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Sample records for abnormal cerebellar development

  1. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.

    PubMed

    Ferland, Russell J; Eyaid, Wafaa; Collura, Randall V; Tully, Laura D; Hill, R Sean; Al-Nouri, Doha; Al-Rumayyan, Ahmed; Topcu, Meral; Gascon, Generoso; Bodell, Adria; Shugart, Yin Yao; Ruvolo, Maryellen; Walsh, Christopher A

    2004-09-01

    Joubert syndrome is a congenital brain malformation of the cerebellar vermis and brainstem with abnormalities of axonal decussation (crossing in the brain) affecting the corticospinal tract and superior cerebellar peduncles. Individuals with Joubert syndrome have motor and behavioral abnormalities, including an inability to walk due to severe clumsiness and 'mirror' movements, and cognitive and behavioral disturbances. Here we identified a locus associated with Joubert syndrome, JBTS3, on chromosome 6q23.2-q23.3 and found three deleterious mutations in AHI1, the first gene to be associated with Joubert syndrome. AHI1 is most highly expressed in brain, particularly in neurons that give rise to the crossing axons of the corticospinal tract and superior cerebellar peduncles. Comparative genetic analysis of AHI1 indicates that it has undergone positive evolutionary selection along the human lineage. Therefore, changes in AHI1 may have been important in the evolution of human-specific motor behaviors.

  2. Cerebellar cortex development in the weaver condition presents regional and age-dependent abnormalities without differences in Purkinje cells neurogenesis.

    PubMed

    Martí, Joaquín; Santa-Cruz, María C; Hervás, José P; Bayer, Shirley A; Villegas, Sandra

    2016-01-01

    Ataxias are neurological disorders associated with the degeneration of Purkinje cells (PCs). Homozygous weaver mice (wv/wv) have been proposed as a model for hereditary cerebellar ataxia because they present motor abnormalities and PC loss. To ascertain the physiopathology of the weaver condition, the development of the cerebellar cortex lobes was examined at postnatal day (P): P8, P20 and P90. Three approaches were used: 1) quantitative determination of several cerebellar features; 2) qualitative evaluation of the developmental changes occurring in the cortical lobes; and 3) autoradiographic analyses of PC generation and placement. Our results revealed a reduction in the size of the wv/wv cerebellum as a whole, confirming previous results. However, as distinguished from these reports, we observed that quantified parameters contribute differently to the abnormal growth of the wv/wv cerebellar lobes. Qualitative analysis showed anomalies in wv/wv cerebellar cytoarchitecture, depending on the age and lobe analyzed. Such abnormalities included the presence of the external granular layer after P20 and, at P90, ectopic cells located in the molecular layer following several placement patterns. Finally, we obtained autoradiographic evidence that wild-type and wv/wv PCs presented similar neurogenetic timetables, as reported. However, the innovative character of this current work lies in the fact that the neurogenetic gradients of wv/wv PCs were not modified from P8 to P90. A tendency for the accumulation of late-formed PCs in the anterior and posterior lobes was found, whereas early-generated PCs were concentrated in the central and inferior lobes. These data suggested that wv/wv PCs may migrate properly to their final destinations. The extrapolation of our results to patients affected with cerebellar ataxias suggests that all cerebellar cortex lobes are affected with several age-dependent alterations in cytoarchitectonics. We also propose that PC loss may be regionally

  3. Cerebellar cortex development in the weaver condition presents regional and age-dependent abnormalities without differences in Purkinje cells neurogenesis.

    PubMed

    Martí, Joaquín; Santa-Cruz, María C; Hervás, José P; Bayer, Shirley A; Villegas, Sandra

    2016-01-01

    Ataxias are neurological disorders associated with the degeneration of Purkinje cells (PCs). Homozygous weaver mice (wv/wv) have been proposed as a model for hereditary cerebellar ataxia because they present motor abnormalities and PC loss. To ascertain the physiopathology of the weaver condition, the development of the cerebellar cortex lobes was examined at postnatal day (P): P8, P20 and P90. Three approaches were used: 1) quantitative determination of several cerebellar features; 2) qualitative evaluation of the developmental changes occurring in the cortical lobes; and 3) autoradiographic analyses of PC generation and placement. Our results revealed a reduction in the size of the wv/wv cerebellum as a whole, confirming previous results. However, as distinguished from these reports, we observed that quantified parameters contribute differently to the abnormal growth of the wv/wv cerebellar lobes. Qualitative analysis showed anomalies in wv/wv cerebellar cytoarchitecture, depending on the age and lobe analyzed. Such abnormalities included the presence of the external granular layer after P20 and, at P90, ectopic cells located in the molecular layer following several placement patterns. Finally, we obtained autoradiographic evidence that wild-type and wv/wv PCs presented similar neurogenetic timetables, as reported. However, the innovative character of this current work lies in the fact that the neurogenetic gradients of wv/wv PCs were not modified from P8 to P90. A tendency for the accumulation of late-formed PCs in the anterior and posterior lobes was found, whereas early-generated PCs were concentrated in the central and inferior lobes. These data suggested that wv/wv PCs may migrate properly to their final destinations. The extrapolation of our results to patients affected with cerebellar ataxias suggests that all cerebellar cortex lobes are affected with several age-dependent alterations in cytoarchitectonics. We also propose that PC loss may be regionally

  4. Abnormal cerebellar volume in acute and remitted major depression.

    PubMed

    Depping, Malte S; Wolf, Nadine D; Vasic, Nenad; Sambataro, Fabio; Hirjak, Dusan; Thomann, Philipp A; Wolf, Robert C

    2016-11-01

    Abnormal cortical volume is well-documented in patients with major depressive disorder (MDD), but cerebellar findings have been heterogeneous. It is unclear whether abnormal cerebellar structure relates to disease state or medication. In this study, using structural MRI, we investigated cerebellar volume in clinically acute (with and without psychotropic treatment) and remitted MDD patients. High-resolution structural MRI data at 3T were obtained from acute medicated (n=29), acute unmedicated (n=14) and remitted patients (n=16). Data from 29 healthy controls were used for comparison purposes. Cerebellar volume was investigated using cerebellum-optimized voxel-based analysis methods. Patients with an acute MDD episode showed increased volume of left cerebellar area IX, and this was true for both medicated and unmedicated individuals (p<0.05 cluster-corrected). Remitted patients exhibited bilaterally increased area IX volume. In remitted, but not in acutely ill patients, area IX volume was significantly associated with measures of depression severity, as assessed by the Hamilton Depression Rating Scale (HAMD). In addition, area IX volume in remitted patients was significantly related to the duration of antidepressant treatment. In acutely ill patients, no significant relationships were established using clinical variables, such as HAMD, illness or treatment duration and number of depressive episodes. The data suggest that cerebellar area IX, a non-motor region that belongs to a large-scale brain functional network with known relevance to core depressive symptom expression, exhibits abnormal volume in patients independent of clinical severity or medication. Thus, the data imply a possible trait marker of the disorder. However, given bilaterality and an association with clinical scores at least in remitted patients, the current findings raise the possibility that cerebellar volume may be reflective of successful treatment as well.

  5. Abnormal Head Impulse Test in a Unilateral Cerebellar Lesion

    PubMed Central

    Baek, Seol-Hee; Jung, Jin-Man; Kwon, Do-Young; Park, Moon Ho; Choi, June; Kim, Ji-Soo

    2015-01-01

    Background The findings of head impulse tests (HIT) are usually normal in cerebellar lesions. Case Report A 46-year-old male presented with progressive dizziness and imbalance of 3 weeks duration. The patient exhibited catch-up saccades during bedside horizontal HIT to either side, which was more evident during the rightward HIT. However, results of bithermal caloric tests and rotatory chair test were normal. MRI revealed a lesion in the inferior cerebellum near the flocculus. Conclusions This case provides additional evidence that damage to the flocculus or its connections may impair the vestibulo-ocular reflex only during high-speed stimuli, especially when the stimuli are applied to the contralesional side. By observing accompanying cerebellar signs, the abnormal HIT findings caused by a cerebellar disorder can be distinguished from those produced by peripheral vestibular disorders. PMID:25749819

  6. Abnormal cerebellar morphometry in abstinent adolescent marijuana users

    PubMed Central

    Medina, Krista Lisdahl; Nagel, Bonnie J.; Tapert, Susan F.

    2010-01-01

    Background Functional neuroimaging data from adults have, in general, found frontocerebellar dysfunction associated with acute and chronic marijuana (MJ) use (Loeber & Yurgelun-Todd, 1999). One structural neuroimaging study found reduced cerebellar vermis volume in young adult MJ users with a history of heavy polysubstance use (Aasly et al., 1993). The goal of this study was to characterize cerebellar volume in adolescent chronic MJ users following one month of monitored abstinence. Method Participants were MJ users (n=16) and controls (n=16) aged 16-18 years. Extensive exclusionary criteria included history of psychiatric or neurologic disorders. Drug use history, neuropsychological data, and structural brain scans were collected after 28 days of monitored abstinence. Trained research staff defined cerebellar volumes (including three cerebellar vermis lobes and both cerebellar hemispheres) on high-resolution T1-weighted magnetic resonance images. Results Adolescent MJ users demonstrated significantly larger inferior posterior (lobules VIII-X) vermis volume (p<.009) than controls, above and beyond effects of lifetime alcohol and other drug use, gender, and intracranial volume. Larger vermis volumes were associated with poorer executive functioning (p’s<.05). Conclusions Following one month of abstinence, adolescent MJ users had significantly larger posterior cerebellar vermis volumes than non-using controls. These greater volumes are suggested to be pathological based on linkage to poorer executive functioning. Longitudinal studies are needed to examine typical cerebellar development during adolescence and the influence of marijuana use. PMID:20413277

  7. Early postnatal ataxia and abnormal cerebellar development in mice lacking Xeroderma pigmentosum Group A and Cockayne syndrome Group B DNA repair genes.

    PubMed

    Murai, M; Enokido, Y; Inamura, N; Yoshino, M; Nakatsu, Y; van der Horst, G T; Hoeijmakers, J H; Tanaka, K; Hatanaka, H

    2001-11-01

    Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are rare autosomal recessive disorders associated with a defect in the nucleotide excision repair (NER) pathway required for the removal of DNA damage induced by UV light and distorting chemical adducts. Although progressive neurological dysfunction is one of the hallmarks of CS and of some groups of XP patients, the causative mechanisms are largely unknown. Here we show that mice lacking both the XPA (XP-group A) and CSB (CS-group B) genes in contrast to the single mutants display severe growth retardation, ataxia, and motor dysfunction during early postnatal development. Their cerebella are hypoplastic and showed impaired foliation and stunted Purkinje cell dendrites. Reduced neurogenesis and increased apoptotic cell death occur in the cerebellar external granular layer. These findings suggest that XPA and CSB have additive roles in the mouse nervous system and support a crucial role for these genes in normal brain development. PMID:11687625

  8. Directional abnormalities of vestibular and optokinetic responses in cerebellar disease

    NASA Technical Reports Server (NTRS)

    Walker, M. F.; Zee, D. S.; Shelhamer, M. J. (Principal Investigator)

    1999-01-01

    Directional abnormalities of vestibular and optokinetic responses in patients with cerebellar degeneration are reported. Three-axis magnetic search-coil recordings of the eye and head were performed in eight cerebellar patients. Among these patients, examples of directional cross-coupling were found during (1) high-frequency, high-acceleration head thrusts; (2) constant-velocity chair rotations with the head fixed; (3) constant-velocity optokinetic stimulation; and (4) following repetitive head shaking. Cross-coupling during horizontal head thrusts consisted of an inappropriate upward eye-velocity component. In some patients, sustained constant-velocity yaw-axis chair rotations produced a mixed horizontal-torsional nystagmus and/or an increase in the baseline vertical slow-phase velocity. Following horizontal head shaking, some patients showed an increase in the slow-phase velocity of their downbeat nystagmus. These various forms of cross-coupling did not necessarily occur to the same degree in a given patient; this suggests that different mechanisms may be responsible. It is suggested that cross-coupling during head thrusts may reflect a loss of calibration of brainstem connections involved in the direct vestibular pathways, perhaps due to dysfunction of the flocculus. Cross-coupling during constant-velocity rotations and following head shaking may result from a misorientation of the angular eye-velocity vector in the velocity-storage system. Finally, responses to horizontal optokinetic stimulation included an inappropriate torsional component in some patients. This suggests that the underlying organization of horizontal optokinetic tracking is in labyrinthine coordinates. The findings are also consistent with prior animal-lesion studies that have shown a role for the vestibulocerebellum in the control of the direction of the VOR.

  9. Cerebellar abnormalities typical of methylmercury poisoning in a fledged saltmarsh sparrow, Ammodramus caudacutus.

    PubMed

    Scoville, Sheila A; Lane, Oksana P

    2013-05-01

    A fledged, 12-15 day-old saltmarsh sparrow, Ammodramus caudacutus, was collected from an accidental kill on Cinder Island, Long Island, NY, USA. The sparrow was assessed for feather mercury levels and the brain analyzed for cerebellar abnormalities by microscopic examination. In humans, fetal Minamata disease is caused by maternal ingestion of mercury. It is characterized by disrupted and disordered cerebellar neuronal migration in the fetus or infant. Results from this sparrow show cerebellar abnormalities typical of Minamata disease. It is the first known avian or mammalian specimen taken from the wild to show the abnormalities typical of the human fetal syndrome.

  10. Insights into cerebellar development and medulloblastoma.

    PubMed

    Bihannic, Laure; Ayrault, Olivier

    2016-01-01

    Cerebellar development is an extensive process that begins during early embryonic stages and persists more than one year after birth in human. Therefore, the cerebellum is susceptible to acquire various developmental abnormalities leading to numerous diseases such as medulloblastoma, the most common pediatric malignant brain tumor. One third of the patients with medulloblastoma are incurable and survivors have a poor quality of life due to the aggressiveness of the broad-spectrum treatments. Within the past few years, it has been highlighted that medulloblastoma is a heterogeneous disease that is divided in four molecular subgroups. This recent advance in the field, combined with the development of associated preclinical models for each subgroup, should enable, in the future, the discovery and use of targeted therapy in clinical treatments for each subtype of medulloblastoma. In this review, we first aim to show how deregulation of cerebellar development can lead to medulloblastoma formation and then to present the advances in the molecular subgrouping of medulloblastoma and the associated preclinical models.

  11. Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans.

    PubMed

    Wang, Yubin; Hersheson, Joshua; Lopez, Dulce; Hammer, Monia; Liu, Yan; Lee, Ka-Hung; Pinto, Vanessa; Seinfeld, Jeff; Wiethoff, Sarah; Sun, Jiandong; Amouri, Rim; Hentati, Faycal; Baudry, Neema; Tran, Jennifer; Singleton, Andrew B; Coutelier, Marie; Brice, Alexis; Stevanin, Giovanni; Durr, Alexandra; Bi, Xiaoning; Houlden, Henry; Baudry, Michel

    2016-06-28

    A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans.

  12. Abnormal cerebellar volume and corticocerebellar dysfunction in early manifest Huntington's disease.

    PubMed

    Wolf, Robert Christian; Thomann, Philipp Arthur; Sambataro, Fabio; Wolf, Nadine Donata; Vasic, Nenad; Landwehrmeyer, G Bernhard; Süßmuth, Sigurd Dietrich; Orth, Michael

    2015-01-01

    Evidence from animal models and neuropathological data has revealed cerebellar pathology in Huntington's disease (HD). The extent of cerebellar dysfunction in preclinical stages and in early manifest HD is unclear. In this study, using MRI we investigated cerebellar changes in preclinical (preHD) and early manifest HD individuals. High-resolution structural MRI data at 3 Tesla were obtained from two independent preHD samples (n = 20/25 participants), from two independent cohorts of healthy controls (n = 20/24 participants) and from patients with early manifest HD (n = 20 participants). Resting-state functional MRI data were acquired from 20 healthy controls and 20 HD patients. Cerebellar volume was investigated using cerebellum-optimized voxel-based analysis methods. Corticocerebellar connectivity at rest was investigated by means of seed-region correlations. In both preHD samples, between-group analyses revealed no change of cerebellar volume. In contrast, early manifest HD patients exhibited lower right cerebellar lobule VIIa volume (p < 0.05 cluster-corrected). Within the control group regions functionally coupled to right cerebellar lobule VII comprised bilateral cerebellar regions, right prefrontal and cingulate areas, whereas within manifest HD, functional coupling was found in paracentral, lingual and inferior frontal areas. Paracentral connectivity strength in patients was associated with disease burden and motor symptoms. These data suggest intact cerebellar volume in preHD. In contrast, early manifest HD patients exhibit atrophy of specific cerebellar subregions and abnormal corticocerebellar functional coupling. In early HD, the association between paracentral lobule function and clinical parameters suggests that corticocerebellar connectivity strength is related to the evolution of HD biology and the severity of HD motor signs.

  13. Abnormal ocular motility with brainstem and cerebellar disorders.

    PubMed

    Carlow, T J; Bicknell, J M

    1978-01-01

    The disorders of ocular motility seen in association with brainstem or cerebellar disorders may point to rather specific anatomical or pathological correlations. Pontine gaze palsy reflects involvement of the pontine paramedian reticular formation. Internuclear ophthalmoplegia signifies a lesion in the medial longitudinal fasciculus. Skew deviation may result from a lesion anywhere in the posterior fossa. Ocular bobbing typically results from a pontine lesion. The Sylvian aqueduct syndrome is characteristic of involvement in the upper midbrain-pretectal region, usually a pinealoma. Cerebellar lesions may be manifested by gaze paresis, skew deviation, disturbances of saccadic or smooth pursuit movements, ocular myoclonus, or several characteristic forms of nystagmus. Familiarity with these disorders may be of great help to the physician dealing with a patient with a possible posterior fossa lesion.

  14. α6 integrin subunit regulates cerebellar development

    PubMed Central

    Marchetti, Giovanni; De Arcangelis, Adèle; Pfister, Véronique; Georges-Labouesse, Elisabeth

    2013-01-01

    Mutations in genes encoding several basal lamina components as well as their cellular receptors disrupt normal deposition and remodeling of the cortical basement membrane resulting in a disorganized cerebral and cerebellar cortex. The α6 integrin was the first α subunit associated with cortical lamination defects and formation of neural ectopias. In order to understand the precise role of α6 integrin in the central nervous system (CNS), we have generated mutant mice carrying specific deletion of α6 integrin in neuronal and glia precursors by crossing α6 conditional knockout mice with Nestin-Cre line. Cerebral cortex development occurred properly in the resulting α6fl/fl;nestin-Cre mutant animals. Interestingly, however, cerebellum displayed foliation pattern defects although granule cell (GC) proliferation and migration were not affected. Intriguingly, analysis of Bergmann glial (BG) scaffold revealed abnormalities in fibers morphology associated with reduced processes outgrowth and altered actin cytoskeleton. Overall, these data show that α6 integrin receptors are required in BG cells to provide a proper fissure formation during cerebellum morphogenesis. PMID:23722246

  15. Eyeblink Conditioning Deficits Indicate Timing and Cerebellar Abnormalities in Schizophrenia

    ERIC Educational Resources Information Center

    Brown, S.M.; Kieffaber, P.D.; Carroll, C.A.; Vohs, J.L.; Tracy, J.A.; Shekhar, A.; O'Donnell, B.F.; Steinmetz, J.E.; Hetrick, W.P.

    2005-01-01

    Accumulating evidence indicates that individuals with schizophrenia manifest abnormalities in structures (cerebellum and basal ganglia) and neurotransmitter systems (dopamine) linked to internal-timing processes. A single-cue tone delay eyeblink conditioning paradigm comprised of 100 learning and 50 extinction trials was used to examine cerebellar…

  16. Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans.

