy (FA) maps were generated from diffusion tensor imaging of 11 patients with heterotopia. Regions of interests (ROI) were placed in cerebral cortex, heterotopic gray matter and deep gray matter, including putamen. ANOVA analysis was performed for comparison of different gray matter tissues. Results Heterotopic gray matter showed signal intensities similar to normal gray matter on T1 and T2 weighted MRI. The measured FA of heterotopic gray matter was higher than that of cortical gray matter (0.236 ± 0.011 vs. 0.169 ± 0.015, p < 0.01, one way ANOVA), and slightly lower than that of deep gray matter (0.236 ± 0.011 vs. 0.259 ± 0.016, p < 0.01). Conclusion Increased FA of heterotopic gray matter suggests arrested neuron during radial migration and provides better understanding of neurodevelopment. PMID:20499428

Neuronal differentiation of hair-follicle-bulge-derived stem cells co-cultured with mouse cochlear modiolus explants.

Directory of Open Access Journals (Sweden)

Timo Schomann

Full Text Available Stem-cell-based repair of auditory neurons may represent an attractive therapeutic option to restore sensorineural hearing loss. Hair-follicle-bulge-derived stem cells (HFBSCs are promising candidates for this type of therapy, because they (1 have migratory properties, enabling migration after transplantation, (2 can differentiate into sensory neurons and glial cells, and (3 can easily be harvested in relatively high numbers. However, HFBSCs have never been used for this purpose. We hypothesized that HFBSCs can be used for cell-based repair of the auditory nerve and we have examined their migration and incorporation into cochlear modiolus explants and their subsequent differentiation. Modiolus explants obtained from adult wild-type mice were cultured in the presence of EF1α-copGFP-transduced HFBSCs, constitutively expressing copepod green fluorescent protein (copGFP. Also, modiolus explants without hair cells were co-cultured with DCX-copGFP-transduced HFBSCs, which demonstrate copGFP upon doublecortin expression during neuronal differentiation. Velocity of HFBSC migration towards modiolus explants was calculated, and after two weeks, co-cultures were fixed and processed for immunohistochemical staining. EF1α-copGFP HFBSC migration velocity was fast: 80.5 ± 6.1 μm/h. After arrival in the explant, the cells formed a fascicular pattern and changed their phenotype into an ATOH1-positive neuronal cell type. DCX-copGFP HFBSCs became green-fluorescent after integration into the explants, confirming neuronal differentiation of the cells. These results show that HFBSC-derived neuronal progenitors are migratory and can integrate into cochlear modiolus explants, while adapting their phenotype depending on this micro-environment. Thus, HFBSCs show potential to be employed in cell-based therapies for auditory nerve repair.

Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility.

LENUS (Irish Health Repository)

O'Dushlaine, C

2011-03-01

Susceptibility to schizophrenia and bipolar disorder may involve a substantial, shared contribution from thousands of common genetic variants, each of small effect. Identifying whether risk variants map to specific molecular pathways is potentially biologically informative. We report a molecular pathway analysis using the single-nucleotide polymorphism (SNP) ratio test, which compares the ratio of nominally significant (P<0.05) to nonsignificant SNPs in a given pathway to identify the \\'enrichment\\' for association signals. We applied this approach to the discovery (the International Schizophrenia Consortium (n=6909)) and validation (Genetic Association Information Network (n=2729)) of schizophrenia genome-wide association study (GWAS) data sets. We investigated each of the 212 experimentally validated pathways described in the Kyoto Encyclopaedia of Genes and Genomes in the discovery sample. Nominally significant pathways were tested in the validation sample, and five pathways were found to be significant (P=0.03-0.001); only the cell adhesion molecule (CAM) pathway withstood conservative correction for multiple testing. Interestingly, this pathway was also significantly associated with bipolar disorder (Wellcome Trust Case Control Consortium (n=4847)) (P=0.01). At a gene level, CAM genes associated in all three samples (NRXN1 and CNTNAP2), which were previously implicated in specific language disorder, autism and schizophrenia. The CAM pathway functions in neuronal cell adhesion, which is critical for synaptic formation and normal cell signaling. Similar pathways have also emerged from a pathway analysis of autism, suggesting that mechanisms involved in neuronal cell adhesion may contribute broadly to neurodevelopmental psychiatric phenotypes.

Axon Development in Health and Disease

NARCIS (Netherlands)

Battum, E.Y. van

2016-01-01

During embryonic development neurons migrate and grow their protrusions (neurites) over long distances in a strictly orchestrated manner to form complex neuronal networks. Subtle changes in neuronal network formation may lead to various neurological disorders ranging from congenital mirror

Mirror neurons: Enigma of the metaphysical modular brain.

Science.gov (United States)

Acharya, Sourya; Shukla, Samarth

2012-07-01

Mirror neurons are one of the most important discoveries in the last decade of neuroscience. These are a variety of visuospatial neurons which indicate fundamentally about human social interaction. Essentially, mirror neurons respond to actions that we observe in others. The interesting part is that mirror neurons fire in the same way when we actually recreate that action ourselves. Apart from imitation, they are responsible for myriad of other sophisticated human behavior and thought processes. Defects in the mirror neuron system are being linked to disorders like autism. This review is a brief introduction to the neurons that shaped our civilization.

Hydrogen migration in Lu at low temperatures

International Nuclear Information System (INIS)

Yamakawa, K.

1997-01-01

The migration of hydrogen in Lu is determined by electrical resistance measurements in temperature range of 140-170 K. Disordered hydrogen atoms, which are formed by quenching, migrate to order during annealing in the above temperature range. The rate of the resistance decrease depends on the ordering rate of hydrogen. From the resistance decrease during isothermal annealings, the activation energy of hydrogen migration is determined as 0.43 eV (41.5 kJ mol -1 ). (orig.)

Serotonin receptor 3A controls interneuron migration into the neocortex

NARCIS (Netherlands)

Murthy, S.; Niquille, M.; Hurni, N.; Limoni, G.; Frazer, S.; Chameau, P.; van Hooft, J.A.; Vitalis, T.; Dayer, A.

2014-01-01

Neuronal excitability has been shown to control the migration and cortical integration of reelin-expressing cortical interneurons (INs) arising from the caudal ganglionic eminence (CGE), supporting the possibility that neurotransmitters could regulate this process. Here we show that the ionotropic

The role of metallothionein II in neuronal differentiation and survival

DEFF Research Database (Denmark)

Køhler, Lene B; Berezin, Vladimir; Bock, Elisabeth

2003-01-01

-I+II can affect neurons directly. It is likely that MT isoforms could be beneficial also during neurodegenerative disorders. In this study, we have examined if MT-II affects survival and neurite extension of dopaminergic and hippocampal neurons. We show for the first time that MT-II treatment can....... Accordingly, treatment with MT-II may be of therapeutic value in neurodegenerative disorders....

Neuronal Networks on Nanocellulose Scaffolds.

Science.gov (United States)

Jonsson, Malin; Brackmann, Christian; Puchades, Maja; Brattås, Karoline; Ewing, Andrew; Gatenholm, Paul; Enejder, Annika

2015-11-01

Proliferation, integration, and neurite extension of PC12 cells, a widely used culture model for cholinergic neurons, were studied in nanocellulose scaffolds biosynthesized by Gluconacetobacter xylinus to allow a three-dimensional (3D) extension of neurites better mimicking neuronal networks in tissue. The interaction with control scaffolds was compared with cationized nanocellulose (trimethyl ammonium betahydroxy propyl [TMAHP] cellulose) to investigate the impact of surface charges on the cell interaction mechanisms. Furthermore, coatings with extracellular matrix proteins (collagen, fibronectin, and laminin) were investigated to determine the importance of integrin-mediated cell attachment. Cell proliferation was evaluated by a cellular proliferation assay, while cell integration and neurite propagation were studied by simultaneous label-free Coherent anti-Stokes Raman Scattering and second harmonic generation microscopy, providing 3D images of PC12 cells and arrangement of nanocellulose fibrils, respectively. Cell attachment and proliferation were enhanced by TMAHP modification, but not by protein coating. Protein coating instead promoted active interaction between the cells and the scaffold, hence lateral cell migration and integration. Irrespective of surface modification, deepest cell integration measured was one to two cell layers, whereas neurites have a capacity to integrate deeper than the cell bodies in the scaffold due to their fine dimensions and amoeba-like migration pattern. Neurites with lengths of >50 μm were observed, successfully connecting individual cells and cell clusters. In conclusion, TMAHP-modified nanocellulose scaffolds promote initial cellular scaffold adhesion, which combined with additional cell-scaffold treatments enables further formation of 3D neuronal networks.

Sensory neurons do not induce motor neuron loss in a human stem cell model of spinal muscular atrophy.

Science.gov (United States)

Schwab, Andrew J; Ebert, Allison D

2014-01-01

Spinal muscular atrophy (SMA) is an autosomal recessive disorder leading to paralysis and early death due to reduced SMN protein. It is unclear why there is such a profound motor neuron loss, but recent evidence from fly and mouse studies indicate that cells comprising the whole sensory-motor circuit may contribute to motor neuron dysfunction and loss. Here, we used induced pluripotent stem cells derived from SMA patients to test whether sensory neurons directly contribute to motor neuron loss. We generated sensory neurons from SMA induced pluripotent stem cells and found no difference in neuron generation or survival, although there was a reduced calcium response to depolarizing stimuli. Using co-culture of SMA induced pluripotent stem cell derived sensory neurons with control induced pluripotent stem cell derived motor neurons, we found no significant reduction in motor neuron number or glutamate transporter boutons on motor neuron cell bodies or neurites. We conclude that SMA sensory neurons do not overtly contribute to motor neuron loss in this human stem cell system.

Nup358 interacts with Dishevelled and aPKC to regulate neuronal polarity

Directory of Open Access Journals (Sweden)

Pankhuri Vyas

2013-10-01

Par polarity complex, consisting of Par3, Par6, and aPKC, plays a conserved role in the establishment and maintenance of polarization in diverse cellular contexts. Recent reports suggest that Dishevelled (Dvl, a cytoplasmic mediator of Wnt signalling, interacts with atypical protein kinase C and regulates its activity during neuronal differentiation and directed cell migration. Here we show that Nup358 (also called RanBP2, a nucleoporin previously implicated in polarity during directed cell migration, interacts with Dishevelled and aPKC through its N-terminal region (BPN and regulates axon–dendrite differentiation of cultured hippocampal neurons. Depletion of endogenous Nup358 leads to generation of multiple axons, whereas overexpression of BPN abrogates the process of axon formation. Moreover, siRNA-mediated knockdown of Dvl or inhibition of aPKC by a pseudosubstrate inhibitor significantly reverses the multiple axon phenotype produced by Nup358 depletion. Collectively, these data suggest that Nup358 plays an important role in regulating neuronal polarization upstream to Dvl and aPKC.

IGF-1: elixir for motor neuron diseases.

Science.gov (United States)

Papanikolaou, Theodora; Ellerby, Lisa M

2009-08-13

Modulation of testosterone levels is a therapeutic approach for spinal and bulbar muscular atrophy (SBMA), a polyglutamine disorder that affects the motor neurons. The article by Palazzolo et al. in this issue of Neuron provides compelling evidence that the expression of insulin growth hormone is a potential therapeutic for SBMA.

Life and death of neurons in the aging brain

Science.gov (United States)

Morrison, J. H.; Hof, P. R.; Bloom, F. E. (Principal Investigator)

1997-01-01

Neurodegenerative disorders are characterized by extensive neuron death that leads to functional decline, but the neurobiological correlates of functional decline in normal aging are less well defined. For decades, it has been a commonly held notion that widespread neuron death in the neocortex and hippocampus is an inevitable concomitant of brain aging, but recent quantitative studies suggest that neuron death is restricted in normal aging and unlikely to account for age-related impairment of neocortical and hippocampal functions. In this article, the qualitative and quantitative differences between aging and Alzheimer's disease with respect to neuron loss are discussed, and age-related changes in functional and biochemical attributes of hippocampal circuits that might mediate functional decline in the absence of neuron death are explored. When these data are viewed comprehensively, it appears that the primary neurobiological substrates for functional impairment in aging differ in important ways from those in neurodegenerative disorders such as Alzheimer's disease.

Motor neuron disease associated with carcinoma | Gritzman | South ...

African Journals Online (AJOL)

Paraneoplastic complications are obscure and difficult to understand. The association of motor neuron disease and carcinoma may sometimes be more than coincidental, and 2 cases are described. One patient had motor neuron disease, limbic encephalitis (a recognized paraneoplastic disorder) and carcinoma of the ...

Fisetin regulates astrocyte migration and proliferation in vitro

OpenAIRE

Wang, Nan; Yao, Fang; Li, Ke; Zhang, Lanlan; Yin, Guo; Du, Mingjun; Wu, Bingyi

2017-01-01

Fisetin (3,3?,4?,7-tetrahydroxyflavone) is a plant flavonol found in fruits and vegetables that has been reported to inhibit migration and proliferation in several types of cancer. Reactive astrogliosis involves astrocyte migration and proliferation, and contributes to the formation of glial scars in central nervous system (CNS) disorders. However, the effect of fisetin on the migration and proliferation of astrocytes remains unclear. In this study, we found that fisetin inhibited astrocyte m...

Chimera states in bursting neurons

OpenAIRE

Bera, Bidesh K.; Ghosh, Dibakar; Lakshmanan, M.

2015-01-01

We study the existence of chimera states in pulse-coupled networks of bursting Hindmarsh-Rose neurons with nonlocal, global and local (nearest neighbor) couplings. Through a linear stability analysis, we discuss the behavior of stability function in the incoherent (i.e. disorder), coherent, chimera and multi-chimera states. Surprisingly, we find that chimera and multi-chimera states occur even using local nearest neighbor interaction in a network of identical bursting neurons alone. This is i...

Pre-migration persecution, post-migration stressors and resources, and post-migration mental health: A study of severely traumatized U.S. Arab immigrant women

Science.gov (United States)

Norris, Anne E.; Aroian, Karen J.; Nickerson, David

2015-01-01

Background Competing theories exist regarding the importance of pre-migration trauma as compared to post-migration stressors and resources with respect to the risk to immigrant mental health. Objective To examine how type of pre-migration trauma, post-migration stressors, and post-migration resources differentially predict PTSD and MDD symptomatology in Arab immigrant women who have been exposed to pre-migration trauma. Design Descriptive; using multinomial logistic regression to explain membership in one of four groups: (a) PTSD only (n = 14); (b) major depressive disorder (MDD) (n = 162), (c) Co-Morbid PTSD-MDD (n = 148), (d) Subclinical Symptoms (n = 209). Results Post-immigration related stressors (as measured by the Demands of Immigration (DI)) had the strongest effect: Parameter estimates indicated that a unit increase in DI scores was associated with a nearly 17 fold increase in the likelihood of being in the Co-morbid relative to the Subclinical group, and a nearly 2.5 increase in the likelihood of being in the Co-Morbid relative to the MDD only group (p Arab immigrant women for depression and PTSD is important given high levels observed in this community based sample. PMID:21835819

BIG1 is required for the survival of deep layer neurons, neuronal polarity, and the formation of axonal tracts between the thalamus and neocortex in developing brain.

Directory of Open Access Journals (Sweden)

Jia-Jie Teoh

Full Text Available BIG1, an activator protein of the small GTPase, Arf, and encoded by the Arfgef1 gene, is one of candidate genes for epileptic encephalopathy. To know the involvement of BIG1 in epileptic encephalopathy, we analyzed BIG1-deficient mice and found that BIG1 regulates neurite outgrowth and brain development in vitro and in vivo. The loss of BIG1 decreased the size of the neocortex and hippocampus. In BIG1-deficient mice, the neuronal progenitor cells (NPCs and the interneurons were unaffected. However, Tbr1+ and Ctip2+ deep layer (DL neurons showed spatial-temporal dependent apoptosis. This apoptosis gradually progressed from the piriform cortex (PIR, peaked in the neocortex, and then progressed into the hippocampus from embryonic day 13.5 (E13.5 to E17.5. The upper layer (UL and DL order in the neocortex was maintained in BIG1-deficient mice, but the excitatory neurons tended to accumulate before their destination layers. Further pulse-chase migration assay showed that the migration defect was non-cell autonomous and secondary to the progression of apoptosis into the BIG1-deficient neocortex after E15.5. In BIG1-deficient mice, we observed an ectopic projection of corticothalamic axons from the primary somatosensory cortex (S1 into the dorsal lateral geniculate nucleus (dLGN. The thalamocortical axons were unable to cross the diencephalon-telencephalon boundary (DTB. In vitro, BIG1-deficient neurons showed a delay in neuronal polarization. BIG1-deficient neurons were also hypersensitive to low dose glutamate (5 μM, and died via apoptosis. This study showed the role of BIG1 in the survival of DL neurons in developing embryonic brain and in the generation of neuronal polarity.

Enhancing action of LSD on neuronal responsiveness to serotonin in a brain structure involved in obsessive-compulsive disorder.

Science.gov (United States)

Zghoul, Tarek; Blier, Pierre

2003-03-01

Potent serotonin (5-HT) reuptake inhibitors are the only drugs that consistently exert a therapeutic action in obsessive-compulsive disorder (OCD). Given that some hallucinogens were reported to exert an anti-OCD effect outlasting their psychotomimetic action, possible modifications of neuronal responsiveness to 5-HT by LSD were examined in two rat brain structures: one associated with OCD, the orbitofrontal cortex (OFC), and another linked to depression, the hippocampus. The effects of concurrent microiontophoretic application of LSD and 5-HT were examined on neuronal firing rate in the rat OFC and hippocampus under chloral hydrate anaesthesia. In order to determine whether LSD could also exert a modification of 5-HT neuronal responsiveness upon systemic administration, after a delay when hallucinosis is presumably no longer present, it was given once daily (100 microg/kg i.p.) for 4 d and the experiments were carried out 24 h after the last dose. LSD attenuated the firing activity of OFC neurons, and enhanced the inhibitory effect of 5-HT when concomitantly ejected on the same neurons. In the hippocampus, LSD also decreased firing rate by itself but decreased the inhibitory action of 5-HT. The inhibitory action of 5-HT was significantly greater in the OFC, but smaller in the hippocampus, when examined after subacute systemic administration of LSD. It is postulated that some hallucinogens could have a beneficial action in OCD by enhancing the responsiveness to 5-HT in the OFC, and not necessarily in direct relation to hallucinosis. The latter observation may have theoretical implications for the pharmacotherapy of OCD.

How to make spinal motor neurons.

Science.gov (United States)

Davis-Dusenbery, Brandi N; Williams, Luis A; Klim, Joseph R; Eggan, Kevin

2014-02-01

All muscle movements, including breathing, walking, and fine motor skills rely on the function of the spinal motor neuron to transmit signals from the brain to individual muscle groups. Loss of spinal motor neuron function underlies several neurological disorders for which treatment has been hampered by the inability to obtain sufficient quantities of primary motor neurons to perform mechanistic studies or drug screens. Progress towards overcoming this challenge has been achieved through the synthesis of developmental biology paradigms and advances in stem cell and reprogramming technology, which allow the production of motor neurons in vitro. In this Primer, we discuss how the logic of spinal motor neuron development has been applied to allow generation of motor neurons either from pluripotent stem cells by directed differentiation and transcriptional programming, or from somatic cells by direct lineage conversion. Finally, we discuss methods to evaluate the molecular and functional properties of motor neurons generated through each of these techniques.

Cell Proliferation, Migration, and Neurogenesis in the Adult Brain of the Pulse Type Weakly Electric Fish, Gymnotus omarorum

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Valentina Olivera-Pasilio

2017-08-01

Full Text Available Adult neurogenesis, an essential mechanism of brain plasticity, enables brain development along postnatal life, constant addition of new neurons, neuronal turnover, and/or regeneration. It is amply distributed but negatively modulated during development and along evolution. Widespread cell proliferation, high neurogenic, and regenerative capacities are considered characteristics of teleost brains during adulthood. These anamniotes are promising models to depict factors that modulate cell proliferation, migration, and neurogenesis, and might be intervened to promote brain plasticity in mammals. Nevertheless, the migration path of derived cells to their final destination was not studied in various teleosts, including most weakly electric fish. In this group adult brain morphology is attributed to sensory specialization, involving the concerted evolution of peripheral electroreceptors and electric organs, encompassed by the evolution of neural networks involved in electrosensory information processing. In wave type gymnotids adult brain morphology is proposed to result from lifelong region specific cell proliferation and neurogenesis. Consistently, pulse type weakly electric gymnotids and mormyrids show widespread distribution of proliferation zones that persists in adulthood, but their neurogenic potential is still unknown. Here we studied the migration process and differentiation of newborn cells into the neuronal phenotype in the pulse type gymnotid Gymnotus omarorum. Pulse labeling of S-phase cells with 5-Chloro-2′-deoxyuridine thymidine followed by 1 to 180 day survivals evidenced long distance migration of newborn cells from the rostralmost telencephalic ventricle to the olfactory bulb, and between layers of all cerebellar divisions. Shorter migration appeared in the tectum opticum and torus semicircularis. In many brain regions, derived cells expressed early neuronal markers doublecortin (chase: 1–30 days and HuC/HuD (chase: 7–180 days

Multi-cellular logistics of collective cell migration.

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Masataka Yamao

Full Text Available During development, the formation of biological networks (such as organs and neuronal networks is controlled by multicellular transportation phenomena based on cell migration. In multi-cellular systems, cellular locomotion is restricted by physical interactions with other cells in a crowded space, similar to passengers pushing others out of their way on a packed train. The motion of individual cells is intrinsically stochastic and may be viewed as a type of random walk. However, this walk takes place in a noisy environment because the cell interacts with its randomly moving neighbors. Despite this randomness and complexity, development is highly orchestrated and precisely regulated, following genetic (and even epigenetic blueprints. Although individual cell migration has long been studied, the manner in which stochasticity affects multi-cellular transportation within the precisely controlled process of development remains largely unknown. To explore the general principles underlying multicellular migration, we focus on the migration of neural crest cells, which migrate collectively and form streams. We introduce a mechanical model of multi-cellular migration. Simulations based on the model show that the migration mode depends on the relative strengths of the noise from migratory and non-migratory cells. Strong noise from migratory cells and weak noise from surrounding cells causes "collective migration," whereas strong noise from non-migratory cells causes "dispersive migration." Moreover, our theoretical analyses reveal that migratory cells attract each other over long distances, even without direct mechanical contacts. This effective interaction depends on the stochasticity of the migratory and non-migratory cells. On the basis of these findings, we propose that stochastic behavior at the single-cell level works effectively and precisely to achieve collective migration in multi-cellular systems.

Disorders of migration and sulcation in infants and children: MR spectrum at 1.5 T

International Nuclear Information System (INIS)

Boyer, R.S.; Nixon, G.W.; Smoker, W.R.K.; Harnsberger, H.R.; Osborn, A.G.

1987-01-01

In 750 consecutive high-field-strength (1.5-T) pediatric brain MR imaging studies the authors encountered a fascinating spectrum of developmental anomalies of migration, gyration, and sulcation in 11 patients. Lesions were characterized by disorder anatomy but normal gray-matter signal. MR imaging was excellent in revealing pachygyria, polymicrogyria, agyria (lissencephaly), heterotopia, and schizencephaly, and in displaying associated development anomalies, such as agenesis of the corpus callosum, encephalocele, Chiari II malformation, septo-optic dysplasia, lobar holoprosencephaly, and unilateral megalencephaly. The improved demonstration of gray-matter abnormalities that is possible with high-field-strength MR imaging facilitates recognition of these lesions and associated anomalies

Fractalkine is a "find-me" signal released by neurons undergoing ethanol-induced apoptosis.

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Sokolowski, Jennifer D; Chabanon-Hicks, Chloe N; Han, Claudia Z; Heffron, Daniel S; Mandell, James W

2014-01-01

Apoptotic neurons generated during normal brain development or secondary to pathologic insults are efficiently cleared from the central nervous system. Several soluble factors, including nucleotides, cytokines, and chemokines are released from injured neurons, signaling microglia to find and clear debris. One such chemokine that serves as a neuronal-microglial communication factor is fractalkine, with roles demonstrated in several models of adult neurological disorders. Lacking, however, are studies investigating roles for fractalkine in perinatal brain injury, an important clinical problem with no effective therapies. We used a well-characterized mouse model of ethanol-induced apoptosis to assess the role of fractalkine in neuronal-microglial signaling. Quantification of apoptotic debris in fractalkine-knockout (KO) and CX3CR1-KO mice following ethanol treatment revealed increased apoptotic bodies compared to wild type mice. Ethanol-induced injury led to release of soluble, extracellular fractalkine. The extracellular media harvested from apoptotic brains induces microglial migration in a fractalkine-dependent manner that is prevented by neutralization of fractalkine with a blocking antibody or by deficiency in the receptor, CX3CR1. This suggests fractalkine acts as a "find-me" signal, recruiting microglial processes toward apoptotic cells to promote their clearance. Next, we aimed to determine whether there are downstream alterations in cytokine gene expression due to fractalkine signaling. We examined mRNA expression in fractalkine-KO and CX3CR1-KO mice after alcohol-induced apoptosis and found differences in cytokine production in the brains of these KOs by 6 h after ethanol treatment. Collectively, this suggests that fractalkine acts as a "find me" signal released by apoptotic neurons, and subsequently plays a critical role in modulating both clearance and inflammatory cytokine gene expression after ethanol-induced apoptosis.

Fractalkine is a "find-me" signal released by neurons undergoing ethanol-induced apoptosis

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Jennifer D Sokolowski

2014-11-01

Full Text Available Apoptotic neurons generated during normal brain development or secondary to pathologic insults are efficiently cleared from the central nervous system. Several soluble factors, including nucleotides, cytokines, and chemokines are released from injured neurons, signaling microglia to find and clear debris. One such chemokine that serves as a neuronal-microglial communication factor is fractalkine, with roles demonstrated in several models of adult neurological disorders. Lacking, however, are studies investigating roles for fractalkine in perinatal brain injury, an important clinical problem with no effective therapies. We used a well-characterized mouse model of ethanol-induced apoptosis to assess the role of fractalkine in neuronal-microglial signaling. Quantification of apoptotic debris in fractalkine-knockout and CX3CR1-knockout mice following ethanol treatment revealed increased apoptotic bodies compared to wild type mice. Ethanol-induced injury led to release of soluble, extracellular fractalkine. The extracellular media harvested from apoptotic brains induces microglial migration in a fractalkine-dependent manner that is prevented by neutralization of fractalkine with a blocking antibody or by deficiency in the receptor, CX3CR1. This suggests fractalkine acts as a ‘find-me’ signal, recruiting microglial processes toward apoptotic cells to promote their clearance. Next, we aimed to determine whether there are downstream alterations in cytokine gene expression due to fractalkine signaling. We examined mRNA expression in fractalkine-knockout and CX3CR1-knockout mice after alcohol-induced apoptosis and found differences in cytokine production in the brains of these knockouts by 6 hours after ethanol treatment. Collectively, this suggests that fractalkine acts as a ‘find me’ signal released by apoptotic neurons, and subsequently plays a critical role in modulating both phagocytic clearance and inflammatory cytokine gene expression after

A chimeric path to neuronal synchronization

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Essaki Arumugam, Easwara Moorthy; Spano, Mark L.

2015-01-01

Synchronization of neuronal activity is associated with neurological disorders such as epilepsy. This process of neuronal synchronization is not fully understood. To further our understanding, we have experimentally studied the progression of this synchronization from normal neuronal firing to full synchronization. We implemented nine FitzHugh-Nagumo neurons (a simplified Hodgkin-Huxley model) via discrete electronics. For different coupling parameters (synaptic strengths), the neurons in the ring were either unsynchronized or completely synchronized when locally coupled in a ring. When a single long-range connection (nonlocal coupling) was introduced, an intermediate state known as a chimera appeared. The results indicate that (1) epilepsy is likely not only a dynamical disease but also a topological disease, strongly tied to the connectivity of the underlying network of neurons, and (2) the synchronization process in epilepsy may not be an "all or none" phenomenon, but can pass through an intermediate stage (chimera).

A chimeric path to neuronal synchronization

Energy Technology Data Exchange (ETDEWEB)

Essaki Arumugam, Easwara Moorthy; Spano, Mark L. [School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona 85287-9709 (United States)

2015-01-15

Synchronization of neuronal activity is associated with neurological disorders such as epilepsy. This process of neuronal synchronization is not fully understood. To further our understanding, we have experimentally studied the progression of this synchronization from normal neuronal firing to full synchronization. We implemented nine FitzHugh-Nagumo neurons (a simplified Hodgkin-Huxley model) via discrete electronics. For different coupling parameters (synaptic strengths), the neurons in the ring were either unsynchronized or completely synchronized when locally coupled in a ring. When a single long-range connection (nonlocal coupling) was introduced, an intermediate state known as a chimera appeared. The results indicate that (1) epilepsy is likely not only a dynamical disease but also a topological disease, strongly tied to the connectivity of the underlying network of neurons, and (2) the synchronization process in epilepsy may not be an “all or none” phenomenon, but can pass through an intermediate stage (chimera)

A chimeric path to neuronal synchronization

International Nuclear Information System (INIS)

Essaki Arumugam, Easwara Moorthy; Spano, Mark L.