    PubMed

    Wang, Yubin; Hersheson, Joshua; Lopez, Dulce; Hammer, Monia; Liu, Yan; Lee, Ka-Hung; Pinto, Vanessa; Seinfeld, Jeff; Wiethoff, Sarah; Sun, Jiandong; Amouri, Rim; Hentati, Faycal; Baudry, Neema; Tran, Jennifer; Singleton, Andrew B; Coutelier, Marie; Brice, Alexis; Stevanin, Giovanni; Durr, Alexandra; Bi, Xiaoning; Houlden, Henry; Baudry, Michel

    2016-06-28

    A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans. PMID:27320912

  17. Defects in the CAPN1 gene result in alterations in cerebellar development and in cerebellar ataxia in mice and humans

    PubMed Central

    Wang, Yubin; Hersheson, Joshua; Lopez, Dulce; Hamad, Monia Ben; Liu, Yan; Lee, Ka-Hung; Pinto, Vanessa; Seinfeld, Jeff; Wiethoff, Sarah; Sun, Jiandong; Amouri, Rim; Hentati, Faycal; Baudry, Neema; Tran, Jennifer; Singleton, Andrew B; Coutelier, Marie; Brice, Alexis; Stevanin, Giovanni; Durr, Alexandra; Bi, Xiaoning; Houlden, Henry; Baudry, Michel

    2016-01-01

    SUMMARY A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous CAPN1 null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knock-out (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1 mediated cleavage of PH domain and Leucine rich repeat Protein Phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis, and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans. PMID:27320912

  18. Abnormal High-Frequency Burst Firing of Cerebellar Neurons in Rapid-Onset Dystonia-Parkinsonism

    PubMed Central

    Fremont, Rachel; Calderon, D. Paola; Maleki, Sara

    2014-01-01

    Loss-of-function mutations in the α3 isoform of the Na+/K+ ATPase (sodium pump) are responsible for rapid-onset dystonia parkinsonism (DYT12). Recently, a pharmacological model of DYT12 was generated implicating both the cerebellum and basal ganglia in the disorder. Notably, partially blocking sodium pumps in the cerebellum was necessary and sufficient for induction of dystonia. Thus, a key question that remains is how partially blocking sodium pumps in the cerebellum induces dystonia. In vivo recordings from dystonic mice revealed abnormal high-frequency bursting activity in neurons of the deep cerebellar nuclei (DCN), which comprise the bulk of cerebellar output. In the same mice, Purkinje cells, which provide strong inhibitory drive to DCN cells, also fired in a similarly erratic manner. In vitro studies demonstrated that Purkinje cells are highly sensitive to sodium pump dysfunction that alters the intrinsic pacemaking of these neurons, resulting in erratic burst firing similar to that identified in vivo. This abnormal firing abates when sodium pump function is restored and dystonia caused by partial block of sodium pumps can be similarly alleviated. These findings suggest that persistent high-frequency burst firing of cerebellar neurons caused by sodium pump dysfunction underlies dystonia in this model of DYT12. PMID:25164667

  19. A gait paradigm reveals different patterns of abnormal cerebellar motor learning in primary focal dystonias.

    PubMed

    Hoffland, B S; Veugen, L C; Janssen, M M H P; Pasman, J W; Weerdesteyn, V; van de Warrenburg, B P

    2014-12-01

    Accumulating evidence points to a role of the cerebellum in the pathophysiology of primary dystonia. The aim of this study was to investigate whether the abnormalities of cerebellar motor learning in primary dystonia are solely detectable in more pure forms of cerebellum-dependent associative motor learning paradigms, or whether these are also present in other motor learning paradigms that rely heavily on the cerebellum but in addition require a more widespread sensorimotor network. Twenty-six patients with various forms of focal dystonia and 10 age-matched healthy controls participated in a motor learning paradigm on a split-belt treadmill. By using reflective markers, three-dimensional kinematics were recorded using a 6-camera motion analysis system. Adaptation walking parameters were analyzed offline, comparing the different dystonia groups and healthy controls. Patients with blepharospasm and writer's cramp were significantly impaired on various adaptation walking parameters. Whereas results of cervical dystonia patients did not differ from healthy controls in terms of adaptation walking parameters, differences in parameters of normal gait were found. We have here demonstrated abnormal sensorimotor adaptation with the split-belt paradigm in patients with blepharospasm and writer's cramp. This reinforces the current concept of cerebellar dysfunction in primary dystonia, and that this extends beyond more pure forms of cerebellum-dependent associative motor learning paradigms. However, the finding of normal adaptation in cervical dystonia patients indicates that the pattern of cerebellar dysfunction may be slightly different for the various forms of primary focal dystonia, suggesting that actual cerebellar pathology may not be a primary driving force in dystonia.

  20. Cerebellar white matter abnormalities following primary blast injury in US military personnel.

    PubMed

    Mac Donald, Christine; Johnson, Ann; Cooper, Dana; Malone, Thomas; Sorrell, James; Shimony, Joshua; Parsons, Matthew; Snyder, Abraham; Raichle, Marcus; Fang, Raymond; Flaherty, Stephen; Russell, Michael; Brody, David L

    2013-01-01

    Little is known about the effects of blast exposure on the human brain in the absence of head impact. Clinical reports, experimental animal studies, and computational modeling of blast exposure have suggested effects on the cerebellum and brainstem. In US military personnel with isolated, primary blast-related 'mild' traumatic brain injury and no other known insult, we found diffusion tensor MRI abnormalities consistent with cerebellar white matter injury in 3 of 4 subjects. No abnormalities in other brain regions were detected. These findings add to the evidence supporting the hypothesis that primary blast exposure contributes to brain injury in the absence of head impact and that the cerebellum may be particularly vulnerable. However, the clinical effects of these abnormalities cannot be determined with certainty; none of the subjects had ataxia or other detected evidence of cerebellar dysfunction. The details of the blast events themselves cannot be disclosed at this time, thus additional animal and computational modeling will be required to dissect the mechanisms underlying primary blast-related traumatic brain injury. Furthermore, the effects of possible subconcussive impacts and other military-related exposures cannot be determined from the data presented. Thus many aspects of topic will require further investigation.

  1. Cerebellar White Matter Abnormalities following Primary Blast Injury in US Military Personnel

    PubMed Central

    Mac Donald, Christine; Johnson, Ann; Cooper, Dana; Malone, Thomas; Sorrell, James; Shimony, Joshua; Parsons, Matthew; Snyder, Abraham; Raichle, Marcus; Fang, Raymond; Flaherty, Stephen; Russell, Michael; Brody, David L.

    2013-01-01

    Little is known about the effects of blast exposure on the human brain in the absence of head impact. Clinical reports, experimental animal studies, and computational modeling of blast exposure have suggested effects on the cerebellum and brainstem. In US military personnel with isolated, primary blast-related ‘mild’ traumatic brain injury and no other known insult, we found diffusion tensor MRI abnormalities consistent with cerebellar white matter injury in 3 of 4 subjects. No abnormalities in other brain regions were detected. These findings add to the evidence supporting the hypothesis that primary blast exposure contributes to brain injury in the absence of head impact and that the cerebellum may be particularly vulnerable. However, the clinical effects of these abnormalities cannot be determined with certainty; none of the subjects had ataxia or other detected evidence of cerebellar dysfunction. The details of the blast events themselves cannot be disclosed at this time, thus additional animal and computational modeling will be required to dissect the mechanisms underlying primary blast-related traumatic brain injury. Furthermore, the effects of possible subconcussive impacts and other military-related exposures cannot be determined from the data presented. Thus many aspects of topic will require further investigation. PMID:23409052

  2. Epistatic interactions between Chd7 and Fgf8 during cerebellar development

    PubMed Central

    Basson, M Albert

    2014-01-01

    CHARGE syndrome is a rare, autosomal dominant condition caused by mutations in the CHD7 gene. Although central nervous system defects have been reported, the detailed description and analysis of these anomalies in CHARGE syndrome patients lag far behind the description of other, more easily observed defects. We recently described cerebellar abnormalities in CHARGE syndrome patients and used mouse models to identify the underlying causes. Our studies identified altered expression of the homeobox genes Otx2 and Gbx2 in the developing neural tube of Chd7−/− embryos. Furthermore, we showed that the expression of Fgf8 is sensitive to Chd7 gene dosage and demonstrated an epistatic relationship between these genes during cerebellar vermis development. These findings provided, for the first time, an example of cerebellar vermis hypoplasia in a human syndrome that can be linked to deregulated FGF signaling. I discuss some of these observations and their implications for CHARGE syndrome. PMID:25054096

  3. Early Disruption of Extracellular Pleiotrophin Distribution Alters Cerebellar Neuronal Circuit Development and Function.

    PubMed

    Hamza, M M; Rey, S A; Hilber, P; Arabo, A; Collin, T; Vaudry, D; Burel, D

    2016-10-01

    The cerebellum is a structure of the central nervous system involved in balance, motor coordination, and voluntary movements. The elementary circuit implicated in the control of locomotion involves Purkinje cells, which receive excitatory inputs from parallel and climbing fibers, and are regulated by cerebellar interneurons. In mice as in human, the cerebellar cortex completes its development mainly after birth with the migration, differentiation, and synaptogenesis of granule cells. These cellular events are under the control of numerous extracellular matrix molecules including pleiotrophin (PTN). This cytokine has been shown to regulate the morphogenesis of Purkinje cells ex vivo and in vivo via its receptor PTPζ. Since Purkinje cells are the unique output of the cerebellar cortex, we explored the consequences of their PTN-induced atrophy on the function of the cerebellar neuronal circuit in mice. Behavioral experiments revealed that, despite a normal overall development, PTN-treated mice present a delay in the maturation of their flexion reflex. Moreover, patch clamp recording of Purkinje cells revealed a significant increase in the frequency of spontaneous excitatory postsynaptic currents in PTN-treated mice, associated with a decrease of climbing fiber innervations and an abnormal perisomatic localization of the parallel fiber contacts. At adulthood, PTN-treated mice exhibit coordination impairment on the rotarod test associated with an alteration of the synchronization gait. Altogether these histological, electrophysiological, and behavior data reveal that an early ECM disruption of PTN composition induces short- and long-term defaults in the establishment of proper functional cerebellar circuit.

  4. Early Disruption of Extracellular Pleiotrophin Distribution Alters Cerebellar Neuronal Circuit Development and Function.

    PubMed

    Hamza, M M; Rey, S A; Hilber, P; Arabo, A; Collin, T; Vaudry, D; Burel, D

    2016-10-01

    The cerebellum is a structure of the central nervous system involved in balance, motor coordination, and voluntary movements. The elementary circuit implicated in the control of locomotion involves Purkinje cells, which receive excitatory inputs from parallel and climbing fibers, and are regulated by cerebellar interneurons. In mice as in human, the cerebellar cortex completes its development mainly after birth with the migration, differentiation, and synaptogenesis of granule cells. These cellular events are under the control of numerous extracellular matrix molecules including pleiotrophin (PTN). This cytokine has been shown to regulate the morphogenesis of Purkinje cells ex vivo and in vivo via its receptor PTPζ. Since Purkinje cells are the unique output of the cerebellar cortex, we explored the consequences of their PTN-induced atrophy on the function of the cerebellar neuronal circuit in mice. Behavioral experiments revealed that, despite a normal overall development, PTN-treated mice present a delay in the maturation of their flexion reflex. Moreover, patch clamp recording of Purkinje cells revealed a significant increase in the frequency of spontaneous excitatory postsynaptic currents in PTN-treated mice, associated with a decrease of climbing fiber innervations and an abnormal perisomatic localization of the parallel fiber contacts. At adulthood, PTN-treated mice exhibit coordination impairment on the rotarod test associated with an alteration of the synchronization gait. Altogether these histological, electrophysiological, and behavior data reveal that an early ECM disruption of PTN composition induces short- and long-term defaults in the establishment of proper functional cerebellar circuit. PMID:26399645

  5. Novel Approaches to Studying the Genetic Basis of Cerebellar Development

    PubMed Central

    Sajan, Samin A.; Waimey, Kathryn E.

    2010-01-01

    The list of genes that when mutated cause disruptions in cerebellar development is rapidly increasing. The study of both spontaneous and engineered mouse mutants has been essential to this progress, as it has revealed much of our current understanding of the developmental processes required to construct the mature cerebellum. Improvements in brain imaging, such as magnetic resonance imaging (MRI) and the emergence of better classification schemes for human cerebellar malformations, have recently led to the identification of a number of genes which cause human cerebellar disorders. In this review we argue that synergistic approaches combining classical molecular techniques, genomics, and mouse models of human malformations will be essential to fuel additional discoveries of cerebellar developmental genes and mechanisms. PMID:20387026

  6. Cerebellar development in the absence of Gbx function in zebrafish.

    PubMed

    Su, Chen-Ying; Kemp, Hilary A; Moens, Cecilia B

    2014-02-01

    The midbrain-hindbrain boundary (MHB) is a well-known organizing center during vertebrate brain development. The MHB forms at the expression boundary of Otx2 and Gbx2, mutually repressive homeodomain transcription factors expressed in the midbrain/forebrain and anterior hindbrain, respectively. The genetic hierarchy of gene expression at the MHB is complex, involving multiple positive and negative feedback loops that result in the establishment of non-overlapping domains of Wnt1 and Fgf8 on either side of the boundary and the consequent specification of the cerebellum. The cerebellum derives from the dorsal part of the anterior-most hindbrain segment, rhombomere 1 (r1), which undergoes a distinctive morphogenesis to give rise to the cerebellar primordium within which the various cerebellar neuron types are specified. Previous studies in the mouse have shown that Gbx2 is essential for cerebellar development. Using zebrafish mutants we show here that in the zebrafish gbx1 and gbx2 are required redundantly for morphogenesis of the cerebellar primordium and subsequent cerebellar differentiation, but that this requirement is alleviated by knocking down Otx. Expression of fgf8, wnt1 and the entire MHB genetic program is progressively lost in gbx1-;gbx2- double mutants but is rescued by Otx knock-down. This rescue of the MHB genetic program depends on rescued Fgf signaling, however the rescue of cerebellar primordium morphogenesis is independent of both Gbx and Fgf. Based on our findings we propose a revised model for the role of Gbx in cerebellar development.

  7. Mapping the development of cerebellar Purkinje cells in zebrafish.

    PubMed

    Hamling, Kyla R; Tobias, Zachary J C; Weissman, Tamily A

    2015-11-01

    The cells that comprise the cerebellum perform a complex integration of neural inputs to influence motor control and coordination. The functioning of this circuit depends upon Purkinje cells and other cerebellar neurons forming in the precise place and time during development. Zebrafish provide a useful platform for modeling disease and studying gene function, thus a quantitative metric of normal zebrafish cerebellar development is key for understanding how gene mutations affect the cerebellum. To begin to quantitatively measure cerebellar development in zebrafish, we have characterized the spatial and temporal patterning of Purkinje cells during the first 2 weeks of development. Differentiated Purkinje cells first emerged by 2.8 days post fertilization and were spatially patterned into separate dorsomedial and ventrolateral clusters that merged at around 4 days. Quantification of the Purkinje cell layer revealed that there was a logarithmic increase in both Purkinje cell number as well as overall volume during the first 2 weeks, while the entire region curved forward in an anterior, then ventral direction. Purkinje cell dendrites were positioned next to parallel fibers as early as 3.3 days, and Purkinje cell diameter decreased significantly from 3.3 to 14 days, possibly due to cytoplasmic reappropriation into maturing dendritic arbors. A nearest neighbor analysis showed that Purkinje cells moved slightly apart from each other from 3 to 14 days, perhaps spreading as the organized monolayer forms. This study establishes a quantitative spatiotemporal map of Purkinje cell development in zebrafish that provides an important metric for studies of cerebellar development and disease.

  8. Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia.

    PubMed

    Ruiz, Marta; Perez-Garcia, Georgina; Ortiz-Virumbrales, Maitane; Méneret, Aurelie; Morant, Andrika; Kottwitz, Jessica; Fuchs, Tania; Bonet, Justine; Gonzalez-Alegre, Pedro; Hof, Patrick R; Ozelius, Laurie J; Ehrlich, Michelle E

    2015-12-20

    DYT6 dystonia is caused by mutations in THAP1 [Thanatos-associated (THAP) domain-containing apoptosis-associated protein] and is autosomal dominant and partially penetrant. Like other genetic primary dystonias, DYT6 patients have no characteristic neuropathology, and mechanisms by which mutations in THAP1 cause dystonia are unknown. Thap1 is a zinc-finger transcription factor, and most pathogenic THAP1 mutations are missense and are located in the DNA-binding domain. There are also nonsense mutations, which act as the equivalent of a null allele because they result in the generation of small mRNA species that are likely rapidly degraded via nonsense-mediated decay. The function of Thap1 in neurons is unknown, but there is a unique, neuronal 50-kDa Thap1 species, and Thap1 levels are auto-regulated on the mRNA level. Herein, we present the first characterization of two mouse models of DYT6, including a pathogenic knockin mutation, C54Y and a null mutation. Alterations in motor behaviors, transcription and brain structure are demonstrated. The projection neurons of the deep cerebellar nuclei are especially altered. Abnormalities vary according to genotype, sex, age and/or brain region, but importantly, overlap with those of other dystonia mouse models. These data highlight the similarities and differences in age- and cell-specific effects of a Thap1 mutation, indicating that the pathophysiology of THAP1 mutations should be assayed at multiple ages and neuronal types and support the notion of final common pathways in the pathophysiology of dystonia arising from disparate mutations. PMID:26376866

  9. Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia.

    PubMed

    Ruiz, Marta; Perez-Garcia, Georgina; Ortiz-Virumbrales, Maitane; Méneret, Aurelie; Morant, Andrika; Kottwitz, Jessica; Fuchs, Tania; Bonet, Justine; Gonzalez-Alegre, Pedro; Hof, Patrick R; Ozelius, Laurie J; Ehrlich, Michelle E

    2015-12-20

    DYT6 dystonia is caused by mutations in THAP1 [Thanatos-associated (THAP) domain-containing apoptosis-associated protein] and is autosomal dominant and partially penetrant. Like other genetic primary dystonias, DYT6 patients have no characteristic neuropathology, and mechanisms by which mutations in THAP1 cause dystonia are unknown. Thap1 is a zinc-finger transcription factor, and most pathogenic THAP1 mutations are missense and are located in the DNA-binding domain. There are also nonsense mutations, which act as the equivalent of a null allele because they result in the generation of small mRNA species that are likely rapidly degraded via nonsense-mediated decay. The function of Thap1 in neurons is unknown, but there is a unique, neuronal 50-kDa Thap1 species, and Thap1 levels are auto-regulated on the mRNA level. Herein, we present the first characterization of two mouse models of DYT6, including a pathogenic knockin mutation, C54Y and a null mutation. Alterations in motor behaviors, transcription and brain structure are demonstrated. The projection neurons of the deep cerebellar nuclei are especially altered. Abnormalities vary according to genotype, sex, age and/or brain region, but importantly, overlap with those of other dystonia mouse models. These data highlight the similarities and differences in age- and cell-specific effects of a Thap1 mutation, indicating that the pathophysiology of THAP1 mutations should be assayed at multiple ages and neuronal types and support the notion of final common pathways in the pathophysiology of dystonia arising from disparate mutations.

  10. LKB1 Regulates Cerebellar Development by Controlling Sonic Hedgehog-mediated Granule Cell Precursor Proliferation and Granule Cell Migration

    PubMed Central

    Men, Yuqin; Zhang, Aizhen; Li, Haixiang; Jin, Yecheng; Sun, Xiaoyang; Li, Huashun; Gao, Jiangang

    2015-01-01

    The Liver Kinase B1 (LKB1) gene plays crucial roles in cell differentiation, proliferation and the establishment of cell polarity. We created LKB1 conditional knockout mice (LKB1Atoh1 CKO) to investigate the function of LKB1 in cerebellar development. The LKB1Atoh1 CKO mice displayed motor dysfunction. In the LKB1Atoh1 CKO cerebellum, the overall structure had a larger volume and morelobules. LKB1 inactivationled to an increased proliferation of granule cell precursors (GCPs), aberrant granule cell migration and overproduction of unipolar brush cells. To investigate the mechanism underlying the abnormal foliation, we examined sonic hedgehog signalling (Shh) by testing its transcriptional mediators, the Gli proteins, which regulate the GCPs proliferation and cerebellar foliation during cerebellar development. The expression levels of Gli genes were significantly increased in the mutant cerebellum. In vitro assays showed that the proliferation of cultured GCPs from mutant cerebellum significantly increased, whereas the proliferation of mutant GCPs significantly decreased in the presence of a Shh inhibitor GDC-0049. Thus, LKB1 deficiency in the LKB1Atoh1 CKO mice enhanced Shh signalling, leading to the excessive GCP proliferation and the formation of extra lobules. We proposed that LKB1 regulates cerebellar development by controlling GCPs proliferation through Shh signalling during cerebellar development. PMID:26549569

  11. Cerebellar function in developmental dyslexia.

    PubMed

    Stoodley, Catherine J; Stein, John F

    2013-04-01

    Developmental dyslexia is a genetically based neurobiological syndrome, which is characterized by reading difficulty despite normal or high general intelligence. Even remediated dyslexic readers rarely achieve fast, fluent reading. Some dyslexics also have impairments in attention, short-term memory, sequencing (letters, word sounds, and motor acts), eye movements, poor balance, and general clumsiness. The presence of "cerebellar" motor and fluency symptoms led to the proposal that cerebellar dysfunction contributes to the etiology of dyslexia. Supporting this, functional imaging studies suggest that the cerebellum is part of the neural network supporting reading in typically developing readers, and reading difficulties have been reported in patients with cerebellar damage. Differences in both cerebellar asymmetry and gray matter volume are some of the most consistent structural brain findings in dyslexics compared with good readers. Furthermore, cerebellar functional activation patterns during reading and motor learning can differ in dyslexic readers. Behaviorally, some children and adults with dyslexia show poorer performance on cerebellar motor tasks, including eye movement control, postural stability, and implicit motor learning. However, many dyslexics do not have cerebellar signs, many cerebellar patients do not have reading problems, and differences in dyslexic brains are found throughout the whole reading network, and not isolated to the cerebellum. Therefore, impaired cerebellar function is probably not the primary cause of dyslexia, but rather a more fundamental neurodevelopmental abnormality leads to differences throughout the reading network.

  12. Ectopic Cerebellar Cell Migration Causes Maldevelopment of Purkinje Cells and Abnormal Motor Behaviour in Cxcr4 Null Mice

    PubMed Central

    Huang, Guo-Jen; Edwards, Andrew; Tsai, Cheng-Yu; Lee, Yi-Shin; Peng, Lei; Era, Takumi; Hirabayashi, Yoshio; Tsai, Ching-Yen; Nishikawa, Shin-Ichi; Iwakura, Yoichiro; Chen, Shu-Jen; Flint, Jonathan

    2014-01-01

    SDF-1/CXCR4 signalling plays an important role in neuronal cell migration and brain development. However, the impact of CXCR4 deficiency in the postnatal mouse brain is still poorly understood. Here, we demonstrate the importance of CXCR4 on cerebellar development and motor behaviour by conditional inactivation of Cxcr4 in the central nervous system. We found CXCR4 plays a key role in cerebellar development. Its loss leads to defects in Purkinje cell dentritogenesis and axonal projection in vivo but not in cell culture. Transcriptome analysis revealed the most significantly affected pathways in the Cxcr4 deficient developing cerebellum are involved in extra cellular matrix receptor interactions and focal adhesion. Consistent with functional impairment of the cerebellum, Cxcr4 knockout mice have poor coordination and balance performance in skilled motor tests. Together, these results suggest ectopic the migration of granule cells impairs development of Purkinje cells, causes gross cerebellar anatomical disruption and leads to behavioural motor defects in Cxcr4 null mice. PMID:24516532

  13. Modulation of p53 and met expression by Krüppel-like factor 8 regulates zebrafish cerebellar development.

    PubMed

    Tsai, Ming-Yuan; Lu, Yu-Fen; Liu, Yu-Hsiu; Lien, Huang-Wei; Huang, Chang-Jen; Wu, Jen-Leih; Hwang, Sheng-Ping L

    2015-09-01

    Krüppel-like factor 8 (Klf8) is a zinc-finger transcription factor implicated in cell proliferation, and cancer cell survival and invasion; however, little is known about its role in normal embryonic development. Here, we show that Klf8 is required for normal cerebellar development in zebrafish embryos. Morpholino knockdown of klf8 resulted in abnormal cerebellar primordium morphology and the induction of p53 in the brain region at 24 hours post-fertilization (hpf). Both p53-dependent reduction of cell proliferation and augmentation of apoptosis were observed in the cerebellar anlage of 24 hpf-klf8 morphants. In klf8 morphants, expression of ptf1a in the ventricular zone was decreased from 48 to 72 hpf; on the other hand, expression of atohla in the upper rhombic lip was unaffected. Consistent with this finding, Purkinje cell development was perturbed and granule cell number was reduced in 72 hpf-klf8 morphants; co-injection of p53 MO(sp) or klf8 mRNA substantially rescued development of cerebellar Purkinje cells in klf8 morphants. Hepatocyte growth factor/Met signaling is known to regulate cerebellar development in zebrafish and mouse. We observed decreased met expression in the tectum and rhombomere 1 of 24 hpf-klf8 morphants, which was largely rescued by co-injection with klf8 mRNA. Moreover, co-injection of met mRNA substantially rescued formation of Purkinje cells in klf8 morphants at 72 hpf. Together, these results demonstrate that Klf8 modulates expression of p53 and met to maintain ptf1a-expressing neuronal progenitors, which are required for the appropriate development of cerebellar Purkinje and granule cells in zebrafish embryos.

  14. Aryl hydrocarbon receptor expression and activity in cerebellar granule neuroblasts: implications for development and dioxin neurotoxicity.

    PubMed

    Williamson, Mary A; Gasiewicz, Thomas A; Opanashuk, Lisa A

    2005-02-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent teratogen that produces neurobehavioral abnormalities associated with both cognitive and locomotor systems, yet the precise regional and cellular targets of developmental neurotoxicity remain largely unknown. Most, if not all, TCDD-induced pathology is mediated via binding to the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that belongs to the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) superfamily. Upon ligand binding, AhR translocates to the nucleus, dimerizes with the AhR nuclear translocator protein (Arnt), and regulates transcription by interaction with dioxin-response elements (DREs) in target genes, most notably specific cytochrome P450 (CYP) family members. To assess whether developing cerebellar granule neuroblasts are potential direct targets for TCDD toxicity, AhR expression and transcriptional activity were examined. AhR and Arnt proteins were present in mouse cerebellum from birth throughout postnatal development. AhR protein levels peaked between postnatal day (PND) 3-10, a critical period for granule neuroblast growth and maturation. Transcriptionally active AhR was detected in immature cerebellar granule cells in a transgenic dioxin-responsive lacZ mouse model after acute TCDD exposure. AhR and Arnt were also expressed in cerebellar granule neuroblast cultures. AhR localized to the nucleus in granule cells 15 min after TCDD treatment. TCCD elicited time-dependent and concentration-dependent increases in CYP1A1 and 1B1 mRNA and protein levels. Moreover, TCDD treatment reduced both thymidine incorporation and granule neuroblast survival in a concentration-dependent manner. These data suggest that (1) granule neuroblasts are direct targets for developmental AhR-mediated TCDD neurotoxicity and (2) TCDD exposure may disrupt granule cell neurogenesis.

  15. Developmental delay in motor skill acquisition in Niemann-Pick C1 mice reveals abnormal cerebellar morphogenesis.

    PubMed

    Caporali, Paola; Bruno, Francesco; Palladino, Giampiero; Dragotto, Jessica; Petrosini, Laura; Mangia, Franco; Erickson, Robert P; Canterini, Sonia; Fiorenza, Maria Teresa

    2016-01-01

    Niemann-Pick type C1 (NPC1) disease is a lysosomal storage disorder caused by defective intracellular trafficking of exogenous cholesterol. Purkinje cell (PC) degeneration is the main sign of cerebellar dysfunction in both NPC1 patients and animal models. It has been recently shown that a significant decrease in Sonic hedgehog (Shh) expression reduces the proliferative potential of granule neuron precursors in the developing cerebellum of Npc1 (-/-) mice. Pursuing the hypothesis that this developmental defect translates into functional impairments, we have assayed Npc1-deficient pups belonging to the milder mutant mouse strain Npc1 (nmf164) for sensorimotor development from postnatal day (PN) 3 to PN21. Npc1 (nmf164) / Npc1 (nmf164) pups displayed a 2.5-day delay in the acquisition of complex motor abilities compared to wild-type (wt) littermates, in agreement with the significant disorganization of cerebellar cortex cytoarchitecture observed between PN11 and PN15. Compared to wt, Npc1 (nmf164) homozygous mice exhibited a poorer morphological differentiation of Bergmann glia (BG), as indicated by thicker radial shafts and less elaborate reticular pattern of lateral processes. Also BG functional development was defective, as indicated by the significant reduction in GLAST and Glutamine synthetase expression. A reduced VGluT2 and GAD65 expression also indicated an overall derangement of the glutamatergic/GABAergic stimulation that PCs receive by climbing/parallel fibers and basket/stellate cells, respectively. Lastly, Npc1-deficiency also affected oligodendrocyte differentiation as indicated by the strong reduction of myelin basic protein. Two sequential 2-hydroxypropyl-β-cyclodextrin administrations at PN4 and PN7 counteract these defects, partially preventing functional impairment of BG and fully restoring the normal patterns of glutamatergic/GABAergic stimulation to PCs.These findings indicate that in Npc1 (nmf164) homozygous mice the derangement of synaptic

  16. Requirement of TrkB for synapse elimination in developing cerebellar Purkinje cells

    PubMed Central

    Bosman, Laurens W. J.; Hartmann, Jana; Barski, Jaroslaw J.; Lepier, Alexandra; Noll-Hussong, Michael; Reichardt, Louis F.; Konnerth, Arthur

    2009-01-01

    The receptor tyrosine kinase TrkB and its ligands, brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5), are critically important for growth, survival and activity-dependent synaptic strengthening in the central nervous system. These TrkB-mediated actions occur in a highly cell-type specific manner. Here we report that cerebellar Purkinje cells, which are richly endowed with TrkB receptors, develop a normal morphology in trkB-deficient mice. Thus, in contrast to other types of neurons, Purkinje cells do not need TrkB for dendritic growth and spine formation. Instead, we find a moderate delay in the maturation of GABAergic synapses and, more importantly, an abnormal multiple climbing fiber innervation in Purkinje cells in trkB-deficient mice. Thus, our results demonstrate an involvement of TrkB receptors in synapse elimination and reveal a new role for receptor tyrosine kinases in the brain. PMID:17940915

  17. Structural and functional MRI abnormalities of cerebellar cortex and nuclei in SCA3, SCA6 and Friedreich's ataxia.

    PubMed

    Stefanescu, Maria R; Dohnalek, Moritz; Maderwald, Stefan; Thürling, Markus; Minnerop, Martina; Beck, Andreas; Schlamann, Marc; Diedrichsen, Joern; Ladd, Mark E; Timmann, Dagmar

    2015-05-01

    Spinocerebellar ataxia type 3, spinocerebellar ataxia type 6 and Friedreich's ataxia are common hereditary ataxias. Different patterns of atrophy of the cerebellar cortex are well known. Data on cerebellar nuclei are sparse. Whereas cerebellar nuclei have long been thought to be preserved in spinocerebellar ataxia type 6, histology shows marked atrophy of the nuclei in Friedreich's ataxia and spinocerebellar ataxia type 3. In the present study susceptibility weighted imaging was used to assess atrophy of the cerebellar nuclei in patients with spinocerebellar ataxia type 6 (n = 12, age range 41-76 years, five female), Friedreich's ataxia (n = 12, age range 21-55 years, seven female), spinocerebellar ataxia type 3 (n = 10, age range 34-67 years, three female), and age- and gender-matched controls (total n = 23, age range 22-75 years, 10 female). T1-weighted magnetic resonance images were used to calculate the volume of the cerebellum. In addition, ultra-high field functional magnetic resonance imaging was performed with optimized normalization methods to assess function of the cerebellar cortex and nuclei during simple hand movements. As expected, the volume of the cerebellum was markedly reduced in spinocerebellar ataxia type 6, preserved in Friedreich's ataxia, and mildy reduced in spinocerebellar ataxia type 3. The volume of the cerebellar nuclei was reduced in the three patient groups compared to matched controls (P-values < 0.05; two-sample t-tests). Atrophy of the cerebellar nuclei was most pronounced in spinocerebellar ataxia type 6. On a functional level, hand-movement-related cerebellar activation was altered in all three disorders. Within the cerebellar cortex, functional magnetic resonance imaging signal was significantly reduced in spinocerebellar ataxia type 6 and Friedreich's ataxia compared to matched controls (P-values < 0.001, bootstrap-corrected cluster-size threshold; two-sample t-tests). The difference missed significance in spinocerebellar ataxia

  18. Cadherins in cerebellar development: translation of embryonic patterning into mature functional compartmentalization.

    PubMed

    Redies, Christoph; Neudert, Franziska; Lin, Juntang

    2011-09-01

    Cadherins are cell adhesion molecules with multiple morphogenic functions in brain development, for example, in neuroblast migration and aggregation, axon navigation, neural circuit formation, and synaptogenesis. More than 100 members of the cadherin superfamily are expressed in the developing and mature brain. Most of the cadherins investigated, in particular classic cadherins and δ-protocadherins, are expressed in the cerebellum. For several cadherin subtypes, expression begins at early embryonic stages and persists until mature stages of cerebellar development. At intermediate stages, distinct Purkinje cell clusters exhibit unique rostrocaudal and mediolateral expression profiles for each cadherin. In the chicken, mouse, and other species, the Purkinje cell clusters are separated by intervening raphes of migrating granule cells. This pattern of Purkinje cell clusters/raphes is, at least in part, continuous with the parasagittal striping pattern that is apparent in the mature cerebellar cortex, for example, for zebrin II/aldolase C. Moreover, subregions of the deep cerebellar nuclei, vestibular nuclei and the olivary complex also express cadherins differentially. Neuroanatomical evidence suggests that the nuclear subregions and cortical domains that express the same cadherin subtype are connected to each other, to form neural subcircuits of the cerebellar system. Cadherins thus provide a molecular code that specifies not only embryonic structures but also functional cerebellar compartmentalization. By following the implementation of this code, it can be revealed how mature functional architecture emerges from embryonic patterning during cerebellar development. Dysfunction of some cadherins is associated with psychiatric diseases and developmental impairments and may also affect cerebellar function.

  19. Normal Cerebellar Development by Qualitative and Quantitative MR Imaging: From the Fetus to the Adolescent.

    PubMed

    Brossard-Racine, Marie; Limperopoulos, Catherine

    2016-08-01

    This article presents an overview of published studies using conventional and quantitative MR imaging to describe normal development of the cerebellum prenatally and postnatally through 18 years of age. Normal cerebellar development and maturational processes are described here within the context of MR imaging morphology, microstructure, metabolism, and functional connectivity. In addition, strengths and weaknesses of these reviewed studies are critically appraised and new directions for future cerebellar MR imaging investigation are made. PMID:27423797

  20. Abnormalities in myelination of the superior cerebellar peduncle in patients with schizophrenia and deficits in movement sequencing.

    PubMed

    Hüttlova, Jitka; Kikinis, Zora; Kerkovsky, Milos; Bouix, Sylvain; Vu, Mai-Anh; Makris, Nikos; Shenton, Martha; Kasparek, Tomas

    2014-08-01

    Deficits in the execution of a sequence of movements are common in schizophrenia. Previous studies reported reduced functional activity in the motor cortex and cerebellum in schizophrenic patients with deficits in movement sequencing. The corticospinal tract (CST) and superior cerebellar peduncle (SCP) are fiber tracts that are involved in movement sequencing. However, the integrity of these tracts has not been evaluated in schizophrenic patients with respect to the performance of movement sequencing yet. Diffusion tensor magnetic resonance images (DT-MRI) were acquired from 24 patients with schizophrenia and 23 matched control subjects. Tractography was applied to reconstruct the CST and SCP and DT-MRI-specific parameters such as fractional anisotropy (FA) and radial diffusivity (RD) were reported. The patient group was further subdivided based on the score of sequencing of complex motor acts subscale of the Neurological Evaluation Scale into those with deficits in sequencing motor acts, the SQ(abn) group (n = 7), and those with normal performance, the SQ(norm) group (n = 17). Schizophrenia patients of the SQ(norm) subgroup had significantly reduced FA and increased RD values in the right CST in comparison to the control group; the SQ(abn) subgroup did not differ from the controls. However, the SQ(abn) subgroup showed impaired integrity of the left SCP, whereas the SQ(norm) subgroup did not. Abnormalities in the right CST in the SQ(norm) and in the left SCP in SQ(abn) groups suggest that the patients with SQ(abn) represent subgroups with distinct deficits. Moreover, these results demonstrate the involvement of the SCP in the pathogenesis of movement sequencing in schizophrenia.

  1. The history of the development of the cerebellar examination.

    PubMed

    Fine, Edward J; Ionita, Catalina C; Lohr, Linda

    2002-12-01

    The cerebellar examination evolved from observations of experimental lesions made by neurophysiologists and clinical descriptions of patients with trauma to the cerebellum. At the beginning of the 19th century, neurophysiologists such as Luigi Rolando, Marie-Jean-Pierre Flourens, and John Call Dalton, Jr. ablated portions of the cerebellum of a variety of animals and observed staggering gait, clumsiness, and falling from side to side without loss of strength. They concluded that the cerebellum coordinated voluntary movements. In 1899, Joseph Francois Félix Babinski observed that patients with cerebellar lesions could not execute complex movements without breaking down into their elemental movements and described the defect as dysmetria. In 1902, Babinski coined the term dysdiodochokinesis to describe the inability to perform rapid execution of movements requiring alternate contractions of agonist and antagonist muscles. Gordon Holmes in 1904 described the phenomena of rebound, noting that if a limb ipsilateral to a cerebellar lesion is suddenly released from tension, the appendage will flail. In 1917, Gordon Holmes reported hypotonia and dysmetria in men wounded by gunshot wounds to their cerebellum. These observations were rapidly included in descriptions of the cerebellar examination in popular contemporaneous textbooks of neurology. Modern observations have demonstrated that the cerebellum influences such cognitive functions such as planning, verbal fluency, abstract reasoning, prosody, and use of correct grammar.

  2. Cerebellar liponeurocytoma in two siblings suggests a possible familial predisposition.

    PubMed

    Pikis, Stylianos; Fellig, Yakov; Margolin, Emil

    2016-10-01

    There is limited data on the genetic origin and natural history of cerebellar liponeurocytoma. To the best of our knowledge there has been only one report of a familial presentation of this rare entity. We report a 72-year-old female with a posterior fossa tumor presenting with progressive cerebellar signs and symptoms. The patient underwent total tumor resection via an uncomplicated sub-occipital craniotomy. Histopathologic examination was diagnostic for cerebellar liponeurocytoma. Her sister was previously treated for a similar tumor. Our report provides further evidence for the possible existence of a hereditary abnormality predisposing afflicted families to cerebellar liponeurocytoma development. PMID:27349466

  3. Cerebro-cerebellar circuits in autism spectrum disorder

    PubMed Central

    D'Mello, Anila M.; Stoodley, Catherine J.

    2015-01-01

    The cerebellum is one of the most consistent sites of abnormality in autism spectrum disorder (ASD) and cerebellar damage is associated with an increased risk of ASD symptoms, suggesting that cerebellar dysfunction may play a crucial role in the etiology of ASD. The cerebellum forms multiple closed-loop circuits with cerebral cortical regions that underpin movement, language, and social processing. Through these circuits, cerebellar dysfunction could impact the core ASD symptoms of social and communication deficits and repetitive and stereotyped behaviors. The emerging topography of sensorimotor, cognitive, and affective subregions in the cerebellum provides a new framework for interpreting the significance of regional cerebellar findings in ASD and their relationship to broader cerebro-cerebellar circuits. Further, recent research supports the idea that the integrity of cerebro-cerebellar loops might be important for early cortical development; disruptions in specific cerebro-cerebellar loops in ASD might impede the specialization of cortical regions involved in motor control, language, and social interaction, leading to impairments in these domains. Consistent with this concept, structural, and functional differences in sensorimotor regions of the cerebellum and sensorimotor cerebro-cerebellar circuits are associated with deficits in motor control and increased repetitive and stereotyped behaviors in ASD. Further, communication and social impairments are associated with atypical activation and structure in cerebro-cerebellar loops underpinning language and social cognition. Finally, there is converging evidence from structural, functional, and connectivity neuroimaging studies that cerebellar right Crus I/II abnormalities are related to more severe ASD impairments in all domains. We propose that cerebellar abnormalities may disrupt optimization of both structure and function in specific cerebro-cerebellar circuits in ASD. PMID:26594140

  4. Cerebro-cerebellar circuits in autism spectrum disorder.

    PubMed

    D'Mello, Anila M; Stoodley, Catherine J

    2015-01-01

    The cerebellum is one of the most consistent sites of abnormality in autism spectrum disorder (ASD) and cerebellar damage is associated with an increased risk of ASD symptoms, suggesting that cerebellar dysfunction may play a crucial role in the etiology of ASD. The cerebellum forms multiple closed-loop circuits with cerebral cortical regions that underpin movement, language, and social processing. Through these circuits, cerebellar dysfunction could impact the core ASD symptoms of social and communication deficits and repetitive and stereotyped behaviors. The emerging topography of sensorimotor, cognitive, and affective subregions in the cerebellum provides a new framework for interpreting the significance of regional cerebellar findings in ASD and their relationship to broader cerebro-cerebellar circuits. Further, recent research supports the idea that the integrity of cerebro-cerebellar loops might be important for early cortical development; disruptions in specific cerebro-cerebellar loops in ASD might impede the specialization of cortical regions involved in motor control, language, and social interaction, leading to impairments in these domains. Consistent with this concept, structural, and functional differences in sensorimotor regions of the cerebellum and sensorimotor cerebro-cerebellar circuits are associated with deficits in motor control and increased repetitive and stereotyped behaviors in ASD. Further, communication and social impairments are associated with atypical activation and structure in cerebro-cerebellar loops underpinning language and social cognition. Finally, there is converging evidence from structural, functional, and connectivity neuroimaging studies that cerebellar right Crus I/II abnormalities are related to more severe ASD impairments in all domains. We propose that cerebellar abnormalities may disrupt optimization of both structure and function in specific cerebro-cerebellar circuits in ASD.

  5. Cerebellar microfolia and other abnormalities of neuronal growth, migration, and lamination in the Pit1dw-J homozygote mutant mouse

    NASA Technical Reports Server (NTRS)

    Sekiguchi, M.; Abe, H.; Moriya, M.; Tanaka, O.; Nowakowski, R. S.

    1998-01-01

    The Snell dwarf mouse (Pit1dw-J homozygote) has a mutation in the Pit1 gene that prevents the normal formation of the anterior pituitary. In neonates and adults there is almost complete absence of growth hormone (GH), prolactin (PRL), thyroxin (T4), and thyroid-stimulating hormone (TSH). Since these hormones have been suggested to play a role in normal development of the central nervous system (CNS), we have investigated the effects of the Pit1dw-J mutation on the cerebellum and hippocampal formation. In the cerebellum, there were abnormalities of both foliation and lamination. The major foliation anomalies were 1) changes in the relative size of specific folia and also the proportional sizes of the anterior vs posterior cerebellum; and 2) the presence of between one and three microfolia per half cerebellum. The microfolia were all in the medial portion of the hemisphere in the caudal part of the cerebellum. Each microfolium was just rostral to a normal fissure and interposed between the fissure and a normal gyrus. Lamination abnormalities included an increase in the number of single ectopic granule cells in the molecular layer in both cerebellar vermis (86%) and hemisphere (40%) in comparison with the wild-type mouse. In the hippocampus of the Pit1dw-J homozygote mouse, the number of pyramidal cells was decreased, although the width of the pyramidal cell layer throughout areas CA1-CA3 appeared to be normal, but less densely populated than in the wild-type mouse. Moreover, the number of granule cells that form the granule cell layer was decreased from the wild-type mouse and some ectopic granule cells (occurring both as single cells and as small clusters) were observed in the innermost portion of the molecular layer. The abnormalities observed in the Pit1dw-J homozygote mouse seem to be caused by both direct and indirect effects of the deficiency of TSH (or T4), PRL, or GH rather than by a direct effect of the deletion of Pit1.

  6. [Cerebellar stroke].

    PubMed

    Paradowski, Michał; Zimny, Anna; Paradowski, Bogusław

    2015-01-01

    Cerebellar stroke belongs to a group of rare diseases of vascular origin. Cerebellum, supplied by three pairs of arteries (AICA, PICA, SCA) with many anastomoses between them is less susceptible for a stroke, especially ischemic one. Diagnosis of the stroke in this region is harder due to lower sensibility of commonly used CT of the head in case of stroke suspicion. The authors highlight clinical symptoms distinguishing between vascular territories or topographical locations of the stroke, diagnostic procedures, classical and surgical treatment, the most common misdiagnoses are also mentioned. The authors suggest a diagnostic and therapeutic algorithm development, including rtPA treatment criteria for ischemic cerebellar stroke. PMID:26181157

  7. Development of motor coordination and cerebellar structure in male and female rat neonates exposed to hypergravity

    NASA Astrophysics Data System (ADS)

    Nguon, K.; Ladd, B.; Baxter, M. G.; Sajdel-Sulkowska, E. M.