2015-01-01

Synchronization of neuronal activity is associated with neurological disorders such as epilepsy. This process of neuronal synchronization is not fully understood. To further our understanding, we have experimentally studied the progression of this synchronization from normal neuronal firing to full synchronization. We implemented nine FitzHugh-Nagumo neurons (a simplified Hodgkin-Huxley model) via discrete electronics. For different coupling parameters (synaptic strengths), the neurons in the ring were either unsynchronized or completely synchronized when locally coupled in a ring. When a single long-range connection (nonlocal coupling) was introduced, an intermediate state known as a chimera appeared. The results indicate that (1) epilepsy is likely not only a dynamical disease but also a topological disease, strongly tied to the connectivity of the underlying network of neurons, and (2) the synchronization process in epilepsy may not be an “all or none” phenomenon, but can pass through an intermediate stage (chimera)

Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration

Science.gov (United States)

Berg, Russell D.; Levitte, Steven; O’Sullivan, Mary P.; O’Leary, Seónadh M.; Cambier, C.J.; Cameron, James; Takaki, Kevin K.; Moens, Cecilia B.; Tobin, David M.; Keane, Joseph; Ramakrishnan, Lalita

2016-01-01

Summary A zebrafish genetic screen for determinants of susceptibility to Mycobacterium marinum identified a hypersusceptible mutant deficient in lysosomal cysteine cathepsins that manifests hallmarks of human lysosomal storage diseases. Under homeostatic conditions, mutant macrophages accumulate undigested lysosomal material, which disrupts endocytic recycling and impairs their migration to, and thus engulfment of, dying cells. This causes a buildup of unengulfed cell debris. During mycobacterial infection, macrophages with lysosomal storage cannot migrate toward infected macrophages undergoing apoptosis in the tuberculous granuloma. The unengulfed apoptotic macrophages undergo secondary necrosis, causing granuloma breakdown and increased mycobacterial growth. Macrophage lysosomal storage similarly impairs migration to newly infecting mycobacteria. This phenotype is recapitulated in human smokers, who are at increased risk for tuberculosis. A majority of their alveolar macrophages exhibit lysosomal accumulations of tobacco smoke particulates and do not migrate to Mycobacterium tuberculosis. The incapacitation of highly microbicidal first-responding macrophages may contribute to smokers’ susceptibility to tuberculosis. PMID:27015311

Local traction force in the proximal leading process triggers nuclear translocation during neuronal migration.

Science.gov (United States)

Umeshima, Hiroki; Nomura, Ken-Ichi; Yoshikawa, Shuhei; Hörning, Marcel; Tanaka, Motomu; Sakuma, Shinya; Arai, Fumihito; Kaneko, Makoto; Kengaku, Mineko

2018-04-05

Somal translocation in long bipolar neurons is regulated by actomyosin contractile forces, yet the precise spatiotemporal sites of force generation are unknown. Here we investigate the force dynamics generated during somal translocation using traction force microscopy. Neurons with a short leading process generated a traction force in the growth cone and counteracting forces in the leading and trailing processes. In contrast, neurons with a long leading process generated a force dipole with opposing traction forces in the proximal leading process during nuclear translocation. Transient accumulation of actin filaments was observed at the dipole center of the two opposing forces, which was abolished by inhibition of myosin II activity. A swelling in the leading process emerged and generated a traction force that pulled the nucleus when nuclear translocation was physically hampered. The traction force in the leading process swelling was uncoupled from somal translocation in neurons expressing a dominant negative mutant of the KASH protein, which disrupts the interaction between cytoskeletal components and the nuclear envelope. Our results suggest that the leading process is the site of generation of actomyosin-dependent traction force in long bipolar neurons, and that the traction force is transmitted to the nucleus via KASH proteins. Copyright © 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.

Current view on the functional regulation of the neuronal K+-Cl- cotransporter KCC2

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Igor eMedina

2014-02-01

Full Text Available In the mammalian central nervous system, the inhibitory strength of chloride (Cl--permeable GABAA and glycine receptors (GABAAR and GlyR depends on the intracellular Cl- concentration ([Cl-]i. Lowering [Cl-]i enhances inhibition, whereas raising [Cl-]i facilitates neuronal activity. A neuron’s basal level of [Cl-]i, as well as its Cl- extrusion capacity, is critically dependent on the activity of the electroneutral K+-Cl- cotransporter KCC2, a member of the SLC12 cation-Cl- cotransporter (CCC family. KCC2 deficiency compromises neuronal migration, formation and the maturation of GABAergic and glutamatergic synaptic connections, and results in network hyperexcitability and seizure activity. Several neurological disorders including multiple epilepsy subtypes, neuropathic pain, and schizophrenia, as well as various insults such as trauma and ischemia, are associated with significant decreases in the Cl- extrusion capacity of KCC2 that result in increases of [Cl-]i and the subsequent hyperexcitability of neuronal networks. Accordingly, identifying the key upstream molecular mediators governing the functional regulation of KCC2, and modifying these signalling pathways with small molecules, might constitute a novel neurotherapeutic strategy for multiple diseases. Here, we discuss recent advances in the understanding of the mechanisms regulating KCC2 activity, and of the role these mechanisms play in neuronal Cl- homeostasis and GABAergic neurotransmission. As KCC2 mediates electroneutral transport, the experimental recording of its activity constitutes an important research challenge; we therefore also, provide an overview of the different methodological approaches utilized to monitor function of KCC2 in both physiological and pathological conditions.

Zinc and Neurogenesis: Making New Neurons from Development to Adulthood12

OpenAIRE

Levenson, Cathy W.; Morris, Deborah

2011-01-01

Stem cell proliferation, neuronal differentiation, cell survival, and migration in the central nervous system are all important steps in the normal process of neurogenesis. These mechanisms are highly active during gestational and early neonatal brain development. Additionally, in select regions of the brain, stem cells give rise to new neurons throughout the human lifespan. Recent work has revealed key roles for the essential trace element zinc in the control of both developmental and adult ...

Npas4: Linking Neuronal Activity to Memory.

Science.gov (United States)

Sun, Xiaochen; Lin, Yingxi

2016-04-01

Immediate-early genes (IEGs) are rapidly activated after sensory and behavioral experience and are believed to be crucial for converting experience into long-term memory. Neuronal PAS domain protein 4 (Npas4), a recently discovered IEG, has several characteristics that make it likely to be a particularly important molecular link between neuronal activity and memory: it is among the most rapidly induced IEGs, is expressed only in neurons, and is selectively induced by neuronal activity. By orchestrating distinct activity-dependent gene programs in different neuronal populations, Npas4 affects synaptic connections in excitatory and inhibitory neurons, neural circuit plasticity, and memory formation. It may also be involved in circuit homeostasis through negative feedback and psychiatric disorders. We summarize these findings and discuss their implications. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cortical and subcortical innervation of band heterotopia after developmental thyroid hormone insufficiency

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The characteristic laminated cytoarchitecture of the neocortex emerges from the orderly proliferation and migration of neurons during corticogenesis. Not surprisingly, developmental disorders affecting the laminar positioning of cortical neurons can have dramatic affects on cogni...

Paracrine Maturation and Migration of SH-SY5Y Cells by Dental Pulp Stem Cells.

Science.gov (United States)

Gervois, P; Wolfs, E; Dillen, Y; Hilkens, P; Ratajczak, J; Driesen, R B; Vangansewinkel, T; Bronckaers, A; Brône, B; Struys, T; Lambrichts, I

2017-06-01

Neurological disorders are characterized by neurodegeneration and/or loss of neuronal function, which cannot be adequately repaired by the host. Therefore, there is need for novel treatment options such as cell-based therapies that aim to salvage or reconstitute the lost tissue or that stimulate host repair. The present study aimed to evaluate the paracrine effects of human dental pulp stem cells (hDPSCs) on the migration and neural maturation of human SH-SY5Y neuroblastoma cells. The hDPSC secretome had a significant chemoattractive effect on SH-SY5Y cells as shown by a transwell assay. To evaluate neural maturation, SH-SY5Y cells were first induced toward neuronal cells, after which they were exposed to the hDPSC secretome. In addition, SH-SY5Y cells subjected to the hDPSC secretome showed increased neuritogenesis compared with nonexposed cells. Maturated cells were shown to increase immune reactivity for neuronal markers compared with controls. Ultrastructurally, retinoic acid (RA) signaling and subsequent exposure to the hDPSC secretome induced a gradual rise in metabolic activity and neuronal features such as multivesicular bodies and cytoskeletal elements associated with cellular communication. In addition, electrophysiological recordings of differentiating cells demonstrated a transition toward a neuronal electrophysiological profile based on the maximum tetrodotoxin (TTX)-sensitive, Na + current. Moreover, conditioned medium (CM)-hDPSC-maturated SH-SY5Y cells developed distinct features including, Cd 2+ -sensitive currents, which suggests that CM-hDPSC-maturated SH-SY5Y acquired voltage-gated Ca 2+ channels. The results reported in this study demonstrate the potential of hDPSCs to support differentiation and recruitment of cells with neuronal precursor characteristics in a paracrine manner. Moreover, this in vitro experimental design showed that the widely used SH-SY5Y cell line can improve and simplify the preclinical in vitro research on the molecular

Effects of oxaliplatin on mouse myenteric neurons and colonic motility

Science.gov (United States)

Wafai, Linah; Taher, Mohammadali; Jovanovska, Valentina; Bornstein, Joel C.; Dass, Crispin R.; Nurgali, Kulmira

2013-01-01

Oxaliplatin, an anti-cancer chemotherapeutic agent used for the treatment of colorectal cancer, commonly causes gastrointestinal side-effects such as constipation, diarrhoea, nausea, and vomiting. Damage to enteric neurons may underlie some of these gastrointestinal side-effects, as the enteric nervous system (ENS) controls functions of the bowel. In this study, neuronal loss and changes to the structure and immunoreactivity of myenteric neuronal nitric oxide synthase (nNOS) neurons were examined in colonic segments from mice following exposure to oxaliplatin ex vivo and following repeated intraperitoneal injections of oxaliplatin over 3 weeks in vivo, using immunohistochemistry and confocal microscopy. Significant morphological alterations and increases in the proportion of NOS-immunoreactive (IR) neurons were associated with both short-term oxaliplatin exposure and long-term oxaliplatin administration, confirming that oxaliplatin causes changes to the myenteric neurons. Long-term oxaliplatin administration induced substantial neuronal loss that was correlated with a reduction in both the frequency and propagation speed of colonic migrating motor complexes (CMMCs) in vitro. Similar changes probably produce some symptoms experienced by patients undergoing oxaliplatin treatment. PMID:23486839

Zinc Promotes Adipose-Derived Mesenchymal Stem Cell Proliferation and Differentiation towards a Neuronal Fate.

Science.gov (United States)

Moon, Mi-Young; Kim, Hyun Jung; Choi, Bo Young; Sohn, Min; Chung, Tae Nyoung; Suh, Sang Won

2018-01-01

Zinc is an essential element required for cell division, migration, and proliferation. Under zinc-deficient conditions, proliferation and differentiation of neural progenitors are significantly impaired. Adipose-derived mesenchymal stem cells (AD-MSCs) are multipotent stem cells that can differentiate into neurons. The aim of this study was to evaluate the effect of zinc on AD-MSC proliferation and differentiation. We initially examined the effect of zinc on stem cell proliferation at the undifferentiated stage. AD-MSCs showed high proliferation rates on day 6 in 30  μ M and 100  μ M of ZnCl 2 . Zinc chelation inhibited AD-MSC proliferation via downregulation of ERK1/2 activity. We then assessed whether zinc was involved in cell migration and neurite outgrowth during differentiation. After three days of neuronal differentiation, TUJ-1-positive cells were observed, implying that AD-MSCs had differentiated into early neuron or neuron-like cells. Neurite outgrowth was increased in the zinc-treated group, while the CaEDTA-treated group showed diminished, shrunken neurites. Furthermore, we showed that zinc promoted neurite outgrowth via the inactivation of RhoA and led to the induction of neuronal gene expression (MAP2 and nestin) in differentiated stem cells. Taken together, zinc promoted AD-MSC proliferation and affected neuronal differentiation, mainly by increasing neurite outgrowth.

Zinc Promotes Adipose-Derived Mesenchymal Stem Cell Proliferation and Differentiation towards a Neuronal Fate

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Mi-Young Moon

2018-01-01

Full Text Available Zinc is an essential element required for cell division, migration, and proliferation. Under zinc-deficient conditions, proliferation and differentiation of neural progenitors are significantly impaired. Adipose-derived mesenchymal stem cells (AD-MSCs are multipotent stem cells that can differentiate into neurons. The aim of this study was to evaluate the effect of zinc on AD-MSC proliferation and differentiation. We initially examined the effect of zinc on stem cell proliferation at the undifferentiated stage. AD-MSCs showed high proliferation rates on day 6 in 30 μM and 100 μM of ZnCl2. Zinc chelation inhibited AD-MSC proliferation via downregulation of ERK1/2 activity. We then assessed whether zinc was involved in cell migration and neurite outgrowth during differentiation. After three days of neuronal differentiation, TUJ-1-positive cells were observed, implying that AD-MSCs had differentiated into early neuron or neuron-like cells. Neurite outgrowth was increased in the zinc-treated group, while the CaEDTA-treated group showed diminished, shrunken neurites. Furthermore, we showed that zinc promoted neurite outgrowth via the inactivation of RhoA and led to the induction of neuronal gene expression (MAP2 and nestin in differentiated stem cells. Taken together, zinc promoted AD-MSC proliferation and affected neuronal differentiation, mainly by increasing neurite outgrowth.

Response variability in Attention-Deficit/Hyperactivity Disorder: a neuronal and glial energetics hypothesis.

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Russell, Vivienne A; Oades, Robert D; Tannock, Rosemary; Killeen, Peter R; Auerbach, Judith G; Johansen, Espen B; Sagvolden, Terje

2006-08-23

Current concepts of Attention-Deficit/Hyperactivity Disorder (ADHD) emphasize the role of higher-order cognitive functions and reinforcement processes attributed to structural and biochemical anomalies in cortical and limbic neural networks innervated by the monoamines, dopamine, noradrenaline and serotonin. However, these explanations do not account for the ubiquitous findings in ADHD of intra-individual performance variability, particularly on tasks that require continual responses to rapid, externally-paced stimuli. Nor do they consider attention as a temporal process dependent upon a continuous energy supply for efficient and consistent function. A consideration of this feature of intra-individual response variability, which is not unique to ADHD but is also found in other disorders, leads to a new perspective on the causes and potential remedies of specific aspects of ADHD. We propose that in ADHD, astrocyte function is insufficient, particularly in terms of its formation and supply of lactate. This insufficiency has implications both for performance and development: H1) In rapidly firing neurons there is deficient ATP production, slow restoration of ionic gradients across neuronal membranes and delayed neuronal firing; H2) In oligodendrocytes insufficient lactate supply impairs fatty acid synthesis and myelination of axons during development. These effects occur over vastly different time scales: those due to deficient ATP (H1) occur over milliseconds, whereas those due to deficient myelination (H2) occur over months and years. Collectively the neural outcomes of impaired astrocytic release of lactate manifest behaviourally as inefficient and inconsistent performance (variable response times across the lifespan, especially during activities that require sustained speeded responses and complex information processing). Multi-level and multi-method approaches are required. These include: 1) Use of dynamic strategies to evaluate cognitive performance under

The Hypocretin/Orexin Neuronal Networks in Zebrafish.

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Elbaz, Idan; Levitas-Djerbi, Talia; Appelbaum, Lior

2017-01-01

The hypothalamic Hypocretin/Orexin (Hcrt) neurons secrete two Hcrt neuropeptides. These neurons and peptides play a major role in the regulation of feeding, sleep wake cycle, reward-seeking, addiction, and stress. Loss of Hcrt neurons causes the sleep disorder narcolepsy. The zebrafish has become an attractive model to study the Hcrt neuronal network because it is a transparent vertebrate that enables simple genetic manipulation, imaging of the structure and function of neuronal circuits in live animals, and high-throughput monitoring of behavioral performance during both day and night. The zebrafish Hcrt network comprises ~16-60 neurons, which similar to mammals, are located in the hypothalamus and widely innervate the brain and spinal cord, and regulate various fundamental behaviors such as feeding, sleep, and wakefulness. Here we review how the zebrafish contributes to the study of the Hcrt neuronal system molecularly, anatomically, physiologically, and pathologically.

A Chaos Theory Perspective on International Migration

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Anca Tănasie

2017-12-01

Full Text Available This paper aims at providing a different approach to international migration analysis, beyond classical models previously proposed by specialized literature. Chaos theory is getting more and more applied into macroeconomics once traditional linear models or even previous dynamic analysis become less suitable. Modern science sees chaos as unpredictable evolution, maybe even disorder. Still, chaos has got its own rules and can describe many dynamic phenomena within our world. Thus, we test whether international migration data falls under the rules of chaos and whether recent developments within the “European migration crisis” (the total daily migration inflows towards the coasts of Italy, by sea, from January 2014 to April 2017 could be described as chaotic.

Axial level-specific regulation of neuronal development: lessons from PITX2.

Science.gov (United States)

Waite, Mindy R; Martin, Donna M

2015-02-01

Transcriptional regulation of gene expression is vital for proper control of proliferation, migration, differentiation, and survival of developing neurons. Pitx2 encodes a homeodomain transcription factor that is highly expressed in the developing and adult mammalian brain. In humans, mutations in PITX2 result in Rieger syndrome, characterized by defects in the development of the eyes, umbilicus, and teeth and variable abnormalities in the brain, including hydrocephalus and cerebellar hypoplasia. Alternative splicing of Pitx2 in the mouse results in three isoforms, Pitx2a, Pitx2b, and Pitx2c, each of which is expressed symmetrically along the left-right axis of the brain throughout development. Here, we review recent evidence for axial and brain region-specific requirements for Pitx2 during neuronal migration and differentiation, highlighting known isoform contributions. © 2014 Wiley Periodicals, Inc.

Turning skin into dopamine neurons

Institute of Scientific and Technical Information of China (English)

Malin Parmar; Johan Jakobsson

2011-01-01

The possibility to generate neurons from fibroblasts became a reality with the development of iPS technology a few years ago.By reprogramming somatic cells using transcription factor (TF) overexpression,it is possible to generate pluripotent stem cells that then can be differentiated into any somatic cell type including various subtypes of neurons.This raises the possibility of using donor-matched or even patientspecific cells for cell therapy of neurological disorders such as Parkinson's disease (PD),Huntington's disease and stroke.Supporting this idea,dopamine neurons,which are the cells dying in PD,derived from human iPS cells have been demonstrated to survive transplantation and reverse motor symptoms in animal models of PD [1].

Developmental wiring of specific neurons is regulated by RET-1/Nogo-A in Caenorhabditis elegans

DEFF Research Database (Denmark)

Torpe, Nanna; Nørgaard, Steffen; Høye, Anette M.

2017-01-01

Nogo-A is a membrane-bound protein that functions to inhibit neuronal migration, adhesion, and neurite outgrowth during development. In the mature nervous system, Nogo-A stabilizes neuronal wiring to inhibit neuronal plasticity and regeneration after injury. Here, we show that RET-1, the sole Nog...... present a previously unidentified function for RET-1 in the nervous system of C. elegans.......-A homolog in Caenorhabditis elegans, is required to control developmental wiring of a specific subset of neurons. In ret-1 deletion mutant animals, specific ventral nerve cord axons are misguided where they fail to respect the ventral midline boundary. We found that ret-1 is expressed in multiple neurons...

Rac1 regulates neuronal polarization through the WAVE complex

DEFF Research Database (Denmark)

Tahirovic, Sabina; Hellal, Farida; Neukirchen, Dorothee

2010-01-01

the physiological function of Rac1 in neuronal development, we have generated a conditional knock-out mouse, in which Rac1 is ablated in the whole brain. Rac1-deficient cerebellar granule neurons, which do not express other Rac isoforms, showed impaired neuronal migration and axon formation both in vivo...... and in vitro. In addition, Rac1 ablation disrupts lamellipodia formation in growth cones. The analysis of Rac1 effectors revealed the absence of the Wiskott-Aldrich syndrome protein (WASP) family verprolin-homologous protein (WAVE) complex from the plasma membrane of knock-out growth cones. Loss of WAVE...... function inhibited axon growth, whereas overexpression of a membrane-tethered WAVE mutant partially rescued axon growth in Rac1-knock-out neurons. In addition, pharmacological inhibition of the WAVE complex effector Arp2/3 also reduced axon growth. We propose that Rac1 recruits the WAVE complex...

The Caenorhabditis elegans NF2/Merlin Molecule NFM-1 Nonautonomously Regulates Neuroblast Migration and Interacts Genetically with the Guidance Cue SLT-1/Slit.

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Josephson, Matthew P; Aliani, Rana; Norris, Megan L; Ochs, Matthew E; Gujar, Mahekta; Lundquist, Erik A

2017-02-01

During nervous system development, neurons and their progenitors migrate to their final destinations. In Caenorhabditis elegans, the bilateral Q neuroblasts and their descendants migrate long distances in opposite directions, despite being born in the same posterior region. QR on the right migrates anteriorly and generates the AQR neuron positioned near the head, and QL on the left migrates posteriorly, giving rise to the PQR neuron positioned near the tail. In a screen for genes required for AQR and PQR migration, we identified an allele of nfm-1, which encodes a molecule similar to vertebrate NF2/Merlin, an important tumor suppressor in humans. Mutations in NF2 lead to neurofibromatosis type II, characterized by benign tumors of glial tissues. Here we demonstrate that in C. elegans, nfm-1 is required for the ability of Q cells and their descendants to extend protrusions and to migrate, but is not required for direction of migration. Using a combination of mosaic analysis and cell-specific expression, we show that NFM-1 is required nonautonomously, possibly in muscles, to promote Q lineage migrations. We also show a genetic interaction between nfm-1 and the C. elegans Slit homolog slt-1, which encodes a conserved secreted guidance cue. Our results suggest that NFM-1 might be involved in the generation of an extracellular cue that promotes Q neuroblast protrusion and migration that acts with or in parallel to SLT-1 In vertebrates, NF2 and Slit2 interact in axon pathfinding, suggesting a conserved interaction of NF2 and Slit2 in regulating migratory events. Copyright © 2017 by the Genetics Society of America.

Migration Theories and Mental Health in Toni Morrison's Jazz

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Leila Tafreshi Motalgh

2015-01-01

Full Text Available This article aims to elaborate the relationship between migration and mental health problems that are evident in migrant women in Toni Morrison's Jazz (1992. To this end, pre-migration, migration and post-migration stress factors are identified in the novel based on Danish Bhugra's theory of migration. It seems that pre-migration stress factors and traumas are associated with the push theory of migration, while post-migration stresses are associated with the pull theory of migration. Despite post-migration stresses, the main female characters who encounter pre-migration stress factors and traumas are more likely to develop mental health problems like Post-traumatic Stress Disorder (PTSD. Although there is extensive literary criticism of Jazz (1992, no theoretical criticism exists that simultaneously covers migration theories and the mental health problems evident in Toni Morrison's female characters. It is worth highlighting that gender is a variable that correlates positively with migration and mental health. This article attempts to fill a gap in literary criticism and contribute to the body of research on mental health problems associated with gender and migration. Keywords: Push-Pull Theory, Great Migration, Black Studies, Gender, Trauma, PTSD

SDF1 Reduces Interneuron Leading Process Branching through Dual Regulation of Actin and Microtubules

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Lysko, Daniel E.; Putt, Mary

2014-01-01

Normal cerebral cortical function requires a highly ordered balance between projection neurons and interneurons. During development these two neuronal populations migrate from distinct progenitor zones to form the cerebral cortex, with interneurons originating in the more distant ganglionic eminences. Moreover, deficits in interneurons have been linked to a variety of neurodevelopmental disorders underscoring the importance of understanding interneuron development and function. We, and others, have identified SDF1 signaling as one important modulator of interneuron migration speed and leading process branching behavior in mice, although how SDF1 signaling impacts these behaviors remains unknown. We previously found SDF1 inhibited leading process branching while increasing the rate of migration. We have now mechanistically linked SDF1 modulation of leading process branching behavior to a dual regulation of both actin and microtubule organization. We find SDF1 consolidates actin at the leading process tip by de-repressing calpain protease and increasing proteolysis of branched-actin-supporting cortactin. Additionally, SDF1 stabilizes the microtubule array in the leading process through activation of the microtubule-associated protein doublecortin (DCX). DCX stabilizes the microtubule array by bundling microtubules within the leading process, reducing branching. These data provide mechanistic insight into the regulation of interneuron leading process dynamics during neuronal migration in mice and provides insight into how cortactin and DCX, a known human neuronal migration disorder gene, participate in this process. PMID:24695713

SDF1 reduces interneuron leading process branching through dual regulation of actin and microtubules.

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Lysko, Daniel E; Putt, Mary; Golden, Jeffrey A

2014-04-02

Normal cerebral cortical function requires a highly ordered balance between projection neurons and interneurons. During development these two neuronal populations migrate from distinct progenitor zones to form the cerebral cortex, with interneurons originating in the more distant ganglionic eminences. Moreover, deficits in interneurons have been linked to a variety of neurodevelopmental disorders underscoring the importance of understanding interneuron development and function. We, and others, have identified SDF1 signaling as one important modulator of interneuron migration speed and leading process branching behavior in mice, although how SDF1 signaling impacts these behaviors remains unknown. We previously found SDF1 inhibited leading process branching while increasing the rate of migration. We have now mechanistically linked SDF1 modulation of leading process branching behavior to a dual regulation of both actin and microtubule organization. We find SDF1 consolidates actin at the leading process tip by de-repressing calpain protease and increasing proteolysis of branched-actin-supporting cortactin. Additionally, SDF1 stabilizes the microtubule array in the leading process through activation of the microtubule-associated protein doublecortin (DCX). DCX stabilizes the microtubule array by bundling microtubules within the leading process, reducing branching. These data provide mechanistic insight into the regulation of interneuron leading process dynamics during neuronal migration in mice and provides insight into how cortactin and DCX, a known human neuronal migration disorder gene, participate in this process.

Synaptic glutamate release by postnatal rat serotonergic neurons in microculture.

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Johnson, M D

1994-02-01

Serotonergic neurons are thought to play a role in depression and obsessive compulsive disorder. However, their functional transmitter repertoire is incompletely known. To investigate this repertoire, intracellular recordings were obtained from 132 cytochemically identified rat mesopontine serotonergic neurons that had re-established synapses in microcultures. Approximately 60% of the neurons evoked excitatory glutamatergic potentials in themselves or in target neurons. Glutamatergic transmission was frequently observed in microcultures containing a solitary serotonergic neuron. Evidence for co-release of serotonin and glutamate from single raphe neurons was also obtained. However, evidence for gamma-aminobutyric acid release by serotonergic neurons was observed in only two cases. These findings indicate that many cultured serotonergic neurons form glutamatergic synapses and may explain several observations in slices and in vivo.

MicroRNA Profiling of Neurons Generated Using Induced Pluripotent Stem Cells Derived from Patients with Schizophrenia and Schizoaffective Disorder, and 22q11.2 Del.

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Dejian Zhao

Full Text Available We are using induced pluripotent stem cell (iPSC technology to study neuropsychiatric disorders associated with 22q11.2 microdeletions (del, the most common known schizophrenia (SZ-associated genetic factor. Several genes in the region have been implicated; a promising candidate is DGCR8, which codes for a protein involved in microRNA (miRNA biogenesis. We carried out miRNA expression profiling (miRNA-seq on neurons generated from iPSCs derived from controls and SZ patients with 22q11.2 del. Using thresholds of p<0.01 for nominal significance and 1.5-fold differences in expression, 45 differentially expressed miRNAs were detected (13 lower in SZ and 32 higher. Of these, 6 were significantly down-regulated in patients after correcting for genome wide significance (FDR<0.05, including 4 miRNAs that map to the 22q11.2 del region. In addition, a nominally significant increase in the expression of several miRNAs was found in the 22q11.2 neurons that were previously found to be differentially expressed in autopsy samples and peripheral blood in SZ and autism spectrum disorders (e.g., miR-34, miR-4449, miR-146b-3p, and miR-23a-5p. Pathway and function analysis of predicted mRNA targets of the differentially expressed miRNAs showed enrichment for genes involved in neurological disease and psychological disorders for both up and down regulated miRNAs. Our findings suggest that: i. neurons with 22q11.2 del recapitulate the miRNA expression patterns expected of 22q11.2 haploinsufficiency, ii. differentially expressed miRNAs previously identified using autopsy samples and peripheral cells, both of which have significant methodological problems, are indeed disrupted in neuropsychiatric disorders and likely have an underlying genetic basis.

Canonical TGF-β Signaling Negatively Regulates Neuronal Morphogenesis through TGIF/Smad Complex-Mediated CRMP2 Suppression.

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Nakashima, Hideyuki; Tsujimura, Keita; Irie, Koichiro; Ishizu, Masataka; Pan, Miao; Kameda, Tomonori; Nakashima, Kinichi

2018-05-16

Functional neuronal connectivity requires proper neuronal morphogenesis and its dysregulation causes neurodevelopmental diseases. Transforming growth factor-β (TGF-β) family cytokines play pivotal roles in development, but little is known about their contribution to morphological development of neurons. Here we show that the Smad-dependent canonical signaling of TGF-β family cytokines negatively regulates neuronal morphogenesis during brain development. Mechanistically, activated Smads form a complex with transcriptional repressor TG-interacting factor (TGIF), and downregulate the expression of a neuronal polarity regulator, collapsin response mediator protein 2. We also demonstrate that TGF-β family signaling inhibits neurite elongation of human induced pluripotent stem cell-derived neurons. Furthermore, the expression of TGF-β receptor 1, Smad4, or TGIF, which have mutations found in patients with neurodevelopmental disorders, disrupted neuronal morphogenesis in both mouse (male and female) and human (female) neurons. Together, these findings suggest that the regulation of neuronal morphogenesis by an evolutionarily conserved function of TGF-β signaling is involved in the pathogenesis of neurodevelopmental diseases. SIGNIFICANCE STATEMENT Canonical transforming growth factor-β (TGF-β) signaling plays a crucial role in multiple organ development, including brain, and mutations in components of the signaling pathway associated with several human developmental disorders. In this study, we found that Smads/TG-interacting factor-dependent canonical TGF-β signaling regulates neuronal morphogenesis through the suppression of collapsin response mediator protein-2 (CRMP2) expression during brain development, and that function of this signaling is evolutionarily conserved in the mammalian brain. Mutations in canonical TGF-β signaling factors identified in patients with neurodevelopmental disorders disrupt the morphological development of neurons. Thus, our

Alterations of GABAergic Signaling in Autism Spectrum Disorders

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Rocco Pizzarelli

2011-01-01

Full Text Available Autism spectrum disorders (ASDs comprise a heterogeneous group of pathological conditions, mainly of genetic origin, characterized by stereotyped behavior, marked impairment in verbal and nonverbal communication, social skills, and cognition. Interestingly, in a small number of cases, ASDs are associated with single mutations in genes encoding for neuroligin-neurexin families. These are adhesion molecules which, by regulating transsynaptic signaling, contribute to maintain a proper excitatory/inhibitory (E/I balance at the network level. Furthermore, GABA, the main inhibitory neurotransmitter in adult life, at late embryonic/early postnatal stages has been shown to depolarize and excite targeted cell through an outwardly directed flux of chloride. The depolarizing action of GABA and associated calcium influx regulate a variety of developmental processes from cell migration and differentiation to synapse formation. Here, we summarize recent data concerning the functional role of GABA in building up and refining neuronal circuits early in development and the molecular mechanisms regulating the E/I balance. A dysfunction of the GABAergic signaling early in development leads to a severe E/I unbalance in neuronal circuits, a condition that may account for some of the behavioral deficits observed in ASD patients.

Developmental time windows for axon growth influence neuronal network topology.

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Lim, Sol; Kaiser, Marcus

2015-04-01

Early brain connectivity development consists of multiple stages: birth of neurons, their migration and the subsequent growth of axons and dendrites. Each stage occurs within a certain period of time depending on types of neurons and cortical layers. Forming synapses between neurons either by growing axons starting at similar times for all neurons (much-overlapped time windows) or at different time points (less-overlapped) may affect the topological and spatial properties of neuronal networks. Here, we explore the extreme cases of axon formation during early development, either starting at the same time for all neurons (parallel, i.e., maximally overlapped time windows) or occurring for each neuron separately one neuron after another (serial, i.e., no overlaps in time windows). For both cases, the number of potential and established synapses remained comparable. Topological and spatial properties, however, differed: Neurons that started axon growth early on in serial growth achieved higher out-degrees, higher local efficiency and longer axon lengths while neurons demonstrated more homogeneous connectivity patterns for parallel growth. Second, connection probability decreased more rapidly with distance between neurons for parallel growth than for serial growth. Third, bidirectional connections were more numerous for parallel growth. Finally, we tested our predictions with C. elegans data. Together, this indicates that time windows for axon growth influence the topological and spatial properties of neuronal networks opening up the possibility to a posteriori estimate developmental mechanisms based on network properties of a developed network.

Hydrogen migration in fast cooled Pd-H alloys around 50 K

International Nuclear Information System (INIS)

Yamakawa, Kohji

2005-01-01

The migration of hydrogen in fast cooled Pd-H alloys is investigated by electrical resistivity measurement around 50 K. The disordered atoms of hydrogen are introduced by fast cooling from around 80 K to around 20 K. The disordered atoms are ordered by migration of the atoms during heating-up of the specimens with the constant rates. The resistivity is measured at the temperatures as done by Vajda et al. to compare our results with their results. The activation energy of migration of hydrogen is obtained from the kinetic analysis of the resistivity change due to the ordering using a so-called cross-cut method. The obtained value is compared with our previous results, which have been obtained with hydrogen disordered by quenching into liquid helium, isothermal annealing of the specimen and resistivity measurement in liquid helium. The present value is in fairly good agreement with the value obtained in the quenched case

Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: studies of lysosomal storage diseases and channelopathy

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Kano, Shin-ichi; Yuan, Ming; Cardarelli, Ross A.; Maegawa, Gustavo; Higurashi, Norimichi; Gaval-Cruz, Meriem; Wilson, Ashley M.; Tristan, Carlos; Kondo, Mari A.; Chen, Yian; Koga, Minori; Obie, Cassandra; Ishizuka, Koko; Seshadri, Saurav; Srivastava, Rupali; Kato, Takahiro A.; Horiuchi, Yasue; Sedlak, Thomas W.; Lee, Yohan; Rapoport, Judith L.; Hirose, Shinichi; Okano, Hideyuki; Valle, David; O'Donnell, Patricio; Sawa, Akira; Kai, Mihoko

2015-01-01

Methodologies for generating functional neuronal cells directly from human fibroblasts [induced neuronal (iN) cells] have been recently developed, but the research so far has only focused on technical refinements or recapitulation of known pathological phenotypes. A critical question is whether this novel technology will contribute to elucidation of novel disease mechanisms or evaluation of therapeutic strategies. Here we have addressed this question by studying Tay-Sachs disease, a representative lysosomal storage disease, and Dravet syndrome, a form of severe myoclonic epilepsy in infancy, using human iN cells with feature of immature postmitotic glutamatergic neuronal cells. In Tay-Sachs disease, we have successfully characterized canonical neuronal pathology, massive accumulation of GM2 ganglioside, and demonstrated the suitability of this novel cell culture for future drug screening. In Dravet syndrome, we have identified a novel functional phenotype that was not suggested by studies of classical mouse models and human autopsied brains. Taken together, the present study demonstrates that human iN cells are useful for translational neuroscience research to explore novel disease mechanisms and evaluate therapeutic compounds. In the future, research using human iN cells with well-characterized genomic landscape can be integrated into multidisciplinary patient-oriented research on neuropsychiatric disorders to address novel disease mechanisms and evaluate therapeutic strategies. PMID:25732146

Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity.

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Hasegawa, Emi; Maejima, Takashi; Yoshida, Takayuki; Masseck, Olivia A; Herlitze, Stefan; Yoshioka, Mitsuhiro; Sakurai, Takeshi; Mieda, Michihiro

2017-04-25

Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing.

A radial glia-specific role of RhoA in double cortex formation

DEFF Research Database (Denmark)

Cappello, Silvia; Böhringer, Christian R J; Bergami, Matteo

2012-01-01

disorders: subcortical band heterotopia (SBH), a heterotopic cortex underlying the normotopic cortex, and cobblestone lissencephaly, in which neurons protrude beyond layer I at the pial surface of the brain. Surprisingly, RhoA(-/-) neurons migrated normally when transplanted into wild-type cerebral cortex...

[Mechanism of disorders of inhibition of electrogenesis in spinal alpha-motor neurons in experimental local botulin poisoning].

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Mikhaĭlov, V V; Barashkov, G N

1977-06-01

Disorders of postsynaptic inhibition and of the spinal cord alpha-motoneurons were studied in cats with experimental local botulinum intoxication. A significant decrease of the reciprocal, and, to a lesser extent, of polysynaptic inhibitory postsynaptic potential (IPSP) was noted. With the appearance of total paralysis of the muscles in the poisoned extremity there proved to be an even greater depression of the reciprocal and polysynaptic IPSP; however, they never disappeared or turned into depolarization potentials. Synaptic permeability of motor neurons as a rule decreased during the IPSP development, this indirectly indicating a reduction of ion transport.

Curcumin is a potent modulator of microglial gene expression and migration

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Aslanidis Alexander

2011-09-01

Full Text Available Abstract Background Microglial cells are important effectors of the neuronal innate immune system with a major role in chronic neurodegenerative diseases. Curcumin, a major component of tumeric, alleviates pro-inflammatory activities of these cells by inhibiting nuclear factor kappa B (NFkB signaling. To study the immuno-modulatory effects of curcumin on a transcriptomic level, DNA-microarray analyses were performed with resting and LPS-challenged microglial cells after short-term treatment with curcumin. Methods Resting and LPS-activated BV-2 cells were stimulated with curcumin and genome-wide mRNA expression patterns were determined using DNA-microarrays. Selected qRT-PCR analyses were performed to confirm newly identified curcumin-regulated genes. The migration potential of microglial cells was determined with wound healing assays and transwell migration assays. Microglial neurotoxicity was estimated by morphological analyses and quantification of caspase 3/7 levels in 661W photoreceptors cultured in the presence of microglia-conditioned medium. Results Curcumin treatment markedly changed the microglial transcriptome with 49 differentially expressed transcripts in a combined analysis of resting and activated microglial cells. Curcumin effectively triggered anti-inflammatory signals as shown by induced expression of Interleukin 4 and Peroxisome proliferator activated receptor α. Several novel curcumin-induced genes including Netrin G1, Delta-like 1, Platelet endothelial cell adhesion molecule 1, and Plasma cell endoplasmic reticulum protein 1, have been previously associated with adhesion and cell migration. Consequently, curcumin treatment significantly inhibited basal and activation-induced migration of BV-2 microglia. Curcumin also potently blocked gene expression related to pro-inflammatory activation of resting cells including Toll-like receptor 2 and Prostaglandin-endoperoxide synthase 2. Moreover, transcription of NO synthase 2 and

Curcumin is a potent modulator of microglial gene expression and migration

Science.gov (United States)

2011-01-01

Background Microglial cells are important effectors of the neuronal innate immune system with a major role in chronic neurodegenerative diseases. Curcumin, a major component of tumeric, alleviates pro-inflammatory activities of these cells by inhibiting nuclear factor kappa B (NFkB) signaling. To study the immuno-modulatory effects of curcumin on a transcriptomic level, DNA-microarray analyses were performed with resting and LPS-challenged microglial cells after short-term treatment with curcumin. Methods Resting and LPS-activated BV-2 cells were stimulated with curcumin and genome-wide mRNA expression patterns were determined using DNA-microarrays. Selected qRT-PCR analyses were performed to confirm newly identified curcumin-regulated genes. The migration potential of microglial cells was determined with wound healing assays and transwell migration assays. Microglial neurotoxicity was estimated by morphological analyses and quantification of caspase 3/7 levels in 661W photoreceptors cultured in the presence of microglia-conditioned medium. Results Curcumin treatment markedly changed the microglial transcriptome with 49 differentially expressed transcripts in a combined analysis of resting and activated microglial cells. Curcumin effectively triggered anti-inflammatory signals as shown by induced expression of Interleukin 4 and Peroxisome proliferator activated receptor α. Several novel curcumin-induced genes including Netrin G1, Delta-like 1, Platelet endothelial cell adhesion molecule 1, and Plasma cell endoplasmic reticulum protein 1, have been previously associated with adhesion and cell migration. Consequently, curcumin treatment significantly inhibited basal and activation-induced migration of BV-2 microglia. Curcumin also potently blocked gene expression related to pro-inflammatory activation of resting cells including Toll-like receptor 2 and Prostaglandin-endoperoxide synthase 2. Moreover, transcription of NO synthase 2 and Signal transducer and activator

Motor neuron, nerve, and neuromuscular junction disease.

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Finsterer, Josef; Papić, Lea; Auer-Grumbach, Michaela

2011-10-01

The aim is to review the most relevant findings published during the last year concerning clinical, genetic, pathogenic, and therapeutic advances in motor neuron disease, neuropathies, and neuromuscular junction disorders. Studies on animal and cell models have improved the understanding of how mutated survival motor neuron protein in spinal muscular atrophy governs the pathogenetic processes. New phenotypes of SOD1 mutations have been described. Moreover, animal models enhanced the insight into the pathogenetic background of sporadic and familial amyotrophic lateral sclerosis. Novel treatment options for motor neuron disease have been described in humans and animal models. Considerable progress has been achieved also in elucidating the genetic background of many forms of inherited neuropathies and high clinical and genetic heterogeneity has been demonstrated. Mutations in MuSK and GFTP1 have been shown to cause new types of congenital myasthenic syndromes. A third type of autoantibodies (Lrp4) has been detected to cause myasthenia gravis. Advances in the clinical and genetic characterization of motor neuron diseases, neuropathies, and neuromuscular transmission defects have important implications on the fundamental understanding, diagnosis, and management of these disorders. Identification of crucial steps of the pathogenetic process may provide the basis for the development of novel therapeutic strategies.

Mirror Neurons and Mirror-Touch Synesthesia.

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Linkovski, Omer; Katzin, Naama; Salti, Moti

2016-05-30

Since mirror neurons were introduced to the neuroscientific community more than 20 years ago, they have become an elegant and intuitive account for different cognitive mechanisms (e.g., empathy, goal understanding) and conditions (e.g., autism spectrum disorders). Recently, mirror neurons were suggested to be the mechanism underlying a specific type of synesthesia. Mirror-touch synesthesia is a phenomenon in which individuals experience somatosensory sensations when seeing someone else being touched. Appealing as it is, careful delineation is required when applying this mechanism. Using the mirror-touch synesthesia case, we put forward theoretical and methodological issues that should be addressed before relying on the mirror-neurons account. © The Author(s) 2016.

Developmental malformations of the cerebral cortex; Heterotopie, Polymikrogyrie, Lissenzephalie und Co. Malformationen der kortikalen Hirnentwicklung

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Reiss-Zimmermann, Martin [Klinik und Poliklinik fuer Diagnostische und Interventionelle Radiologie, Universitaetsklinikum Leipzig AoeR (Germany); Weber, D.; Sorge, I.; Hirsch, W. [Abt. Paediatrische Radiologie, Universitaetsklinikum Leipzig AoeR (Germany); Merkenschlager, A. [Universitaetsklinik und Poliklinik fuer Kinder und Jugendliche, Universitaetsklinikum Leipzig AoeR (Germany)

2010-06-15

Migration disorders (MD) are increasingly recognized as an important cause of epilepsy and developmental delay. Up to 25% of children with refractory epilepsy have a cortical malformation. MD encompass a wide spectrum with underlying genetic etiologies and clinical manifestations. Research regarding the delineation of the genetic and molecular basis of these disorders has provided greater insight into the pathogenesis of not only the malformation but also the process involved in normal cortical development. Diagnosis of MD is important since patients who fail three antiepileptic medications are less likely to have their seizures controlled with additional trials of medications and therefore epilepsy surgery should be considered. Recent improvements in neuroimaging have resulted in a significant increase in the recognition of MD. Findings can be subdivided in disorders due to abnormal neurogenesis, neuronal migration, neuronal migration arrest and neuronal organization resulting in different malformations like microcephaly, lissencephaly, schizencephaly and heterotopia. The examination protocol should include T1-w and T2-w sequences in adequate slice orientation. T1-w turbo-inversion recovery sequences (TIR) can be helpful to diagnose heterotopia. Contrast agent is needed only to exclude other differential diagnoses. (orig.)

Developmental malformations of the cerebral cortex

International Nuclear Information System (INIS)

Reiss-Zimmermann, Martin; Weber, D.; Sorge, I.; Hirsch, W.; Merkenschlager, A.

2010-01-01

Migration disorders (MD) are increasingly recognized as an important cause of epilepsy and developmental delay. Up to 25% of children with refractory epilepsy have a cortical malformation. MD encompass a wide spectrum with underlying genetic etiologies and clinical manifestations. Research regarding the delineation of the genetic and molecular basis of these disorders has provided greater insight into the pathogenesis of not only the malformation but also the process involved in normal cortical development. Diagnosis of MD is important since patients who fail three antiepileptic medications are less likely to have their seizures controlled with additional trials of medications and therefore epilepsy surgery should be considered. Recent improvements in neuroimaging have resulted in a significant increase in the recognition of MD. Findings can be subdivided in disorders due to abnormal neurogenesis, neuronal migration, neuronal migration arrest and neuronal organization resulting in different malformations like microcephaly, lissencephaly, schizencephaly and heterotopia. The examination protocol should include T1-w and T2-w sequences in adequate slice orientation. T1-w turbo-inversion recovery sequences (TIR) can be helpful to diagnose heterotopia. Contrast agent is needed only to exclude other differential diagnoses. (orig.)

The functional significance of newly born neurons integrated into olfactory bulb circuits.

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Sakamoto, Masayuki; Kageyama, Ryoichiro; Imayoshi, Itaru

2014-01-01

The olfactory bulb (OB) is the first central processing center for olfactory information connecting with higher areas in the brain, and this neuronal circuitry mediates a variety of odor-evoked behavioral responses. In the adult mammalian brain, continuous neurogenesis occurs in two restricted regions, the subventricular zone (SVZ) of the lateral ventricle and the hippocampal dentate gyrus. New neurons born in the SVZ migrate through the rostral migratory stream and are integrated into the neuronal circuits of the OB throughout life. The significance of this continuous supply of new neurons in the OB has been implicated in plasticity and memory regulation. Two decades of huge investigation in adult neurogenesis revealed the biological importance of integration of new neurons into the olfactory circuits. In this review, we highlight the recent findings about the physiological functions of newly generated neurons in rodent OB circuits and then discuss the contribution of neurogenesis in the brain function. Finally, we introduce cutting edge technologies to monitor and manipulate the activity of new neurons.

The functional significance of newly born neurons integrated into olfactory bulb circuits

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Masayuki eSakamoto

2014-05-01

Full Text Available The olfactory bulb (OB is the first central processing center for olfactory information connecting with higher areas in the brain, and this neuronal circuitry mediates a variety of odor-evoked behavioral responses. In the adult mammalian brain, continuous neurogenesis occurs in two restricted regions, the subventricular zone (SVZ of the lateral ventricle and the hippocampal dentate gyrus. New neurons born in the SVZ migrate through the rostral migratory stream and are integrated into the neuronal circuits of the OB throughout life. The significance of this continuous supply of new neurons in the OB has been implicated in plasticity and memory regulation. Two decades of huge investigation in adult neurogenesis revealed the biological importance of integration of new neurons into the olfactory circuits. In this review, we highlight the recent findings about the physiological functions of newly generated neurons in rodent OB circuits and then discuss the contribution of neurogenesis in the brain function. Finally, we introduce cutting edge technologies to monitor and manipulate the activity of new neurons.

Food for thought: Impact of metabolism on neuronal excitability.

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Katsu-Jiménez, Yurika; Alves, Renato M P; Giménez-Cassina, Alfredo

2017-11-01

Neuronal excitability is a highly demanding process that requires high amounts of energy and needs to be exquisitely regulated. For this reason, brain cells display active energy metabolism to support their activity. Independently of their roles as energy substrates, compelling evidence shows that the nature of the fuels that neurons use contribute to fine-tune neuronal excitability. Crosstalk of neurons with glial populations also plays a prominent role in shaping metabolic flow in the brain. In this review, we provide an overview on how different carbon substrates and metabolic pathways impact neurotransmission, and the potential implications for neurological disorders in which neuronal excitability is deregulated, such as epilepsy. Copyright © 2017 Elsevier Inc. All rights reserved.

Zebrafish chemical screening reveals the impairment of dopaminergic neuronal survival by cardiac glycosides.

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Yaping Sun

Full Text Available Parkinson's disease is a neurodegenerative disorder characterized by the prominent degeneration of dopaminergic (DA neurons among other cell types. Here we report a first chemical screen of over 5,000 compounds in zebrafish, aimed at identifying small molecule modulators of DA neuron development or survival. We find that Neriifolin, a member of the cardiac glycoside family of compounds, impairs survival but not differentiation of both zebrafish and mammalian DA neurons. Cardiac glycosides are inhibitors of Na(+/K(+ ATPase activity and widely used for treating heart disorders. Our data suggest that Neriifolin impairs DA neuronal survival by targeting the neuronal enriched Na(+/K(+ ATPase α3 subunit (ATP1A3. Modulation of ionic homeostasis, knockdown of p53, or treatment with antioxidants protects DA neurons from Neriifolin-induced death. These results reveal a previously unknown effect of cardiac glycosides on DA neuronal survival and suggest that it is mediated through ATP1A3 inhibition, oxidative stress, and p53. They also elucidate potential approaches for counteracting the neurotoxicity of this valuable class of medications.

Gemfibrozil, a lipid-lowering drug, upregulates interleukin-1 receptor antagonist in mouse cortical neurons: Implications for neuronal self-defense

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Corbett, Grant T.; Roy, Avik; Pahan, Kalipada

2012-01-01

Chronic inflammation is becoming a hallmark of several neurodegenerative disorders and accordingly, interleukin-1 beta (IL-1β), a proinflammatory cytokine, is implicated in the pathogenesis of neurodegenerative diseases. While IL-1β binds to its high-affinity receptor, interleukin-1 receptor (IL-1R), and upregulates proinflammatory signaling pathways, interleukin-1 receptor antagonist (IL-1Ra) adheres to the same receptor and inhibits proinflammatory cell signaling. Therefore, upregulation of IL-1Ra is considered important in attenuating inflammation. The present study underlines a novel application of gemfibrozil, an FDA-approved lipid-lowering drug, in increasing the expression of IL-1Ra in primary mouse and human neurons. Gemfibrozil alone induced an early and pronounced increase in the expression of IL-1Ra in primary mouse cortical neurons. Activation of type IA p110α phosphatidylinositol 3-kinase (PI3-K) and Akt by gemfibrozil and abrogation of gemfibrozil-induced upregulation of IL-1Ra by inhibitors of PI3-K and Akt indicate a role of the PI3-K – Akt pathway in the upregulation of IL-1Ra. Gemfibrozil also induced the activation of cAMP response element-binding (CREB) via the PI3-K – Akt pathway and siRNA attenuation of CREB abolished the gemfibrozil-mediated increase in IL-1Ra. Furthermore, gemfibrozil was able to protect neurons from IL-1β insult. However, siRNA knockdown of neuronal IL-1Ra abrogated the protective effect of gemfibrozil against IL-1β suggesting that this drug increases the defense mechanism of cortical neurons via upregulation of IL-1Ra. Together, these results highlight the importance of the PI3-K – Akt – CREB pathway in mediating gemfibrozil-induced upregulation of IL-1Ra in neurons and suggest gemfibrozil as a possible therapeutic treatment for propagating neuronal self defense in neuroinflammatory and neurodegenerative disorders. PMID:22706077

Spider Silk as Guiding Biomaterial for Human Model Neurons

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Frank Roloff

2014-01-01

Full Text Available Over the last years, a number of therapeutic strategies have emerged to promote axonal regeneration. An attractive strategy is the implantation of biodegradable and nonimmunogenic artificial scaffolds into injured peripheral nerves. In previous studies, transplantation of decellularized veins filled with spider silk for bridging critical size nerve defects resulted in axonal regeneration and remyelination by invading endogenous Schwann cells. Detailed interaction of elongating neurons and the spider silk as guidance material is unknown. To visualize direct cellular interactions between spider silk and neurons in vitro, we developed an in vitro crossed silk fiber array. Here, we describe in detail for the first time that human (NT2 model neurons attach to silk scaffolds. Extending neurites can bridge gaps between single silk fibers and elongate afterwards on the neighboring fiber. Culturing human neurons on the silk arrays led to an increasing migration and adhesion of neuronal cell bodies to the spider silk fibers. Within three to four weeks, clustered somata and extending neurites formed ganglion-like cell structures. Microscopic imaging of human neurons on the crossed fiber arrays in vitro will allow for a more efficient development of methods to maximize cell adhesion and neurite growth on spider silk prior to transplantation studies.

Decreased pyramidal neuron size in Brodmann areas 44 and 45 in patients with autism.

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Jacot-Descombes, Sarah; Uppal, Neha; Wicinski, Bridget; Santos, Micaela; Schmeidler, James; Giannakopoulos, Panteleimon; Heinsen, Helmut; Heinsein, Helmut; Schmitz, Christoph; Hof, Patrick R

2012-07-01

Autism is a neurodevelopmental disorder characterized by deficits in social interaction and social communication, as well as by the presence of repetitive and stereotyped behaviors and interests. Brodmann areas 44 and 45 in the inferior frontal cortex, which are involved in language processing, imitation function, and sociality processing networks, have been implicated in this complex disorder. Using a stereologic approach, this study aims to explore the presence of neuropathological differences in areas 44 and 45 in patients with autism compared to age- and hemisphere-matched controls. Based on previous evidence in the fusiform gyrus, we expected to find a decrease in the number and size of pyramidal neurons as well as an increase in volume of layers III, V, and VI in patients with autism. We observed significantly smaller pyramidal neurons in patients with autism compared to controls, although there was no difference in pyramidal neuron numbers or layer volumes. The reduced pyramidal neuron size suggests that a certain degree of dysfunction of areas 44 and 45 plays a role in the pathology of autism. Our results also support previous studies that have shown specific cellular neuropathology in autism with regionally specific reduction in neuron size, and provide further evidence for the possible involvement of the mirror neuron system, as well as impairment of neuronal networks relevant to communication and social behaviors, in this disorder.

Forced migration and mental health: prolonged internal displacement, return migration and resilience.

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Siriwardhana, Chesmal; Stewart, Robert

2013-03-01

Forced internal displacement has been rising steadily, mainly due to conflict. Many internally displaced people (IDP) experience prolonged displacement. Global research evidence suggests that many of these IDP are at high risk for developing mental disorders, adding weight to the global burden of disease. However, individual and community resilience may act as protective factors. Return migration may be an option for some IDP populations, especially when conflicts end, although return migration may itself be associated with worse mental health. Limited evidence is available on effects of resettlement or return migration following prolonged forced internal displacement on mental health. Also, the role of resilience factors remains to be clarified following situations of prolonged displacement. The public health impact of internal displacement is not clearly understood. Epidemiological and interventional research in IDP mental health needs to look beyond medicalised models and encompass broader social and cultural aspects. The resilience factor should be integrated and explored more in mental health research among IDP and a clearly focused multidisciplinary approach is advocated.

Iron deposits in the chronically inflamed central nervous system and contributes to neurodegeneration.

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Andersen, Hjalte Holm; Johnsen, Kasper Bendix; Moos, Torben

2014-05-01

Neurodegenerative disorders are characterized by the presence of inflammation in areas with neuronal cell death and a regional increase in iron that exceeds what occurs during normal aging. The inflammatory process accompanying the neuronal degeneration involves glial cells of the central nervous system (CNS) and monocytes of the circulation that migrate into the CNS while transforming into phagocytic macrophages. This review outlines the possible mechanisms responsible for deposition of iron in neurodegenerative disorders with a main emphasis on how iron-containing monocytes may migrate into the CNS, transform into macrophages, and die out subsequently to their phagocytosis of damaged and dying neuronal cells. The dying macrophages may in turn release their iron, which enters the pool of labile iron to catalytically promote formation of free-radical-mediated stress and oxidative damage to adjacent cells, including neurons. Healthy neurons may also chronically acquire iron from the extracellular space as another principle mechanism for oxidative stress-mediated damage. Pharmacological handling of monocyte migration into the CNS combined with chelators that neutralize the effects of extracellular iron occurring due to the release from dying macrophages as well as intraneuronal chelation may denote good possibilities for reducing the deleterious consequences of iron deposition in the CNS.

Reproduction, Smell and Neurodevelopmental disorders: Genetic defects in different hypogonadotropic hypogonadal syndromes.

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Hernan G VALDES-SOCIN

2014-07-01

Full Text Available The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH secreting neurons that modulate the activity of the reproductive axis across life. Congenital hypogonadotropic hypogonadism (HH is a clinical syndrome that is characterized by partial or complete pubertal failure. HH may result from inadequate hypothalamic GnRH axis activation, or a failure of pituitary gonadotropin secretion/effects. In man, several genes that participate in olfactory and GnRH neuronal migration are thought to interact during the embryonic life. A growing number of mutations in different genes are responsible for congenital HH. Based on the presence or absence of olfaction dysfunction, HH is divided in two syndromes: HH with olfactory alterations (Kallmann syndrome and idiopathic hypogonadotropic hypogonadism (IHH with normal smell (normosmic IHH. Kallmann syndrome (KS is a heterogeneous disorder affecting 1 in 5000 males, with a 3-5 fold of males over females. KS is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, NELF and WDR11 genes that are related to defects in neuronal migration. These reproductive and olfactory deficits include a variable non reproductive phenotype, including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities and/or renal agenesis. Interestingly, defects in PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11 genes are also associated with normosmic IHH, whereas mutations in KISS1/KISSR, TAC3/TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB and LHB are only present in patients with normosmic IHH. In this paper, we summarize the reproductive, neurodevelopmental and genetic aspects of HH in human pathology.

POMT1-associated walker-warburg syndrome: a disorder of dendritic development of neocortical neurons.