    2006-01-01

    We previously reported that the developing rat cerebellum is affected by exposure to hypergravity. In the present study, we explored the hypothesis that the changes in cerebellar structure in hypergravity-exposed rat neonates may affect their motor coordination. Furthermore, we hypothesized that the changes observed at 1.5G will be magnified at higher gravitational loading. To test this hypothesis, we compared motor behavior, cerebellar structure, and protein expression in rat neonates exposed to 1.5 1.75G on a 24-ft centrifuge daily for 22.5 h starting on gestational day (G) 10, through birth on G22/G23 and through postnatal day (P) 21. Exposure to hypergravity impacted the neurodevelopmental process as indicated by: (1) impaired righting response on P3, more than doubling the righting time at 1.75G, and (2) delayed onset of the startle response by one day, from P9 in controls to P10 in hypergravity-exposed pups. Hypergravity exposure resulted in impaired motor functions as evidenced by performance on a rotarod on P21; the duration of the stay on the rotarod recorded for 1.75G pups of both sexes was one tenth that of the stationary control (SC) pups. These changes in motor behavior were associated with cerebellar changes: (1) cerebellar mass on P6 was decreased by 7.5% in 1.5G-exposed male pups, 27.5% in 1.75G-exposed male pups, 17.5% in 1.5G-exposed female pups, and 22.5% in 1.75G female pups and (2) changes in the expression of glial and neuronal proteins. The results of this study suggest that perinatal exposure to hypergravity affects cerebellar development as evidenced by decreased cerebellar mass and altered cerebellar protein expression; cerebellar changes observed in hypergravity-exposed rat neonates are associated with impaired motor behavior. Furthermore, the response to hypergravity appears to be different in male and female neonates. If one accepts that the hypergravity paradigm is a useful animal model with which to predict those biological processes

  8. Impaired tooth root development after treatment of a cerebellar astrocytoma: A case report

    SciTech Connect

    Eckles, T.A.; Kalkwarf, K.L.

    1989-10-01

    A young man, previously treated by surgical resection of a grade III cerebellar astrocytoma in combination with irradiation and chemotherapy, was found to display severe generalized root agenesis. This patient also exhibited secondary hypothyroidism and decreased levels of growth hormone. These factors are discussed in relation to their possible role in impaired root development.

  9. Development of external surfaces of human cerebellar lobes in the fetal period.

    PubMed

    Nowakowska-Kotas, Marta; Kędzia, Alicja; Dudek, Krzysztof

    2014-10-01

    In the fetal period, development of cerebellar lobes may proceed dissimilarly due to possible differentiated origins of the cells and diversified times of their migration to certain cerebellum regions. This can cause various growth trajectories for the external surfaces of cerebellar lobes. The goal of the study was to describe the development of the external surface of cerebellum lobes and fissures delineating them in the fetal period. The material consisted of 101 fetuses (48 males and 53 females)-crown rump length 89-229 mm corresponding to 15-28 weeks of fetal life. The methods were based on anthropometric measurements and preparation techniques combined with elicited image computer analysis. At the largest values of the cerebellum posterior lobe surface, the most dynamic growth rate was observed in the case of the anterior lobe. Among the cerebellar lobes, proportional change was observed as well as a gradual increase in anterior lobe surface area and a simultaneous decrease in the surface area of the flocculonodular lobe part of the cerebellum total external surface. This paper presents the different growth trajectories of cerebellar lobes and demonstrates the importance of the primary fissure as a delineating mark for two regions with different dynamics of development.

  10. Cellular and genetic regulation of the development of the cerebellar system.

    PubMed

    Sotelo, Constantino

    2004-04-01

    Recent advances in molecular biology have drastically changed our vision on the development of the nervous system, the cerebellum in particular. After a classical descriptive period, we are now in a modern mechanistic epoch as we begin to answer crucial questions in our quest to understand the mechanisms underlying the emergence of brain complexity. This review begins with an analysis of the role of the "isthmic organizer" in the induction and specification of the cerebellar territory and progresses through cerebellar development to the formation of cerebellar maps. It gathers information about the control of the proliferation of granule cell precursors by Purkinje cells and the role of Shh/Gli-patched signaling. The migratory routes for cerebellar and precerebellar neurons, together with the long-range and short-range cues guiding gliophilic and, particularly, neurophilic migrations, are also discussed. Because these cues are similar to those involved in axon guidance, both processes are under the same molecular constraints. Finally, using primarily the olivocerebellar projection as a model, the cellular and molecular mechanisms involved in the formation of cerebellar maps are discussed. During embryonic development, Purkinje cells in the cerebellum and neurons in the inferior olive follow a simultaneous, but independent, process of intrinsic parcellation, giving rise to subsets of biochemically different cortical compartments. The occurrence of positional information shared between olivary axons and their postsynaptic targets, the Purkinje cells, provides a molecular code for the formation of coarse-grained maps. Activity-dependent mechanisms are required for the transition from crude to fine-grained maps. This important refinement, which confers ultimate specificity to the maps, is under the regulation of parallel fiber-Purkinje cell synaptic activity.

  11. AMPA receptors in cerebellar granule cells during development in culture.

    PubMed

    Hack, N J; Sluiter, A A; Balázs, R

    1995-06-27

    The survival and maturation of differentiating cerebellar granule cells in culture are known to be promoted by excitatory amino acids (EAAs) which, however, compromise the survival of mature cells. In contrast to the trophic effect, the toxic effect of alpha-amino-3-hydroxy-5-methyl-4-isoxasolepropiate (AMPA) could only be elicited when the desensitisation of AMPA receptors was blocked, cyclothiazide being used in this study. Nevertheless, even under these conditions, toxicity induced by AMPA in contrast to kainate was, at 9 DIV, only half of the maximal toxicity attained by 13-16 DIV. Since cellular responses to AMPA depend so dramatically on the maturational stage of granule cells, we examined here whether this characteristic is related to developmental changes in AMPA receptor properties, which may result from changes in the subunit composition of the receptor. In contrast to toxicity, AMPA-induced 45Ca2+ influx (determined in the presence of cyclothiazide and the NMDA receptor blocker MK-801) reached a maximum already at 9 DIV. This also applied to a fraction of the 45Ca2+ uptake which persisted either after Cd2+ application or under Na(+)-free conditions and therefore presumably was mediated directly through AMPA receptor channels. Quantitative analysis of Western blots showed that the amounts of GluR4 and to a lesser extent GluR2/3/4c are substantial already at 2 DIV, remaining fairly constant until 9 DIV, followed by an increase by 16 DIV. However GluR1, which is hardly detectable in granule cells in vivo and is also low early in vitro, increased almost linearly with cultivation time.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Effect of methotrexate on cerebellar development in infant rats.

    PubMed

    Sugiyama, Akihiko; Sun, Jing; Ueda, Kota; Furukawa, Satoshi; Takeuchi, Takashi

    2015-07-01

    Six-day-old rats were treated intraperitoneal injections with methotrexate 1 mg/kg, and the cerebellum was examined. Both the length and width of the vermis decreased in the methotrexate-treated group instead of the control from 4 day after treatment (DAT) onward. A significant reduction in the width of the external granular layer was detected on 2 and 3 DAT in the methotrexate group. By 4 DAT, the width of the external granular layer of the methotrexate group was indistinguishable from the control, and by 8 DAT, it was greater than that of the control. The molecular layer of methotrexate group on 8 and 15 DAT was thinner than that of the control. On 1 DAT, in the methotrexate group, there were many TUNEL and cleaved caspase-3-positive granular cells throughout the external granular layer, and they decreased time-dependently. On 1 DAT, in the methotrexate group, phospho-histone H3-positive cells in the external granular layer were fewer than in the control and tended to increase on 2-4 DAT. The p21-positive-rate of the external granule cells in the MTX group was higher than in the control on 1-4 DAT. These results suggested that methotrexate exposure on postnatal day 6 induces a delay, slowing in the migration of external granular cells to the inner granular layer, attributed to decrease or inhibition in the production of external granular cells that had arisen from apoptosis and the decrease in cell proliferative activity, resulting in cerebellar hypoplasia.

  13. Cerebellar disorders in childhood: cognitive problems.

    PubMed

    Steinlin, Maja

    2008-01-01

    Over the last decade, increasing evidence of cognitive functions of the cerebellum during development and learning processes could be ascertained. Posterior fossa malformations such as cerebellar hypoplasia or Joubert syndrome are known to be related to developmental problems in a marked to moderate extent. More detailed analyses reveal special deficits in attention, processing speed, visuospatial functions, and language. A study about Dandy Walker syndrome states a relationship of abnormalities in vermis lobulation with developmental problems. Further lobulation or volume abnormalities of the cerebellum and/or vermis can be detected in disorders as fragile X syndrome, Downs's syndrome, William's syndrome, and autism. Neuropsychological studies reveal a relation of dyslexia and attention deficit disorder with cerebellar functions. These functional studies are supported by structural abnormalities in neuroimaging in these disorders. Acquired cerebellar or vermis atrophy was found in groups of children with developmental problems such as prenatal alcohol exposure or extreme prematurity. Also, focal lesions during childhood or adolescence such as cerebellar tumor or stroke are related with neuropsychological abnormalities, which are most pronounced in visuospatial, language, and memory functions. In addition, cerebellar atrophy was shown to be a bad prognostic factor considering cognitive outcome in children after brain trauma and leukemia. In ataxia teleangiectasia, a neurodegenerative disorder affecting primarily the cerebellar cortex, a reduced verbal intelligence quotient and problems of judgment of duration are a hint of the importance of the cerebellum in cognition. In conclusion, the cerebellum seems to play an important role in many higher cognitive functions, especially in learning. There is a suggestion that the earlier the incorrect influence, the more pronounced the problems.

  14. [A case of cerebral gigantism with cerebellar atrophy].

    PubMed

    Kitazawa, K; Ikeda, M; Tsukagoshi, H

    1990-05-01

    A 37-year-old housewife, who had physical characteristics of cerebral gigantism, such as the tall stature, acromegaly, macrocephalia, high arched palate and antimongoloid slant, developed cerebellar ataxia and dysarthria. Her mother, uncle and grandmother were also reported to have slowly progressive gait disturbance. Her mother was also tall. Endocrinological studies failed to show any definite abnormality. CT and MRI revealed remarkable cerebellar atrophy. Though cerebral gigantism is often associated with clumsiness and incoordination, the etiology of the ataxia is poorly understood. This case indicates that the ataxia in cerebral gigantism may be, at least partly, caused by cerebellar atrophy. PMID:2401112

  15. Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

    PubMed Central

    Baldarçara, Leonardo; Currie, Stuart; Hadjivassiliou, M.; Hoggard, Nigel; Jack, Allison; Jackowski, Andrea P.; Mascalchi, Mario; Parazzini, Cecilia; Reetz, Kathrin; Righini, Andrea; Schulz, Jörg B.; Vella, Alessandra; Webb, Sara Jane; Habas, Christophe

    2016-01-01

    Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine. PMID:25382714

  16. Establishment of Gal4 transgenic zebrafish lines for analysis of development of cerebellar neural circuitry.

    PubMed

    Takeuchi, Miki; Matsuda, Koji; Yamaguchi, Shingo; Asakawa, Kazuhide; Miyasaka, Nobuhiko; Lal, Pradeep; Yoshihara, Yoshihiro; Koga, Akihiko; Kawakami, Koichi; Shimizu, Takashi; Hibi, Masahiko

    2015-01-01

    The cerebellum is involved in some forms of motor coordination and motor learning. Here we isolated transgenic (Tg) zebrafish lines that express a modified version of Gal4-VP16 (GFF) in the cerebellar neural circuits: granule, Purkinje, or eurydendroid cells, Bergmann glia, or the neurons in the inferior olive nuclei (IO) which send climbing fibers to Purkinje cells, with the transposon Tol2 system. By combining GFF lines with Tg lines carrying a reporter gene located downstream of Gal4 binding sequences (upstream activating sequence: UAS), we investigated the anatomy and developmental processes of the cerebellar neural circuitry. Combining an IO-specific Gal4 line with a UAS reporter line expressing the photoconvertible fluorescent protein Kaede demonstrated the contralateral projections of climbing fibers. Combining a granule cell-specific Gal4 line with a UAS reporter line expressing wheat germ agglutinin (WGA) confirmed direct and/or indirect connections of granule cells with Purkinje cells, eurydendroid cells, and IO neurons in zebrafish. Time-lapse analysis of a granule cell-specific Gal4 line revealed initial random movements and ventral migration of granule cell nuclei. Transgenesis of a reporter gene with another transposon Tol1 system visualized neuronal structure at a single cell resolution. Our findings indicate the usefulness of these zebrafish Gal4 Tg lines for studying the development and function of cerebellar neural circuits.

  17. CNS development under altered gravity: cerebellar glial and neuronal protein expression in rat neonates exposed to hypergravity

    NASA Astrophysics Data System (ADS)

    Nguon, K.; Li, G.-H.; Sajdel-Sulkowska, E. M.

    2004-01-01

    The future of space exploration depends on a solid understanding of the developmental process under microgravity, specifically in relation to the central nervous system (CNS). We have previously employed a hypergravity paradigm to assess the impact of altered gravity on the developing rat cerebellum [Exp. Biol. Med. 226 (2000) 790]. The present study addresses the molecular mechanisms involved in the cerebellar response to hypergravity. Specifically, the study focuses on the expression of selected glial and neuronal cerebellar proteins in rat neonates exposed to hypergravity (1.5 G) from embryonic day (E)11 to postnatal day (P)6 or P9 (the time of maximal cerebellar changes) comparing them against their expression in rat neonates developing under normal gravity. Proteins were analyzed by quantitative Western blots of cerebellar homogenates; RNA analysis was performed in the same samples using quantitative PCR. Densitometric analysis of Western blots suggested a reduction in glial (glial acidic protein, GFAP) and neuronal (neuronal cell adhesion moiecule, NCAM-L1, synaptophysin) proteins, but the changes in individual cerebellar proteins in hypergravity-exposed neonates appeared both age- and gender-specific. RNA analysis suggested a reduction in GFAP and synaptophysin mRNAs on P6. These data suggest that exposure to hypergravity may interfere with the expression of selected cerebellar proteins. These changes in protein expression may be involved in mediating the effect of hypergravity on the developing rat cerebellum.

  18. CNS development under altered gravity: cerebellar glial and neuronal protein expression in rat neonates exposed to hypergravity

    NASA Technical Reports Server (NTRS)

    Nguon, K.; Li, G-H; Sajdel-Sulkowska, E. M.

    2004-01-01

    The future of space exploration depends on a solid understanding of the developmental process under microgravity, specifically in relation to the central nervous system (CNS). We have previously employed a hypergravity paradigm to assess the impact of altered gravity on the developing rat cerebellum. The present study addresses the molecular mechanisms involved in the cerebellar response to hypergravity. Specifically, the study focuses on the expression of selected glial and neuronal cerebellar proteins in rat neonates exposed to hypergravity (1.5 G) from embryonic day (E)11 to postnatal day (P)6 or P9 (the time of maximal cerebellar changes) comparing them against their expression in rat neonates developing under normal gravity. Proteins were analyzed by quantitative Western blots of cerebellar homogenates; RNA analysis was performed in the same samples using quantitative PCR. Densitometric analysis of Western blots suggested a reduction in glial (glial acidic protein, GFAP) and neuronal (neuronal cell adhesion molecule, NCAM-L1, synaptophysin) proteins, but the changes in individual cerebellar proteins in hypergravity-exposed neonates appeared both age- and gender-specific. RNA analysis suggested a reduction in GFAP and synaptophysin mRNAs on P6. These data suggest that exposure to hypergravity may interfere with the expression of selected cerebellar proteins. These changes in protein expression may be involved in mediating the effect of hypergravity on the developing rat cerebellum. c2003 COSPAR. Published by Elsevier Ltd. All rights reserved.

  19. Mice lacking the transcription factor SHOX2 display impaired cerebellar development and deficits in motor coordination.

    PubMed

    Rosin, Jessica M; McAllister, Brendan B; Dyck, Richard H; Percival, Christopher J; Kurrasch, Deborah M; Cobb, John

    2015-03-01

    Purkinje cells of the developing cerebellum secrete the morphogen sonic hedgehog (SHH), which is required to maintain the proliferative state of granule cell precursors (GCPs) prior to their differentiation and migration to form the internal granule layer (IGL). Despite a wealth of knowledge regarding the function of SHH during cerebellar development, the upstream regulators of Shh expression during this process remain largely unknown. Here we report that the murine short stature homeobox 2 (Shox2) gene is required for normal Shh expression in dorsal-residing Purkinje cells. Using two different Cre drivers, we show that elimination of Shox2 in the brain results in developmental defects in the inferior colliculus and cerebellum. Specifically, loss of Shox2 in the cerebellum results in precocious differentiation and migration of GCPs from the external granule layer (EGL) to the IGL. This correlates with premature bone morphogenetic protein 4 (Bmp4) expression in granule cells of the dorsal cerebellum. The size of the neonatal cerebellum is reduced in Shox2-mutant animals, which is consistent with a reduction in the number of GCPs present in the EGL, and could account for the smaller vermis and thinner IGL present in adult Shox2mutants. Shox2-mutant mice also display reduced exploratory activity, altered gait and impaired motor coordination. Our findings are the first to show a role for Shox2 in brain development. We provide evidence that Shox2 plays an important role during cerebellar development, perhaps to maintain the proper balance of Shh and Bmp expression levels in the dorsal vermis, and demonstrate that in the absence of Shox2, mice display both cerebellar impairments and deficits in motor coordination, ultimately highlighting the importance of Shox2 in the cerebellum.

  20. Neurotoxicological effects of nicotine on the embryonic development of cerebellar cortex of chick embryo during various stages of incubation.

    PubMed

    El-Beltagy, Abd El-Fattah B M; Abou-El-Naga, Amoura M; Sabry, Dalia M

    2015-10-01

    Long-acting nicotine is known to exert pathological effects on almost all tissues including the cerebellar cortex. The present work was designed to elucidate the effect of nicotine on the development of cerebellar cortex of chick embryo during incubation period. The fertilized eggs of hen (Gallus gallus domesticus) were injected into the air space by a single dose of long acting nicotine (1.6 mg/kg/egg) at the 4th day of incubation. The embryos were taken out of the eggs on days 8, 12 and 16 of incubation. The cerebellum of the control and treated embryos at above ages were processed for histopathological examination. The TEM were examined at 16th day of incubation. The results of the present study revealed that, exposure to long-acting nicotine markedly influence the histogenesis of cerebellar cortex of chick embryo during the incubation period. At 8th day of incubation, nicotine delayed the differentiation of the cerebellar analge; especially the external granular layer (EGL) and inner cortical layer (ICL). Furthermore, at 12th day of incubation, the cerebellar foliation was irregular and the Purkinje cells not recognized. By 16th day of incubation, the cerebellar foliations were irregular with interrupted cerebellar cortex and irregular arrangement of Purkinje cells. Immunohistochemical analysis for antibody P53 protein revealed that the cerebellar cortex in all stages of nicotine treated groups possessed a moderate to weak reaction for P53 protein however; this reaction was markedly stronger in the cerebellar cortex of control groups. Moreover, the flow cytometric analysis confirmed that the percentage of apoptosis in control group was significantly higher compared with that of nicotine treated group. At the TEM level, the cerebellar Purkinje cells of 16th day of treated groups showed multiple subcellular alterations in compared with those of the corresponding control group. Such changes represented by appearing of vacuolated mitochondria, cisternal

  1. Nuclear factor I and cerebellar granule neuron development: an intrinsic-extrinsic interplay.

    PubMed

    Kilpatrick, Daniel L; Wang, Wei; Gronostajski, Richard; Litwack, E David

    2012-03-01

    Granule neurons have a central role in cerebellar function via their synaptic interactions with other neuronal cell types both within and outside this structure. Establishment of these synaptic connections and its control is therefore essential to their function. Both intrinsic as well as environmental mechanisms are required for neuronal development and formation of neuronal circuits, and a key but poorly understood question is how these various events are coordinated and integrated in maturing neurons. In this review, we summarize recent work on the role of the Nuclear Factor I family in the transcriptional programming of cerebellar granule neuron maturation and synapse formation. In particular, we describe (1) the involvement of this family of factors in key developmental steps occurring throughout postmitotic granule neuron development, including dendrite and synapse formation and synaptic receptor expression, and (2) the mediation of these actions by critical downstream gene targets that control cell-cell interactions. These findings illustrate how Nuclear Factor I proteins and their regulons function as a “bridge” between cell-intrinsic and cell-extrinsic interactions to control multiple phases of granule neuron development.

  2. Ethanol exposure during development reduces GABAergic/glycinergic neuron numbers and lobule volumes in the mouse cerebellar vermis.

    PubMed

    Nirgudkar, Pranita; Taylor, Devin H; Yanagawa, Yuchio; Valenzuela, C Fernando

    2016-10-01

    Cerebellar alterations are a hallmark of Fetal Alcohol Spectrum Disorders and are thought to be responsible for deficits in fine motor control, motor learning, balance, and higher cognitive functions. These deficits are, in part, a consequence of dysfunction of cerebellar circuits. Although the effect of developmental ethanol exposure on Purkinje and granule cells has been previously characterized, its actions on other cerebellar neuronal populations are not fully understood. Here, we assessed the impact of repeated ethanol exposure on the number of inhibitory neurons in the cerebellar vermis. We exposed pregnant mice to ethanol in vapor inhalation chambers during gestational days 12-19 and offspring during postnatal days 2-9. We used transgenic mice expressing the fluorescent protein, Venus, in GABAergic/glycinergic neurons. Using unbiased stereology techniques, we detected a reduction in Venus positive neurons in the molecular and granule cell layers of lobule II in the ethanol exposed group at postnatal day 16. In contrast, ethanol produced a more widespread reduction in Purkinje cell numbers that involved lobules II, IV-V and IX. We also found a reduction in the volume of lobules II, IV-V, VI-VII, IX and X in ethanol-exposed pups. These findings indicate that second and third trimester-equivalent ethanol exposure has a greater impact on Purkinje cells than interneurons in the developing cerebellar vermis. The decrease in the volume of most lobules could be a consequence of a reduction in cell numbers, dendritic arborizations, or axonal projections.