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Judas, M; Sedmak, G; Rados, M; Sarnavka, V; Fumić, K; Willer, T; Gross, C; Hehr, U; Strahl, S; Cuk, M; Barić, I

2009-02-01

We have analyzed the morphology and dendritic development of neocortical neurons in a 2.5-month-old infant with Walker-Warburg syndrome homozygotic for a novel POMT1 gene mutation, by Golgi methods. We found that pyramidal neurons frequently displayed abnormal (oblique, horizontal, or inverted) orientation. A novel finding of this study is that members of the same population of pyramidal neurons display different stages of development of their dendritic arborizations: some neurons had poorly developed dendrites and thus resembled pyramidal neurons of the late fetal cortex; for some neurons, the level of differentiation corresponded to that in the newborn cortex; finally, some neurons had quite elaborate dendritic trees as expected for the cortex of 2.5-month-old infant. In addition, apical dendrites of many pyramidal neurons were conspiciously bent to one side, irrespective to the general orientation of the pyramidal neuron. These findings suggest that Walker-Warburg lissencephaly is characterized by two hitherto unnoticed pathogenetic changes in the cerebral cortex: (a) heterochronic decoupling of dendritic maturation within the same neuronal population (with some members significantly lagging behind the normal maturational schedule) and (b) anisotropically distorted shaping of dendritic trees, probably caused by patchy displacement of molecular guidance cues for dendrites in the malformed cortex. Copyright Georg Thieme Verlag KG Stuttgart New York.

Transgenic miR132 alters neuronal spine density and impairs novel object recognition memory.

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Katelin F Hansen

2010-11-01

Full Text Available Inducible gene expression plays a central role in neuronal plasticity, learning, and memory, and dysfunction of the underlying molecular events can lead to severe neuronal disorders. In addition to coding transcripts (mRNAs, non-coding microRNAs (miRNAs appear to play a role in these processes. For instance, the CREB-regulated miRNA miR132 has been shown to affect neuronal structure in an activity-dependent manner, yet the details of its physiological effects and the behavioral consequences in vivo remain unclear. To examine these questions, we employed a transgenic mouse strain that expresses miR132 in forebrain neurons. Morphometric analysis of hippocampal neurons revealed that transgenic miR132 triggers a marked increase in dendritic spine density. Additionally, miR132 transgenic mice exhibited a decrease in the expression of MeCP2, a protein implicated in Rett Syndrome and other disorders of mental retardation. Consistent with these findings, miR132 transgenic mice displayed significant deficits in novel object recognition. Together, these data support a role for miR132 as a regulator of neuronal structure and function, and raise the possibility that dysregulation of miR132 could contribute to an array of cognitive disorders.

Conditional induction of Math1 specifies embryonic stem cells to cerebellar granule neuron lineage and promotes differentiation into mature granule neurons.

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Srivastava, Rupali; Kumar, Manoj; Peineau, Stéphane; Csaba, Zsolt; Mani, Shyamala; Gressens, Pierre; El Ghouzzi, Vincent

2013-04-01

Directing differentiation of embryonic stem cells (ESCs) to specific neuronal subtype is critical for modeling disease pathology in vitro. An attractive means of action would be to combine regulatory differentiation factors and extrinsic inductive signals added to the culture medium. In this study, we have generated mature cerebellar granule neurons by combining a temporally controlled transient expression of Math1, a master gene in granule neuron differentiation, with inductive extrinsic factors involved in cerebellar development. Using a Tetracyclin-On transactivation system, we overexpressed Math1 at various stages of ESCs differentiation and found that the yield of progenitors was considerably increased when Math1 was induced during embryonic body stage. Math1 triggered expression of Mbh1 and Mbh2, two target genes directly involved in granule neuron precursor formation and strong expression of early cerebellar territory markers En1 and NeuroD1. Three weeks after induction, we observed a decrease in the number of glial cells and an increase in that of neurons albeit still immature. Combining Math1 induction with extrinsic factors specifically increased the number of neurons that expressed Pde1c, Zic1, and GABAα6R characteristic of mature granule neurons, formed "T-shaped" axons typical of granule neurons, and generated synaptic contacts and action potentials in vitro. Finally, in vivo implantation of Math1-induced progenitors into young adult mice resulted in cell migration and settling of newly generated neurons in the cerebellum. These results show that conditional induction of Math1 drives ESCs toward the cerebellar fate and indicate that acting on both intrinsic and extrinsic factors is a powerful means to modulate ESCs differentiation and maturation into a specific neuronal lineage. Copyright © 2012 AlphaMed Press.

A COMPUTATIONAL MODEL OF MOTOR NEURON DEGENERATION

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Le Masson, Gwendal; Przedborski, Serge; Abbott, L.F.

2014-01-01

SUMMARY To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations. PMID:25088365

A computational model of motor neuron degeneration.

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Le Masson, Gwendal; Przedborski, Serge; Abbott, L F

2014-08-20

To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations. Copyright © 2014 Elsevier Inc. All rights reserved.

Computational model of neuron-astrocyte interactions during focal seizure generation

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Davide eReato

2012-10-01

Full Text Available Empirical research in the last decade revealed that astrocytes can respond to neurotransmitters with Ca2+ elevations and generate feedback signals to neurons which modulate synaptic transmission and neuronal excitability. This discovery changed our basic understanding of brain function and provided new perspectives for how astrocytes can participate not only to information processing, but also to the genesis of brain disorders, such as epilepsy. Epilepsy is a neurological disorder characterized by recurrent seizures that can arise focally at restricted areas and propagate throughout the brain. Studies in brain slice models suggest that astrocytes contribute to epileptiform activity by increasing neuronal excitability through a Ca2+-dependent release of glutamate. The underlying mechanism remains, however, unclear. In this study, we implemented a parsimonious network model of neurons and astrocytes. The model consists of excitatory and inhibitory neurons described by Izhikevich's neuron dynamics. The experimentally observed Ca2+ change in astrocytes in response to neuronal activity was modeled with linear equations. We considered that glutamate is released from astrocytes above certain intracellular Ca2+ concentrations thus providing a non-linear positive feedback signal to neurons. Propagating seizure-like ictal discharges (IDs were reliably evoked in our computational model by repeatedly exciting a small area of the network, which replicates experimental results in a slice model of focal ID in entorhinal cortex. We found that the threshold of focal ID generation was lowered when an excitatory feedback-loop between astrocytes and neurons was included. Simulations show that astrocytes can contribute to ID generation by directly affecting the excitatory/inhibitory balance of the neuronal network. Our model can be used to obtain mechanistic insights into the distinct contributions of the different signaling pathways to the generation and

MRI visualization of endogenous neural progenitor cell migration along the RMS in the adult mouse brain

DEFF Research Database (Denmark)

Vreys, Ruth; Vande Velde, Greetje; Krylychkina, Olga

2010-01-01

The adult rodent brain contains neural progenitor cells (NPCs), generated in the subventricular zone (SVZ), which migrate along the rostral migratory stream (RMS) towards the olfactory bulb (OB) where they differentiate into neurons. The aim of this study was to visualize endogenous NPC migration...... by a longitudinal MRI study and validated with histology. Here, we visualized endogenous NPC migration in the mouse brain by in vivo MRI and demonstrated accumulation of MPIO-labeled NPCs in the OB over time with ex vivo MRI. Furthermore, we investigated the influence of in situ injection of MPIOs on adult...

Migration and depressive symptoms in migrant-sending areas: findings from the survey of internal migration and health in China.

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Lu, Yao; Hu, Peifeng; Treiman, Donald J

2012-08-01

China has experienced large-scale internal migration and growing mental health disorders. Limited research has examined the relationship between the two processes. We examined the association between labor out-migration and depressive symptoms of family members left behind in migrant-sending areas. We conducted a multistage probability sample survey of Chinese adults in 2008 ("Internal Migration and Health in China"), including 787 people in rural migrant-sending areas. To study whether adults in out-migrant households were more likely to experience depressive symptoms (CES-D) than were adults in non-migrant households, we used multivariate regressions and adjusted for a wide range of confounding factors and for the complex sampling design. Adults in households with labor out-migrants were more likely to report depressive symptoms than those in households without out-migrants, presumably a result of the absence of family members. However, monetary remittances from labor migrants buffered the mental health costs of out-migration. Labor out-migration has important consequences for the mental health in migrant-sending communities. There is an urgent need to address the psychological costs of migration and to promote regular remittances.

Temporal structure of neuronal population oscillations with empirical model decomposition

International Nuclear Information System (INIS)

Li Xiaoli

2006-01-01

Frequency analysis of neuronal oscillation is very important for understanding the neural information processing and mechanism of disorder in the brain. This Letter addresses a new method to analyze the neuronal population oscillations with empirical mode decomposition (EMD). Following EMD of neuronal oscillation, a series of intrinsic mode functions (IMFs) are obtained, then Hilbert transform of IMFs can be used to extract the instantaneous time frequency structure of neuronal oscillation. The method is applied to analyze the neuronal oscillation in the hippocampus of epileptic rats in vivo, the results show the neuronal oscillations have different descriptions during the pre-ictal, seizure onset and ictal periods of the epileptic EEG at the different frequency band. This new method is very helpful to provide a view for the temporal structure of neural oscillation

A life course perspective on migration and mental health among Asian immigrants: the role of human agency.

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Gong, Fang; Xu, Jun; Fujishiro, Kaori; Takeuchi, David T

2011-12-01

The relationship between human agency and health is an important yet under-researched topic. This study uses a life course perspective to examine how human agency (measured by voluntariness, migratory reasons, and planning) and timing (measured by age at immigration) affect mental health outcomes among Asian immigrants in the United States. Data from the National Latino and Asian American Study showed that Asian immigrants (n=1491) with multiple strong reasons to migrate were less likely to suffer from mental health problems (i.e., psychological distress and psychiatric disorders in the past 12 months) than those without clear goals. Moreover, Asian immigrants with adequate migratory planning had lower levels of distress and lower rates of 12-month psychiatric disorders than those with poorly planned migration. Compared with migrants of the youngest age category (six or younger), those who migrated during preteen and adolescent years without clear goals had higher levels of psychological distress, and those who migrated during adulthood (25 years or older) were less likely to suffer from recent depressive disorders (with the exception of those migrating for life-improving goals). Furthermore, we found that well-planned migration lowered acculturative stress, and multiple strong reasons for migration buffered the negative effect of acculturative stress upon mental health. Findings from this study advance research on immigrant health from the life course perspective by highlighting the effects of exercising human agency during the pre-migration stage upon post-migration mental health. Copyright © 2011 Elsevier Ltd. All rights reserved.

Pre-migration and post-migration factors associated with mental health in humanitarian migrants in Australia and the moderation effect of post-migration stressors: findings from the first wave data of the BNLA cohort study.

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Chen, Wen; Hall, Brian J; Ling, Li; Renzaho, Andre Mn

2017-03-01

The process of becoming a humanitarian migrant is potentially damaging to mental health. We examined the association between pre-migration and post-migration potentially traumatic events and stressors and mental health, and assessed the moderating effect of post-migration stressors in humanitarian migrants in Australia. In this study, we used the first wave of data between 2013 and 2014 from the Building a New Life in Australia survey. The survey included 2399 migrants who had arrived in Australia holding a permanent humanitarian visa 3-6 months preceding the survey, with 77% and 23% of participants being granted visas through offshore and onshore humanitarian programmes, respectively. Post-traumatic stress disorder (PTSD) was measured with the Post-traumatic Stress Disorder 8 items (PTSD-8) and severe mental illness was measured with the Kessler Screening Scale for Psychological Distress (K6). Pre-migration potentially traumatic events and post-migration stressors related to asylum process and resettlement were measured with a self-reported questionnaire. Of the 2399 participants, 762 (31%; 95% CI 29·4-33·2) had PTSD and 394 (16%; 95% CI 14·2-17·2) had severe mental illness. The mean number of pre-migration potentially traumatic events was 2·1 (SD 1·4). 64%, 59%, 49%, and 18% of participants reported poor social integration, economic problems, worrying about family or friends overseas, and loneliness as post-migration stressors. Pre-migration potentially traumatic events and post-migration stressors were positively associated with PTSD and severe mental illness. Factors significantly modifying the association between pre-migration potentially traumatic events and mental health after controlling for confounding factors were resettlement related stressors, including loneliness (odds ratio 1·17, 95% CI 1·05-1·28 for PTSD and 1·28, 1·16-1·41 for severe mental illness) and the number of social integration stressors (1·10, 1·05-1·16 for PTSD). Our data

Long-range seasonal migration in insects: mechanisms, evolutionary drivers and ecological consequences.

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Chapman, Jason W; Reynolds, Don R; Wilson, Kenneth

2015-03-01

Myriad tiny insect species take to the air to engage in windborne migration, but entomology also has its 'charismatic megafauna' of butterflies, large moths, dragonflies and locusts. The spectacular migrations of large day-flying insects have long fascinated humankind, and since the advent of radar entomology much has been revealed about high-altitude night-time insect migrations. Over the last decade, there have been significant advances in insect migration research, which we review here. In particular, we highlight: (1) notable improvements in our understanding of lepidopteran navigation strategies, including the hitherto unsuspected capabilities of high-altitude migrants to select favourable winds and orientate adaptively, (2) progress in unravelling the neuronal mechanisms underlying sun compass orientation and in identifying the genetic complex underpinning key traits associated with migration behaviour and performance in the monarch butterfly, and (3) improvements in our knowledge of the multifaceted interactions between disease agents and insect migrants, in terms of direct effects on migration success and pathogen spread, and indirect effects on the evolution of migratory systems. We conclude by highlighting the progress that can be made through inter-phyla comparisons, and identify future research areas that will enhance our understanding of insect migration strategies within an eco-evolutionary perspective. © 2015 John Wiley & Sons Ltd/CNRS.

Mechanisms underlying prorenin actions on hypothalamic neurons implicated in cardiometabolic control

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Soledad Pitra

2016-10-01

Conclusions: We identified novel neuronal targets and cellular mechanisms underlying PR/PRR actions in critical hypothalamic neurons involved in cardiometabolic regulation. This fundamental mechanistic information regarding central PR/PRR actions is essential for the development of novel RAS-based therapeutic targets for the treatment of cardiometabolic disorders in obesity and hypertension.

Dysfunctions of the migration and of the furrowed cerebral

International Nuclear Information System (INIS)

Borrero B, Leonidas

1992-01-01

This article deals with migration disorders and brain sulcation anomalies, revising most of the available bibliography and showing some relevant examples. Emphasis is given in imaging modalities of these entities

Neuronal markers are expressed in human gliomas and NSE knockdown sensitizes glioblastoma cells to radiotherapy and temozolomide

International Nuclear Information System (INIS)

Yan, Tao; Skaftnesmo, Kai Ove; Leiss, Lina; Sleire, Linda; Wang, Jian; Li, Xingang; Enger, Per Øyvind

2011-01-01

Expression of neuronal elements has been identified in various glial tumors, and glioblastomas (GBMs) with neuronal differentiation patterns have reportedly been associated with longer survival. However, the neuronal class III β-tubulin has been linked to increasing malignancy in astrocytomas. Thus, the significance of neuronal markers in gliomas is not established. The expressions of class III β-tubulin, neurofilament protein (NFP), microtubule-associated protein 2 (MAP2) and neuron-specific enolase (NSE) were investigated in five GBM cell lines and two GBM biopsies with immunocytochemistry and Western blot. Moreover, the expression levels were quantified by real-time qPCR under different culture conditions. Following NSE siRNA treatment we used Electric cell-substrate impedance sensing (ECIS) to monitor cell growth and migration and MTS assays to study viability after irradiation and temozolomide treatment. Finally, we quantitated NSE expression in a series of human glioma biopsies with immunohistochemistry using a morphometry software, and collected survival data for the corresponding patients. The biopsies were then grouped according to expression in two halves which were compared by survival analysis. Immunocytochemistry and Western blotting showed that all markers except NFP were expressed both in GBM cell lines and biopsies. Notably, qPCR demonstrated that NSE was upregulated in cellular stress conditions, such as serum-starvation and hypoxia, while we found no uniform pattern for the other markers. NSE knockdown reduced the migration of glioma cells, sensitized them to hypoxia, radio- and chemotherapy. Furthermore, we found that GBM patients in the group with the highest NSE expression lived significantly shorter than patients in the low-expression group. Neuronal markers are aberrantly expressed in human GBMs, and NSE is consistently upregulated in different cellular stress conditions. Knockdown of NSE reduces the migration of GBM cells and sensitizes

Multiple Modes of Communication between Neurons and Oligodendrocyte Precursor Cells.

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Maldonado, Paloma P; Angulo, María Cecilia

2015-06-01

The surprising discovery of bona fide synapses between neurons and oligodendrocytes precursor cells (OPCs) 15 years ago placed these progenitors as real partners of neurons in the CNS. The role of these synapses has not been established yet, but a main hypothesis is that neuron-OPC synaptic activity is a signaling pathway controlling OPC proliferation/differentiation, influencing the myelination process. However, new evidences describing non-synaptic mechanisms of communication between neurons and OPCs have revealed that neuron-OPC interactions are more complex than expected. The activation of extrasynaptic receptors by ambient neurotransmitter or local spillover and the ability of OPCs to sense neuronal activity through a potassium channel suggest that distinct modes of communication mediate different functions of OPCs in the CNS. This review discusses different mechanisms used by OPCs to interact with neurons and their potential roles during postnatal development and in brain disorders. © The Author(s) 2014.

Deleterious effects of neuronal accumulation of glycogen in flies and mice.

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Duran, Jordi; Tevy, María Florencia; Garcia-Rocha, Mar; Calbó, Joaquim; Milán, Marco; Guinovart, Joan J

2012-08-01

Under physiological conditions, most neurons keep glycogen synthase (GS) in an inactive form and do not show detectable levels of glycogen. Nevertheless, aberrant glycogen accumulation in neurons is a hallmark of patients suffering from Lafora disease or other polyglucosan disorders. Although these diseases are associated with mutations in genes involved in glycogen metabolism, the role of glycogen accumulation remains elusive. Here, we generated mouse and fly models expressing an active form of GS to force neuronal accumulation of glycogen. We present evidence that the progressive accumulation of glycogen in mouse and Drosophila neurons leads to neuronal loss, locomotion defects and reduced lifespan. Our results highlight glycogen accumulation in neurons as a direct cause of neurodegeneration. Copyright © 2012 EMBO Molecular Medicine.

Synaptic synthesis, dephosphorylation, and degradation: a novel paradigm for an activity-dependent neuronal control of CDKL5.

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La Montanara, Paolo; Rusconi, Laura; Locarno, Albina; Forti, Lia; Barbiero, Isabella; Tramarin, Marco; Chandola, Chetan; Kilstrup-Nielsen, Charlotte; Landsberger, Nicoletta

2015-02-13

Mutations in the X-linked CDKL5 (cyclin-dependent kinase-like 5) gene have been associated with several forms of neurodevelopmental disorders, including atypical Rett syndrome, autism spectrum disorders, and early infantile epileptic encephalopathy. Accordingly, loss of CDKL5 in mice results in autistic-like features and impaired neuronal communication. Although the biological functions of CDKL5 remain largely unknown, recent pieces of evidence suggest that CDKL5 is involved in neuronal plasticity. Herein, we show that, at all stages of development, neuronal depolarization induces a rapid increase in CDKL5 levels, mostly mediated by extrasomatic synthesis. In young neurons, this induction is prolonged, whereas in more mature neurons, NMDA receptor stimulation induces a protein phosphatase 1-dependent dephosphorylation of CDKL5 that is mandatory for its proteasome-dependent degradation. As a corollary, neuronal activity leads to a prolonged induction of CDKL5 levels in immature neurons but to a short lasting increase of the kinase in mature neurons. Recent results demonstrate that many genes associated with autism spectrum disorders are crucial components of the activity-dependent signaling networks regulating the composition, shape, and strength of the synapse. Thus, we speculate that CDKL5 deficiency disrupts activity-dependent signaling and the consequent synapse development, maturation, and refinement. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The Role of Adult-Born Neurons in the Constantly Changing Olfactory Bulb Network

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Sarah Malvaut

2016-01-01

Full Text Available The adult mammalian brain is remarkably plastic and constantly undergoes structurofunctional modifications in response to environmental stimuli. In many regions plasticity is manifested by modifications in the efficacy of existing synaptic connections or synapse formation and elimination. In a few regions, however, plasticity is brought by the addition of new neurons that integrate into established neuronal networks. This type of neuronal plasticity is particularly prominent in the olfactory bulb (OB where thousands of neuronal progenitors are produced on a daily basis in the subventricular zone (SVZ and migrate along the rostral migratory stream (RMS towards the OB. In the OB, these neuronal precursors differentiate into local interneurons, mature, and functionally integrate into the bulbar network by establishing output synapses with principal neurons. Despite continuous progress, it is still not well understood how normal functioning of the OB is preserved in the constantly remodelling bulbar network and what role adult-born neurons play in odor behaviour. In this review we will discuss different levels of morphofunctional plasticity effected by adult-born neurons and their functional role in the adult OB and also highlight the possibility that different subpopulations of adult-born cells may fulfill distinct functions in the OB neuronal network and odor behaviour.

The Role of Adult-Born Neurons in the Constantly Changing Olfactory Bulb Network

Science.gov (United States)

Malvaut, Sarah; Saghatelyan, Armen

2016-01-01

The adult mammalian brain is remarkably plastic and constantly undergoes structurofunctional modifications in response to environmental stimuli. In many regions plasticity is manifested by modifications in the efficacy of existing synaptic connections or synapse formation and elimination. In a few regions, however, plasticity is brought by the addition of new neurons that integrate into established neuronal networks. This type of neuronal plasticity is particularly prominent in the olfactory bulb (OB) where thousands of neuronal progenitors are produced on a daily basis in the subventricular zone (SVZ) and migrate along the rostral migratory stream (RMS) towards the OB. In the OB, these neuronal precursors differentiate into local interneurons, mature, and functionally integrate into the bulbar network by establishing output synapses with principal neurons. Despite continuous progress, it is still not well understood how normal functioning of the OB is preserved in the constantly remodelling bulbar network and what role adult-born neurons play in odor behaviour. In this review we will discuss different levels of morphofunctional plasticity effected by adult-born neurons and their functional role in the adult OB and also highlight the possibility that different subpopulations of adult-born cells may fulfill distinct functions in the OB neuronal network and odor behaviour. PMID:26839709

Control of proliferation rate of N27 dopaminergic neurons using Transcranial Magnetic Stimulation orientation

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Meng, Yiwen; Hadimani, Ravi; Anantharam, Vellareddy; Kanthasamy, Anumantha; Jiles, David

2015-03-01

Transcranial magnetic stimulation (TMS) has been used to investigate possible treatments for a variety of neurological disorders. However, the effect that magnetic fields have on neurons has not been well documented in the literature. We have investigated the effect of different orientation of magnetic field generated by TMS coils with a monophasic stimulator on the proliferation rate of N27 neuronal cells cultured in flasks and multi-well plates. The proliferation rate of neurons would increase by exposed horizontally adherent N27 cells to a magnetic field pointing upward through the neuronal proliferation layer compared with the control group. On the other hand, proliferation rate would decrease in cells exposed to a magnetic field pointing downward through the neuronal growth layer compared with the control group. We confirmed results obtained from the Trypan-blue and automatic cell counting methods with those from the CyQuant and MTS cell viability assays. Our findings could have important implications for the preclinical development of TMS treatments of neurological disorders and represents a new method to control the proliferation rate of neuronal cells.

Human endogenous retrovirus W env increases nitric oxide production and enhances the migration ability of microglia by regulating the expression of inducible nitric oxide synthase.

Science.gov (United States)

Xiao, Ran; Li, Shan; Cao, Qian; Wang, Xiuling; Yan, Qiujin; Tu, Xiaoning; Zhu, Ying; Zhu, Fan

2017-06-01

Human endogenous retrovirus W env (HERV-W env) plays a critical role in many neuropsychological diseases such as schizophrenia and multiple sclerosis (MS). These diseases are accompanied by immunological reactions in the central nervous system (CNS). Microglia are important immunocytes in brain inflammation that can produce a gasotransmitter-nitric oxide (NO). NO not only plays a role in the function of neuronal cells but also participates in the pathogenesis of various neuropsychological diseases. In this study, we reported increased NO production in CHME-5 microglia cells after they were transfected with HERV-W env. Moreover, HERV-W env increased the expression and function of human inducible nitric oxide synthase (hiNOS) and enhanced the promoter activity of hiNOS. Microglial migration was also enhanced. These data revealed that HERV-W env might contribute to increase NO production and microglial migration ability in neuropsychological disorders by regulating the expression of inducible NOS. Results from this study might lead to the identification of novel targets for the treatment of neuropsychological diseases, including neuroinflammatory diseases, stroke, and neurodegenerative diseases.

Methylcobalamin promotes proliferation and migration and inhibits apoptosis of C2C12 cells via the Erk1/2 signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Okamoto, Michio [Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Tanaka, Hiroyuki, E-mail: tanahiro-osk@umin.ac.jp [Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Okada, Kiyoshi [Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Kuroda, Yusuke [Department of Orthopaedic Surgery, Kansai Rosai Hospital, 3-1-69 Inabaso, Amagasaki, Hyogo 660-8511 (Japan); Nishimoto, Shunsuke; Murase, Tsuyoshi; Yoshikawa, Hideki [Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan)

2014-01-17

Highlights: •Methylcobalamin activated the Erk1/2 signaling pathway in C2C12 cells. •Methylcobalamin promoted the proliferation and migration in C2C12 cells. •C2C12 cell apoptosis during differentiation was inhibited by methylcobalamin. -- Abstract: Methylcobalamin (MeCbl) is a vitamin B12 analog that has some positive effects on peripheral nervous disorders. Although some previous studies revealed the effects of MeCbl on neurons, its effect on the muscle, which is the final target of motoneuron axons, remains to be elucidated. This study aimed to determine the effect of MeCbl on the muscle. We found that MeCbl promoted the proliferation and migration of C2C12 myoblasts in vitro and that these effects are mediated by the Erk1/2 signaling pathway without affecting the activity of the Akt signaling pathway. We also demonstrated that MeCbl inhibits C2C12 cell apoptosis during differentiation. Our results suggest that MeCbl has beneficial effects on the muscle in vitro. MeCbl administration may provide a novel therapeutic approach for muscle injury or degenerating muscle after denervation.

Securitization of Migration: an Australian case study of global trends

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Michael Humphrey

2014-08-01

Full Text Available Post September 11 migration has increasingly been framed as a security problem. In the 2010 Australian election campaign migration was connected to security (defense of our borders, terrorism and social cohesion and to related issues of insecurity about the future (population size,sustainability and economic growth. Thisframing of migration as a national security issue overlooks the reality that Australian immigration is part of the global flow of population. Migration is an international issue experienced by states as a national question of border control and sovereignty seeking to manage the consequences of global inequality and mobility. This paper analyses the 'security turn' in migration debates in Australia and the North and the way the securitization of migration signifies the transformation of security from the problem of producing national order to the problem of managing global disorder resulting in the merging of national and international security strategies.

Choline metabolism as a basis for the selective vulnerability of cholinergic neurons

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Wurtman, R. J.

1992-01-01

The unique propensity of cholinergic neurons to use choline for two purposes--ACh and membrane phosphatidylcholine synthesis--may contribute to their selective vulnerability in Alzheimer's disease and other cholinergic neurodegenerative disorders. When physiologically active, the neurons use free choline taken from the 'reservoir' in membrane phosphatidylcholine to synthesize ACh; this can lead to an actual decrease in the quantity of membrane per cell. Alzheimer's disease (but not Down's syndrome, or other neurodegenerative disorders) is associated with characteristic neurochemical lesions involving choline and ethanolamine: brain levels of these compounds are diminished, while those of glycerophosphocholine and glycerophosphoethanolamine (breakdown products of their respective membrane phosphatides) are increased, both in cholinergic and noncholinergic brain regions. Perhaps this metabolic disturbance and the tendency of cholinergic neurons to 'export' choline--in the form of ACh--underlie the selective vulnerability of the neurons. Resulting changes in membrane composition could abnormally expose intramembraneous proteins such as amyloid precursor protein to proteases.

CXCL12-mediated feedback from granule neurons regulates generation and positioning of new neurons in the dentate gyrus.

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Abe, Philipp; Wüst, Hannah M; Arnold, Sebastian J; van de Pavert, Serge A; Stumm, Ralf

2018-03-14

Adult hippocampal neurogenesis is implicated in learning and memory processing. It is tightly controlled at several levels including progenitor proliferation as well as migration, differentiation and integration of new neurons. Hippocampal progenitors and immature neurons reside in the subgranular zone (SGZ) and are equipped with the CXCL12-receptor CXCR4 which contributes to defining the SGZ as neurogenic niche. The atypical CXCL12-receptor CXCR7 functions primarily by sequestering extracellular CXCL12 but whether CXCR7 is involved in adult neurogenesis has not been assessed. We report that granule neurons (GN) upregulate CXCL12 and CXCR7 during dentate gyrus maturation in the second postnatal week. To test whether GN-derived CXCL12 regulates neurogenesis and if neuronal CXCR7 receptors influence this process, we conditionally deleted Cxcl12 and Cxcr7 from the granule cell layer. Cxcl12 deletion resulted in lower numbers, increased dispersion and abnormal dendritic growth of immature GN and reduced neurogenesis. Cxcr7 ablation caused an increase in progenitor proliferation and progenitor numbers and reduced dispersion of immature GN. Thus, we provide a new mechanism where CXCL12-signals from GN prevent dispersion and support maturation of newborn GN. CXCR7 receptors of GN modulate the CXCL12-mediated feedback from GN to the neurogenic niche. © 2018 Wiley Periodicals, Inc.