  3. Ethanol exposure during development reduces GABAergic/glycinergic neuron numbers and lobule volumes in the mouse cerebellar vermis.

    PubMed

    Nirgudkar, Pranita; Taylor, Devin H; Yanagawa, Yuchio; Valenzuela, C Fernando

    2016-10-01

    Cerebellar alterations are a hallmark of Fetal Alcohol Spectrum Disorders and are thought to be responsible for deficits in fine motor control, motor learning, balance, and higher cognitive functions. These deficits are, in part, a consequence of dysfunction of cerebellar circuits. Although the effect of developmental ethanol exposure on Purkinje and granule cells has been previously characterized, its actions on other cerebellar neuronal populations are not fully understood. Here, we assessed the impact of repeated ethanol exposure on the number of inhibitory neurons in the cerebellar vermis. We exposed pregnant mice to ethanol in vapor inhalation chambers during gestational days 12-19 and offspring during postnatal days 2-9. We used transgenic mice expressing the fluorescent protein, Venus, in GABAergic/glycinergic neurons. Using unbiased stereology techniques, we detected a reduction in Venus positive neurons in the molecular and granule cell layers of lobule II in the ethanol exposed group at postnatal day 16. In contrast, ethanol produced a more widespread reduction in Purkinje cell numbers that involved lobules II, IV-V and IX. We also found a reduction in the volume of lobules II, IV-V, VI-VII, IX and X in ethanol-exposed pups. These findings indicate that second and third trimester-equivalent ethanol exposure has a greater impact on Purkinje cells than interneurons in the developing cerebellar vermis. The decrease in the volume of most lobules could be a consequence of a reduction in cell numbers, dendritic arborizations, or axonal projections. PMID:27565053

  4. [EXPRESSION OF DOUBLECORTIN AND NeuN IN THE DEVELOPING CEREBELLAR NEURONS IN RAT].

    PubMed

    Zimatkin, S M; Karniushko, O A

    2016-01-01

    This work was performed on the offspring of 5 outbred female albino rats to give a comparative immunohistochemical evaluation of doublecortin (DCX) and NeuN expression in the neurons of the cerebellar cortex and nucleus interpositus in the early postnatal ontogenesis (postnatal days 2-15). DCX expression was detected in postmitotic neurons of the external granular layer and migrating neurons of the cerebellar cortex. At postnatal days 2 and 7 DCX expression in neocerebellum was higher than in paleocerebellum. NeuN expression was found to appear in migrating granule neurons, and reach the maximum in mature neurons of internal granular layer. DCX expression was not detected in Purkinje cells and in the nucleus interpositus of the cerebellum. In neurons of the nucleus interpositus the expression of NeuN progressively increased from postnatal days 2 to 15. Thus, a comparative immunohistochemical study of the dynamics of the expression of the pair of molecular markers studied proved to be an effective way of the assessment of the development of granular neurons of the cerebellum in early postnatal ontogenesis. PMID:27487661

  5. [EXPRESSION OF DOUBLECORTIN AND NeuN IN THE DEVELOPING CEREBELLAR NEURONS IN RAT].

    PubMed

    Zimatkin, S M; Karniushko, O A

    2016-01-01

    This work was performed on the offspring of 5 outbred female albino rats to give a comparative immunohistochemical evaluation of doublecortin (DCX) and NeuN expression in the neurons of the cerebellar cortex and nucleus interpositus in the early postnatal ontogenesis (postnatal days 2-15). DCX expression was detected in postmitotic neurons of the external granular layer and migrating neurons of the cerebellar cortex. At postnatal days 2 and 7 DCX expression in neocerebellum was higher than in paleocerebellum. NeuN expression was found to appear in migrating granule neurons, and reach the maximum in mature neurons of internal granular layer. DCX expression was not detected in Purkinje cells and in the nucleus interpositus of the cerebellum. In neurons of the nucleus interpositus the expression of NeuN progressively increased from postnatal days 2 to 15. Thus, a comparative immunohistochemical study of the dynamics of the expression of the pair of molecular markers studied proved to be an effective way of the assessment of the development of granular neurons of the cerebellum in early postnatal ontogenesis.

  6. Twitch-related and rhythmic activation of the developing cerebellar cortex

    PubMed Central

    Plumeau, Alan M.; Mukherjee, Didhiti; Blumberg, Mark S.

    2015-01-01

    The cerebellum is a critical sensorimotor structure that exhibits protracted postnatal development in mammals. Many aspects of cerebellar circuit development are activity dependent, but little is known about the nature and sources of the activity. Based on previous findings in 6-day-old rats, we proposed that myoclonic twitches, the spontaneous movements that occur exclusively during active sleep (AS), provide generalized as well as topographically precise activity to the developing cerebellum. Taking advantage of known stages of cerebellar cortical development, we examined the relationship between Purkinje cell activity (including complex and simple spikes), nuchal and hindlimb EMG activity, and behavioral state in unanesthetized 4-, 8-, and 12-day-old rats. AS-dependent increases in complex and simple spike activity peaked at 8 days of age, with 60% of units exhibiting significantly more activity during AS than wakefulness. Also, at all three ages, approximately one-third of complex and simple spikes significantly increased their activity within 100 ms of twitches in one of the two muscles from which we recorded. Finally, we observed rhythmicity of complex and simple spikes that was especially prominent at 8 days of age and was greatly diminished by 12 days of age, likely due to developmental changes in climbing fiber and mossy fiber innervation patterns. All together, these results indicate that the neurophysiological activity of the developing cerebellum can be used to make inferences about changes in its microcircuitry. They also support the hypothesis that sleep-related twitches are a prominent source of discrete climbing and mossy fiber activity that could contribute to the activity-dependent development of this critical sensorimotor structure. PMID:26156383

  7. NMDA receptor-dependent CREB activation in survival of cerebellar granule cells during in vivo and in vitro development.

    PubMed

    Monti, Barbara; Marri, Lucia; Contestabile, Antonio

    2002-10-01

    During both in vivo and in vitro development, cerebellar granule cells depend on the activity of the NMDA glutamate receptor subtype for survival and full differentiation. With the present results, we demonstrate that CREB activation, downstream of the NMDA receptor, is a necessary step to ensure survival of these neurons. The levels of CREB expression and activity increase progressively during the second week of postnatal cerebellar development and the phosphorylated form of CREB is localized selectively to cerebellar granule cells during the critical developmental stages examined. Chronically blocking the NMDA receptor through systemic administration of the competitive antagonist, CGP 39551, during the in vivo critical developmental period, between 7-11 postnatal days, results in increased apoptotic elimination of differentiating granule neurons in the cerebellum [Monti & Contestabile, Eur. J. Neurosci., 12, 3117-3123 (2000)]. We report here that this event is accompanied by a significant decrease of CREB phosphorylation in the cerebellum of treated rat pups. When cerebellar granule neurons are explanted and maintained in dissociated cultures, the levels of CREB phosphorylation increase with differentiation, similar to that which happens during in vivo development. When granule cells are kept in non-trophic conditions, their viability is affected and both CREB phosphorylation and transcriptional activity are decreased significantly. The neuronal viability and the deficiency of CREB activity, are both rescued by the pharmacological activation of the NMDA receptor. These results provide good circumstantial evidence for a functional link between the NMDA receptor and CREB activity in promoting neuronal survival during development.

  8. A new autosomal recessive non-progressive congenital cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities (CAMOS) maps to chromosome 15q24-q26 in a large consanguineous Lebanese Druze Family.

    PubMed

    Delague, Valérie; Bareil, Corinne; Bouvagnet, Patrice; Salem, Nabiha; Chouery, Eliane; Loiselet, Jacques; Mégarbané, André; Claustres, Mireille

    2002-03-01

    Congenital cerebellar ataxias are a heterogeneous group of non-progressive disorders characterized by hypotonia and developmental delay followed by the appearance of ataxia, and often associated with dysarthria, mental retardation, and atrophy of the cerebellum. We report the mapping of a disease gene in a large inbred Lebanese Druze family, with five cases of a new form of non-progressive autosomal recessive congenital ataxia associated with optic atrophy, severe mental retardation, and structural skin abnormalities, to a 3.6-cM interval on chromosome 15q24-15q26.

  9. Cerebellar Hypoplasia

    MedlinePlus

    ... disorders that begin in early childhood, such as ataxia telangiectasia. In an infant or young child, symptoms of a disorder that features cerebellar hypoplasia might include floppy muscle tone, developmental or ...

  10. Cerebellar Degeneration

    MedlinePlus

    ... Degeneration? Cerebellar degeneration is a process in which neurons in the cerebellum - the area of the brain ... proteins that are necessary for the survival of neurons. Associated diseases: Diseases that are specific to the ...

  11. The anatomy and development of normal and abnormal coronary arteries.

    PubMed

    Spicer, Diane E; Henderson, Deborah J; Chaudhry, Bill; Mohun, Timothy J; Anderson, Robert H

    2015-12-01

    At present, there is significant interest in the morphology of the coronary arteries, not least due to the increasingly well-recognised association between anomalous origin of the arteries and sudden cardiac death. Much has also been learnt over the last decade regarding the embryology of the arteries. In this review, therefore, we provide a brief introduction into the recent findings regarding their development. In particular, we emphasise that new evidence, derived using the developing murine heart, points to the arterial stems growing out from the adjacent sinuses of the aortic root, rather than the arteries growing in, as is currently assumed. As we show, the concept of outgrowth provides an excellent explanation for several of the abnormal arrangements encountered in the clinical setting. Before summarising these abnormal features, we draw attention to the need to describe the heart in an attitudinally appropriate manner, following the basic rule of human anatomy, rather than describing the cardiac components with the heart in the "Valentine" orientation. We then show how the major abnormalities involving the coronary arteries in humans can be summarised in terms of abnormal origin from the pulmonary circulation, abnormal aortic origin, or fistulous communications between the coronary arteries and the cardiac cavities. In the case of abnormal aortic origin, we highlight those malformations known to be associated with sudden cardiac death.

  12. Gross Motor Development, Movement Abnormalities, and Early Identification of Autism

    ERIC Educational Resources Information Center

    Ozonoff, Sally; Young, Gregory S.; Goldring, Stacy; Greiss-Hess, Laura; Herrera, Adriana M.; Steele, Joel; Macari, Suzanne; Hepburn, Susan; Rogers, Sally J.

    2008-01-01

    Gross motor development (supine, prone, rolling, sitting, crawling, walking) and movement abnormalities were examined in the home videos of infants later diagnosed with autism (regression and no regression subgroups), developmental delays (DD), or typical development. Group differences in maturity were found for walking, prone, and supine, with…

  13. Prenatal exposure to bisphenol A interferes with the development of cerebellar granule neurons in mice and chicken.

    PubMed

    Mathisen, Gro H; Yazdani, Mazyar; Rakkestad, Kirsten E; Aden, Petra K; Bodin, Johanna; Samuelsen, Mari; Nygaard, Unni C; Goverud, Ingeborg L; Gaarder, Mona; Løberg, Else Marit; Bølling, Anette K; Becher, Rune; Paulsen, Ragnhild E

    2013-12-01

    In mice, prenatal exposure to low doses of bisphenol A has been shown to affect neurogenesis and neuronal migration in cortex, resulting in disturbance of both neuronal positioning and the network formation between thalamus and cortex in the offspring brain. In the present study we investigated whether prenatal exposure to bisphenol A disturbs the neurodevelopment of the cerebellum. Two different model systems were used; offspring from two strains of mice from mothers receiving bisphenol A in the drinking water before mating, during gestation and lactation, and chicken embryos exposed to bisphenol A (in the egg) on embryonic day 16 for 24h before preparation of cerebellar granule cell cultures. In the cerebellum, tight regulation of the level of transcription factor Pax6 is critical for correct development of granule neurons. During the development, the Pax6 level in granule neurons is high when these cells are located in the external granule layer and during their migration to the internal granule layer, and it is then reduced. We report that bisphenol A induced an increase in the thickness of the external granule layer and also an increase in the total cerebellar Pax6 level in 11 days old mice offspring. In cultured chicken cerebellar granule neurons from bisphenol A injected eggs the Pax6 level was increased day 6 in vitro. Together, these findings indicate that bisphenol A may affect the granule neurons in the developing cerebellum and thereby may disturb the correct development of the cerebellum.

  14. Rapid development of Purkinje cell excitability, functional cerebellar circuit, and afferent sensory input to cerebellum in zebrafish.

    PubMed

    Hsieh, Jui-Yi; Ulrich, Brittany; Issa, Fadi A; Wan, Jijun; Papazian, Diane M

    2014-01-01

    The zebrafish has significant advantages for studying the morphological development of the brain. However, little is known about the functional development of the zebrafish brain. We used patch clamp electrophysiology in live animals to investigate the emergence of excitability in cerebellar Purkinje cells, functional maturation of the cerebellar circuit, and establishment of sensory input to the cerebellum. Purkinje cells are born at 3 days post-fertilization (dpf). By 4 dpf, Purkinje cells spontaneously fired action potentials in an irregular pattern. By 5 dpf, the frequency and regularity of tonic firing had increased significantly and most cells fired complex spikes in response to climbing fiber activation. Our data suggest that, as in mammals, Purkinje cells are initially innervated by multiple climbing fibers that are winnowed to a single input. To probe the development of functional sensory input to the cerebellum, we investigated the response of Purkinje cells to a visual stimulus consisting of a rapid change in light intensity. At 4 dpf, sudden darkness increased the rate of tonic firing, suggesting that afferent pathways carrying visual information are already active by this stage. By 5 dpf, visual stimuli also activated climbing fibers, increasing the frequency of complex spiking. Our results indicate that the electrical properties of zebrafish and mammalian Purkinje cells are highly conserved and suggest that the same ion channels, Nav1.6 and Kv3.3, underlie spontaneous pacemaking activity. Interestingly, functional development of the cerebellum is temporally correlated with the emergence of complex, visually-guided behaviors such as prey capture. Because of the rapid formation of an electrically-active cerebellum, optical transparency, and ease of genetic manipulation, the zebrafish has great potential for functionally mapping cerebellar afferent and efferent pathways and for investigating cerebellar control of motor behavior.

  15. CLP1 Founder Mutation Links tRNA Splicing and Maturation to Cerebellar Development and Neurodegeneration

    PubMed Central

    Schaffer, Ashleigh E.; Eggens, Veerle R.C.; Caglayan, Ahmet Okay; Reuter, Miriam S.; Scott, Eric; Coufal, Nicole G.; Silhavy, Jennifer L.; Xue, Yuanchao; Kayserili, Hulya; Yasuno, Katsuhito; Rosti, Rasim Ozgur; Abdellateef, Mostafa; Caglar, Caner; Kasher, Paul R.; Cazemier, J. Leonie; Weterman, Marian A.; Cantagrel, Vincent; Cai, Na; Zweier, Christiane; Altunoglu, Umut; Satkin, N. Bilge; Aktar, Fesih; Tuysuz, Beyhan; Yalcinkaya, Cengiz; Caksen, Huseyin; Bilguvar, Kaya; Fu, Xiang-Dong; Trotta, Christopher; Gabriel, Stacey; Reis, André; Gunel, Murat; Baas, Frank; Gleeson, Joseph G.

    2014-01-01

    SUMMARY Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of over 2000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild type but not mutant human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data links tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans. PMID:24766810

  16. Development of voltage-activated potassium currents in cultured cerebellar granule neurons under different growth conditions.

    PubMed

    Gorter, J A; Aronica, E; Hack, N J; Balázs, R; Wadman, W J

    1995-07-01

    1. The functional expression of two potassium currents in cultured cerebellar granule cells was investigated with the whole cell patch-clamp technique in relation to development and growth condition. Cells were grown in medium containing different concentrations of potassium: 25 mM (K25) and 40 mM (K40), together referred to as "high K+"; 10 mM (K10) or "low K+"; and K10 with 100 microM N-methyl-D-aspartate (KNMDA). All conditions are known to influence maturation and survival of granule cells in culture. 2. At 2 days in vitro (DIV) the membrane capacitance, taken as index of membrane surface area, was the same for cells grown in each growth condition. At 7-9 DIV it had increased in each condition, but to a substantially larger extent in cells grown in KNMDA, K25, and K40 than in cells grown in K10. During development the input resistance only decreased in cells grown in KNMDA and high K+. 3. A delayed potassium current (IK) and a fast transient potassium current (IA) could both be recorded at 2 DIV in each growth condition, although a few neurons only expressed the IK. The IK was partially suppressed by tetraethylammonium (5 mM), whereas IA was predominantly sensitive to 4-aminopyridine (5 mM). 4. Normalized for cell capacitance, the specific IA conductance hardly changed during development in cells grown in high K+ and KNMDA. Cells in K10, however, displayed an IA with totally different properties in 23 of 24 cells; the specific IA conductance in these cells was considerably smaller at 7-9 DIV, suggesting a deletion of these channels during development.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Unilateral cerebellar aplasia.

    PubMed

    Boltshauser, E; Steinlin, M; Martin, E; Deonna, T

    1996-02-01

    We describe three children with unilateral cerebellar aplasia (UCA). Deliveries at term and neonatal periods were uneventful. Pregnancy was normal in one and complicated by mild bleeding (in second and fourth month respectively) in two instances. Presenting signs were delayed motor development with marked contralateral torticollis (n = 1), hemiplegia (n = 1) and unusual head nodding (n = 1). Neuroradiological investigations revealed complete aplasia (n = 1) and subtotal aplasia (n = 2) of one cerebellar hemisphere with only a residual wing-like structure below the tentorium. There was contralateral underdevelopment of the brainstem. The infant with hemiplegic cerebral palsy had an additional supratentorial periventricular parenchymal defect, contralateral to the cerebellar hypoplasia. In view of literature reports, describing similar neuroradiological or neuropathological findings in asymptomatic individuals, it is doubtful whether UCA is responsible for our patient's problems. In our cases UCA has presumably resulted from a prenatal destructive lesion, possibly an infarct, but the timing and exact nature are unknown. PMID:8677027

  18. Development of the cerebellar afferent system in the shark Scyliorhinus canicula: insights into the basal organization of precerebellar nuclei in gnathostomes.

    PubMed

    Pose-Méndez, Sol; Candal, Eva; Adrio, Fátima; Rodríguez-Moldes, Isabel

    2014-01-01

    The cerebellum is recognized as an evolutionary innovation of jawed vertebrates, whose most primitive group is represented by the chondrichthyans, or cartilaginous fishes. A comprehensive knowledge of cerebellar connections in these fishes might shed light on the basal organization of the cerebellar system. Although the organization of the precerebellar system is known in adults, developmental studies are essential for understanding the origin and evolution of precerebellar nuclei. In the present work we performed a developmental study of cerebellar connections in embryos and juveniles of an advanced shark species, Scyliorhinus canicula, by application of tract tracing in combination with immunohistochemical techniques. Main precerebellar cell populations were located in the diencephalon (pretectum and thalamus), mesencephalon (reticular formation and nucleus ruber), rhombencephalon (cerebellar nucleus, reticular formation, and inferior olive), and spinal cord (ventral horn). The order of arrival of cerebellar afferent projections throughout development revealed a common pattern with other jawed vertebrates, which was helpful for comparison of stages of cerebellar development. The neurochemical study of the inferior olive and other precerebellar nuclei revealed many shared features with other gnathostomes. Furthermore, because many precerebellar nuclei originate from rhombic lips, the first analysis of neuronal migrations from these lips was performed with markers of neuroblasts. The shared features of development and organization of precerebellar connections observed between sharks and amniotes suggest that their basic pattern was established early in gnathostome evolution. PMID:23818330

  19. Pulmonary vascular development goes awry in congenital lung abnormalities.

    PubMed

    Kool, Heleen; Mous, Daphne; Tibboel, Dick; de Klein, Annelies; Rottier, Robbert J

    2014-12-01

    Pulmonary vascular diseases of the newborn comprise a wide range of pathological conditions with developmental abnormalities in the pulmonary vasculature. Clinically, pulmonary arterial hypertension (PH) is characterized by persistent increased resistance of the vasculature and abnormal vascular response. The classification of PH is primarily based on clinical parameters instead of morphology and distinguishes five groups of PH. Congenital lung anomalies, such as alveolar capillary dysplasia (ACD) and PH associated with congenital diaphragmatic hernia (CDH), but also bronchopulmonary dysplasia (BPD), are classified in group three. Clearly, tight and correct regulation of pulmonary vascular development is crucial for normal lung development. Human and animal model systems have increased our knowledge and make it possible to identify and characterize affected pathways and study pivotal genes. Understanding of the normal development of the pulmonary vasculature will give new insights in the origin of the spectrum of rare diseases, such as CDH, ACD, and BPD, which render a significant clinical problem in neonatal intensive care units around the world. In this review, we describe normal pulmonary vascular development, and focus on four diseases of the newborn in which abnormal pulmonary vascular development play a critical role in morbidity and mortality. In the future perspective, we indicate the lines of research that seem to be very promising for elucidating the molecular pathways involved in the origin of congenital pulmonary vascular disease. PMID:25424472

  20. Acute cerebellar ataxia

    MedlinePlus

    Cerebellar ataxia; Ataxia - acute cerebellar; Cerebellitis; Post-varicella acute cerebellar ataxia; PVACA ... virus. Viral infections that may cause this include chickenpox , Coxsackie disease, Epstein-Barr, and echovirus . Other causes ...

  1. Increase in Cerebellar Volume in Cavalier King Charles Spaniels with Chiari-like Malformation and Its Role in the Development of Syringomyelia

    PubMed Central

    Shaw, Thomas A.; McGonnell, Imelda M.; Driver, Colin J.; Rusbridge, Clare; Volk, Holger A.

    2012-01-01

    Previous research in Cavalier King Charles Spaniels (CKCS) has found that Chiari-like malformation and syringomyelia (CM/SM) are associated with a volume mismatch between the caudal cranial fossa (CCF) and the brain parenchyma contained within. The objectives of this study were to i) compare cerebellar volume in CKCS (a “high risk’ group which frequently develops CM/SM), small breed dogs (medium risk – occasionally develop CM/SM), and Labradors (low risk – CM/SM not reported); ii) evaluate a possible association between increased cerebellar volume and CM/SM in CKCS; iii) investigate the relationship between increased cerebellar volume and crowding of the cerebellum in the caudal part of the CCF (i.e. the region of the foramen magnum). Volumes of three-dimensional, magnetic resonance imaging derived models of the CCF and cerebellum were obtained from 75 CKCS, 44 small breed dogs, and 31 Labradors. As SM is thought to be a late onset disease process, two subgroups were formed for comparison: 18 CKCS younger than 2 years with SM (CM/SM group) and 13 CKCS older than 5 years without SM (CM group). Relative cerebellar volume was defined as the volume of the cerebellum divided by the total volume of brain parenchyma. Our results show that the CKCS has a relatively larger cerebellum than small breed dogs and Labradors and provide evidence that increased cerebellar volume in CKCS is associated with crowding of cerebellum in the caudal part of the CCF. In CKCS there is an association between increased cerebellar volume and SM. These findings have implications for the understanding of the pathological mechanisms of CM/SM, and support the hypothesis that it is a multifactorial disease process governed by increased cerebellar volume and failure of the CCF to reach a commensurate size. PMID:22506005

  2. A de novo 0.63 Mb 6q25.1 deletion associated with growth failure, congenital heart defect, underdeveloped cerebellar vermis, abnormal cutaneous elasticity and joint laxity.

    PubMed

    Salpietro, Vincenzo; Ruggieri, Martino; Mankad, Kshitij; Di Rosa, Gabriella; Granata, Francesca; Loddo, Italia; Moschella, Emanuela; Calabro, Maria Pia; Capalbo, Anna; Bernardini, Laura; Novelli, Antonio; Polizzi, Agata; Seidler, Daniela G; Arrigo, Teresa; Briuglia, Silvana

    2015-09-01

    Deletions of the long arm of chromosome 6 are rare and are characterized by great clinical variability according to the deletion breakpoint. We report a on 6-year-old girl with a de novo 0.63 Mb deletion on chromosome 6q25.1 who demonstrated multiple congenital anomalies including a ventricular septal defect and an underdeveloped cerebellar vermis. She presented with severe pre- and post-natal growth failure, hyperextensible small joints (Beighton scores = 8/9; with normal parental scores), and an abnormally elastic, redundant skin. Abnormally high upper/lower segment ratio (i.e., 1.34 = > 3SD), mild dysmorphic facial features and developmental delay were also present. The girl's phenotype was compared with: (i) two girls, each previously reported by Bisgaard et al. and Caselli et al. with similar albeit larger (2.6-7.21 Mb) deletions; (ii) seven additional individuals (6 M; 1 F) harboring deletions within the 6q25.1 region reported in the literature; and (iii) ten further patients (5 M; 4 F; 1 unrecorded sex) recorded in the DECIPHER 6.0 database. We reported on the present girl as her findings could contribute to advance the phenotype of 6q deletions. In addition, the present deletion is the smallest so far recorded in the 6q25 region encompassing eight known genes [vs. 41 of Bisgaard et al., and 23 of Caselli et al.,], including the TAB2 (likely responsible for the girl's congenital heart defect), LATS1 gene, and the UST gene (a regulator of the homeostasis of proteoglycans, which could have played a role in the abnormal dermal and cartilage elasticity).

  3. A de novo 0.63 Mb 6q25.1 deletion associated with growth failure, congenital heart defect, underdeveloped cerebellar vermis, abnormal cutaneous elasticity and joint laxity.

    PubMed

    Salpietro, Vincenzo; Ruggieri, Martino; Mankad, Kshitij; Di Rosa, Gabriella; Granata, Francesca; Loddo, Italia; Moschella, Emanuela; Calabro, Maria Pia; Capalbo, Anna; Bernardini, Laura; Novelli, Antonio; Polizzi, Agata; Seidler, Daniela G; Arrigo, Teresa; Briuglia, Silvana

    2015-09-01

    Deletions of the long arm of chromosome 6 are rare and are characterized by great clinical variability according to the deletion breakpoint. We report a on 6-year-old girl with a de novo 0.63 Mb deletion on chromosome 6q25.1 who demonstrated multiple congenital anomalies including a ventricular septal defect and an underdeveloped cerebellar vermis. She presented with severe pre- and post-natal growth failure, hyperextensible small joints (Beighton scores = 8/9; with normal parental scores), and an abnormally elastic, redundant skin. Abnormally high upper/lower segment ratio (i.e., 1.34 = > 3SD), mild dysmorphic facial features and developmental delay were also present. The girl's phenotype was compared with: (i) two girls, each previously reported by Bisgaard et al. and Caselli et al. with similar albeit larger (2.6-7.21 Mb) deletions; (ii) seven additional individuals (6 M; 1 F) harboring deletions within the 6q25.1 region reported in the literature; and (iii) ten further patients (5 M; 4 F; 1 unrecorded sex) recorded in the DECIPHER 6.0 database. We reported on the present girl as her findings could contribute to advance the phenotype of 6q deletions. In addition, the present deletion is the smallest so far recorded in the 6q25 region encompassing eight known genes [vs. 41 of Bisgaard et al., and 23 of Caselli et al.,], including the TAB2 (likely responsible for the girl's congenital heart defect), LATS1 gene, and the UST gene (a regulator of the homeostasis of proteoglycans, which could have played a role in the abnormal dermal and cartilage elasticity). PMID:25940952

  4. Altered cerebellar feedback projections in Asperger syndrome.

    PubMed

    Catani, Marco; Jones, Derek K; Daly, Eileen; Embiricos, Nitzia; Deeley, Quinton; Pugliese, Luca; Curran, Sarah; Robertson, Dene; Murphy, Declan G M

    2008-07-15

    It has been proposed that the biological basis of autism spectrum disorder includes cerebellar 'disconnection'. However, direct in vivo evidence in support of this is lacking. Here, the microstructural integrity of cerebellar white matter in adults with Asperger syndrome was studied using diffusion tensor magnetic resonance tractography. Fifteen adults with Asperger syndrome and 16 age-IQ-gender-matched healthy controls underwent diffusion tensor magnetic resonance imaging. For each subject, tract-specific measurements of mean diffusivity and fractional anisotropy were made within the inferior, middle, superior cerebellar peduncles and short intracerebellar fibres. No group differences were observed in mean diffusivity. However, people with Asperger syndrome had significantly lower fractional anisotropy in the short intracerebellar fibres (p<0.001) and right superior cerebellar (output) peduncle (p<0.001) compared to controls; but no difference in the input tracts. Severity of social impairment, as measured by the Autistic Diagnostic Interview, was negatively correlated with diffusion anisotropy in the fibres of the left superior cerebellar peduncle. These findings suggest a vulnerability of specific cerebellar neural pathways in people with Asperger syndrome. The localised abnormalities in the main cerebellar outflow pathway may prevent the cerebral cortex from receiving those cerebellar feedback inputs necessary for a successful adaptive social behaviour.

  5. Inborn errors of metabolism: a cause of abnormal brain development.

    PubMed

    Nissenkorn, A; Michelson, M; Ben-Zeev, B; Lerman-Sagie, T

    2001-05-22

    Brain malformations are caused by a disruption in the sequence of normal development by various environmental or genetic factors. By modifying the intrauterine milieu, inborn errors of metabolism may cause brain dysgenesis. However, this association is typically described in single case reports. The authors review the relationship between brain dysgenesis and specific inborn errors of metabolism. Peroxisomal disorders and fatty acid oxidation defects can produce migration defects. Pyruvate dehydrogenase deficiency, nonketotic hyperglycinemia, and maternal phenylketonuria preferentially cause a dysgenetic corpus callosum. Abnormal metabolism of folic acid causes neural tube defects, whereas defects in cholesterol metabolism may produce holoprosencephaly. Various mechanisms have been proposed to explain abnormal brain development in inborn errors of metabolism: production of a toxic or energy-deficient intrauterine milieu, modification of the content and function of membranes, or disturbance of the normal expression of intrauterine genes responsible for morphogenesis. The recognition of a metabolic disorder as the cause of the brain malformation has implications for both the care of the patient and for genetic counseling to prevent recurrence in subsequent pregnancies. PMID:11383558

  6. Early maternal deprivation in rats induces gender-dependent effects on developing hippocampal and cerebellar cells.

    PubMed

    Llorente, Ricardo; Gallardo, Meritxell López; Berzal, Alvaro Llorente; Prada, Carmen; Garcia-Segura, Luis Miguel; Viveros, María-Paz

    2009-05-01

    Adult animals submitted to a single prolonged episode of maternal deprivation [24h, postnatal day 9-10] show behavioral alterations that resemble specific symptoms of schizophrenia. According to the neurodevelopmental theory, these behavioral deficits might be mediated by detrimental neurodevelopmental processes that might be associated, at least partially, with stress-induced corticosterone responses. In order to address this hypothesis, we have focused on the hippocampus and cerebellar cortex, two brain regions that show high density of glucocorticoid receptors, and analyzed possible neuronal and glial alterations by immunohistochemical techniques. To evaluate the presence of degenerated neurons we used Fluoro-Jade-C (FJ-C) staining and for the study of astrocytes we employed glial fibrillary acidic protein (GFAP). Within control animals, females showed significantly more GFAP positive cells than males and a trend towards more FJ-C positive cells. Maternal deprivation induced neuronal degeneration and astroglial changes in the hippocampus and cerebellar cortex of neonatal rats that, in general, were more marked in males. This differential effect may be attributable to a greater vulnerability of males to this kind of early environmental insult and/or to sex-dependent differences in the onset and/or progression of the effects. The present experimental procedure may be instrumental in elucidating sex-dependent mechanisms of neurodevelopmental psychiatric disorders with a basis in early environmental insults.

  7. Male prevalent enhancement of leftward asymmetric development of the cerebellar cortex in ferrets (Mustela putorius).

    PubMed

    Sawada, Kazuhiko; Horiuchi-Hirose, Miwa; Saito, Shigeyoshi; Aoki, Ichio

    2015-01-01

    The present study was conducted in MRI-based volumetry to characterize the sexual dimorphism of the cerebellum in young adult ferrets. High spatial resolution 3D anatomical MRI at 7-tesla were acquired ex vivo from fixed cerebella of 90-day-old male and female ferrets. The 3D morphology and topology of cerebellar structures were reproduced well by volume-rendered images obtained from MRI. Volume of the whole cerebellum was significantly larger in males than in females. The cerebellar cortex was further divided into five transverse domains: the anterior zone (AZ; lobules I-V), central zone anterior (lobule VI), central zone posterior (CZp; lobule VII), posterior zone (PZ; lobules VIII-IXa) and nodular zone (NZ; lobules IXb -X). Significantly greater volumes in males than in females were detected bilaterally in the AZ, CZp, and NZ, and leftward in PZ. Notably, the significant volume asymmetry was detected leftward in the CZp of males. By asymmetry quotient analysis, the counterclockwise torque asymmetry of the cerebellum was revealed, and it was more striking in males than in females. The present results suggest that sexual dimorphism of the ferret cerebellum is characterized by enhancing the leftward laterality in the CZp in males, forming the distinctive counterclockwise torque asymmetry. PMID:26102223

  8. CHRONIC PERCHLORATE EXPOSURE CAUSES MORPHOLOGICAL ABNORMALITIES IN DEVELOPING STICKLEBACK

    PubMed Central

    Bernhardt, Richard R.; Von Hippel, Frank A.; O’Hara, Todd M.

    2011-01-01

    Few studies have examined the effects of chronic perchlorate exposure during growth and development, and fewer still have analyzed the effects of perchlorate over multiple generations. We describe morphological and developmental characteristics for threespine stickleback (Gasterosteus aculeatus) that were spawned and raised to sexual maturity in perchlorate-treated water (G1,2003) and for their offspring (G2,2004) that were not directly treated with perchlorate. The G1,2003 displayed a variety of abnormalities, including impaired formation of calcified traits, slower growth rates, aberrant sexual development, poor survivorship, and reduced pigmentation that allowed internal organs to be visible. Yet these conditions were absent when the offspring of contaminated fish (G2,2004) were raised in untreated water, suggesting a lack of transgenerational effects and that surviving populations may be able to recover following remediation of perchlorate-contaminated sites PMID:21465539

  9. Proneurotrophin-3 promotes cell cycle withdrawal of developing cerebellar granule cell progenitors via the p75 neurotrophin receptor.

    PubMed

    Zanin, Juan Pablo; Abercrombie, Elizabeth; Friedman, Wilma J

    2016-07-19

    Cerebellar granule cell progenitors (GCP) proliferate extensively in the external granule layer (EGL) of the developing cerebellum prior to differentiating and migrating. Mechanisms that regulate the appropriate timing of cell cycle withdrawal of these neuronal progenitors during brain development are not well defined. The p75 neurotrophin receptor (p75(NTR)) is highly expressed in the proliferating GCPs, but is downregulated once the cells leave the cell cycle. This receptor has primarily been characterized as a death receptor for its ability to induce neuronal apoptosis following injury. Here we demonstrate a novel function for p75(NTR) in regulating proper cell cycle exit of neuronal progenitors in the developing rat and mouse EGL, which is stimulated by proNT3. In the absence of p75(NTR), GCPs continue to proliferate beyond their normal period, resulting in a larger cerebellum that persists into adulthood, with consequent motor deficits.

  10. Normal and Abnormal Development in the Arabidopsis Vegetative Shoot Apex.

    PubMed Central

    Medford, JI; Behringer, FJ; Callos, JD; Feldmann, KA

    1992-01-01

    Vegetative development in the Arabidopsis shoot apex follows both sequential and repetitive steps. Early in development, the young vegetative meristem is flat and has a rectangular shape with bilateral symmetry. The first pair of leaf primordia is radially symmetrical and is initiated on opposite sides of the meristem. As development proceeds, the meristem changes first to a bilaterally symmetrical trapezoid and then to a radially symmetrical dome. Vegetative development from the domed meristem continues as leaves are initiated in a repetitive manner. Abnormal development of the vegetative shoot apex is described for a number of mutants. The mutants we describe fall into at least three classes: (1) lesions in the shoot apex that do not show an apparent alteration in the shoot apical meristem, (2) lesions in the apical meristem that also (directly or indirectly) alter leaf primordia, and (3) lesions in the apical meristem that alter meristem size and leaf number but not leaf morphology. These mutations provide tools both to genetically analyze vegetative development of the shoot apex and to learn how vegetative development influences floral development. PMID:12297656

  11. Metronidazole induced cerebellar ataxia

    PubMed Central

    Hari, Aditya; Srikanth, B. Akshaya; Lakshmi, G. Sriranga

    2013-01-01

    Metronidazole is a widely used antimicrobial usually prescribed by many specialist doctors for a short duration of 10-15 days. Prolonged use of metronidazole is rare. The present case is of a patient who used the drug for 4 months and developed peripheral neuropathy, convulsions, and cerebellar ataxia. He was treated with diazepam and levetiracetam. The patient recovered completely following discontinuation of metronidazole. PMID:23833378

  12. Effects of Transforming Growth Factor Beta 1 in Cerebellar Development: Role in Synapse Formation

    PubMed Central

    Araujo, Ana P. B.; Diniz, Luan P.; Eller, Cristiane M.; de Matos, Beatriz G.; Martinez, Rodrigo; Gomes, Flávia C. A.

    2016-01-01

    Granule cells (GC) are the most numerous glutamatergic neurons in the cerebellar cortex and represent almost half of the neurons of the central nervous system. Despite recent advances, the mechanisms of how the glutamatergic synapses are formed in the cerebellum remain unclear. Among the TGF-β family, TGF-beta 1 (TGF-β1) has been described as a synaptogenic molecule in invertebrates and in the vertebrate peripheral nervous system. A recent paper from our group demonstrated that TGF-β1 increases the excitatory synapse formation in cortical neurons. Here, we investigated the role of TGF-β1 in glutamatergic cerebellar neurons. We showed that the expression profile of TGF-β1 and its receptor, TβRII, in the cerebellum is consistent with a role in synapse formation in vitro and in vivo. It is low in the early postnatal days (P1–P9), increases after postnatal day 12 (P12), and remains high until adulthood (P30). We also found that granule neurons express the TGF-β receptor mRNA and protein, suggesting that they may be responsive to the synaptogenic effect of TGF-β1. Treatment of granular cell cultures with TGF-β1 increased the number of glutamatergic excitatory synapses by 100%, as shown by immunocytochemistry assays for presynaptic (synaptophysin) and post-synaptic (PSD-95) proteins. This effect was dependent on TβRI activation because addition of a pharmacological inhibitor of TGF-β, SB-431542, impaired the formation of synapses between granular neurons. Together, these findings suggest that TGF-β1 has a specific key function in the cerebellum through regulation of excitatory synapse formation between granule neurons. PMID:27199658

  13. Crossed Cerebellar Diaschisis

    PubMed Central

    Han, Shuguang; Wang, Xiaopeng; Xu, Kai; Hu, Chunfeng

    2016-01-01

    Abstract Crossed cerebellar diaschisis (CCD) describes a depression of oxidative metabolism glucose and blood flow in the cerebellum secondary to a supratentorial lesion in the contralateral cerebral hemisphere. PET/MR has the potential to become a powerful tool for demonstrating and imaging intracranial lesions .We herein report 3 cases of CCD imaging using a tri-modality PET/CT–MR set-up for investigating the value of adding MRI rather than CT to PET in clinical routine. We describe 3 patients with CCD and neurological symptoms in conjunction with abnormal cerebral fluorodeoxyglucose (FDG) positron emission tomography/computed tomography-magnetic resonance imaging (PET/CT–MR) manifestations including arterial spin-labeling (ASL) and T2-weighted images. In all, 18FDG-PET/CT detected positive FDG uptake in supratentorial lesions, and hypometabolism with atrophy in the contralateral cerebellum. More than that, hybrid PET/MRI provided a more accurate anatomic localization and ASL indicated disruption of the cortico-ponto-cerebellar pathway. Using pathology or long-term clinical follow-up to confirm the PET and ASL findings, the supratentorial lesions of the 3 patients were respectively diagnosed with cerebral infarction, recurrent glioma, and metastasis. The reports emphasize the significance of multimodality radiological examinations. Multimodality imaging contributes to proper diagnosis, management, and follow-up of supratentorial lesions with CCD. PMID:26765477

  14. Motor training compensates for cerebellar dysfunctions caused by oligodendrocyte ablation.

    PubMed

    Collin, Ludovic; Usiello, Alessandro; Erbs, Eric; Mathis, Carole; Borrelli, Emiliana

    2004-01-01

    The role played by oligodendrocytes (OLs), the myelinating cells of the CNS, during brain development has not been fully explored. We have addressed this question by inducing a temporal and reversible ablation of OLs on postnatal CNS development. OL ablation in newborn mice leads to a profound alteration in the structure of the cerebellar cortex, which can be progressively rescued by newly generated cells, leading to a delayed myelination. Nevertheless, the temporal shift of the OL proliferation and myelinating program cannot completely compensate for developmental defects, resulting in impaired motor functions in the adult. Strikingly, we show that, despite these abnormalities, epigenetic factors, such as motor training, are able to fully rescue cerebellar-directed motor skills. PMID:14694200

  15. Motor training compensates for cerebellar dysfunctions caused by oligodendrocyte ablation

    PubMed Central

    Collin, Ludovic; Usiello, Alessandro; Erbs, Eric; Mathis, Carole; Borrelli, Emiliana

    2004-01-01

    The role played by oligodendrocytes (OLs), the myelinating cells of the CNS, during brain development has not been fully explored. We have addressed this question by inducing a temporal and reversible ablation of OLs on postnatal CNS development. OL ablation in newborn mice leads to a profound alteration in the structure of the cerebellar cortex, which can be progressively rescued by newly generated cells, leading to a delayed myelination. Nevertheless, the temporal shift of the OL proliferation and myelinating program cannot completely compensate for developmental defects, resulting in impaired motor functions in the adult. Strikingly, we show that, despite these abnormalities, epigenetic factors, such as motor training, are able to fully rescue cerebellar-directed motor skills. PMID:14694200

  16. Normal and abnormal spine and thoracic cage development

    PubMed Central

    Canavese, Federico; Dimeglio, Alain

    2013-01-01

    Development of the spine and thoracic cage consists of a complex series of events involving multiple metabolic processes, genes and signaling pathways. During growth, complex phenomena occur in rapid succession. This succession of events, this establishment of elements, is programmed according to a hierarchy. These events are well synchronized to maintain harmonious limb, spine and thoracic cage relationships, as growth in the various body segments does not occur simultaneously at the same magnitude or rate. In most severe cases of untreated progressive early-onset spinal deformities, respiratory insufficiency and pulmonary and cardiac hypertension (cor pulmonale), which characterize thoracic insufficiency syndrome (TIS), can develop, sometimes leading to death. TIS is the inability of the thorax to ensure normal breathing. This clinical condition can be linked to costo-vertebral malformations (e.g., fused ribs, hemivertebrae, congenital bars), neuromuscular diseases (e.g., expiratory congenital hypotonia), Jeune or Jarcho-Levin syndromes or to 50% to 75% fusion of the thoracic spine before seven years of age. Complex spinal deformities alter normal growth plate development, and vertebral bodies become progressively distorted, perpetuating the disorder. Therefore, many scoliotic deformities can become growth plate disorders over time. This review aims to provide a comprehensive review of how spinal deformities can affect normal spine and thoracic cage growth. Previous conceptualizations are integrated with more recent scientific data to provide a better understanding of both normal and abnormal spine and thoracic cage growth. PMID:24147251

  17. Orthostatic tremor: a cerebellar pathology?

    PubMed Central

    Popa, Traian; García-Lorenzo, Daniel; Valabregue, Romain; Legrand, André-Pierre; Apartis, Emmanuelle; Marais, Lea; Degos, Bertrand; Hubsch, Cecile; Fernández-Vidal, Sara; Bardinet, Eric; Roze, Emmanuel; Lehéricy, Stéphane; Meunier, Sabine; Vidailhet, Marie

    2016-01-01

    See Muthuraman et al. (doi:10.1093/aww164) for a scientific commentary on this article. Primary orthostatic tremor is characterized by high frequency tremor affecting the legs and trunk during the standing position. Cerebellar defects were suggested in orthostatic tremor without direct evidence. We aimed to characterize the anatomo-functional defects of the cerebellar motor pathways in orthostatic tremor. We used multimodal neuroimaging to compare 17 patients with orthostatic tremor and 17 age- and gender-matched healthy volunteers. Nine of the patients with orthostatic tremor underwent repetitive transcranial stimulation applied over the cerebellum during five consecutive days. We quantified the duration of standing position and tremor severity through electromyographic recordings. Compared to healthy volunteers, grey matter volume in patients with orthostatic tremor was (i) increased in the cerebellar vermis and correlated positively with the duration of the standing position; and (ii) increased in the supplementary motor area and decreased in the lateral cerebellum, which both correlated with the disease duration. Functional connectivity between the lateral cerebellum and the supplementary motor area was abnormally increased in patients with orthostatic tremor, and correlated positively with tremor severity. After repetitive transcranial stimulation, tremor severity and functional connectivity between the lateral cerebellum and the supplementary motor area were reduced. We provide an explanation for orthostatic tremor pathophysiology, and demonstrate the functional relevance of cerebello-thalamo-cortical connections in tremor related to cerebellar defects. PMID:27329770

  18. Growth conditions differentially modulate the vulnerability of developing cerebellar granule cells to excitatory amino acids.