Incontinentia pigmenti with neurologic and oculodental disorders

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Jorge Arturo Avina Fierro

2016-01-01

Full Text Available Incontinentia pigmenti is a genodermatosis with X-linked dominant inheritance, characterized by cutaneous, neurologic, ophthalmologic, and dental abnormalities with a pattern suggestive of somatic mosaicism. We describe a 21-month-old girl showing characteristic cutaneous findings of incontinentia pigmenti in chronic evolution of hyperpigmented, hypopigmented, and atrophic stages, linear and whorled pattern involving the Blaschko's lines. The patient has history of seizures, and electroencephalography showed epileptiform discharges at temporal lobule, cranial magnetic resonance imaging revealed cerebral dysgenesis, neuronal migration disorder, and hypoplasia of the corpus callosum. She has motor and mental delay with spastic quadriplegia, and ophthalmologic loss of central vision by ischemic optic neuropathy with decreased blood flow to eye's optic nerve. The dermatologic features were confirmed by skin biopsy that showed slight atrophy and some scattered apoptotic cells in the epidermis, epidermal hypopigmentation, and reduced melanocyte number, these histological features confirmed the genodermatosis diagnosis: Bloch-Sulzberger syndrome.

Transcranial magnetic stimulation promotes the proliferation of dopaminergic neuronal cells in vitro

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Zhong, Xiaojing; Luo, Jie; Rastogi, Priyam; Kanthasamy, Anumantha G.; Jiles, David C.; Fellow, IEEE

2018-05-01

Transcranial magnetic stimulation (TMS) is a safe and non-invasive treatment for neurological disorders. TMS has been approved as a treatment for major depressive disorders by the US Food and Drug Administration (FDA) in 2008. Due to the phenomenon of electromagnetic induction, a time-varying magnetic field induces an electric field in the conductive tissues in the brain, TMS has the ability to activate neurons in vivo. However, the effects of the magnetic fields on neurons in cell culture have not been investigated adequately. The magnetic fields affect the neurons when the potential across the neuronal membrane exceeds the threshold which in turn causes an action potential. Based on these theories, we investigated the effects of the magnetic fields generated by a monophasic stimulator with a 70 mm double coil on rat dopaminergic neuronal cell lines (N27). The directions of the magnetic fields in each coil of the double coil oppose each other. The effects of changing the direction of the magnetic field on N27 neurons was also investigated. The results of the experiments showed that both of the fields perpendicular to the coil surface promoted the proliferation of N27 dopaminergic neurons. In order to investigate the gene expression and protein expression affected by TMS, quantitative Polymerase Chain Reaction (qPCR) was used. Here we report changes in glial cell line-derived neurotrophic factor (GDNF) in dopaminergic neuronal cells (N27) after TMS treatment.

Transcranial magnetic stimulation promotes the proliferation of dopaminergic neuronal cells in vitro

Directory of Open Access Journals (Sweden)

Xiaojing Zhong

2018-05-01

Full Text Available Transcranial magnetic stimulation (TMS is a safe and non-invasive treatment for neurological disorders. TMS has been approved as a treatment for major depressive disorders by the US Food and Drug Administration (FDA in 2008. Due to the phenomenon of electromagnetic induction, a time-varying magnetic field induces an electric field in the conductive tissues in the brain, TMS has the ability to activate neurons in vivo. However, the effects of the magnetic fields on neurons in cell culture have not been investigated adequately. The magnetic fields affect the neurons when the potential across the neuronal membrane exceeds the threshold which in turn causes an action potential. Based on these theories, we investigated the effects of the magnetic fields generated by a monophasic stimulator with a 70 mm double coil on rat dopaminergic neuronal cell lines (N27. The directions of the magnetic fields in each coil of the double coil oppose each other. The effects of changing the direction of the magnetic field on N27 neurons was also investigated. The results of the experiments showed that both of the fields perpendicular to the coil surface promoted the proliferation of N27 dopaminergic neurons. In order to investigate the gene expression and protein expression affected by TMS, quantitative Polymerase Chain Reaction (qPCR was used. Here we report changes in glial cell line-derived neurotrophic factor (GDNF in dopaminergic neuronal cells (N27 after TMS treatment.

Achalasia: virus-induced euthanasia of neurons?

NARCIS (Netherlands)

Boeckxstaens, Guy E.

2008-01-01

Achalasia, a motor disorder of the esophagus, is characterized by myenteric plexitis leading to neuronal loss. Cytotoxic T cells, isolated from the lower esophageal sphincter of achalasia patients, respond to human herpes virus-1 (HSV-1) with gamma-IFN (and to a lesser extent IL-2) production and

Embryonic cerebellar neurons accumulate [3H-gamma-aminobutyric acid: visualization of developing gamma-aminobutyric acid-utilizing neurons in vitro and in vivo

International Nuclear Information System (INIS)

Hatten, M.E.; Francois, A.M.; Napolitano, E.; Roffler-Tarlov, S.

1984-01-01

gamma-Aminobutyric acid (GABA) is the proposed neurotransmitter for four types of cerebellar neurons-Purkinje, Golgi, basket, and stellate neurons. With this investigation we have begun studies to establish when these neurons acquire their neurotransmitter ''identification''. Autoradiographic studies of both cultured embryonic (embryonic day 13) cerebellar cells and of intact embryonic cerebellum (embryonic day 13) were conducted with tritiated GABA. Two to 5% of the embryonic cerebellar cells accumulated [ 3 H]GABA in vitro. By morphological and immunocytochemical criteria, labeled cells were large neurons with either a thick, apical process, a multipolar shape, or were bipolar with longer processes. The identification of cells which accumulated [ 3 H]GABA as neuronal precursors was supported by the differential sensitivity to drugs that preferentially inhibit accumulation of [ 3 H]GABA by neurons and glia. The results of the in vitro experiments were confirmed and extended with in vivo experiments. When intact cerebellar tissue was removed at embryonic day 13, stripped of meninges and choroid plexus, exposed to low concentrations of [ 3 H]GABA, and processed for light microscopic autoradiography, heavily labeled cells were seen in the middle of the cerebellar anlage. Labeled cells were not seen in the ventricular zone of proliferating neuroblasts lining the fourth ventricle or in the external granular layer emerging at the lateral aspect of the pial surface. The accumulation of [ 3 H]GABA by these cells also showed the pharmacological characteristics of uptake by neurons. This study shows that among migrating, immature forms of the larger neurons of the embryonic cerebellum, there is a select group which accumulates [ 3 H]GABA and other classes of cells which do not. These results indicate very early acquisition of transmitter expression by cerebellar neurons, far in advance of their final positioning and establishment of synapses

Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders

OpenAIRE

Dapretto, Mirella; Davies, Mari S; Pfeifer, Jennifer H; Scott, Ashley A; Sigman, Marian; Bookheimer, Susan Y; Iacoboni, Marco

2005-01-01

To examine mirror neuron abnormalities in autism, high-functioning children with autism and matched controls underwent fMRI while imitating and observing emotional expressions. Although both groups performed the tasks equally well, children with autism showed no mirror neuron activity in the inferior frontal gyrus (pars opercularis). Notably, activity in this area was inversely related to symptom severity in the social domain, suggesting that a dysfunctional ‘mirror neuron system’ may underli...

EBF factors drive expression of multiple classes of target genes governing neuronal development.

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Green, Yangsook S; Vetter, Monica L

2011-04-30

Early B cell factor (EBF) family members are transcription factors known to have important roles in several aspects of vertebrate neurogenesis, including commitment, migration and differentiation. Knowledge of how EBF family members contribute to neurogenesis is limited by a lack of detailed understanding of genes that are transcriptionally regulated by these factors. We performed a microarray screen in Xenopus animal caps to search for targets of EBF transcriptional activity, and identified candidate targets with multiple roles, including transcription factors of several classes. We determined that, among the most upregulated candidate genes with expected neuronal functions, most require EBF activity for some or all of their expression, and most have overlapping expression with ebf genes. We also found that the candidate target genes that had the most strongly overlapping expression patterns with ebf genes were predicted to be direct transcriptional targets of EBF transcriptional activity. The identification of candidate targets that are transcription factor genes, including nscl-1, emx1 and aml1, improves our understanding of how EBF proteins participate in the hierarchy of transcription control during neuronal development, and suggests novel mechanisms by which EBF activity promotes migration and differentiation. Other candidate targets, including pcdh8 and kcnk5, expand our knowledge of the types of terminal differentiated neuronal functions that EBF proteins regulate.

Characterization of neurons in the cortical white matter in human temporal lobe epilepsy.

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Richter, Zsófia; Janszky, József; Sétáló, György; Horváth, Réka; Horváth, Zsolt; Dóczi, Tamás; Seress, László; Ábrahám, Hajnalka

2016-10-01

The aim of the present work was to characterize neurons in the archi- and neocortical white matter, and to investigate their distribution in mesial temporal sclerosis. Immunohistochemistry and quantification of neurons were performed on surgically resected tissue sections of patients with therapy-resistant temporal lobe epilepsy. Temporal lobe tissues of patients with tumor but without epilepsy and that from autopsy were used as controls. Neurons were identified with immunohistochemistry using antibodies against NeuN, calcium-binding proteins, transcription factor Tbr1 and neurofilaments. We found significantly higher density of neurons in the archi- and neocortical white matter of patients with temporal lobe epilepsy than in that of controls. Based on their morphology and neurochemical content, both excitatory and inhibitory cells were present among these neurons. A subset of neurons in the white matter was Tbr-1-immunoreactive and these neurons coexpressed NeuN and neurofilament marker SMI311R. No colocalization of Tbr1 was observed with the inhibitory neuronal markers, calcium-binding proteins. We suggest that a large population of white matter neurons comprises remnants of the subplate. Furthermore, we propose that a subset of white matter neurons was arrested during migration, highlighting the role of cortical maldevelopment in epilepsy associated with mesial temporal sclerosis. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Multi-Scale Molecular Deconstruction of the Serotonin Neuron System.

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Okaty, Benjamin W; Freret, Morgan E; Rood, Benjamin D; Brust, Rachael D; Hennessy, Morgan L; deBairos, Danielle; Kim, Jun Chul; Cook, Melloni N; Dymecki, Susan M

2015-11-18

Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-seq to deconstruct the mouse 5HT system at multiple levels of granularity-from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal principles underlying system organization, 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers sertonergic subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance. Copyright © 2015 Elsevier Inc. All rights reserved.

The Social Determinants of Refugee Mental Health in the Post-Migration Context: A Critical Review.

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Hynie, Michaela

2018-05-01

With the global increase in the number of refugees and asylum seekers, mental health professionals have become more aware of the need to understand and respond to the mental health needs of forced migrants. This critical review summarizes the findings of recent systematic reviews and primary research on the impact of post-migration conditions on mental disorders and PTSD among refugees and asylum seekers. Historically, the focus of mental health research and interventions with these populations has been on the impact of pre-migration trauma. Pre-migration trauma does predict mental disorders and PTSD, but the post-migration context can be an equally powerful determinant of mental health. Moreover, post-migration factors may moderate the ability of refugees to recover from pre-migration trauma. The importance of post-migration stressors to refugee mental health suggests the need for therapeutic interventions with psychosocial elements that address the broader conditions of refugee and asylum seekers' lives. However, there are few studies of multimodal interventions with refugees, and even fewer with control conditions that allow for conclusions about their effectiveness. These findings are interpreted using a social determinants of health framework that connects the risk and protective factors in the material and social conditions of refugees' post-migration lives to broader social, economic and political factors.

Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders.

Science.gov (United States)

Dapretto, Mirella; Davies, Mari S; Pfeifer, Jennifer H; Scott, Ashley A; Sigman, Marian; Bookheimer, Susan Y; Iacoboni, Marco

2006-01-01

To examine mirror neuron abnormalities in autism, high-functioning children with autism and matched controls underwent fMRI while imitating and observing emotional expressions. Although both groups performed the tasks equally well, children with autism showed no mirror neuron activity in the inferior frontal gyrus (pars opercularis). Notably, activity in this area was inversely related to symptom severity in the social domain, suggesting that a dysfunctional 'mirror neuron system' may underlie the social deficits observed in autism.

Modulation of GABAergic Transmission in Development and Neurodevelopmental Disorders: Investigating Physiology and Pathology to Gain Therapeutic Perspectives

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Gabriele eDeidda

2014-05-01

Full Text Available During mammalian ontogenesis, the neurotransmitter GABA is a fundamental regulator of neuronal networks. In neuronal development, GABAergic signaling regulates neural proliferation, migration, differentiation, and neuronal-network wiring. In the adult, GABA orchestrates the activity of different neuronal cell-types largely interconnected, by powerfully modulating synaptic activity. GABA exerts these functions by binding to chloride-permeable ionotropic GABAA receptors and metabotropic GABAB receptors. According to its functional importance during development, GABA is implicated in a number of neurodevelopmental disorders such as autism, Fragile X, Rett syndrome, Down syndrome, schizophrenia, Tourette's syndrome and neurofibromatosis.The strength and polarity of GABAergic transmission is continuously modulated during physiological, but also pathological conditions. For GABAergic transmission through GABAA receptors, strength regulation is achieved by different mechanisms such as modulation of GABAA receptors themselves, variation of intracellular chloride concentration, and alteration in GABA metabolism. In the never-ending effort to find possible treatments for GABA-related neurological diseases, of great importance would be modulating GABAergic transmission in a safe and possibly physiological way, without the dangers of either silencing network activity or causing epileptic seizures. In this review, we will discuss the different ways to modulate GABAergic transmission normally at work both during physiological and pathological conditions. Our aim is to highlight new research perspectives for therapeutic treatments that reinstate natural and physiological brain functions in neuro-pathological conditions.

Distinct membrane effects of spinal nerve ligation on injured and adjacent dorsal root ganglion neurons in rats

NARCIS (Netherlands)

Sapunar, Damir; Ljubkovic, Marko; Lirk, Philipp; McCallum, J. Bruce; Hogan, Quinn H.

2005-01-01

Painful peripheral nerve injury results in disordered sensory neuron function that contributes to the pathogenesis of neuropathic pain. However, the relative roles of neurons with transected axons versus intact adjacent neurons have not been resolved. An essential first step is identification of

Dysregulation of RNA Mediated Gene Expression in Motor Neuron Diseases.

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Gonçalves, Inês do Carmo G; Rehorst, Wiebke A; Kye, Min Jeong

2016-01-01

Recent findings indicate an important role for RNA-mediated gene expression in motor neuron diseases, including ALS (amyotrophic lateral sclerosis) and SMA (spinal muscular atrophy). ALS, also known as Lou Gehrig's disease, is an adult-onset progressive neurodegenerative disorder, whereby SMA or "children's Lou Gehrig's disease" is considered a pediatric neurodevelopmental disorder. Despite the difference in genetic causes, both ALS and SMA share common phenotypes; dysfunction/loss of motor neurons that eventually leads to muscle weakness and atrophy. With advanced techniques in molecular genetics and cell biology, current data suggest that these two distinct motor neuron diseases share more than phenotypes; ALS and SMA have similar cellular pathological mechanisms including mitochondrial dysfunction, oxidative stress and dysregulation in RNA-mediated gene expression. Here, we will discuss the current findings on these two diseases with specific focus on RNA-mediated gene regulation including miRNA expression, pre-mRNA processing and RNA binding proteins.

Synaptic potentiation onto habenula neurons in the learned helplessness model of depression.

Science.gov (United States)

Li, Bo; Piriz, Joaquin; Mirrione, Martine; Chung, ChiHye; Proulx, Christophe D; Schulz, Daniela; Henn, Fritz; Malinow, Roberto

2011-02-24

The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.

Synaptic potentiation onto habenula neurons in the learned helplessness model of depression

International Nuclear Information System (INIS)

Li, B.; Schulz, D.; Piriz, J.; Mirrione, M.; Chung, C.H.; Proulx, C.D.; Schulz, D.; Henn, F.; Malinow, R.

2011-01-01

The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.

The changing roles of neurons in the cortical subplate

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Michael J Friedlander

2009-08-01

Full Text Available Neurons may serve different functions over the course of an organism’s life. Recent evidence suggests that cortical subplate neurons including those that reside in the white matter may perform longitudinal multi-tasking at different stages of development. These cells play a key role in early cortical development in coordinating thalamocortical reciprocal innervation. At later stages of development, they become integrated within the cortical microcircuitry. This type of longitudinal multi-tasking can enhance the capacity for information processing by populations of cells serving different functions over the lifespan. Subplate cells are initially derived when cells from the ventricular zone underlying the cortex migrate to the cortical preplate that is subsequently split by the differentiating neurons of the cortical plate with some neurons locating in the marginal zone and others settling below in the subplate (SP. While the cortical plate neurons form most of the cortical layers (layers 2-6, the marginal zone neurons form layer 1 and the SP neurons become interstitial cells of the white matter as well as forming a compact sublayer along the bottom of layer 6. After serving as transient innervation targets for thalamocortical axons, most of these cells die and layer 4 neurons become innervated by thalamic axons. However, 10-20% survives, remaining into adulthood along the bottom of layer 6 and as a scattered population of interstitial neurons in the white matter. Surviving subplate cells’ axons project throughout the overlying laminae, reaching layer 1 and issuing axon collaterals within white matter and in lower layer 6. This suggests that they participate in local synaptic networks, as well. Moreover, they receive excitatory and inhibitory synaptic inputs, potentially monitoring outputs from axon collaterals of cortical efferents, from cortical afferents and/or from each other. We explore our understanding of the functional connectivity of

Primary cell culture of LHRH neurones from embryonic olfactory placode in the sheep (Ovis aries).

Science.gov (United States)

Duittoz, A H; Batailler, M; Caldani, M

1997-09-01

The aim of this study was to establish an in vitro model of ovine luteinizing hormone-releasing hormone (LHRH) neurones. Olfactory placodes from 26 day-old sheep embryos (E26) were used for explant culture. Cultures were maintained successfully up to 35 days, but were usually used at 17 days for immunocytochemistry. LHRH and neuronal markers such as neurofilament (NF) were detected by immunocytochemistry within and/or outside the explant. Three main types of LHRH positive cells are described: (1) neuroblastic LHRH and NF immunoreactive cells with round cell body and very short neurites found mainly within the explant, (2) migrating LHRH bipolar neurones with an fusiform cell body, found outside the explant, (3) network LHRH neuron, bipolar or multipolar with long neurites connecting other LHRH neurons. Cell morphology was very similar to that which has been described in the adult sheep brain. These results strongly suggest that LHRH neurones in the sheep originate from the olfactory placode. This mode may represent a useful tool to study LHRH neurones directly in the sheep.

Multiplexed Neurochemical Signaling by Neurons of the Ventral Tegmental Area

Science.gov (United States)

Barker, David J.; Root, David H.; Zhang, Shiliang; Morales, Marisela

2016-01-01

The ventral tegmental area (VTA) is an evolutionarily conserved structure that has roles in reward-seeking, safety-seeking, learning, motivation, and neuropsychiatric disorders such as addiction and depression. The involvement of the VTA in these various behaviors and disorders is paralleled by its diverse signaling mechanisms. Here we review recent advances in our understanding of neuronal diversity in the VTA with a focus on cell phenotypes that participate in ‘multiplexed’ neurotransmission involving distinct signaling mechanisms. First, we describe the cellular diversity within the VTA, including neurons capable of transmitting dopamine, glutamate or GABA as well as neurons capable of multiplexing combinations of these neurotransmitters. Next, we describe the complex synaptic architecture used by VTA neurons in order to accommodate the transmission of multiple transmitters. We specifically cover recent findings showing that VTA multiplexed neurotransmission may be mediated by either the segregation of dopamine and glutamate into distinct microdomains within a single axon or by the integration of glutamate and GABA into a single axon terminal. In addition, we discuss our current understanding of the functional role that these multiplexed signaling pathways have in the lateral habenula and the nucleus accumbens. Finally, we consider the putative roles of VTA multiplexed neurotransmission in synaptic plasticity and discuss how changes in VTA multiplexed neurons may relate to various psychopathologies including drug addiction and depression. PMID:26763116

Synaptic potentiation onto habenula neurons in learned helplessness model of depression

Science.gov (United States)

Li, Bo; Piriz, Joaquin; Mirrione, Martine; Chung, ChiHye; Proulx, Christophe D.; Schulz, Daniela; Henn, Fritz; Malinow, Roberto

2010-01-01

The cellular basis of depressive disorders is poorly understood1. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (i.e. disappointment or anticipation of a negative outcome)2, 3, 4. LHb neurons project to and modulate dopamine-rich regions such as the ventral-tegmental area (VTA)2, 5 that control reward-seeking behavior6 and participate in depressive disorders7. Here we show in two learned helplessness models of depression that excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal’s helplessness behavior and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective on depressed patients8, 9, dramatically suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behavior in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression. PMID:21350486

Hyperactivity of newborn Pten knock-out neurons results from increased excitatory synaptic drive.

Science.gov (United States)

Williams, Michael R; DeSpenza, Tyrone; Li, Meijie; Gulledge, Allan T; Luikart, Bryan W

2015-01-21

Developing neurons must regulate morphology, intrinsic excitability, and synaptogenesis to form neural circuits. When these processes go awry, disorders, including autism spectrum disorder (ASD) or epilepsy, may result. The phosphatase Pten is mutated in some patients having ASD and seizures, suggesting that its mutation disrupts neurological function in part through increasing neuronal activity. Supporting this idea, neuronal knock-out of Pten in mice can cause macrocephaly, behavioral changes similar to ASD, and seizures. However, the mechanisms through which excitability is enhanced following Pten depletion are unclear. Previous studies have separately shown that Pten-depleted neurons can drive seizures, receive elevated excitatory synaptic input, and have abnormal dendrites. We therefore tested the hypothesis that developing Pten-depleted neurons are hyperactive due to increased excitatory synaptogenesis using electrophysiology, calcium imaging, morphological analyses, and modeling. This was accomplished by coinjecting retroviruses to either "birthdate" or birthdate and knock-out Pten in granule neurons of the murine neonatal dentate gyrus. We found that Pten knock-out neurons, despite a rapid onset of hypertrophy, were more active in vivo. Pten knock-out neurons fired at more hyperpolarized membrane potentials, displayed greater peak spike rates, and were more sensitive to depolarizing synaptic input. The increased sensitivity of Pten knock-out neurons was due, in part, to a higher density of synapses located more proximal to the soma. We determined that increased synaptic drive was sufficient to drive hypertrophic Pten knock-out neurons beyond their altered action potential threshold. Thus, our work contributes a developmental mechanism for the increased activity of Pten-depleted neurons. Copyright © 2015 the authors 0270-6474/15/350943-17$15.00/0.

IBS, NERD and functional dyspepsia are immuno-neuronal disorders of mucosal cytokine imbalances clinically reversible with high potency sucralfate.

Science.gov (United States)

McCullough, Ricky W

2013-03-01

Irritable bowel syndrome (IBS), non-erosive reflux disorder (NERD), and functional dyspepsia (FD) are best classified as immuno-neuronal disorders of the mucosa or functional mucosal syndromes (FMS). Each appears to be clinically reversible using high potency sucralfate (HPS). In FMS of the GI tract, postprandial nausea, altered motility, discordant peristalsis, vomiting, diarrhea, and hyperalgesia are the clinical expressions of a mucosal imbalance between pro-inflammatory cytokines of up-regulated intra-epithelial lymphocytes (IELs) and feedback anti-inflammatory cytokines tasked with moderating the antigenic response of IELs. Normal functioning GI tract requires an operative balance between pro-inflammatory and anti-inflammatrory cytokines, a balance governed by locally expressed growth factors. The surface concentration of sucralfate can be enhanced 7-23-fold by suspending it in a select concentration of cations and multi-dentate cationic chelators. Increased surface concentration of sucralfate facilitates novel dose effects which include efficient activation of growth factors, quiescence of gated-nociceptor firing and resultant restoration of normal GI function. Published by Elsevier Ltd.

Influence of post-traumatic stress disorder on neuroinflammation and cell proliferation in a rat model of traumatic brain injury.

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Sandra A Acosta

Full Text Available Long-term consequences of traumatic brain injury (TBI are closely associated with the development of severe psychiatric disorders, such as post-traumatic stress disorder (PTSD, yet preclinical studies on pathological changes after combined TBI with PTSD are lacking. In the present in vivo study, we assessed chronic neuroinflammation, neuronal cell loss, cell proliferation and neuronal differentiation in specific brain regions of adult Sprague-Dawley male rats following controlled cortical impact model of moderate TBI with or without exposure to PTSD. Eight weeks post-TBI, stereology-based histological analyses revealed no significant differences between sham and PTSD alone treatment across all brain regions examined, whereas significant exacerbation of OX6-positive activated microglial cells in the striatum, thalamus, and cerebral peduncle, but not cerebellum, in animals that received TBI alone and combined TBI-PTSD compared with PTSD alone and sham treatment. Additional immunohistochemical results revealed a significant loss of CA3 pyramidal neurons in the hippocampus of TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Further examination of neurogenic niches revealed a significant downregulation of Ki67-positive proliferating cells, but not DCX-positive neuronally migrating cells in the neurogenic subgranular zone and subventricular zone for both TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Comparisons of levels of neuroinflammation and neurogenesis between TBI alone and TBI+PTSD revealed that PTSD did not exacerbate the neuropathological hallmarks of TBI. These results indicate a progressive deterioration of the TBI brain, which, under the conditions of the present approach, was not intensified by PTSD, at least within our time window and within the examined areas of the brain. Although the PTSD manipulation employed here did not exacerbate the pathological effects of TBI, the observed long

Influence of post-traumatic stress disorder on neuroinflammation and cell proliferation in a rat model of traumatic brain injury.

Science.gov (United States)

Acosta, Sandra A; Diamond, David M; Wolfe, Steven; Tajiri, Naoki; Shinozuka, Kazutaka; Ishikawa, Hiroto; Hernandez, Diana G; Sanberg, Paul R; Kaneko, Yuji; Borlongan, Cesar V

2013-01-01

Long-term consequences of traumatic brain injury (TBI) are closely associated with the development of severe psychiatric disorders, such as post-traumatic stress disorder (PTSD), yet preclinical studies on pathological changes after combined TBI with PTSD are lacking. In the present in vivo study, we assessed chronic neuroinflammation, neuronal cell loss, cell proliferation and neuronal differentiation in specific brain regions of adult Sprague-Dawley male rats following controlled cortical impact model of moderate TBI with or without exposure to PTSD. Eight weeks post-TBI, stereology-based histological analyses revealed no significant differences between sham and PTSD alone treatment across all brain regions examined, whereas significant exacerbation of OX6-positive activated microglial cells in the striatum, thalamus, and cerebral peduncle, but not cerebellum, in animals that received TBI alone and combined TBI-PTSD compared with PTSD alone and sham treatment. Additional immunohistochemical results revealed a significant loss of CA3 pyramidal neurons in the hippocampus of TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Further examination of neurogenic niches revealed a significant downregulation of Ki67-positive proliferating cells, but not DCX-positive neuronally migrating cells in the neurogenic subgranular zone and subventricular zone for both TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Comparisons of levels of neuroinflammation and neurogenesis between TBI alone and TBI+PTSD revealed that PTSD did not exacerbate the neuropathological hallmarks of TBI. These results indicate a progressive deterioration of the TBI brain, which, under the conditions of the present approach, was not intensified by PTSD, at least within our time window and within the examined areas of the brain. Although the PTSD manipulation employed here did not exacerbate the pathological effects of TBI, the observed long-term inflammation and suppressed

Influence of Post-Traumatic Stress Disorder on Neuroinflammation and Cell Proliferation in a Rat Model of Traumatic Brain Injury

Science.gov (United States)

Diamond, David M.; Shinozuka, Kazutaka; Ishikawa, Hiroto; Hernandez, Diana G.; Sanberg, Paul R.; Kaneko, Yuji; Borlongan, Cesar V.

2013-01-01

Long-term consequences of traumatic brain injury (TBI) are closely associated with the development of severe psychiatric disorders, such as post-traumatic stress disorder (PTSD), yet preclinical studies on pathological changes after combined TBI with PTSD are lacking. In the present in vivo study, we assessed chronic neuroinflammation, neuronal cell loss, cell proliferation and neuronal differentiation in specific brain regions of adult Sprague-Dawley male rats following controlled cortical impact model of moderate TBI with or without exposure to PTSD. Eight weeks post-TBI, stereology-based histological analyses revealed no significant differences between sham and PTSD alone treatment across all brain regions examined, whereas significant exacerbation of OX6-positive activated microglial cells in the striatum, thalamus, and cerebral peduncle, but not cerebellum, in animals that received TBI alone and combined TBI-PTSD compared with PTSD alone and sham treatment. Additional immunohistochemical results revealed a significant loss of CA3 pyramidal neurons in the hippocampus of TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Further examination of neurogenic niches revealed a significant downregulation of Ki67-positive proliferating cells, but not DCX-positive neuronally migrating cells in the neurogenic subgranular zone and subventricular zone for both TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Comparisons of levels of neuroinflammation and neurogenesis between TBI alone and TBI+PTSD revealed that PTSD did not exacerbate the neuropathological hallmarks of TBI. These results indicate a progressive deterioration of the TBI brain, which, under the conditions of the present approach, was not intensified by PTSD, at least within our time window and within the examined areas of the brain. Although the PTSD manipulation employed here did not exacerbate the pathological effects of TBI, the observed long-term inflammation and suppressed

Quinolinic acid induces disrupts cytoskeletal homeostasis in striatal neurons. Protective role of astrocyte-neuron interaction.

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Pierozan, Paula; Ferreira, Fernanda; de Lima, Bárbara Ortiz; Pessoa-Pureur, Regina

2015-02-01

Quinolinic acid (QUIN) is an endogenous metabolite of the kynurenine pathway involved in several neurological disorders. Among the several mechanisms involved in QUIN-mediated toxicity, disruption of the cytoskeleton has been demonstrated in striatally injected rats and in striatal slices. The present work searched for the actions of QUIN in primary striatal neurons. Neurons exposed to 10 µM QUIN presented hyperphosphorylated neurofilament (NF) subunits (NFL, NFM, and NFH). Hyperphosphorylation was abrogated in the presence of protein kinase A and protein kinase C inhibitors H89 (20 μM) and staurosporine (10 nM), respectively, as well as by specific antagonists to N-methyl-D-aspartate (50 µM DL-AP5) and metabotropic glutamate receptor 1 (100 µM MPEP). Also, intra- and extracellular Ca(2+) chelators (10 µM BAPTA-AM and 1 mM EGTA, respectively) and Ca(2+) influx through L-type voltage-dependent Ca(2+) channel (10 µM verapamil) are implicated in QUIN-mediated effects. Cells immunostained for the neuronal markers βIII-tubulin and microtubule-associated protein 2 showed altered neurite/neuron ratios and neurite outgrowth. NF hyperphosphorylation and morphological alterations were totally prevented by conditioned medium from QUIN-treated astrocytes. Cocultured astrocytes and neurons interacted with one another reciprocally, protecting them against QUIN injury. Cocultured cells preserved their cytoskeletal organization and cell morphology together with unaltered activity of the phosphorylating system associated with the cytoskeleton. This article describes cytoskeletal disruption as one of the most relevant actions of QUIN toxicity in striatal neurons in culture with soluble factors secreted by astrocytes, with neuron-astrocyte interaction playing a role in neuroprotection. © 2014 Wiley Periodicals, Inc.

The aging brain and neurodegenerative disorders

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Braffman, B.H.; Trojanowski, J.Q.; Atlas, S.W.

1991-01-01

Both the aging brain and neurodegenerative disorders are characterized by a lack of vital endurance of affected neurons resulting in their premature death. Neuronal shrinkage or atrophy and death are normal and inevitable aspects of normal or successful aging; this is unexpected, excessive, and premature in neurodegenerative disorders. These histologic changes result in the neuroimaging findings of focal and/or diffuse atrophy with consequent enlargement of cerebrospinal fluid (CSF) spaces. The aging brain and neurodegenerative disorders share other magnetic resonance (MR) changes, i.e., markedly hypointense extrapyramidal nuclei and hyperintense white matter foci. The sequelae of senescent vascular changes result in additional characteristic features of the aging brain. This paper presents the MR and neuropathologic manifestations of both the normal aging brain and the brain affected by neurodegenerative disorders

Focusing on neuronal cell-type specific mechanisms for brain circuit organization, function and dysfunction

Institute of Scientific and Technical Information of China (English)

Lu Li

2017-01-01

Mammalian brain circuits consist of dynamically interconnected neurons with characteristic morphology, physiology, connectivity and genetics which are often called neuronal cell types. Neuronal cell types have been considered as building blocks of brain circuits, but knowledge of how neuron types or subtypes connect to and interact with each other to perform neural computation is still lacking. Such mechanistic insights are critical not only to our understanding of normal brain functions, such as perception, motion and cognition, but also to brain disorders including Alzheimer's disease, Schizophrenia and epilepsy, to name a few. Thus it is necessary to carry out systematic and standardized studies on neuronal cell-type specific mechanisms for brain circuit organization and function, which will provide good opportunities to bridge basic and clinical research. Here based on recent technology advancements, we discuss the strategy to target and manipulate specific populations of neuronsin vivo to provide unique insights on how neuron types or subtypes behave, interact, and generate emergent properties in a fully connected brain network. Our approach is highlighted by combining transgenic animal models, targeted electrophysiology and imaging with robotics, thus complete and standardized mapping ofin vivo properties of genetically defined neuron populations can be achieved in transgenic mouse models, which will facilitate the development of novel therapeutic strategies for brain disorders.

Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons.

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Prouty, Eric W; Chandler, Daniel J; Waterhouse, Barry D

2017-11-15

Serotonin (5-HT)-containing neurons in the dorsal raphe (DR) nucleus project throughout the forebrain and are implicated in many physiological processes and neuropsychiatric disorders. Diversity among these neurons has been characterized in terms of their neurochemistry and anatomical organization, but a clear sense of whether these attributes align with specific brain functions or terminal fields is lacking. DR 5-HT neurons can co-express additional neuroactive substances, increasing the potential for individualized regulation of target circuits. The goal of this study was to link DR neurons to a specific functional role by characterizing cells according to both their neurotransmitter expression and efferent connectivity; specifically, cells projecting to the medial prefrontal cortex (mPFC), a region implicated in cognition, emotion, and responses to stress. Following retrograde tracer injection, brainstem sections from Sprague-Dawley rats were immunohistochemically stained for markers of serotonin, glutamate, GABA, and nitric oxide (NO). 98% of the mPFC-projecting serotonergic neurons co-expressed the marker for glutamate, while the markers for NO and GABA were observed in 60% and less than 1% of those neurons, respectively. To identify potential target-specific differences in co-transmitter expression, we also characterized DR neurons projecting to a visual sensory structure, the lateral geniculate nucleus (LGN). The proportion of serotonergic neurons co-expressing NO was greater amongst cells targeting the mPFC vs LGN (60% vs 22%). The established role of 5-HT in affective disorders and the emerging role of NO in stress signaling suggest that the impact of 5-HT/NO co-localization in DR neurons that regulate mPFC circuit function may be clinically relevant. Copyright © 2017 Elsevier B.V. All rights reserved.

Hippocampal adaptive response following extensive neuronal loss in an inducible transgenic mouse model.

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Kristoffer Myczek

Full Text Available Neuronal loss is a common component of a variety of neurodegenerative disorders (including Alzheimer's, Parkinson's, and Huntington's disease and brain traumas (stroke, epilepsy, and traumatic brain injury. One brain region that commonly exhibits neuronal loss in several neurodegenerative disorders is the hippocampus, an area of the brain critical for the formation and retrieval of memories. Long-lasting and sometimes unrecoverable deficits caused by neuronal loss present a unique challenge for clinicians and for researchers who attempt to model these traumas in animals. Can these deficits be recovered, and if so, is the brain capable of regeneration following neuronal loss? To address this significant question, we utilized the innovative CaM/Tet-DT(A mouse model that selectively induces neuronal ablation. We found that we are able to inflict a consistent and significant lesion to the hippocampus, resulting in hippocampally-dependent behavioral deficits and a long-lasting upregulation in neurogenesis, suggesting that this process might be a critical part of hippocampal recovery. In addition, we provide novel evidence of angiogenic and vasculature changes following hippocampal neuronal loss in CaM/Tet-DTA mice. We posit that angiogenesis may be an important factor that promotes neurogenic upregulation following hippocampal neuronal loss, and both factors, angiogenesis and neurogenesis, can contribute to the adaptive response of the brain for behavioral recovery.

The role of ASTN2 variants in childhood and adult ADHD, comorbid disorders and associated personality traits.

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Freitag, Christine M; Lempp, Thomas; Nguyen, T Trang; Jacob, Christian P; Weissflog, Lena; Romanos, Marcel; Renner, Tobias J; Walitza, Susanne; Warnke, Andreas; Rujescu, Dan; Lesch, Klaus-Peter; Reif, Andreas

2016-08-01

Previous linkage and genome wide association (GWA) studies in ADHD indicated astrotactin 2 (ASTN2) as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). ASTN2 plays a key role in glial-guided neuronal migration. To investigate whether common variants in ASTN2 contribute to ADHD disorder risk, we tested 63 SNPs spanning ASTN2 for association with ADHD and specific comorbid disorders in two samples: 171 families of children with ADHD and their parents (N = 592), and an adult sample comprising 604 adult ADHD cases and 974 controls. The C-allele of rs12376789 in ASTN2 nominally increased the risk for ADHD in the trio sample (p = 0.025). This was not observed in the adult case-control sample alone, but retained in the combined sample (nominal p = 0.030). Several other SNPs showed nominally significant association with comorbid disorders, especially anxiety disorder, in the childhood and adult ADHD samples. Some ASTN2 variants were nominally associated with personality traits in the adult ADHD sample and overlapped with risk alleles for comorbid disorders in childhood. None of the findings survived correction for multiple testing, thus, results do not support a major role of common variants in ASTN2 in the pathogenesis of ADHD, its comorbid disorders or ADHD associated personality traits.

Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases.

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Kline, Rachel A; Kaifer, Kevin A; Osman, Erkan Y; Carella, Francesco; Tiberi, Ariana; Ross, Jolill; Pennetta, Giuseppa; Lorson, Christian L; Murray, Lyndsay M

2017-03-01

The term "motor neuron disease" encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers

Expression of polysialylated neural cell adhesion molecules on adult stem cells after neuronal differentiation of inner ear spiral ganglion neurons

International Nuclear Information System (INIS)

Park, Kyoung Ho; Yeo, Sang Won; Troy, Frederic A.

2014-01-01

Highlights: • PolySia expressed on neurons primarily during early stages of neuronal development. • PolySia–NCAM is expressed on neural stem cells from adult guinea pig spiral ganglion. • PolySia is a biomarker that modulates neuronal differentiation in inner ear stem cells. - Abstract: During brain development, polysialylated (polySia) neural cell adhesion molecules (polySia–NCAMs) modulate cell–cell adhesive interactions involved in synaptogenesis, neural plasticity, myelination, and neural stem cell (NSC) proliferation and differentiation. Our findings show that polySia–NCAM is expressed on NSC isolated from adult guinea pig spiral ganglion (GPSG), and in neurons and Schwann cells after differentiation of the NSC with epidermal, glia, fibroblast growth factors (GFs) and neurotrophins. These differentiated cells were immunoreactive with mAb’s to polySia, NCAM, β-III tubulin, nestin, S-100 and stained with BrdU. NSC could regenerate and be differentiated into neurons and Schwann cells. We conclude: (1) polySia is expressed on NSC isolated from adult GPSG and on neurons and Schwann cells differentiated from these NSC; (2) polySia is expressed on neurons primarily during the early stage of neuronal development and is expressed on Schwann cells at points of cell–cell contact; (3) polySia is a functional biomarker that modulates neuronal differentiation in inner ear stem cells. These new findings suggest that replacement of defective cells in the inner ear of hearing impaired patients using adult spiral ganglion neurons may offer potential hope to improve the quality of life for patients with auditory dysfunction and impaired hearing disorders

Expression of polysialylated neural cell adhesion molecules on adult stem cells after neuronal differentiation of inner ear spiral ganglion neurons

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Park, Kyoung Ho [Department of Otolaryngology Head and Neck Surgery, College of Medicine, Catholic University, Seoul (Korea, Republic of); Yeo, Sang Won, E-mail: swyeo@catholic.ac.kr [Department of Otolaryngology Head and Neck Surgery, College of Medicine, Catholic University, Seoul (Korea, Republic of); Troy, Frederic A., E-mail: fatroy@ucdavis.edu [Department of Biochemistry and Molecular Medicine, University of California, School of Medicine, Davis, CA 95616 (United States); Xiamen University, School of Medicine, Xiamen City (China)

2014-10-17

Highlights: • PolySia expressed on neurons primarily during early stages of neuronal development. • PolySia–NCAM is expressed on neural stem cells from adult guinea pig spiral ganglion. • PolySia is a biomarker that modulates neuronal differentiation in inner ear stem cells. - Abstract: During brain development, polysialylated (polySia) neural cell adhesion molecules (polySia–NCAMs) modulate cell–cell adhesive interactions involved in synaptogenesis, neural plasticity, myelination, and neural stem cell (NSC) proliferation and differentiation. Our findings show that polySia–NCAM is expressed on NSC isolated from adult guinea pig spiral ganglion (GPSG), and in neurons and Schwann cells after differentiation of the NSC with epidermal, glia, fibroblast growth factors (GFs) and neurotrophins. These differentiated cells were immunoreactive with mAb’s to polySia, NCAM, β-III tubulin, nestin, S-100 and stained with BrdU. NSC could regenerate and be differentiated into neurons and Schwann cells. We conclude: (1) polySia is expressed on NSC isolated from adult GPSG and on neurons and Schwann cells differentiated from these NSC; (2) polySia is expressed on neurons primarily during the early stage of neuronal development and is expressed on Schwann cells at points of cell–cell contact; (3) polySia is a functional biomarker that modulates neuronal differentiation in inner ear stem cells. These new findings suggest that replacement of defective cells in the inner ear of hearing impaired patients using adult spiral ganglion neurons may offer potential hope to improve the quality of life for patients with auditory dysfunction and impaired hearing disorders.

Plasticity in neurons synthesizing wake/arousal promoting hormone hypocretin/orexin.

Science.gov (United States)

Gao, Xiao-Bing

2012-01-01

The hypothalamus is a critical brain structure regulating physiological functions essential to the survival of individuals and species. One of the striking characteristics of this brain region is the abundance of nerve cells (neurons) expressing a great numbers of neurotransmitters and neuromodulators, among which are hormones released into the blood stream through brain neuroendocrinological routes. The neurons in the lateral hypothalamus take part in intra- and extrahypothalamic circuits controlling basic physiological functions essential for the well being of animal bodies (such as cardiovascular function, respiratory function, immune responses, etc.), animal behaviors required for the maintenance of the survival of individuals (food foraging, flight, fight, etc.) and species (reproductive function), and higher brain functions (learning and memory, mental state, etc.). Hypocretin (also called orexin) comprises of two neuropeptides exclusively synthesized by neurons in the perifornical/lateral hypothalamus. Although hypocretin/orexin was initially found to enhance food intake, it is now clear that the functions mediated by hypocretin/orexin are well beyond what were originally proposed. Specifically, hypocretin/orexin is a crucial promoter of wakefulness; deficiency in the hypocretin/orexin system leads to diseases and disorders such as narcolepsy. It is clear that neurons synthesizing hypocretin/orexin are consistently under regulation originating from various parts of the brain and that the status of activity in hypocretin/orexin neurons is closely related with the nutritional and behavioral state of animals. Therefore, the demand to make adaptive changes in hypocretin/orexin neurons to accommodate the changes in the external environment and behavioral state of animals is expected. The latest developments in the studies of plasticity in hypocretin/orexin neurons under the challenges from environmental and behavioral factors have dramatically shaped the

Mapping pathological phenotypes in a mouse model of CDKL5 disorder.

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Elena Amendola

Full Text Available Mutations in cyclin-dependent kinase-like 5 (CDKL5 cause early-onset epileptic encephalopathy, a neurodevelopmental disorder with similarities to Rett Syndrome. Here we describe the physiological, molecular, and behavioral phenotyping of a Cdkl5 conditional knockout mouse model of CDKL5 disorder. Behavioral analysis of constitutive Cdkl5 knockout mice revealed key features of the human disorder, including limb clasping, hypoactivity, and abnormal eye tracking. Anatomical, physiological, and molecular analysis of the knockout uncovered potential pathological substrates of the disorder, including reduced dendritic arborization of cortical neurons, abnormal electroencephalograph (EEG responses to convulsant treatment, decreased visual evoked responses (VEPs, and alterations in the Akt/rpS6 signaling pathway. Selective knockout of Cdkl5 in excitatory and inhibitory forebrain neurons allowed us to map the behavioral features of the disorder to separable cell-types. These findings identify physiological and molecular deficits in specific forebrain neuron populations as possible pathological substrates in CDKL5 disorder.

Mapping pathological phenotypes in a mouse model of CDKL5 disorder.

Science.gov (United States)

Amendola, Elena; Zhan, Yang; Mattucci, Camilla; Castroflorio, Enrico; Calcagno, Eleonora; Fuchs, Claudia; Lonetti, Giuseppina; Silingardi, Davide; Vyssotski, Alexei L; Farley, Dominika; Ciani, Elisabetta; Pizzorusso, Tommaso; Giustetto, Maurizio; Gross, Cornelius T

2014-01-01

Mutations in cyclin-dependent kinase-like 5 (CDKL5) cause early-onset epileptic encephalopathy, a neurodevelopmental disorder with similarities to Rett Syndrome. Here we describe the physiological, molecular, and behavioral phenotyping of a Cdkl5 conditional knockout mouse model of CDKL5 disorder. Behavioral analysis of constitutive Cdkl5 knockout mice revealed key features of the human disorder, including limb clasping, hypoactivity, and abnormal eye tracking. Anatomical, physiological, and molecular analysis of the knockout uncovered potential pathological substrates of the disorder, including reduced dendritic arborization of cortical neurons, abnormal electroencephalograph (EEG) responses to convulsant treatment, decreased visual evoked responses (VEPs), and alterations in the Akt/rpS6 signaling pathway. Selective knockout of Cdkl5 in excitatory and inhibitory forebrain neurons allowed us to map the behavioral features of the disorder to separable cell-types. These findings identify physiological and molecular deficits in specific forebrain neuron populations as possible pathological substrates in CDKL5 disorder.

Enhancing excitability of dopamine neurons promotes motivational behaviour through increased action initiation.

Science.gov (United States)

Boekhoudt, Linde; Wijbrans, Ellen C; Man, Jodie H K; Luijendijk, Mieneke C M; de Jong, Johannes W; van der Plasse, Geoffrey; Vanderschuren, Louk J M J; Adan, Roger A H

2018-01-01

Motivational deficits are a key symptom in multiple psychiatric disorders, including major depressive disorder, schizophrenia and addiction. A likely neural substrate for these motivational deficits is the brain dopamine (DA) system. In particular, DA signalling in the nucleus accumbens, which originates from DA neurons in the ventral tegmental area (VTA), has been identified as a crucial substrate for effort-related and activational aspects of motivation. Unravelling how VTA DA neuronal activity relates to motivational behaviours is required to understand how motivational deficits in psychiatry can be specifically targeted. In this study, we therefore used designer receptors exclusively activated by designer drugs (DREADD) in TH:Cre rats, in order to determine the effects of chemogenetic DA neuron activation on different aspects of motivational behaviour. We found that chemogenetic activation of DA neurons in the VTA, but not substantia nigra, significantly increased responding for sucrose under a progressive ratio schedule of reinforcement. More specifically, high effort exertion was characterized by increased initiations of reward-seeking actions. This effect was dependent on effort requirements and instrumental contingencies, but was not affected by sucrose pre-feeding. Together, these findings indicate that VTA DA neuronal activation drives motivational behaviour by facilitating action initiation. With this study, we show that enhancing excitability of VTA DA neurons is a viable strategy to improve motivational behaviour. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Subependymal heterotopia: a distinct neuronal migration disorder associated with epilepsy.

Science.gov (United States)

Raymond, A A; Fish, D R; Stevens, J M; Sisodiya, S M; Alsanjari, N; Shorvon, S D

1994-01-01

Subependymal heterotopia has recently been recognised as a cause of epilepsy, but the clinical and investigational features have not been fully described. The clinical, psychometric, imaging, and electroencephalographic features of 13 adult patients with subependymal heterotopia and epilepsy have been reviewed. Age at seizure onset ranged from 18 months to 20 years (median 13 years). There were significantly more female (12) than male (1) patients (p < 0.01). Diagnosis of subependymal heterotopia was made by MRI in 11 patients and CT in two. The heterotopic grey matter was nodular in 11 patients and diffuse in two; bilateral in eight and unilateral in five. There were significantly more patients with predominant right than left cerebral hemisphere involvement (p < 0.01). The most commonly involved site was the occipital horn of the lateral ventricles (10 of 13 patients). Eleven patients presented with partial epilepsy, 10 of whom also had secondarily generalised seizures. The clinical description of the seizures often suggested either an occipital (four patients) or temporal (five patients) onset. Two patients presented with absence attacks without clear focal features. Patients demonstrated normal early milestones (12 of 13 patients), including normal motor development (all patients) and average or above average intelligence (10 of 13 patients). An EEG examination showed normal background activity in all but two patients, one of whom had large intracranial haematomas. Epileptiform activity was usually widespread (10 of 13 patients) and in three patients, there was generalised 3-Hz spike and wave activity that had previously led to an erroneous diagnosis of concomitant primary generalised epilepsy. Onset of epilepsy in the second decade of life, normal developmental milestones and intelligence, and the finding of an overwhelming female preponderance differentiates subependymal heterotopia from other cortical dysgeneses. The female preponderance supports the importance of the X chromosome and sex steroids in the maturation and development of the cerebral cortex. Images PMID:7931380

EBF factors drive expression of multiple classes of target genes governing neuronal development

Directory of Open Access Journals (Sweden)

Vetter Monica L

2011-04-01

Full Text Available Abstract Background Early B cell factor (EBF family members are transcription factors known to have important roles in several aspects of vertebrate neurogenesis, including commitment, migration and differentiation. Knowledge of how EBF family members contribute to neurogenesis is limited by a lack of detailed understanding of genes that are transcriptionally regulated by these factors. Results We performed a microarray screen in Xenopus animal caps to search for targets of EBF transcriptional activity, and identified candidate targets with multiple roles, including transcription factors of several classes. We determined that, among the most upregulated candidate genes with expected neuronal functions, most require EBF activity for some or all of their expression, and most have overlapping expression with ebf genes. We also found that the candidate target genes that had the most strongly overlapping expression patterns with ebf genes were predicted to be direct transcriptional targets of EBF transcriptional activity. Conclusions The identification of candidate targets that are transcription factor genes, including nscl-1, emx1 and aml1, improves our understanding of how EBF proteins participate in the hierarchy of transcription control during neuronal development, and suggests novel mechanisms by which EBF activity promotes migration and differentiation. Other candidate targets, including pcdh8 and kcnk5, expand our knowledge of the types of terminal differentiated neuronal functions that EBF proteins regulate.

Molecular hierarchy in neurons differentiated from mouse ES cells containing a single human chromosome 21.

Science.gov (United States)

Wang, Chi Chiu; Kadota, Mitsutaka; Nishigaki, Ryuichi; Kazuki, Yasuhiro; Shirayoshi, Yasuaki; Rogers, Michael Scott; Gojobori, Takashi; Ikeo, Kazuho; Oshimura, Mitsuo

2004-02-06

Defects in neurogenesis and neuronal differentiation in the fetal brain of Down syndrome (DS) patients lead to the apparent neuropathological abnormalities and contribute to the phenotypic characters of mental retardation, and premature development of Alzheimer's disease, those being the most common phenotype in DS. In order to understand the molecular mechanism underlying the cause of phenotypic abnormalities in the DS brain, we have utilized an in vitro model of TT2F mouse embryonic stem cells containing a single human chromosome 21 (hChr21) to study neuron development and neuronal differentiation by microarray containing 15K developmentally expressed cDNAs. Defective neuronal differentiation in the presence of extra hChr21 manifested primarily the post-transcriptional and translational modification, such as Mrpl10, SNAPC3, Srprb, SF3a60 in the early neuronal stem cell stage, and Mrps18a, Eef1g, and Ubce8 in the late differentiated stage. Hierarchical clustering patterned specific expression of hChr21 gene dosage effects on neuron outgrowth, migration, and differentiation, such as Syngr2, Dncic2, Eif3sf, and Peg3.

Modeling motor neuron disease: the matter of time

NARCIS (Netherlands)

Arbab, Manda; Baars, S.E.; geijsen, n

2014-01-01

Stem cell technologies have created new opportunities to generate unlimited numbers of human neurons in the lab and study neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Although some disease hallmarks have been reported in patient-derived

Modeling motor neuron disease : the matter of time

NARCIS (Netherlands)

Arbab, Mandana; Baars, Susanne; Geijsen, Niels

2014-01-01

Stem cell technologies have created new opportunities to generate unlimited numbers of human neurons in the lab and study neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Although some disease hallmarks have been reported in patient-derived

Structural and functional deficits in a neuronal calcium sensor-1 mutant identified in a case of autistic spectrum disorder.

Directory of Open Access Journals (Sweden)

Mark T W Handley

2010-05-01

Full Text Available Neuronal calcium sensor-1 (NCS-1 is a Ca(2+ sensor protein that has been implicated in the regulation of various aspects of neuronal development and neurotransmission. It exerts its effects through interactions with a range of target proteins one of which is interleukin receptor accessory protein like-1 (IL1RAPL1 protein. Mutations in IL1RAPL1 have recently been associated with autism spectrum disorders and a missense mutation (R102Q on NCS-1 has been found in one individual with autism. We have examined the effect of this mutation on the structure and function of NCS-1. From use of NMR spectroscopy, it appeared that the R102Q affected the structure of the protein particularly with an increase in the extent of conformational exchange in the C-terminus of the protein. Despite this change NCS-1(R102Q did not show changes in its affinity for Ca(2+ or binding to IL1RAPL1 and its intracellular localisation was unaffected. Assessment of NCS-1 dynamics indicated that it could rapidly cycle between cytosolic and membrane pools and that the cycling onto the plasma membrane was specifically changed in NCS-1(R102Q with the loss of a Ca(2+ -dependent component. From these data we speculate that impairment of the normal cycling of NCS-1 by the R102Q mutation could have subtle effects on neuronal signalling and physiology in the developing and adult brain.

Nerve Growth Factor Gene Therapy Activates Neuronal Responses in Alzheimer’s Disease

Science.gov (United States)

Tuszynski, Mark H.; Yang, Jennifer H.; Barba, David; U, H S.; Bakay, Roy; Pay, Mary M.; Masliah, Eliezer; Conner, James M.; Kobalka, Peter; Roy, Subhojit; Nagahara, Alan H.

2016-01-01

IMPORTANCE Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and lacks effective disease modifying therapies. In 2001 we initiated a clinical trial of Nerve Growth Factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in AD patients. We present post-mortem findings in 10 subjects with survival times ranging from 1 to 10 years post-treatment. OBJECTIVE To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset. DESIGN, SETTING, AND PARTICIPANTS 10 patients with early AD underwent NGF gene therapy using either ex vivo or in vivo gene transfer. The brains of all eight patients in the first Phase 1 ex vivo trial and two patients in a subsequent Phase 1 in vivo trial were examined. MAIN OUTCOME MEASURES Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In two cases, NGF protein levels were measured by ELISA. RESULTS Degenerating neurons in the AD brain respond to NGF. All patients exhibited a trophic response to NGF, in the form of axonal sprouting toward the NGF source. Comparing treated and non-treated sides of the brain in three patients that underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P>0.05). Activation of cellular signaling and functional markers were present in two patients that underwent AAV2-mediated NGF gene transfer. Neurons exhibiting tau pathology as well as neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes with resulting activation of cell signaling. No adverse pathological effects related to NGF were observed. CONCLUSIONS AND RELEVANCE These findings indicate that

Possible Links among Mirror Neurons and Genes Related to Autism

OpenAIRE

MOCHIZUKI, Mai; 望月，麻衣

2016-01-01

Autism includes many neurodevelopmental disorders and defi cits in communication. Althoughresearchers have considered various origins, the onset mechanism is still not clear. The aim ofthis article is to provide some clues for interaction of autism with mirror neuronal and geneticfactors. First, the impact of neural brain cells considered to infl uence autism will be discussedwith reference to mirror neurons. Then, the discussion will move to genes related to autism.Consequently, it is argued...

Spiral Waves and Multiple Spatial Coherence Resonances Induced by Colored Noise in Neuronal Network

International Nuclear Information System (INIS)

Tang Zhao; Li Yuye; Xi Lei; Jia Bing; Gu Huaguang

2012-01-01

Gaussian colored noise induced spatial patterns and spatial coherence resonances in a square lattice neuronal network composed of Morris-Lecar neurons are studied. Each neuron is at resting state near a saddle-node bifurcation on invariant circle, coupled to its nearest neighbors by electronic coupling. Spiral waves with different structures and disordered spatial structures can be alternately induced within a large range of noise intensity. By calculating spatial structure function and signal-to-noise ratio (SNR), it is found that SNR values are higher when the spiral structures are simple and are lower when the spatial patterns are complex or disordered, respectively. SNR manifest multiple local maximal peaks, indicating that the colored noise can induce multiple spatial coherence resonances. The maximal SNR values decrease as the correlation time of the noise increases. These results not only provide an example of multiple resonances, but also show that Gaussian colored noise play constructive roles in neuronal network. (general)

To Ingest or Rest? Specialized Roles of Lateral Hypothalamic Area Neurons in Coordinating Energy Balance

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Juliette A. Brown

2015-02-01

Full Text Available Survival depends on an organism’s ability to sense nutrient status and accordingly regulate intake and energy expenditure behaviors. Uncoupling of energy sensing and behavior, however, underlies energy balance disorders such as anorexia or obesity. The hypothalamus regulates energy balance, and in particular the lateral hypothalamic area (LHA is poised to coordinate peripheral cues of energy status and behaviors that impact weight, such as drinking, locomotor behavior, arousal/sleep and autonomic output. There are several populations of LHA neurons that are defined by their neuropeptide content and contribute to energy balance. LHA neurons that express the neuropeptides melanin-concentrating hormone (MCH or orexins/hypocretins (OX are best characterized and these neurons play important roles in regulating ingestion, arousal, locomotor behavior and autonomic function via distinct neuronal circuits. Recently, another population of LHA neurons containing the neuropeptide Neurotensin (Nts has been implicated in coordinating anorectic stimuli and behavior to regulate hydration and energy balance. Understanding the specific roles of MCH, OX and Nts neurons in harmonizing energy sensing and behavior thus has the potential to inform pharmacological strategies to modify behaviors and treat energy balance disorders.

Alteration of protein folding and degradation in motor neuron diseases : Implications and protective functions of small heat shock proteins

NARCIS (Netherlands)

Carra, Serena; Crippa, Valeria; Rusmini, Paola; Boncoraglio, Alessandra; Minoia, Melania; Giorgetti, Elisa; Kampinga, Harm H.; Poletti, Angelo

Motor neuron diseases (MNDs) are neurodegenerative disorders that specifically affect the survival and function of upper and/or lower motor neurons. Since motor neurons are responsible for the control of voluntary muscular movement, MNDs are characterized by muscle spasticity, weakness and atrophy.