    PubMed

    Resink, A; Hack, N; Boer, G J; Balázs, R

    1994-08-29

    The survival of immature nerve cells in a cerebellar culture, predominantly excitatory granule cells, is known to be promoted by chronic exposure to high K+ (> 20 mM) or glutamate (Glu) receptor agonists. These treatments are believed to mimic the in vivo effect of the incoming glutamatergic afferents, the mossy fibres. Here we report that with maturation the cells become vulnerable to excitatory amino acids (EAAs) and that the characteristics of EAA sensitivity are dependent on the environmental influences being either "trophic" (25 mM K+ or 140 microM NMDA, K25 or K10 + NMDA) or "non-trophic" (10 mM K+, K10). Toxicity was assayed routinely at 9 days in vitro (DIV) after 24 h exposure to EAAs. Under all the tested conditions, the effect of Glu was mediated exclusively through NMDA receptors. However, the efficacy and potency of Glu were high in K25- and K10 + NMDA-grown cells compared with K10-grown cells. Growth conditions had the same influence on NMDA as on Glu-induced toxicity, but with the following special features: (1) in comparison with K25 cells, the potency of NMDA was significantly lower in K10 + NMDA cells. The K10 + NMDA cultures behaved as if they were completely insensitive to the NMDA which is present in their growth medium. (2) The K10-grown cells were not vulnerable to NMDA, unless the cell membrane was depolarised by shifting the cells into K25 medium. The efficacy of NMDA became then similar to that in K25 cultures, although the potency was about 7-fold less. Thus NMDA receptors can be activated by the depolarisation of K10 cells, implying the operation of Mg2+ blockade of the channel at normal resting membrane potential. Although non-NMDA receptors did not seem to be involved in Glu toxicity, cells were vulnerable to kainate, which killed significantly more cells than Glu (about 80% vs 70%). This was partly due to the resistance of GABAergic interneurons present in the cultures to Glu- or NMDA-induced toxicity. In contrast to the effects of

  19. Paraneoplastic cerebellar degeneration with anti-Yo antibodies - a review.

    PubMed

    Venkatraman, Anand; Opal, Puneet

    2016-08-01

    The ataxic syndrome associated with Anti-Yo antibody, or Purkinje cell cytoplasmic antibody type 1 (PCA1), is the most common variant of paraneoplastic cerebellar degeneration (PCD). The typical presentation involves the subacute development of pancerebellar deficits with a clinical plateau within 6 months. The vast majority of cases have been reported in women with pelvic or breast tumors. Magnetic resonance imaging of the brain is often normal in the early stages, with cerebellar atrophy seen later. The underlying mechanism is believed to be an immunological reaction to cerebellar degeneration-related protein 2 (CDR2), a protein usually found in the cerebellum that is ectopically produced by tumor cells. Although both B- and T-cell abnormalities are seen, there is debate about the relative importance of the autoantibodies and cytotoxic T lymphocytes in the neuronal loss. Cerebrospinal fluid abnormalities, primarily elevated protein, lymphocytic pleocytosis, and oligoclonal bands, are common in the early stages. The low prevalence of this condition has not allowed for large-scale randomized controlled trials. Immunotherapies, such as steroids, intravenous immune globulins, and plasma exchange, have been extensively used in managing this condition, with limited success. Although some reports indicate benefit from antitumor therapies like surgery and chemotherapy, this has not been consistently observed. The prognosis for anti-Yo PCD is almost uniformly poor, with most patients left bedridden. Further studies are required to clarify the pathophysiology and provide evidence-based treatment options. PMID:27606347

  20. Paraneoplastic cerebellar degeneration with anti-Yo antibodies - a review.

    PubMed

    Venkatraman, Anand; Opal, Puneet

    2016-08-01

    The ataxic syndrome associated with Anti-Yo antibody, or Purkinje cell cytoplasmic antibody type 1 (PCA1), is the most common variant of paraneoplastic cerebellar degeneration (PCD). The typical presentation involves the subacute development of pancerebellar deficits with a clinical plateau within 6 months. The vast majority of cases have been reported in women with pelvic or breast tumors. Magnetic resonance imaging of the brain is often normal in the early stages, with cerebellar atrophy seen later. The underlying mechanism is believed to be an immunological reaction to cerebellar degeneration-related protein 2 (CDR2), a protein usually found in the cerebellum that is ectopically produced by tumor cells. Although both B- and T-cell abnormalities are seen, there is debate about the relative importance of the autoantibodies and cytotoxic T lymphocytes in the neuronal loss. Cerebrospinal fluid abnormalities, primarily elevated protein, lymphocytic pleocytosis, and oligoclonal bands, are common in the early stages. The low prevalence of this condition has not allowed for large-scale randomized controlled trials. Immunotherapies, such as steroids, intravenous immune globulins, and plasma exchange, have been extensively used in managing this condition, with limited success. Although some reports indicate benefit from antitumor therapies like surgery and chemotherapy, this has not been consistently observed. The prognosis for anti-Yo PCD is almost uniformly poor, with most patients left bedridden. Further studies are required to clarify the pathophysiology and provide evidence-based treatment options.

  1. Maternal immune activation and abnormal brain development across CNS disorders.

    PubMed

    Knuesel, Irene; Chicha, Laurie; Britschgi, Markus; Schobel, Scott A; Bodmer, Michael; Hellings, Jessica A; Toovey, Stephen; Prinssen, Eric P

    2014-11-01

    Epidemiological studies have shown a clear association between maternal infection and schizophrenia or autism in the progeny. Animal models have revealed maternal immune activation (mIA) to be a profound risk factor for neurochemical and behavioural abnormalities in the offspring. Microglial priming has been proposed as a major consequence of mIA, and represents a critical link in a causal chain that leads to the wide spectrum of neuronal dysfunctions and behavioural phenotypes observed in the juvenile, adult or aged offspring. Such diversity of phenotypic outcomes in the mIA model are mirrored by recent clinical evidence suggesting that infectious exposure during pregnancy is also associated with epilepsy and, to a lesser extent, cerebral palsy in children. Preclinical research also suggests that mIA might precipitate the development of Alzheimer and Parkinson diseases. Here, we summarize and critically review the emerging evidence that mIA is a shared environmental risk factor across CNS disorders that varies as a function of interactions between genetic and additional environmental factors. We also review ongoing clinical trials targeting immune pathways affected by mIA that may play a part in disease manifestation. In addition, future directions and outstanding questions are discussed, including potential symptomatic, disease-modifying and preventive treatment strategies.

  2. Purkinje cell heterotopy with cerebellar hypoplasia in two free-living American kestrels (Falco sparverius).

    PubMed

    Armién, A G; McRuer, D L; Ruder, M G; Wünschmann, A

    2013-01-01

    Two wild fledgling kestrels exhibited lack of motor coordination, postural reaction deficits, and abnormal propioception. At necropsy, the cerebellum and brainstem were markedly underdeveloped. Microscopically, there was Purkinje cells heterotopy, abnormal circuitry, and hypoplasia with defective foliation. Heterotopic neurons were identified as immature Purkinje cells by their size, location, immunoreactivity for calbindin D-28 K, and ultrastructural features. The authors suggest that this cerebellar abnormality was likely due to a disruption of molecular mechanisms that dictate Purkinje cell migration, placement, and maturation in early embryonic development. The etiology of this condition remains undetermined. Congenital central nervous system disorders have rarely been reported in birds.

  3. PSD-95 regulates NMDA receptors in developing cerebellar granule neurons of the rat

    PubMed Central

    Losi, Gabriele; Prybylowski, Kate; Fu, Zhanyan; Luo, Jianhong; Wenthold, Robert J; Vicini, Stefano

    2003-01-01

    We transfected a green fluorescent protein-tagged PSD-95 (PSD-95gfp) into cultured rat cerebellar granule cells (CGCs) to investigate the role of PSD-95 in excitatory synapse maturation. Cells were grown in low potassium to favour functional synapse formation in vitro. Transfected cells displayed clear clusters of PSD-95gfp, often at the extremities of the short dendritic trees. We recorded NMDA and AMPA miniature excitatory postsynaptic currents (NMDA- and AMPA-mESPCs) in the presence of TTX and bicuculline. At days in vitro (DIV) 7–8 PSD-95gfp-transfected cells had NMDA-mEPSCs with faster decay and smaller amplitudes than matching controls. In contrast, AMPA-mEPSC frequencies and amplitudes were increased. Whole-cell current density and ifenprodil sensitivity were reduced in PSD-95gfp cells, indicating a reduction of NR2B subunits containing NMDA receptors. No changes were observed compared to control when cells were transfected with cDNA for PSD-95gfp with palmitoylation site mutations that prevent targeting to the synapse. Overexpression of the NMDA receptor NR2A subunit, but not the NR2B subunit, prevented NMDA-mEPSC amplitude reduction when cotransfected with PSD-95gfp. PSD-95gfp overexpression produced faster NMDA-mEPSC decay when transfected alone or with either NR2 subunit. Surface staining of the epitope-tagged NR2 subunits revealed that colocalization with PSD-95gfp was higher for flag-tagged NR2A subunit clusters than for flag-tagged NR2B subunit clusters. These data suggest that PSD-95 overexpression in CGCs favours synaptic maturation by allowing synaptic insertion of NR2A and depressing expression of NR2B subunits. PMID:12576494

  4. Consensus Paper: Management of Degenerative Cerebellar Disorders

    PubMed Central

    Ilg, W.; Bastian, A. J.; Boesch, S.; Burciu, R. G.; Celnik, P.; Claaßen, J.; Feil, K.; Kalla, R.; Miyai, I.; Nachbauer, W.; Schöls, L.; Strupp, M.; Synofzik, M.; Teufel, J.

    2015-01-01

    Treatment of motor symptoms of degenerative cerebellar ataxia remains difficult. Yet there are recent developments that are likely to lead to significant improvements in the future. Most desirable would be a causative treatment of the underlying cerebellar disease. This is currently available only for a very small subset of cerebellar ataxias with known metabolic dysfunction. However, increasing knowledge of the pathophysiology of hereditary ataxia should lead to an increasing number of medically sensible drug trials. In this paper, data from recent drug trials in patients with recessive and dominant cerebellar ataxias will be summarized. There is consensus that up to date, no medication has been proven effective. Aminopyridines and acetazolamide are the only exception, which are beneficial in patients with episodic ataxia type 2. Aminopyridines are also effective in a subset of patients presenting with downbeat nystagmus. As such, all authors agreed that the mainstays of treatment of degenerative cerebellar ataxia are currently physiotherapy, occupational therapy, and speech therapy. For many years, well-controlled rehabilitation studies in patients with cerebellar ataxia were lacking. Data of recently published studies show that coordinative training improves motor function in both adult and juvenile patients with cerebellar degeneration. Given the well-known contribution of the cerebellum to motor learning, possible mechanisms underlying improvement will be outlined. There is consensus that evidence-based guidelines for the physiotherapy of degenerative cerebellar ataxia need to be developed. Future developments in physiotherapeutical interventions will be discussed including application of non-invasive brain stimulation. PMID:24222635

  5. X Chromosome Abnormalities and Cognitive Development: Implications for Understanding Normal Human Development.

    ERIC Educational Resources Information Center

    Walzer, Stanley

    1985-01-01

    Argues that knowledge from studies of individuals with sex chromosome abnormalities can further understanding of aspects of normal human development. Studies of XO girls, XXY boys, XXX girls, and males with a fragile X chromosome are summarized to demonstrate how results contribute to knowledge about normal cognitive development and about…

  6. Abnormal Canine Bone Development Associated with Hypergravity Exposure

    NASA Technical Reports Server (NTRS)

    Morgan, J. P.; Fisher, G. L.; McNeill, K. L.; Oyama, J.

    1979-01-01

    Chronic centrifugation of 85- to 92-day-old Beagles at 2.0 x g and 2.6 x g for 26 weeks during the time of active skeletal growth caused skeletal abnormalities in the radius and the ulna of ten of 11 dogs. The pattern of change mimicked that found in naturally occurring and experimentally induced premature distal ulnar physeal closure or delayed growth at this physis. Minimal changes in bone density were detected by sensitive photon absorptiometric techniques. Skeletal abnormalities also were found in five of the six cage-control dogs, although the run-control dogs were radiographically normal.

  7. Talpid3-binding centrosomal protein Cep120 is required for centriole duplication and proliferation of cerebellar granule neuron progenitors.

    PubMed

    Wu, Chuanqing; Yang, Mei; Li, Juan; Wang, Chengbing; Cao, Ting; Tao, Kaixiong; Wang, Baolin

    2014-01-01

    Granule neuron progenitors (GNPs) are the most abundant neuronal type in the cerebellum. GNP proliferation and thus cerebellar development require Sonic hedgehog (Shh) secreted from Purkinje cells. Shh signaling occurs in primary cilia originating from the mother centriole. Centrioles replicate only once during a typical cell cycle and are responsible for mitotic spindle assembly and organization. Recent studies have linked cilia function to cerebellar morphogenesis, but the role of centriole duplication in cerebellar development is not known. Here we show that centrosomal protein Cep120 is asymmetrically localized to the daughter centriole through its interaction with Talpid3 (Ta3), another centrosomal protein. Cep120 null mutant mice die in early gestation with abnormal heart looping. Inactivation of Cep120 in the central nervous system leads to both hydrocephalus, due to the loss of cilia on ependymal cells, and severe cerebellar hypoplasia, due to the failed proliferation of GNPs. The mutant GNPs lack Hedgehog pathway activity. Cell biological studies show that the loss of Cep120 results in failed centriole duplication and consequently ciliogenesis, which together underlie Cep120 mutant cerebellar hypoplasia. Thus, our study for the first time links a centrosomal protein necessary for centriole duplication to cerebellar morphogenesis.

  8. Cerebellar Stroke-manifesting as Mania

    PubMed Central

    Jagadesan, Venkatesan; Thiruvengadam, Kannapiran R.; Muralidharan, Rengarajalu

    2014-01-01

    Secondary mania resulting from cerebral Cortex are described commonly. But secondary mania produced by cerebellar lesions are relatively uncommon. This case report describes a patient who developed cerebellar stoke and manic features simultaneously. 28 years old male developed giddiness and projectile vomiting. Then he would lie down for about an hour only to find that he could not walk. He became quarrelsome. His Psycho motor activities and speech were increased. He was euphoric and was expressing grandiose ideas. Bender Gestalt Test showed signs of organicity. Score in Young mania relating scale was 32; productivity was low in Rorschach. Neurological examination revealed left cerebellar signs like ataxia and slurring of speech. Computed tomography of brain showed left cerebellar infarct. Relationship between Psychiatric manifestations and cerebellar lesion are discussed. PMID:25035567

  9. Cerebellar Stroke-manifesting as Mania.

    PubMed

    Jagadesan, Venkatesan; Thiruvengadam, Kannapiran R; Muralidharan, Rengarajalu

    2014-07-01

    Secondary mania resulting from cerebral Cortex are described commonly. But secondary mania produced by cerebellar lesions are relatively uncommon. This case report describes a patient who developed cerebellar stoke and manic features simultaneously. 28 years old male developed giddiness and projectile vomiting. Then he would lie down for about an hour only to find that he could not walk. He became quarrelsome. His Psycho motor activities and speech were increased. He was euphoric and was expressing grandiose ideas. Bender Gestalt Test showed signs of organicity. Score in Young mania relating scale was 32; productivity was low in Rorschach. Neurological examination revealed left cerebellar signs like ataxia and slurring of speech. Computed tomography of brain showed left cerebellar infarct. Relationship between Psychiatric manifestations and cerebellar lesion are discussed. PMID:25035567

  10. Proneurotrophin-3 promotes cell cycle withdrawal of developing cerebellar granule cell progenitors via the p75 neurotrophin receptor

    PubMed Central

    Zanin, Juan Pablo; Abercrombie, Elizabeth; Friedman, Wilma J

    2016-01-01

    Cerebellar granule cell progenitors (GCP) proliferate extensively in the external granule layer (EGL) of the developing cerebellum prior to differentiating and migrating. Mechanisms that regulate the appropriate timing of cell cycle withdrawal of these neuronal progenitors during brain development are not well defined. The p75 neurotrophin receptor (p75NTR) is highly expressed in the proliferating GCPs, but is downregulated once the cells leave the cell cycle. This receptor has primarily been characterized as a death receptor for its ability to induce neuronal apoptosis following injury. Here we demonstrate a novel function for p75NTR in regulating proper cell cycle exit of neuronal progenitors in the developing rat and mouse EGL, which is stimulated by proNT3. In the absence of p75NTR, GCPs continue to proliferate beyond their normal period, resulting in a larger cerebellum that persists into adulthood, with consequent motor deficits. DOI: http://dx.doi.org/10.7554/eLife.16654.001 PMID:27434667

  11. Development of Abnormality Detection System for Bathers using Ultrasonic Sensors

    NASA Astrophysics Data System (ADS)

    Ohnishi, Yosuke; Abe, Takehiko; Nambo, Hidetaka; Kimura, Haruhiko; Ogoshi, Yasuhiro

    This paper proposes an abnormality detection system for bather sitting in bathtub. Increasing number of in-bathtub drowning accidents in Japan draws attention. Behind this large number of bathing accidents, Japan's unique social and cultural background come surface. For majority of people in Japan, bathing serves purpose in deep warming up of body, relax and enjoyable time. Therefore it is the custom for the Japanese to soak in bathtub. However overexposure to hot water may cause dizziness or fainting, which is possible to cause in-bathtub drowning. For drowning prevention, the system detects bather's abnormal state using an ultrasonic sensor array. The array, which has many ultrasonic sensors, is installed on the ceiling of bathroom above bathtub. The abnormality detection system uses the following two methods: posture detection and behavior detection. The function of posture detection is to estimate the risk of drowning by monitoring bather's posture. Meanwhile, the function of behavior detection is to estimate the risk of drowning by monitoring bather's behavior. By using these methods, the system detects bathers' different state from normal. As a result of experiment with a subject in the bathtub, the system was possible to detect abnormal state using subject's posture and behavior. Therefore the system is useful for monitoring bather to prevent drowning in bathtub.

  12. Regional cerebellar volumes predict functional outcome in children with cerebellar malformations.

    PubMed

    Bolduc, Marie-Eve; du Plessis, Adre J; Sullivan, Nancy; Guizard, Nicolas; Zhang, Xun; Robertson, Richard L; Limperopoulos, Catherine

    2012-06-01

    The cerebellum has recently been recognized for its role in high-order functions, including cognition, language, and behavior. Recent studies have also begun to describe a functional topography of the mature cerebellum that includes organization on a mediolateral axis. However, no study to date has examined the relationship between regional cerebellar volume and developmental disabilities in children with cerebellar malformations. The objective of this study was to estimate the extent to which total and regional cerebellar volumes are associated with developmental disabilities in a cohort of children with cerebellar malformations. Children aged 1 to 6 years with a diagnosis of cerebellar malformation underwent standardized outcome measures and quantitative magnetic resonance scanning. The cerebellum was parcellated into seven mediolateral zones (three for each hemisphere plus the vermis) for regional volume analysis. In children with cerebellar malformations, decreased total cerebellar volume was associated with delays in global development, expressive language, cognition, as well as gross and fine motor function. Decreased volume in the right lateral cerebellar hemisphere was related to impaired cognition, expressive language, and gross motor function. Additionally, reduced vermis volume was associated with impaired global development, cognition, expressive language, and gross and fine motor skills, as well as behavior problems and a higher rate of positive autism spectrum screening test. These results begin to define the structural topography of functional outcome in children with cerebellar malformations and should lead to greater accuracy of prognostication as well as timely early developmental interventions.