Effects of tamoxifen on neuronal morphology, connectivity and biochemistry of hypothalamic ventromedial neurons: Impact on the modulators of sexual behavior.

Science.gov (United States)

Sá, Susana I; Teixeira, Natércia; Fonseca, Bruno M

2018-01-01

Tamoxifen (TAM) is a selective estrogen receptor modulator, widely used in the treatment and prevention of estrogen-dependent breast cancer. Although with great clinical results, women on TAM therapy still report several side effects, such as sexual dysfunction, which impairs quality of life. The anatomo-functional substrates of the human sexual behavior are still unknown; however, these same substrates are very well characterized in the rodent female sexual behavior, which has advantage of being a very simple reflexive response, dependent on the activation of estrogen receptors (ERs) in the ventrolateral division of the hypothalamic ventromedial nucleus (VMNvl). In fact, in the female rodent, the sexual behavior is triggered by increasing circulation levels of estradiol that changes the nucleus neurochemistry and modulates its intricate neuronal network. Therefore, we considered of notice the examination of the possible neurochemical alterations and the synaptic plasticity impairment in VMNvl neurons of estradiol-primed female rats treated with TAM that may be in the basis of this neurological disorder. Accordingly, we used stereological and biochemical methods to study the action of TAM in axospinous and axodendritic synaptic plasticity and on ER expression. The administration of TAM changed the VMNvl neurochemistry by reducing ERα mRNA and increasing ERβ mRNA expression. Furthermore, present results show that TAM induced neuronal atrophy and reduced synaptic connectivity, favoring electrical inactivity. These data suggest that these cellular and molecular changes may be a possible neuronal mechanism of TAM action in the disruption of the VMNvl network, leading to the development of behavioral disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

Postoperative conversion disorder.

Science.gov (United States)

Afolabi, Kola; Ali, Sameer; Gahtan, Vivian; Gorji, Reza; Li, Fenghua; Nussmeier, Nancy A

2016-05-01

Conversion disorder is a psychiatric disorder in which psychological stress causes neurologic deficits. A 28-year-old female surgical patient had uneventful general anesthesia and emergence but developed conversion disorder 1 hour postoperatively. She reported difficulty speaking, right-hand numbness and weakness, and right-leg paralysis. Neurologic examination and imaging revealed no neuronal damage, herniation, hemorrhage, or stroke. The patient mentioned failing examinations the day before surgery and discontinuing her prescribed antidepressant medication, leading us to diagnose conversion disorder, with eventual confirmation by neuroimaging and follow-up examinations. Copyright © 2016 Elsevier Inc. All rights reserved.

In vivo tracking of neuronal-like cells by magnetic resonance in rabbit models of spinal cord injury

Science.gov (United States)

Zhang, Ruiping; Zhang, Kun; Li, Jianding; Liu, Qiang; Xie, Jun

2013-01-01

In vitro experiments have demonstrated that neuronal-like cells derived from bone marrow mesenchymal stem cells can survive, migrate, integrate and help to restore the function and behaviors of spinal cord injury models, and that they may serve as a suitable approach to treating spinal cord injury. However, it is very difficult to track transplanted cells in vivo. In this study, we injected superparamagnetic iron oxide-labeled neuronal-like cells into the subarachnoid space in a rabbit model of spinal cord injury. At 7 days after cell transplantation, a small number of dot-shaped low signal intensity shadows were observed in the spinal cord injury region, and at 14 days, the number of these shadows increased on T2-weighted imaging. Perl's Prussian blue staining detected dot-shaped low signal intensity shadows in the spinal cord injury region, indicative of superparamagnetic iron oxide nanoparticle-labeled cells. These findings suggest that transplanted neuronal-like cells derived from bone marrow mesenchymal stem cells can migrate to the spinal cord injury region and can be tracked by magnetic resonance in vivo. Magnetic resonance imaging represents an efficient noninvasive technique for visually tracking transplanted cells in vivo. PMID:25206659

Detection and Characterization of Autoantibodies to Neuronal Cell-Surface Antigens in the Central Nervous System

Directory of Open Access Journals (Sweden)

Marleen eVan Coevorden-Hameete

2016-05-01

Full Text Available Autoimmune encephalitis (AIE is a group of disorders in which autoantibodies directed at antigens located on the plasma membrane of neurons induce severe neurological symptoms. In contrast to classical paraneoplastic disorders, AIE patients respond well to immunotherapy. The detection of neuronal surface autoantibodies in patients’ serum or CSF therefore has serious consequences for the patients’ treatment and follow-up and requires the availability of sensitive and specific diagnostic tests. This mini-review provides a guideline for both diagnostic and research laboratories that work on the detection of known surface autoantibodies and/or the identification of novel surface antigens. We discuss the strengths and pitfalls of different techniques for anti-neuronal antibody detection: 1 Immunohistochemistry and immunofluorescence on rat/ primate brain sections, 2 Immunocytochemistry of living cultured hippocampal neurons, 3 Cell Based Assay (CBA. In addition, we discuss the use of immunoprecipitation and mass spectrometry analysis for the detection of novel neuronal surface antigens, which is a crucial step in further disease classification and the development of novel CBAs.

N-acetyl-aspartate (NAA) as a correlate of pharmacological treatment in psychiatric disorders: a systematic review.

Science.gov (United States)

Paslakis, Georgios; Träber, Frank; Roberz, Jens; Block, Wolfgang; Jessen, Frank

2014-10-01

The amino-acid N-acetyl-aspartate (NAA) is located in neurons and the concentration of NAA correlates with neuronal mitochondrial function. The signal of NAA, as measured with proton magnetic resonance spectroscopy (1H-MRS), is considered to reflect both, neuronal density and integrity of neuronal mitochondria. A reduction of the NAA concentrations has been found in several psychiatric disorders. Newer studies report reversal of decreased NAA concentration with treatment. The objective of this review is to summarize the literature on NAA changes in association with psychopharmacological treatment in psychiatric disorders (affective disorders, obsessive-compulsive disorder, schizophrenia and dementia). The majority of studies identified increased NAA concentrations in response to treatment, while a smaller number of studies did not find this effect. The NAA increase seems to be neither specific for a certain disorder nor for a specific intervention. This suggests that the reduction of NAA may represent an altered functional (metabolic) state of neurons common to different psychiatric disorders and the increase after treatment to indicate functional restoration as one general effect of interventions. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

NKCC1 controls GABAergic signaling and neuroblast migration in the postnatal forebrain

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Murray Kerren

2011-02-01

Full Text Available Abstract From an early postnatal period and throughout life there is a continuous production of olfactory bulb (OB interneurons originating from neuronal precursors in the subventricular zone. To reach the OB circuits, immature neuroblasts migrate along the rostral migratory stream (RMS. In the present study, we employed cultured postnatal mouse forebrain slices and used lentiviral vectors to label neuronal precursors with GFP and to manipulate the expression levels of the Na-K-2Cl cotransporter NKCC1. We investigated the role of this Cl- transporter in different stages of postnatal neurogenesis, including neuroblast migration and integration in the OB networks once they have reached the granule cell layer (GCL. We report that NKCC1 activity is necessary for maintaining normal migratory speed. Both pharmacological and genetic manipulations revealed that NKCC1 maintains high [Cl-]i and regulates the resting membrane potential of migratory neuroblasts whilst its functional expression is strongly reduced at the time cells reach the GCL. As in other developing systems, NKCC1 shapes GABAA-dependent signaling in the RMS neuroblasts. Also, we show that NKCC1 controls the migration of neuroblasts in the RMS. The present study indeed indicates that the latter effect results from a novel action of NKCC1 on the resting membrane potential, which is independent of GABAA-dependent signaling. All in all, our findings show that early stages of the postnatal recruitment of OB interneurons rely on precise, orchestrated mechanisms that depend on multiple actions of NKCC1.

A small population of hypothalamic neurons govern fertility: the critical role of VAX1 in GnRH neuron development and fertility maintenance.

Science.gov (United States)

Hoffmann, Hanne M; Mellon, Pamela L

2016-01-01

Fertility depends on the correct maturation and function of approximately 800 gonadotropin-releasing hormone (GnRH) neurons in the brain. GnRH neurons are at the apex of the hypothalamic-pituitary-gonadal axis that regulates fertility. In adulthood, GnRH neurons are scattered throughout the anterior hypothalamic area and project to the median eminence, where GnRH is released into the portal vasculature to stimulate release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. LH and FSH then regulate gonadal steroidogenesis and gametogenesis. Absence of GnRH neurons or inappropriate GnRH release leads to infertility. Despite the critical role of GnRH neurons in fertility, we still have a limited understanding of the genes responsible for proper GnRH neuron development and function in adulthood. GnRH neurons originate in the olfactory placode then migrate into the brain. Homeodomain transcription factors expressed within GnRH neurons or along their migratory path are candidate genes for inherited infertility. Using a combined in vitro and in vivo approach, we have identified Ventral Anterior Homeobox 1 ( Vax1 ) as a novel homeodomain transcription factor responsible for GnRH neuron maturation and fertility. GnRH neuron counts in Vax1 knock-out embryos revealed Vax1 to be required for the presence of GnRH-expressing cells at embryonic day 17.5 (E17.5), but not at E13.5. To localize the effects of Vax1 on fertility, we generated Vax1 flox mice and crossed them with Gnrh cre mice to specifically delete Vax1 within GnRH neurons. GnRH staining in Vax1 flox/flox :GnRH cre mice show a total absence of GnRH expression in the adult. We performed lineage tracing in Vax1 flox/flox :GnRH cre :RosaLacZ mice which proved GnRH neurons to be alive, but incapable of expressing GnRH. The absence of GnRH leads to delayed puberty, hypogonadism and complete infertility in both sexes. Finally, using the immortalized model GnRH neuron cell lines, GN11 and

ENA/VASP downregulation triggers cell death by impairing axonal maintenance in hippocampal neurons.

Science.gov (United States)

Franco, D Lorena; Rezával, Carolina; Cáceres, Alfredo; Schinder, Alejandro F; Ceriani, M Fernanda

2010-06-01

Neurodegenerative diseases encompass a broad variety of motor and cognitive disorders that are accompanied by death of specific neuronal populations or brain regions. Cellular and molecular mechanisms underlying these complex disorders remain largely unknown. In a previous work we searched for novel Drosophila genes relevant for neurodegeneration and singled out enabled (ena), which encodes a protein involved in cytoskeleton remodeling. To extend our understanding on the mechanisms of ENA-triggered degeneration we now investigated the effect of silencing ena ortholog genes in mouse hippocampal neurons. We found that ENA/VASP downregulation led to neurite retraction and concomitant neuronal cell death through an apoptotic pathway. Remarkably, this retraction initially affected the axonal structure, showing no effect on dendrites. Reduction in ENA/VASP levels blocked the neuritogenic effect of a specific RhoA kinase (ROCK) inhibitor, thus suggesting that these proteins could participate in the Rho-signaling pathway. Altogether these observations demonstrate that ENA/VASP proteins are implicated in the establishment and maintenance of the axonal structure and that a change on their expression levels triggers neuronal degeneration. 2010 Elsevier Inc. All rights reserved.

Deleterious effects of neuronal accumulation of glycogen in flies and mice

OpenAIRE

Duran, Jordi; Tevy, María Florencia; Garcia-Rocha, Mar; Calbó, Joaquim; Milán, Marco; Guinovart, Joan J

2012-01-01

Under physiological conditions, most neurons keep glycogen synthase (GS) in an inactive form and do not show detectable levels of glycogen. Nevertheless, aberrant glycogen accumulation in neurons is a hallmark of patients suffering from Lafora disease or other polyglucosan disorders. Although these diseases are associated with mutations in genes involved in glycogen metabolism, the role of glycogen accumulation remains elusive. Here, we generated mouse and fly models expressing an active form...

Identification of distinct telencephalic progenitor pools for neuronal diversity in the amygdala.

Science.gov (United States)

Hirata, Tsutomu; Li, Peijun; Lanuza, Guillermo M; Cocas, Laura A; Huntsman, Molly M; Corbin, Joshua G

2009-02-01

The development of the amygdala, a central structure of the limbic system, remains poorly understood. We found that two spatially distinct and early-specified telencephalic progenitor pools marked by the homeodomain transcription factor Dbx1 are major sources of neuronal cell diversity in the mature mouse amygdala. We found that Dbx1-positive cells of the ventral pallium generate the excitatory neurons of the basolateral complex and cortical amygdala nuclei. Moreover, Dbx1-derived cells comprise a previously unknown migratory stream that emanates from the preoptic area (POA), a ventral telencephalic domain adjacent to the diencephalic border. The Dbx1-positive, POA-derived population migrated specifically to the amygdala and, as defined by both immunochemical and electrophysiological criteria, generated a unique subclass of inhibitory neurons in the medial amygdala nucleus. Thus, this POA-derived population represents a previously unknown progenitor pool dedicated to the limbic system.

Atypical cross talk between mentalizing and mirror neuron networks in autism spectrum disorder.

Science.gov (United States)

Fishman, Inna; Keown, Christopher L; Lincoln, Alan J; Pineda, Jaime A; Müller, Ralph-Axel

2014-07-01

Converging evidence indicates that brain abnormalities in autism spectrum disorder (ASD) involve atypical network connectivity, but it is unclear whether altered connectivity is especially prominent in brain networks that participate in social cognition. To investigate whether adolescents with ASD show altered functional connectivity in 2 brain networks putatively impaired in ASD and involved in social processing, theory of mind (ToM) and mirror neuron system (MNS). Cross-sectional study using resting-state functional magnetic resonance imaging involving 25 adolescents with ASD between the ages of 11 and 18 years and 25 typically developing adolescents matched for age, handedness, and nonverbal IQ. Statistical parametric maps testing the degree of whole-brain functional connectivity and social functioning measures. Relative to typically developing controls, participants with ASD showed a mixed pattern of both over- and underconnectivity in the ToM network, which was associated with greater social impairment. Increased connectivity in the ASD group was detected primarily between the regions of the MNS and ToM, and was correlated with sociocommunicative measures, suggesting that excessive ToM-MNS cross talk might be associated with social impairment. In a secondary analysis comparing a subset of the 15 participants with ASD with the most severe symptomology and a tightly matched subset of 15 typically developing controls, participants with ASD showed exclusive overconnectivity effects in both ToM and MNS networks, which were also associated with greater social dysfunction. Adolescents with ASD showed atypically increased functional connectivity involving the mentalizing and mirror neuron systems, largely reflecting greater cross talk between the 2. This finding is consistent with emerging evidence of reduced network segregation in ASD and challenges the prevailing theory of general long-distance underconnectivity in ASD. This excess ToM-MNS connectivity may reflect

Diversity in the neuronal machine: order and variability in interneuronal microcircuits

National Research Council Canada - National Science Library

Soltesz, Ivan

2006-01-01

... Disorders 42 3: Order in Diversity: From Phenomenology to Function 45 Diversity at Multiple Levels of Neuronal Organization 45 Linnean Order in Diversity: A Modern Compendium of Interneuronal Spe...

Storage and Effective Migration of Li-Ion for Defected β-LiFePO4 Phase Nanocrystals.

Science.gov (United States)

Guo, Hua; Song, Xiaohe; Zhuo, Zengqing; Hu, Jiangtao; Liu, Tongchao; Duan, Yandong; Zheng, Jiaxin; Chen, Zonghai; Yang, Wanli; Amine, Khalil; Pan, Feng

2016-01-13

Lithium iron phosphate, a widely used cathode material, crystallizes typically in olivine-type phase, α-LiFePO4 (αLFP). However, the new phase β-LiFePO4 (βLFP), which can be transformed from αLFP under high temperature and pressure, is originally almost electrochemically inactive with no capacity for Li-ion battery, because the Li-ions are stored in the tetrahedral [LiO4] with very high activation barrier for migration and the one-dimensional (1D) migration channels for Li-ion diffusion in αLFP disappear, while the Fe ions in the β-phase are oriented similar to the 1D arrangement instead. In this work, using experimental studies combined with density functional theory calculations, we demonstrate that βLFP can be activated with creation of effective paths of Li-ion migration by optimized disordering. Thus, the new phase of βLFP cathode achieved a capacity of 128 mAh g(-1) at a rate of 0.1 C (1C = 170 mA g(-1)) with extraordinary cycling performance that 94.5% of the initial capacity retains after 1000 cycles at 1 C. The activation mechanism can be attributed to that the induced disorder (such as FeLiLiFe antisite defects, crystal distortion, and amorphous domains) creates new lithium migration passages, which free the captive stored lithium atoms and facilitate their intercalation/deintercalation from the cathode. Such materials activated by disorder are promising candidate cathodes for lithium batteries, and the related mechanism of storage and effective migration of Li-ions also provides new clues for future design of disordered-electrode materials with high capacity and high energy density.

Neurons Containing Orexin or Melanin Concentrating Hormone Reciprocally Regulate Wake and Sleep

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Roda Rani eKonadhode

2015-01-01

Full Text Available There is considerable amount of data on arousal neurons whereas there is a paucity of knowledge regarding neurons that make us fall asleep. Indeed, current network models of sleep-wake regulation list many arousal neuronal populations compared to only one sleep group located in the preoptic area. There are neurons outside the preoptic area that are active during sleep, but they have never been selectively manipulated. Indeed, none of the sleep-active neurons have been selectively stimulated. To close this knowledge gap we used optogenetics to selectively manipulate neurons containing melanin concentrating hormone (MCH. The MCH neurons are located in the posterior hypothalamus intermingled with the orexin arousal neurons. Our data indicated that optogenetic stimulation of MCH neurons in wildtype mice (J Neuroscience, 2013 robustly increased both non-REM and REM sleep. MCH neuron stimulation increased sleep during the animal’s normal active period, which is compelling evidence that stimulation of MCH neurons has a powerful effect in counteracting the strong arousal signal from all of the arousal neurons. The MCH neurons represent the only group of sleep-active neurons that when selectively stimulated induce sleep. From a translational perspective this is potentially useful in sleep disorders, such as insomnia, where sleep needs to be triggered against a strong arousal drive. Our studies indicate that the MCH neurons belong within an overall model of sleep-wake regulation.

Quantitative analysis of intraneuronal transport in human iPS neurons

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Haruko Nakamura

2015-08-01

Full Text Available Induced pluripotent stem (iPS cells are promising tools to investigate disease mechanism and develop new drugs. Intraneuronal transport, which is fundamental for neuronal survival and function, is vulnerable to various pharmacological and chemical agents and is disrupted in some neurodegenerative disorders. We applied a quantification method for axonal transport by counting CM-DiI–labeled particles traveling along the neurite, which allowed us to monitor and quantitate, for the first time, intraneuronal transport in human neurons differentiated from iPS cells (iCell neurons. We evaluated the acute effects of several anti-neoplastic agents that have been previously shown to affect intraneuronal transport. Vincristine, paclitaxel and oxaliplatin decreased the number of moving particle along neurites. Cisplatin, however, produced no effect on intraneuronal transport, which is in contrast to our previous report indicating that it inhibits transport in chick dorsal root ganglion neurons. Our system may be a useful method for assessing intraneuronal transport and neurotoxicity in human iPS neurons.

Macrophage migration inhibitory factor as an incriminating agent in vitiligo.

Science.gov (United States)

Farag, Azza Gaber Antar; Hammam, Mostafa Ahmed; Habib, Mona SalahEldeen; Elnaidany, Nada Farag; Kamh, Mona Eaid

2018-03-01

Vitiligo is an autoimmune skin disorder in which the loss of melanocytes is mainly attributed to defective autoimmune mechanisms and, lately, there has been more emphasis on autoinflammatory mediators. Among these is the macrophage migration inhibitory factor, which is involved in many autoimmune skin diseases. However, little is known about the contribution of this factor to vitiligo vulgaris. To determine the hypothesized role of migration inhibitory factor in vitiligo via estimation of serum migration inhibitory factor levels and migration inhibitory factor mRNA concentrations in patients with vitiligo compared with healthy controls. We also aimed to assess whether there is a relationship between the values of serum migration inhibitory factor and/or migration inhibitory factor mRNA with disease duration, clinical type and severity in vitiligo patients. Evaluation of migration inhibitory factor serum level and migration inhibitory factor mRNA expression by ELISA and real-time PCR, respectively, were performed for 50 patients with different degrees of vitiligo severity and compared to 15 age- and gender-matched healthy volunteers as controls. There was a highly significant increase in serum migration inhibitory factor and migration inhibitory factor mRNA levels in vitiligo cases when compared to controls (pvitiligo patients, and each of them with duration and severity of vitiligo. In addition, patients with generalized vitiligo have significantly elevated serum migration inhibitory factor and mRNA levels than control subjects. Small number of investigated subjects. Migration inhibitory factor may have an active role in the development of vitiligo, and it may also be a useful index of disease severity. Consequently, migration inhibitory factor may be a new treatment target for vitiligo patients.

Inhibition of glycogen synthase kinase-3 reduces extension of the axonal leading process by destabilizing microtubules in cerebellar granule neurons.

Science.gov (United States)

Inami, Yoshihiro; Omura, Mitsuru; Kubota, Kenta; Konishi, Yoshiyuki

2018-07-01

Recent studies have uncovered various molecules that play key roles in neuronal morphogenesis. Nevertheless, the mechanisms underlying the neuron-type-dependent regulation of morphogenesis remain unknown. We have previously reported that inhibition of glycogen synthase kinase-3 (GSK3) markedly reduced axonal length of cerebellar granule neurons (CGNs) in a neuron-type-dependent manner. In the present study, we investigated the mechanisms by which the growth of CGN axons was severely suppressed upon GSK3 inhibition. Using time-lapse imaging of cultured CGNs at early morphogenesis, we found that extension of the leading process was severely inhibited by the pharmacological inhibition of GSK3. The rate of somal migration was also reduced with a GSK3 inhibitor in dissociated culture as well as in microexplant culture. In addition, CGNs ectopically expressed with a catalytically inactive mutant of GSK3 exhibited a migration defect in vivo. In axonal leading processes of CGNs, detyrosination and acetylation of α-tubulin, which are known to correlate with microtubule stability, were decreased by GSK3 inhibition. A photoconversion analysis found that inhibition of GSK3 increases the turnover of microtubules. Furthermore, in the presence of paclitaxel, a microtubule-stabilizing reagent, inhibition of GSK3 recovered the axonal leading process extension that was reduced by paclitaxel. Our results suggest that GSK3 supports the extension of axonal processes by stabilizing microtubules, contrary to its function in other neuron-types, lending mechanical insight into neuron-type-dependent morphological regulation. Copyright © 2018 Elsevier B.V. All rights reserved.

Neuronal Entropy-Rate Feature of Entopeduncular Nucleus in Rat Model of Parkinson's Disease.

Science.gov (United States)

Darbin, Olivier; Jin, Xingxing; Von Wrangel, Christof; Schwabe, Kerstin; Nambu, Atsushi; Naritoku, Dean K; Krauss, Joachim K; Alam, Mesbah

2016-03-01

The function of the nigro-striatal pathway on neuronal entropy in the basal ganglia (BG) output nucleus, i.e. the entopeduncular nucleus (EPN) was investigated in the unilaterally 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD). In both control subjects and subjects with 6-OHDA lesion of dopamine (DA) the nigro-striatal pathway, a histological hallmark for parkinsonism, neuronal entropy in EPN was maximal in neurons with firing rates ranging between 15 and 25 Hz. In 6-OHDA lesioned rats, neuronal entropy in the EPN was specifically higher in neurons with firing rates above 25 Hz. Our data establishes that the nigro-striatal pathway controls neuronal entropy in motor circuitry and that the parkinsonian condition is associated with abnormal relationship between firing rate and neuronal entropy in BG output nuclei. The neuronal firing rates and entropy relationship provide putative relevant electrophysiological information to investigate the sensory-motor processing in normal condition and conditions such as movement disorders.

Positive modulation of delta-subunit containing GABAA receptors in mouse neurons

DEFF Research Database (Denmark)

Vardya, Irina; Hoestgaard-Jensen, Kirsten; Nieto-Gonzalez, Jose Luis

2012-01-01

δ-subunit containing extrasynaptic GABA(A) receptors are potential targets for modifying neuronal activity in a range of brain disorders. With the aim of gaining more insight in synaptic and extrasynaptic inhibition, we used a new positive modulator, AA29504, of δ-subunit containing GABA(A) recep......δ-subunit containing extrasynaptic GABA(A) receptors are potential targets for modifying neuronal activity in a range of brain disorders. With the aim of gaining more insight in synaptic and extrasynaptic inhibition, we used a new positive modulator, AA29504, of δ-subunit containing GABA......(A) receptors in mouse neurons in vitro and in vivo. Whole-cell patch-clamp recordings were carried out in the dentate gyrus in mouse brain slices. In granule cells, AA29504 (1 μM) caused a 4.2-fold potentiation of a tonic current induced by THIP (1 μM), while interneurons showed a potentiation of 2.6-fold......-free environment using Ca²⁺ imaging in cultured neurons, AA29504 showed GABA(A) receptor agonism in the absence of agonist. Finally, AA29504 exerted dose-dependent stress-reducing and anxiolytic effects in mice in vivo. We propose that AA29504 potentiates δ-containing GABA(A) receptors to enhance tonic inhibition...

Chemogenetic activation of dopamine neurons in the ventral tegmental area, but not substantia nigra, induces hyperactivity in rats

NARCIS (Netherlands)

Boekhoudt, Linde; Omrani, Azar; Luijendijk, Mieneke C M; Wolterink-Donselaar, Inge G; Wijbrans, Ellen C; van der Plasse, Geoffrey; Adan, Roger A H

2016-01-01

Hyperactivity is a core symptom in various psychiatric disorders, including attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorders, and anorexia nervosa. Although hyperactivity has been linked to dopaminergic  signalling, the causal relationship between midbrain dopamine neuronal

Characterization of neurons from immortalized dental pulp stem cells for the study of neurogenetic disorders

Directory of Open Access Journals (Sweden)

Nora Urraca

2015-11-01

Full Text Available A major challenge to the study and treatment of neurogenetic syndromes is accessing live neurons for study from affected individuals. Although several sources of stem cells are currently available, acquiring these involve invasive procedures, may be difficult or expensive to generate and are limited in number. Dental pulp stem cells (DPSCs are multipotent stem cells that reside deep the pulp of shed teeth. To investigate the characteristics of DPSCs that make them a valuable resource for translational research, we performed a set of viability, senescence, immortalization and gene expression studies on control DPSC and derived neurons. We investigated the basic transport conditions and maximum passage number for primary DPSCs. We immortalized control DPSCs using human telomerase reverse transcriptase (hTERT and evaluated neuronal differentiation potential and global gene expression changes by RNA-seq. We show that neurons from immortalized DPSCs share morphological and electrophysiological properties with non-immortalized DPSCs. We also show that differentiation of DPSCs into neurons significantly alters gene expression for 1305 transcripts. Here we show that these changes in gene expression are concurrent with changes in protein levels of the transcriptional repressor REST/NRSF, which is known to be involved in neuronal differentiation. Immortalization significantly altered the expression of 183 genes after neuronal differentiation, 94 of which also changed during differentiation. Our studies indicate that viable DPSCs can be obtained from teeth stored for ≥72 h, these can then be immortalized and still produce functional neurons for in vitro studies, but that constitutive hTERT immortalization is not be the best approach for long term use of patient derived DPSCs for the study of disease.

Retinoic acid reduces human neuroblastoma cell migration and invasiveness: effects on DCX, LIS1, neurofilaments-68 and vimentin expression

International Nuclear Information System (INIS)

Messi, Elio; Florian, Maria C; Caccia, Claudio; Zanisi, Mariarosa; Maggi, Roberto

2008-01-01

Neuroblastoma is a severe pediatric tumor, histologically characterised by a variety of cellular phenotypes. One of the pharmacological approaches to neuroblastoma is the treatment with retinoic acid. The mechanism of action of retinoic acid is still unclear, and the development of resistance to this differentiating agent is a great therapy problem. Doublecortin, a microtubule-associated protein involved in neuronal migration, has recently been proposed as a molecular marker for the detection of minimal residual disease in human neuroblastoma. Nevertheless, no information is available on the expression of doublecortin in the different cell-types composing human neuroblastoma, its correlation with neuroblastoma cell motility and invasiveness, and the possible modulations exerted by retinoic acid treatment. We analysed by immunofluorescence and by Western blot analysis the presence of doublecortin, lissencephaly-1 (another protein involved in neuronal migration) and of two intermediate filaments proteins, vimentin and neurofilament-68, in SK-N-SH human neuroblastoma cell line both in control conditions and under retinoic acid treatment. Migration and cell invasiveness studies were performed by wound scratch test and a modified microchemotaxis assay, respectively. Doublecortin is expressed in two cell subtypes considered to be the more aggressive and that show high migration capability and invasiveness. Vimentin expression is excluded by these cells, while lissencephaly-1 and neurofilaments-68 are immunodetected in all the cell subtypes of the SK-N-SH cell line. Treatment with retinoic acid reduces cell migration and invasiveness, down regulates doublecortin and lissencephaly-1 expression and up regulates neurofilament-68 expression. However, some cells that escape from retinoic acid action maintain migration capability and invasiveness and express doublecortin. a) Doublecortin is expressed in human neuroblastoma cells that show high motility and invasiveness; b

Cadherin-8 expression, synaptic localization, and molecular control of neuronal form in prefrontal corticostriatal circuits.

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Friedman, Lauren G; Riemslagh, Fréderike W; Sullivan, Josefa M; Mesias, Roxana; Williams, Frances M; Huntley, George W; Benson, Deanna L

2015-01-01

Neocortical interactions with the dorsal striatum support many motor and executive functions, and such underlying functional networks are particularly vulnerable to a variety of developmental, neurological, and psychiatric brain disorders, including autism spectrum disorders, Parkinson's disease, and Huntington's disease. Relatively little is known about the development of functional corticostriatal interactions, and in particular, virtually nothing is known of the molecular mechanisms that control generation of prefrontal cortex-striatal circuits. Here, we used regional and cellular in situ hybridization techniques coupled with neuronal tract tracing to show that Cadherin-8 (Cdh8), a homophilic adhesion protein encoded by a gene associated with autism spectrum disorders and learning disability susceptibility, is enriched within striatal projection neurons in the medial prefrontal cortex and in striatal medium spiny neurons forming the direct or indirect pathways. Developmental analysis of quantitative real-time polymerase chain reaction and western blot data show that Cdh8 expression peaks in the prefrontal cortex and striatum at P10, when cortical projections start to form synapses in the striatum. High-resolution immunoelectron microscopy shows that Cdh8 is concentrated at excitatory synapses in the dorsal striatum, and Cdh8 knockdown in cortical neurons impairs dendritic arborization and dendrite self-avoidance. Taken together, our findings indicate that Cdh8 delineates developing corticostriatal circuits where it is a strong candidate for regulating the generation of normal cortical projections, neuronal morphology, and corticostriatal synapses. © 2014 Wiley Periodicals, Inc.

The diagnostic value of clinical EEG in detecting abnormal synchronicity in panic disorder.

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Adamaszek, Michael; Olbrich, Sebastian; Gallinat, Jürgen

2011-07-01

Electroencephalographic (EEG) findings repeatedly reported abnormal synchronous or even epileptiform discharges in panic disorder. Although less frequently occurring in patients with panic disorder, these deviant EEG features during panic attacks were also observed in intracranial EEG. For this purpose, our article reviews the consideration of abnormal synchronous neuronal activity in different neurocircuits, particularly limbic, as a suggested condition of panic attacks. Therapeutic approaches of anticonvulsants have shown reductions of symptoms and frequency of attacks in numerous patients suffering from panic disorder, supporting the presumption of underlying abnormal synchronous neuronal activity. Thus, scalp EEG recordings are still recommended for discovering indications of abnormal synchronous neuronal activity in panic patients.

The challenges of dysphagia in treating motor neurone disease.

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Vesey, Siobhan

2017-07-01

Motor neurone disease (MND) is a relatively rare degenerative disorder. Its impacts are manifested in progressive loss of motor function and often accompanied by wider non-motor changes. Swallowing and speech abilities are frequently severely impaired. Effective management of dysphagia (swallowing difficulty) symptoms and nutritional care requires a holistic multidisciplinary approach. Care must be patient focused, facilitate patient decision making, and support planning towards end of life care. This article discusses the challenges of providing effective nutritional care to people living with motor neurone disease who have dysphagia.

Neuronal Cell Death Induced by Mechanical Percussion Trauma in Cultured Neurons is not Preceded by Alterations in Glucose, Lactate and Glutamine Metabolism

DEFF Research Database (Denmark)

Jayakumar, A R; Bak, L K; Rama Rao, K V

2016-01-01

Traumatic brain injury (TBI) is a devastating neurological disorder that usually presents in acute and chronic forms. Brain edema and associated increased intracranial pressure in the early phase following TBI are major consequences of acute trauma. On the other hand, neuronal injury, leading to ...

Prevalence of serum anti-neuronal autoantibodies in patients admitted to acute psychiatric care

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Schou, M; Sæther, S G; Borowski, K

2016-01-01

BACKGROUND: Autoimmune encephalitis associated with anti-neuronal antibodies may be challenging to distinguish from primary psychiatric disorders. The significance of anti-neuronal antibodies in psychiatric patients without clear evidence of autoimmune encephalitis is unknown. We investigated...... the serum prevalence of six anti-neuronal autoantibodies in a cohort of unselected patients admitted to acute psychiatric care. METHOD: Serum was drawn from 925 patients admitted to acute psychiatric in-patient care. Psychiatric diagnoses were set according to International Classification of Diseases (ICD......)-10 criteria. Antibody analysis was performed with an indirect immunofluorescence test for N-methyl d-aspartate receptor (NMDAR) antibodies and five other anti-neuronal autoantibodies of the immunoglobulin (Ig) classes IgA, IgG and IgM isotype. RESULTS: Anti-neuronal autoantibodies were found in 11...

Activation of CRH receptor type 1 expressed on glutamatergic neurons increases excitability of CA1 pyramidal neurons by the modulation of voltage-gated ion channels

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Stephan eKratzer

2013-07-01

Full Text Available Corticotropin-releasing hormone (CRH plays an important role in a substantial number of patients with stress-related mental disorders, such as anxiety disorders and depression. CRH has been shown to increase neuronal excitability in the hippocampus, but the underlying mechanisms are poorly understood. The effects of CRH on neuronal excitability were investigated in acute hippocampal brain slices. Population spikes (PS and field excitatory postsynaptic potentials (fEPSP were evoked by stimulating Schaffer-collaterals and recorded simultaneously from the somatic and dendritic region of CA1 pyramidal neurons. CRH was found to increase PS amplitudes (mean  Standard error of the mean; 231.8  31.2% of control; n=10 while neither affecting fEPSPs (104.3 ± 4.2%; n=10 nor long-term potentiation (LTP. However, when Schaffer-collaterals were excited via action potentials (APs generated by stimulation of CA3 pyramidal neurons, CRH increased fEPSP amplitudes (119.8 ± 3.6%; n=8 and the magnitude of LTP in the CA1 region. Experiments in slices from transgenic mice revealed that the effect on PS amplitude is mediated exclusively by CRH receptor 1 (CRHR1 expressed on glutamatergic neurons. The effects of CRH on PS were dependent on phosphatase-2B, L- and T-type calcium channels and voltage-gated potassium channels but independent on intracellular Ca2+-elevation. In patch-clamp experiments, CRH increased the frequency and decay times of APs and decreased currents through A-type and delayed-rectifier potassium channels. These results suggest that CRH does not affect synaptic transmission per se, but modulates voltage-gated ion currents important for the generation of APs and hence elevates by this route overall neuronal activity.

Role of the Orexin/Hypocretin System in Stress-Related Psychiatric Disorders.

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James, Morgan H; Campbell, Erin J; Dayas, Christopher V

2017-01-01

Orexins (hypocretins) are critically involved in coordinating appropriate physiological and behavioral responses to aversive and threatening stimuli. Acute stressors engage orexin neurons via direct projections from stress-sensitive brain regions. Orexin neurons, in turn, facilitate adaptive behavior via reciprocal connections as well as via direct projections to the hypophysiotropic neurons that coordinate the hypothalamic-pituitary-adrenal (HPA) axis response to stress. Consequently, hyperactivity of the orexin system is associated with increased motivated arousal and anxiety, and is emerging as a key feature of panic disorder. Accordingly, there has been significant interest in the therapeutic potential of pharmacological agents that antagonize orexin signaling at their receptors for the treatment of anxiety disorders. In contrast, disorders characterized by inappropriately low levels of motivated arousal, such as depression, generally appear to be associated with hypoactivity of the orexin system. This includes narcolepsy with cataplexy, a disorder characterized by the progressive loss of orexin neurons and increased rates of moderate/severe depression symptomology. Here, we provide a comprehensive overview of both clinical and preclinical evidence highlighting the role of orexin signaling in stress reactivity, as well as how perturbations to this system can result in dysregulated behavioral phenotypes.

Prolonged Minocycline Treatment Impairs Motor Neuronal Survival and Glial Function in Organotypic Rat Spinal Cord Cultures

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Pinkernelle, Josephine; Fansa, Hisham; Ebmeyer, Uwe; Keilhoff, Gerburg

2013-01-01

Background Minocycline, a second-generation tetracycline antibiotic, exhibits anti-inflammatory and neuroprotective effects in various experimental models of neurological diseases, such as stroke, Alzheimer’s disease, amyotrophic lateral sclerosis and spinal cord injury. However, conflicting results have prompted a debate regarding the beneficial effects of minocycline. Methods In this study, we analyzed minocycline treatment in organotypic spinal cord cultures of neonatal rats as a model of motor neuron survival and regeneration after injury. Minocycline was administered in 2 different concentrations (10 and 100 µM) at various time points in culture and fixed after 1 week. Results Prolonged minocycline administration decreased the survival of motor neurons in the organotypic cultures. This effect was strongly enhanced with higher concentrations of minocycline. High concentrations of minocycline reduced the number of DAPI-positive cell nuclei in organotypic cultures and simultaneously inhibited microglial activation. Astrocytes, which covered the surface of the control organotypic cultures, revealed a peripheral distribution after early minocycline treatment. Thus, we further analyzed the effects of 100 µM minocycline on the viability and migration ability of dispersed primary glial cell cultures. We found that minocycline reduced cell viability, delayed wound closure in a scratch migration assay and increased connexin 43 protein levels in these cultures. Conclusions The administration of high doses of minocycline was deleterious for motor neuron survival. In addition, it inhibited microglial activation and impaired glial viability and migration. These data suggest that especially high doses of minocycline might have undesired affects in treatment of spinal cord injury. Further experiments are required to determine the conditions for the safe clinical administration of minocycline in spinal cord injured patients. PMID:23967343

Characterization of neurons from immortalized dental pulp stem cells for the study of neurogenetic disorders.

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Urraca, Nora; Memon, Rawaha; El-Iyachi, Ikbale; Goorha, Sarita; Valdez, Colleen; Tran, Quynh T; Scroggs, Reese; Miranda-Carboni, Gustavo A; Donaldson, Martin; Bridges, Dave; Reiter, Lawrence T

2015-11-01

A major challenge to the study and treatment of neurogenetic syndromes is accessing live neurons for study from affected individuals. Although several sources of stem cells are currently available, acquiring these involve invasive procedures, may be difficult or expensive to generate and are limited in number. Dental pulp stem cells (DPSCs) are multipotent stem cells that reside deep the pulp of shed teeth. To investigate the characteristics of DPSCs that make them a valuable resource for translational research, we performed a set of viability, senescence, immortalization and gene expression studies on control DPSC and derived neurons. We investigated the basic transport conditions and maximum passage number for primary DPSCs. We immortalized control DPSCs using human telomerase reverse transcriptase (hTERT) and evaluated neuronal differentiation potential and global gene expression changes by RNA-seq. We show that neurons from immortalized DPSCs share morphological and electrophysiological properties with non-immortalized DPSCs. We also show that differentiation of DPSCs into neurons significantly alters gene expression for 1305 transcripts. Here we show that these changes in gene expression are concurrent with changes in protein levels of the transcriptional repressor REST/NRSF, which is known to be involved in neuronal differentiation. Immortalization significantly altered the expression of 183 genes after neuronal differentiation, 94 of which also changed during differentiation. Our studies indicate that viable DPSCs can be obtained from teeth stored for ≥72 h, these can then be immortalized and still produce functional neurons for in vitro studies, but that constitutive hTERT immortalization is not be the best approach for long term use of patient derived DPSCs for the study of disease. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease.

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Tuszynski, Mark H; Yang, Jennifer H; Barba, David; U, Hoi-Sang; Bakay, Roy A E; Pay, Mary M; Masliah, Eliezer; Conner, James M; Kobalka, Peter; Roy, Subhojit; Nagahara, Alan H

2015-10-01

Alzheimer disease (AD) is the most common neurodegenerative disorder and lacks effective disease-modifying therapies. In 2001, we initiated a clinical trial of nerve growth factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment. To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset. Patients in this anatomicopathological study were enrolled in clinical trials from March 2001 to October 2012 at the University of California, San Diego, Medical Center in La Jolla. Ten patients with early AD underwent NGF gene therapy using ex vivo or in vivo gene transfer. The brains of all 8 patients in the first phase 1 ex vivo trial and of 2 patients in a subsequent phase 1 in vivo trial were examined. Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In 2 patients, NGF protein levels were measured by enzyme-linked immunosorbent assay. Among 10 patients, degenerating neurons in the AD brain responded to NGF. All patients exhibited a trophic response to NGF in the form of axonal sprouting toward the NGF source. Comparing treated and nontreated sides of the brain in 3 patients who underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P < .05). Activation of cellular signaling and functional markers was present in 2 patients who underwent adeno-associated viral vectors (serotype 2)-mediated NGF gene transfer. Neurons exhibiting tau pathology and neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic

Neuron density is decreased in the prefrontal cortex in Williams syndrome.

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Lew, Caroline Horton; Brown, Chelsea; Bellugi, Ursula; Semendeferi, Katerina

2017-01-01

Williams Syndrome (WS) is a rare neurodevelopmental disorder associated with a hemideletion in chromosome 7, which manifests a distinct behavioral phenotype characterized by a hyperaffiliative social drive, in striking contrast to the social avoidance behaviors that are common in Autism Spectrum Disorder (ASD). MRI studies have observed structural and functional abnormalities in WS cortex, including the prefrontal cortex (PFC), a region implicated in social cognition. This study utilizes the Bellugi Williams Syndrome Brain Collection, a unique resource that comprises the largest WS postmortem brain collection in existence, and is the first to quantitatively examine WS PFC cytoarchitecture. We measured neuron density in layers II/III and V/VI of five cortical areas: PFC areas BA 10 and BA 11, primary motor BA 4, primary somatosensory BA 3, and visual area BA 18 in six matched pairs of WS and typically developing (TD) controls. Neuron density in PFC was lower in WS relative to TD, with layers V/VI demonstrating the largest decrease in density, reaching statistical significance in BA 10. In contrast, BA 3 and BA 18 demonstrated a higher density in WS compared to TD, although this difference was not statistically significant. Neuron density in BA 4 was similar in WS and TD. While other cortical areas were altered in WS, prefrontal areas appeared to be most affected. Neuron density is also altered in the PFC of individuals with ASD. Together these findings suggest that the PFC is targeted in neurodevelopmental disorders associated with sociobehavioral alterations. Autism Res 2017, 10: 99-112. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Increased opioid dependence in a mouse model of panic disorder

Directory of Open Access Journals (Sweden)

Xavier Gallego

2010-02-01

Full Text Available Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3. Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 locus coeruleus neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in locus coeruleus and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients.

PPARbeta agonists trigger neuronal differentiation in the human neuroblastoma cell line SH-SY5Y.

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Di Loreto, S; D'Angelo, B; D'Amico, M A; Benedetti, E; Cristiano, L; Cinque, B; Cifone, M G; Cerù, M P; Festuccia, C; Cimini, A

2007-06-01

Neuroblastomas are pediatric tumors originating from immature neuroblasts in the developing peripheral nervous system. Differentiation therapies could help lowering the high mortality due to rapid tumor progression to advanced stages. Oleic acid has been demonstrated to promote neuronal differentiation in neuronal cultures. Herein we report on the effects of oleic acid and of a specific synthetic PPARbeta agonist on cell growth, expression of differentiation markers and on parameters responsible for the malignancy such as adhesion, migration, invasiveness, BDNF, and TrkB expression of SH-SY5Y neuroblastoma cells. The results obtained demonstrate that many, but not all, oleic acid effects are mediated by PPARbeta and support a role for PPARbeta in neuronal differentiation strongly pointing towards PPAR ligands as new therapeutic strategies against progression and recurrences of neuroblastoma.

[Subcortical laminar heterotopia 'double cortex syndrome'].

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Teplyshova, A M; Gaskin, V V; Kustov, G V; Gudkova, A A; Luzin, R V; Trifonov, I S; Lebedeva, A V

2017-01-01

This article presents a clinical case of a 29-year-old patient with 'Double cortex syndrome' with epilepsy, intellectual and mental disorders. Subcortical band heterotopia is a rare disorder of neuronal migration. Such patients typically present with epilepsy and variable degrees of mental retardation and behavioral and intellectual disturbances. The main diagnostic method is magnetic resonance imaging (MRI).

A proteomics study of hyperhomocysteinemia injury of the hippocampal neurons using iTRAQ.

Science.gov (United States)

Fang, Min; Wang, Jing; Yan, Han; Zhao, Yan-Xin; Liu, Xue-Yuan

2014-11-01

High levels of homocysteine, caused by abnormal methionine metabolism, can induce degeneration of mouse hippocampal neurons. iTRAQ™ technology has been widely used in the field of proteomics research and through employing this technology, the present study identified that hyperhomocysteinemia induced the downregulation of 52 proteins and upregulation of 44 proteins in the mouse hippocampus. Through gene ontology and pathway analysis, the upregulation of components of the cytoskeleton, actin, regulators of focal adhesion, calcium signaling pathways, tight junctions, ErbB and gonadotrophin‑releasing hormone signaling, leukocyte, transendothelial migration, propanoate and pyruvate metabolism, valine, leucine and isoleucine biosynthesis, synthesis and degradation of ketone bodies and benzoate degradation via CoA ligation pathway, was identified. It was additionally verified that tau protein was highly expressed in the hyperhomocysteinemic neurons. Further analysis revealed that tau network proteins played functional roles in homocysteine‑induced neuronal damage.

Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia

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Ferland, Russell J.; Batiz, Luis Federico; Neal, Jason; Lian, Gewei; Bundock, Elizabeth; Lu, Jie; Hsiao, Yi-Chun; Diamond, Rachel; Mei, Davide; Banham, Alison H.; Brown, Philip J.; Vanderburg, Charles R.; Joseph, Jeffrey; Hecht, Jonathan L.; Folkerth, Rebecca; Guerrini, Renzo; Walsh, Christopher A.; Rodriguez, Esteban M.; Sheen, Volney L.

2009-01-01

Periventricular heterotopia (PH) is a disorder characterized by neuronal nodules, ectopically positioned along the lateral ventricles of the cerebral cortex. Mutations in either of two human genes, Filamin A (FLNA) or ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2), cause PH (Fox et al. in ‘Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia'. Neuron, 21, 1315–1325, 1998; Sheen et al. in ‘Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex'. Nat. Genet., 36, 69–76, 2004). Recent studies have shown that mutations in mitogen-activated protein kinase kinase kinase-4 (Mekk4), an indirect interactor with FlnA, also lead to periventricular nodule formation in mice (Sarkisian et al. in ‘MEKK4 signaling regulates filamin expression and neuronal migration'. Neuron, 52, 789–801, 2006). Here we show that neurons in post-mortem human PH brains migrated appropriately into the cortex, that periventricular nodules were primarily composed of later-born neurons, and that the neuroependyma was disrupted in all PH cases. As studied in the mouse, loss of FlnA or Big2 function in neural precursors impaired neuronal migration from the germinal zone, disrupted cell adhesion and compromised neuroepithelial integrity. Finally, the hydrocephalus with hop gait (hyh) mouse, which harbors a mutation in Napa [encoding N-ethylmaleimide-sensitive factor attachment protein alpha (α-SNAP)], also develops a progressive denudation of the neuroepithelium, leading to periventicular nodule formation. Previous studies have shown that Arfgef2 and Napa direct vesicle trafficking and fusion, whereas FlnA associates dynamically with the Golgi membranes during budding and trafficking of transport vesicles. Our current findings suggest that PH formation arises from a final common pathway involving disruption of vesicle trafficking, leading to impaired cell

Theoretical analysis of transcranial magneto-acoustical stimulation with Hodgkin–Huxley neuron model

Directory of Open Access Journals (Sweden)

Yi eYuan

2016-04-01

Full Text Available Transcranial magneto-acoustical stimulation (TMAS is a novel stimulation technology in which an ultrasonic wave within a magnetostatic field generates an electric current in an area of interest in the brain to modulate neuronal activities. As a key part of the neural network, neurons transmit information in the nervous system. However, the effect of TMAS on the neuronal firing rhythm remains unknown. To address this problem, we investigated the stimulatory mechanism of TMAS on neurons with a Hodgkin-Huxley neuron model. The simulation results indicate that the magnetostatic field intensity and ultrasonic power can affect the amplitude and interspike interval of neuronal action potential under continuous wave ultrasound. The simulation results also show that the ultrasonic power, duty cycle and repetition frequency can alter the firing rhythm of neural action potential under pulsed ultrasound. This study can help to reveal and explain the biological mechanism of TMAS and to provide a theoretical basis for TMAS in the treatment or rehabilitation of neuropsychiatric disorders.

Sexually dimorphic distribution of Prokr2 neurons revealed by the Prokr2-Cre mouse model.

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Mohsen, Zaid; Sim, Hosung; Garcia-Galiano, David; Han, Xingfa; Bellefontaine, Nicole; Saunders, Thomas L; Elias, Carol F

2017-12-01

Prokineticin receptor 2 (PROKR2) is predominantly expressed in the mammalian central nervous system. Loss-of-function mutations of PROKR2 in humans are associated with Kallmann syndrome due to the disruption of gonadotropin releasing hormone neuronal migration and deficient olfactory bulb morphogenesis. PROKR2 has been also implicated in the neuroendocrine control of GnRH neurons post-migration and other physiological systems. However, the brain circuitry and mechanisms associated with these actions have been difficult to investigate mainly due to the widespread distribution of Prokr2-expressing cells, and the lack of animal models and molecular tools. Here, we describe the generation, validation and characterization of a new mouse model that expresses Cre recombinase driven by the Prokr2 promoter, using CRISPR-Cas9 technology. Cre expression was visualized using reporter genes, tdTomato and GFP, in males and females. Expression of Cre-induced reporter genes was found in brain sites previously described to express Prokr2, e.g., the paraventricular and the suprachiasmatic nuclei, and the area postrema. The Prokr2-Cre mouse model was further validated by colocalization of Cre-induced GFP and Prokr2 mRNA. No disruption of Prokr2 expression, GnRH neuronal migration or fertility was observed. Comparative analysis of Prokr2-Cre expression in male and female brains revealed a sexually dimorphic distribution confirmed by in situ hybridization. In females, higher Cre activity was found in the medial preoptic area, ventromedial nucleus of the hypothalamus, arcuate nucleus, medial amygdala and lateral parabrachial nucleus. In males, Cre was higher in the amygdalo-hippocampal area. The sexually dimorphic pattern of Prokr2 expression indicates differential roles in reproductive function and, potentially, in other physiological systems.

Multiple zebrafish atoh1 genes specify a diversity of neuronal types in the zebrafish cerebellum.

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Kidwell, Chelsea U; Su, Chen-Ying; Hibi, Masahiko; Moens, Cecilia B

2018-06-01

A single Atoh1 basic-helix-loop-helix transcription factor specifies multiple neuron types in the mammalian cerebellum and anterior hindbrain. The zebrafish genome encodes three paralagous atoh1 genes whose functions in cerebellum and anterior hindbrain development we explore here. With use of a transgenic reporter, we report that zebrafish atoh1c-expressing cells are organized in two distinct domains that are separated both by space and developmental time. An early isthmic expression domain gives rise to an extracerebellar population in rhombomere 1 and an upper rhombic lip domain gives rise to granule cell progenitors that migrate to populate all four granule cell territories of the fish cerebellum. Using genetic mutants we find that of the three zebrafish atoh1 paralogs, atoh1c and atoh1a are required for the full complement of granule neurons. Surprisingly, the two genes are expressed in non-overlapping granule cell progenitor populations, indicating that fish use duplicate atoh1 genes to generate granule cell diversity that is not detected in mammals. Finally, live imaging of granule cell migration in wildtype and atoh1c mutant embryos reveals that while atoh1c is not required for granule cell specification per se, it is required for granule cells to delaminate and migrate away from the rhombic lip. Copyright © 2018 Elsevier Inc. All rights reserved.

Bilateral front-parietal polymicrogyria accompanied by cobblestone lissencephaly: 3T MR imaging findings of a case

International Nuclear Information System (INIS)

Bozkurt, Y.; Battal, B.; Ozcan, E.; Kocaoglu, M.

2012-01-01

Full text: Background: The cerebral cortex develops in three overlapping stages: cell proliferation, neuronal migration, and cortical organization. Lissencephaly (smooth brain) is a severe malformation of the cerebral cortex that results from impaired neuronal migration. Polymicrogyria is a disorder of late migration or cortical organization, and supposed to reflect a disruption of normal neuronal migration with subsequent disordered cortical organization. A combination of cobblestone lissencephaly and polymicrogyria is very rare in the same patient's brain. Objective: To present clinical and 3T magnetic resonance (MR) imaging findings of a 17-year-old male with bilateral fronto-parietal polimicrogyria accompanied by cobblestone lissencaphaly. Materials and methods: A 17-year-old male who had seizures and involuntary muscular spasm from birth, was referred to our Hospital. The patient was evaluated by a complete history, physical examination, a laboratory work-up, and cranial MR examination for evaluate the central nervous system. Results: A sharp wave paroxysm in the left temporal area was observed in the electroencephalogram (EEG). The neurological examination of our patient was normal. A slight increase have seen in the aspartate aminotransferase (SGOT) levels. The other biochemical tests were found to be normal. Cranial MR imaging showed an irregular nodular cortex with hypomyelination of the white matter at the lateral and posterior part of the right occipital lobe. We also observed the changes compatible with polymicrogyria in a large area of the medial parts of the bilateral temporal and parietal lobes. Conclusion: The role of radiological modalities for diagnosis of cortical formation disorders are very important. MR imaging are fairly useful for evaluation of these anomalies

The Mexican migration to the US and substance use in Northern Mexico

Science.gov (United States)

Borges, Guilherme; Medina-Mora, Maria-Elena; Orozco, Ricardo; Fleiz, Clara; Cherpitel, Cheryl; Breslau, Joshua

2009-01-01

Aims To examine the impact of migration to the US on substance use and substance use disorders in three urban areas of Northern Mexico. Design Cross-sectional survey of immigration related experiences and lifetime and past-year alcohol and drug use, in a representative sample of respondents ages 12 to 65. Setting Interviews were conducted in the cities of Tijuana, Ciudad Juarez, and Monterrey during 2005. Respondents were classified into three groups: 1) “return migrants”, 2) “relatives of migrants” and 3) “others in the general population”. Findings A total of 1,630 completed interviews were obtained for a response rate of 70.5%. “Return migrants” were more likely to have used alcohol, marijuana or cocaine at least once in their lifetime and in the last 12-months, more likely to develop a substance use disorder, and more likely to have a 12-month substance use disorder, compared with “others in the general population”. Among “return migrants”, longer length of time in the US and type of work performed as an immigrant were related to higher prevalence of substance use. Among “relatives of migrants”, migration experiences were not associated with increased prevalence of substance use compared with “others in the general population”. Conclusion This study found a link between migration to the US and the transformation of substance use norms and pathology in Mexico. Future research of pre-migration involvement in substance use and data on the timing of events among return migrants is needed. Public health measures are likely to require cross-border coordination of research and service development. PMID:19215601

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

Science.gov (United States)

Bagher, Zohreh; Kamrava, Seyed Kamran; Alizadeh, Rafieh; Farhadi, Mohammad; Absalan, Moloud; Falah, Masoumeh; Faghihi, Faezeh; Zare-Sadeghi, Arash; Komeili, Ali

2018-05-25

Cell transplantation is a potential therapeutic approach for repairing neuropathological and neurodegenerative disorders of central nervous system by replacing the degenerated cells with new ones. Among a variety of stem cell candidates to provide these new cells, olfactory ectomesenchymal stem cells (OE-MSCs) have attracted a great attention due to their neural crest origin, easy harvest, high proliferation, and autologous transplantation. Since there is no report on differentiation potential of these cells into motor neuron-like cells, we evaluated this potential using Real-time PCR, flowcytometry and immunocytochemistry after the treatment with differentiation cocktail containing retinoic acid and Sonic Hedgehog. Immunocytochemistry staining of the isolated OE-MSCs demonstrated their capability to express nestin and vimentin, as the two markers of primitive neuroectoderm. The motor neuron differentiation of OE-MSCs resulted in changing their morphology into bipolar cells with high expression of motor neuron markers of ChAT, Hb-9 and Islet-1 at the level of mRNA and protein. Consequently, we believe that the OE-MSCs have great potential to differentiate into motor neuron-like cells and can be an ideal stem cell source for the treatment of motor neuron-related disorders of central nervous system. Copyright © 2018 Elsevier B.V. All rights reserved.

Endothelial HIF-1α Enables Hypothalamic Glucose Uptake to Drive POMC Neurons.

Science.gov (United States)

Varela, Luis; Suyama, Shigetomo; Huang, Yan; Shanabrough, Marya; Tschöp, Matthias H; Gao, Xiao-Bing; Giordano, Frank J; Horvath, Tamas L

2017-06-01

Glucose is the primary driver of hypothalamic proopiomelanocortin (POMC) neurons. We show that endothelial hypoxia-inducible factor 1α (HIF-1α) controls glucose uptake in the hypothalamus and that it is upregulated in conditions of undernourishment, during which POMC neuronal activity is decreased. Endothelium-specific knockdown of HIF-1α impairs the ability of POMC neurons to adapt to the changing metabolic environment in vivo, resulting in overeating after food deprivation in mice. The impaired functioning of POMC neurons was reversed ex vivo or by parenchymal glucose administration. These observations indicate an active role for endothelial cells in the central control of metabolism and suggest that central vascular impairments may cause metabolic disorders. © 2017 by the American Diabetes Association.