  13. Metabolic anatomy of paraneoplastic cerebellar degeneration

    SciTech Connect

    Anderson, N.E.; Posner, J.B.; Sidtis, J.J.; Moeller, J.R.; Strother, S.C.; Dhawan, V.; Rottenberg, D.A.

    1988-06-01

    Eleven patients with acquired cerebellar degeneration (10 of whom had paraneoplastic cerebellar degeneration (PCD)) were evaluated using neuropsychological tests and /sup 18/F-fluorodeoxyglucose/positron emission tomography to (1) quantify motor, cognitive, and metabolic abnormalities; (2) determine if characteristic alterations in the regional cerebral metabolic rate for glucose (rCMRGlc) are associated with PCD; and (3) correlate behavioral and metabolic measures of disease severity. Eighteen volunteer subjects served as normal controls. Although some PCD neuropsychological test scores were abnormal, these results could not, in general, be dissociated from the effects of dysarthria and ataxia. rCMRGlc was reduced in patients with PCD (versus normal control subjects) in all regions except the brainstem. Analysis of patient and control rCMRGlc data using a mathematical model of regional metabolic interactions revealed two metabolic pattern descriptors, SSF1 and SSF2, which distinguished patients with PCD from normal control subjects; SSF2, which described a metabolic coupling between cerebellum, cuneus, and posterior temporal, lateral frontal, and paracentral cortex, correlated with quantitative indices of cerebellar dysfunction. Our inability to document substantial intellectual impairment in 7 of 10 patients with PCD contrasts with the 50% incidence of dementia in PCD reported by previous investigators. Widespread reductions in PCD rCMRGlc may result from the loss of cerebellar efferents to thalamus and forebrain structures, a reverse cerebellar diaschisis.

  14. Alcohol Withdrawal and Cerebellar Mitochondria.

    PubMed

    Jung, Marianna E

    2015-08-01

    Cerebellar disorders trigger the symptoms of movement problems, imbalance, incoordination, and frequent fall. Cerebellar disorders are shown in various CNS illnesses including a drinking disorder called alcoholism. Alcoholism is manifested as an inability to control drinking in spite of adverse consequences. Human and animal studies have shown that cerebellar symptoms persist even after complete abstinence from drinking. In particular, the abrupt termination (ethanol withdrawal) of long-term excessive ethanol consumption has shown to provoke a variety of neuronal and mitochondrial damage to the cerebellum. Upon ethanol withdrawal, excitatory neurotransmitter molecules such as glutamate are overly released in brain areas including cerebellum. This is particularly relevant to the cerebellar neuronal network as glutamate signals are projected to Purkinje neurons through granular cells that are the most populated neuronal type in CNS. This excitatory neuronal signal may be elevated by ethanol withdrawal stress, which promotes an increase in intracellular Ca(2+) level and a decrease in a Ca(2+)-binding protein, both of which result in the excessive entry of Ca(2+) to the mitochondria. Subsequently, mitochondria undergo a prolonged opening of mitochondrial permeability transition pore and the overproduction of harmful free radicals, impeding adenosine triphosphate (ATP)-generating function. This in turn provokes the leakage of mitochondrial molecule cytochrome c to the cytosol, which triggers a cascade of adverse cytosol reactions. Upstream to this pathway, cerebellum under the condition of ethanol withdrawal has shown aberrant gene modifications through altered DNA methylation, histone acetylation, or microRNA expression. Interplay between these events and molecules may result in functional damage to cerebellar mitochondria and consequent neuronal degeneration, thereby contributing to motoric deficit. Mitochondria-targeting research may help develop a powerful new

  15. Alcohol Withdrawal and Cerebellar Mitochondria.

    PubMed

    Jung, Marianna E

    2015-08-01

    Cerebellar disorders trigger the symptoms of movement problems, imbalance, incoordination, and frequent fall. Cerebellar disorders are shown in various CNS illnesses including a drinking disorder called alcoholism. Alcoholism is manifested as an inability to control drinking in spite of adverse consequences. Human and animal studies have shown that cerebellar symptoms persist even after complete abstinence from drinking. In particular, the abrupt termination (ethanol withdrawal) of long-term excessive ethanol consumption has shown to provoke a variety of neuronal and mitochondrial damage to the cerebellum. Upon ethanol withdrawal, excitatory neurotransmitter molecules such as glutamate are overly released in brain areas including cerebellum. This is particularly relevant to the cerebellar neuronal network as glutamate signals are projected to Purkinje neurons through granular cells that are the most populated neuronal type in CNS. This excitatory neuronal signal may be elevated by ethanol withdrawal stress, which promotes an increase in intracellular Ca(2+) level and a decrease in a Ca(2+)-binding protein, both of which result in the excessive entry of Ca(2+) to the mitochondria. Subsequently, mitochondria undergo a prolonged opening of mitochondrial permeability transition pore and the overproduction of harmful free radicals, impeding adenosine triphosphate (ATP)-generating function. This in turn provokes the leakage of mitochondrial molecule cytochrome c to the cytosol, which triggers a cascade of adverse cytosol reactions. Upstream to this pathway, cerebellum under the condition of ethanol withdrawal has shown aberrant gene modifications through altered DNA methylation, histone acetylation, or microRNA expression. Interplay between these events and molecules may result in functional damage to cerebellar mitochondria and consequent neuronal degeneration, thereby contributing to motoric deficit. Mitochondria-targeting research may help develop a powerful new

  16. A case of follicular lymphoma associated with paraneoplastic cerebellar degeneration.

    PubMed

    Shimazu, Yayoi; Minakawa, Eiko N; Nishikori, Momoko; Ihara, Masafumi; Hashi, Yuichiro; Matsuyama, Hirofumi; Hishizawa, Masakatsu; Yoshida, Sonoyo; Kitano, Toshiyuki; Kondo, Tadakazu; Ishikawa, Takayuki; Takahashi, Ryosuke; Takaori-Kondo, Akifumi

    2012-01-01

    Paraneoplastic neurological disorders (PND) are neurological effects of malignancy that are recognized as immune-mediated disorders caused by aberrant expression of a tumor antigen that is normally expressed in the nervous system. We report a case of cerebellar ataxia which turned out to be paraneoplastic cerebellar degeneration, a subtype of PND that develops cerebellar symptoms, that was caused by follicular lymphoma. After chemotherapy, the patient attained sufficient improvement of cerebellar symptoms along with complete remission of lymphoma. Paraneoplastic cerebellar degeneration should be recognized as a rare complication of lymphoma as it is important to start proper treatment before the neurological symptoms become irreversible.

  17. FoxP2 expression in the cerebellum and inferior olive: development of the transverse stripe-shaped expression pattern in the mouse cerebellar cortex.

    PubMed

    Fujita, Hirofumi; Sugihara, Izumi

    2012-02-15

    Many molecules are expressed heterogeneously in subpopulations of cerebellar Purkinje cells (PCs) and inferior olive (IO) neurons during development or in adulthood. These expression patterns are often organized in longitudinal stripes in the cerebellar cortex, which may be related to functional compartmentalization. FoxP2, a transcription factor, is expressed in PCs and IO neurons, but the details of its expression pattern remain unclear. Here we examined FoxP2 expression patterns systematically by immunostaining serial sections of the hindbrain from embryonic day 14.5 to adulthood in mice. FoxP2 was highly expressed in virtually all PCs at and before postnatal day 6 (P6), except for those in the flocculus and small parts of the nodulus (vermal lobule X), where FoxP2 expression was moderate or absent. After P6, FoxP2 expression gradually diminished in PCs in some areas. In adults, FoxP2 was expressed, less intensely than in earlier stages, in subsets of PCs that were mostly arranged transversely along the folial apices. In contrast, FoxP2 was expressed intensely in most IO neurons during development and in adulthood. FoxP2 was also expressed in a small population of neurons in the cerebellar nuclei. FoxP2 expression in adult rats and chicks was generally comparable to that in adult mice, suggesting evolutionary conservation of the expression pattern. Thus, the FoxP2 expression pattern reflects new transverse compartmentalization in the adult cerebellar cortex, although its functional significance remains unclear.

  18. Abnormal Eye Movements in Creutzfeldt-Jakob Disease

    NASA Technical Reports Server (NTRS)

    Grant, Michael P.; Cohen, Mark; Petersen, Robert B.; Halmagyi, G. Michael; McDougall, Alan; Tusa, Ronald J.; Leigh, R. John

    1993-01-01

    We report 3 patients with autopsy-proven Creutzfeldt-Jakob disease who, early in their course, developed abnormal eye movements that included periodic alternating nystagmus and slow vertical saccades. These findings suggested involvement of the cerebellar nodulus and uvula, and the brainstem reticular formation, respectively. Cerebellar ataxia was also an early manifestation and, in one patient, a frontal lobe brain biopsy was normal at a time when ocular motor and cerebellar signs were conspicuous. As the disease progressed, all saccades and quick phases of nystagmus were lost, but periodic alternating gaze deviation persisted. At autopsy, 2 of the 3 patients had pronounced involvement of the cerebellum, especially of the midline structures. Creutzfeldt-Jakob disease should be considered in patients with subacute progressive neurological disease when cognitive changes are overshadowed by ocular motor findings or ataxia.

  19. Normal and abnormal neuronal migration in the developing cerebral cortex.

    PubMed

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

    2002-08-01

    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 unknown extracellular factors, and local signaling to stop neuronal migration. This process is also highly sensitive to various physical, chemical and biological agents as well as to genetic mutations. Any disturbance of the normal process may result in neuronal migration disorder. Such neuronal migration disorder is believed as major cause of both gross brain malformation and more special cerebral structural and functional abnormalities in experimental animals and in humans. An increasing number of instructive studies on experimental models and several genetic model systems of neuronal migration disorder have established the foundation of cortex formation and provided deeper insights into the genetic and molecular mechanisms underlying normal and abnormal neuronal migration.

  20. Clinical and MRI findings of cerebellar agenesis in two living adult patients

    PubMed Central

    Gelal, Fazıl Mustafa; Kalaycı, Tuğçe Özlem; Çelebisoy, Mehmet; Karakaş, Levent; Akkurt, Hülya Erdoğan; Koç, Feray

    2016-01-01

    Cerebellar agenesis (CA) is an extremely rare entity. We present two adult patients with CA. The 61-year-old man had ataxia, dysarthria, abnormalities in cerebellar tests, severe cognitive impairment, and moderate mental retardation. The 26-year-old woman had dysmetria, dysdiadochokinesia, and dysarthria as well as mild cognitive impairment and mild mental retardation. Magnetic resonance imaging (MRI) showed complete absence of the cerebellum with small residual vermis. Brainstem was hypoplastic and structures above tentorium were normal. Supratentorial white matter bundles were unaffected in diffusion tensor tractography. Only few adult patients with CA have so far been published. These cases show that patients with CA present with a variety of developmental, clinical, and mental abnormalities; and emphasize the role of the cerebellum in normal motor, language, and mental development. PMID:27293341

  1. Chlorpyrifos Toxicity in Mouse Cultured Cerebellar Granule Neurons at Different Stages of Development: Additive Effect on Glutamate-Induced Excitotoxicity

    PubMed Central

    Amani, Nahid; Soodi, Maliheh; Daraei, Bahram; Dashti, Abolfazl

    2016-01-01

    Objective Chlorpyrifos (CPF) is a neurotoxic organophosphorus (OP) insecticide. Its mechanism of action includes oxidative stress, excitotoxicity, and inhibition of the acetylcholinesterase enzyme (AChE). The aim of the present study is to investigate CPF toxicity in mature and immature cerebellar granule neurons (CGNs), as well as its effect on glutamate induced excitotoxicity. Materials and Methods This study was an in vitro experimental study performed on mice cultured CGNs. Immature and mature neurons were exposed to different concentrations of CPF (1-1000 µM) and glutamate (10-600 µM) for 48 hours after which we used the MTT assay to measure cytotoxicity. Immature neurons had exposure to CPF for 5 days in order to evaluate the cytotoxic effect on developing neurons. Mature neurons received sub-lethal concentrations of CPF (10, 100 µM) combined with different concentrations of glutamate. AChE activity and reactive oxygen species (ROS) generation were assessed after treatments. Results Immature CGNs had increased sensitivity to CPF toxicity compared to mature neurons. We observed significantly greater ROS production in immature compared to mature neurons, however AChE activity was more inhibited in mature neurons. Although CPF toxicity was not well correlated with AChE inhibition, it correlated well with ROS production. Glutamate toxicity was potentiated by sub-lethal concentration of CPF, however glutamate induced ROS production was not affected. The results suggested that CPF potentiated glutamate toxicity by mechanisms other than oxidative stress. Conclusion CPF toxicity differed in mature and immature neurons. Potentiated glutamate toxicity by CPF implied that CPF exposure might be a risk factor for neurodegenerative disease. PMID:27602329

  2. Chlorpyrifos Toxicity in Mouse Cultured Cerebellar Granule Neurons at Different Stages of Development: Additive Effect on Glutamate-Induced Excitotoxicity

    PubMed Central

    Amani, Nahid; Soodi, Maliheh; Daraei, Bahram; Dashti, Abolfazl

    2016-01-01

    Objective Chlorpyrifos (CPF) is a neurotoxic organophosphorus (OP) insecticide. Its mechanism of action includes oxidative stress, excitotoxicity, and inhibition of the acetylcholinesterase enzyme (AChE). The aim of the present study is to investigate CPF toxicity in mature and immature cerebellar granule neurons (CGNs), as well as its effect on glutamate induced excitotoxicity. Materials and Methods This study was an in vitro experimental study performed on mice cultured CGNs. Immature and mature neurons were exposed to different concentrations of CPF (1-1000 µM) and glutamate (10-600 µM) for 48 hours after which we used the MTT assay to measure cytotoxicity. Immature neurons had exposure to CPF for 5 days in order to evaluate the cytotoxic effect on developing neurons. Mature neurons received sub-lethal concentrations of CPF (10, 100 µM) combined with different concentrations of glutamate. AChE activity and reactive oxygen species (ROS) generation were assessed after treatments. Results Immature CGNs had increased sensitivity to CPF toxicity compared to mature neurons. We observed significantly greater ROS production in immature compared to mature neurons, however AChE activity was more inhibited in mature neurons. Although CPF toxicity was not well correlated with AChE inhibition, it correlated well with ROS production. Glutamate toxicity was potentiated by sub-lethal concentration of CPF, however glutamate induced ROS production was not affected. The results suggested that CPF potentiated glutamate toxicity by mechanisms other than oxidative stress. Conclusion CPF toxicity differed in mature and immature neurons. Potentiated glutamate toxicity by CPF implied that CPF exposure might be a risk factor for neurodegenerative disease.

  3. Abnormal ventricular development in preterm neonates with visually normal MRIs

    NASA Astrophysics Data System (ADS)

    Shi, Jie; Wang, Yalin; Lao, Yi; Ceschin, Rafael; Mi, Liang; Nelson, Marvin D.; Panigrahy, Ashok; Leporé, Natasha

    2015-12-01

    Children born preterm are at risk for a wide range of neurocognitive and neurobehavioral disorders. Some of these may stem from early brain abnormalities at the neonatal age. Hence, a precise characterization of neonatal neuroanatomy may help inform treatment strategies. In particular, the ventricles are often enlarged in neurocognitive disorders, due to atrophy of surrounding tissues. Here we present a new pipeline for the detection of morphological and relative pose differences in the ventricles of premature neonates compared to controls. To this end, we use a new hyperbolic Ricci flow based mapping of the ventricular surfaces of each subjects to the Poincaré disk. Resulting surfaces are then registered to a template, and a between group comparison is performed using multivariate tensor-based morphometry. We also statistically compare the relative pose of the ventricles within the brain between the two groups, by performing a Procrustes alignment between each subject's ventricles and an average shape. For both types of analyses, differences were found in the left ventricles between the two groups.

  4. Anomalous Cerebellar Anatomy in Chinese Children with Dyslexia

    PubMed Central

    Yang, Yang; Chen, Bao-Guo; Zhang, Yi-Wei; Bi, Hong-Yan

    2016-01-01

    The cerebellar deficit hypothesis for developmental dyslexia claims that cerebellar dysfunction causes the failures in the acquisition of visuomotor skills and automatic reading and writing skills. In people with dyslexia in the alphabetic languages, the abnormal activation and structure of the right or bilateral cerebellar lobes have been identified. Using a typical implicit motor learning task, however, one neuroimaging study demonstrated the left cerebellar dysfunction in Chinese children with dyslexia. In the present study, using voxel-based morphometry, we found decreased gray matter volume in the left cerebellum in Chinese children with dyslexia relative to age-matched controls. The positive correlation between reading performance and regional gray matter volume suggests that the abnormal structure in the left cerebellum is responsible for reading disability in Chinese children with dyslexia. PMID:27047403

  5. Anomalous Cerebellar Anatomy in Chinese Children with Dyslexia.

    PubMed

    Yang, Ying-Hui; Yang, Yang; Chen, Bao-Guo; Zhang, Yi-Wei; Bi, Hong-Yan

    2016-01-01

    The cerebellar deficit hypothesis for developmental dyslexia claims that cerebellar dysfunction causes the failures in the acquisition of visuomotor skills and automatic reading and writing skills. In people with dyslexia in the alphabetic languages, the abnormal activation and structure of the right or bilateral cerebellar lobes have been identified. Using a typical implicit motor learning task, however, one neuroimaging study demonstrated the left cerebellar dysfunction in Chinese children with dyslexia. In the present study, using voxel-based morphometry, we found decreased gray matter volume in the left cerebellum in Chinese children with dyslexia relative to age-matched controls. The positive correlation between reading performance and regional gray matter volume suggests that the abnormal structure in the left cerebellum is responsible for reading disability in Chinese children with dyslexia. PMID:27047403

  6. The influence of brain abnormalities on psychosocial development, criminal history and paraphilias in sexual murderers.

    PubMed

    Briken, Peer; Habermann, Niels; Berner, Wolfgang; Hill, Andreas

    2005-09-01

    The aim of this study was to investigate the number and type of brain abnormalities and their influence on psychosocial development, criminal history and paraphilias in sexual murderers. We analyzed psychiatric court reports of 166 sexual murderers and compared a group with notable signs of brain abnormalities (N = 50) with those without any signs (N = 116). Sexual murderers with brain abnormalities suffered more from early behavior problems. They were less likely to cohabitate with the victim at the time of the homicide and had more victims at the age of six years or younger. Psychiatric diagnoses revealed a higher total number of paraphilias: Transvestic fetishism and paraphilias not otherwise specified were more frequent in offenders with brain abnormalities. A binary logistic regression identified five predictors that accounted for 46.8% of the variance explaining the presence of brain abnormalities. Our results suggest the importance of a comprehensive neurological and psychological examination of this special offender group. PMID:16225232

  7. Constitutive Notch Signaling Causes Abnormal Development of the Oviducts, Abnormal Angiogenesis, and Cyst Formation in Mouse Female Reproductive Tract.

    PubMed

    Ferguson, Lydia; Kaftanovskaya, Elena M; Manresa, Carmen; Barbara, Agustin M; Poppiti, Robert J; Tan, Yingchun; Agoulnik, Alexander I

    2016-03-01

    The Notch signaling pathway is critical for the differentiation of many tissues and organs in the embryo. To study the consequences of Notch1 gain-of-function signaling on female reproductive tract development, we used a cre-loxP strategy and Amhr2-cre transgene to generate mice with conditionally activated Notch1 (Rosa(Notch1)). The Amhr2-cre transgene is expressed in the mesenchyme of developing female reproductive tract and in granulosa cells in the ovary. Double transgenic Amhr2-cre, Rosa(Notch1) females were infertile, whereas control Rosa(Notch1) mice had normal fertility. All female reproductive organs in mutants showed hemorrhaging of blood vessels progressing with age. The mutant oviducts did not develop coiling, and were instead looped around the ovary. There were multiple blockages in the lumen along the oviduct length, creating a barrier for sperm or oocyte passage. Mutant females demonstrated inflamed uteri with increased vascularization and an influx of inflammatory cells. Additionally, older females developed ovarian, oviductal, and uterine cysts. The significant change in gene expression was detected in the mutant oviduct expression of Wnt4, essential for female reproductive tract development. Similar oviductal phenotypes have been detected previously in mice with activated Smo and in beta-catenin, Wnt4, Wnt7a, and Dicer conditional knockouts, indicating a common regulatory pathway disrupted by these genetic abnormalities. PMID:26843448

  8. Primary cerebellar agenesis presenting as isolated cognitive impairment

    PubMed Central

    Ashraf, Obaid; Jabeen, Shumyla; Khan, Azhar; Shaheen, Feroze

    2016-01-01

    Primary cerebellar agenesis is a rare entity. To the best of our knowledge, eleven living cases have been reported till date. Most of these were associated with some degree of motor impairment. We present a case of cerebellar agenesis in a child who presented with cognitive abnormalities leading to poor performance at school. No motor impairment was seen. Among the eleven cases reported earlier, only one case showed lack of motor impairment.

  9. Primary cerebellar agenesis presenting as isolated cognitive impairment

    PubMed Central

    Ashraf, Obaid; Jabeen, Shumyla; Khan, Azhar; Shaheen, Feroze

    2016-01-01

    Primary cerebellar agenesis is a rare entity. To the best of our knowledge, eleven living cases have been reported till date. Most of these were associated with some degree of motor impairment. We present a case of cerebellar agenesis in a child who presented with cognitive abnormalities leading to poor performance at school. No motor impairment was seen. Among the eleven cases reported earlier, only one case showed lack of motor impairment. PMID:27606028

  10. Contemporary issues in the management of abnormal placentation during pregnancy in developing nations: An Indian perspective.

    PubMed

    Bajwa, Sukhwinder Kaur; Singh, Anita; Bajwa, Sukhminder Jit Singh

    2013-07-01

    The gap between the developed and developing nations with regards to maternal mortality and morbidity may have narrowed but still a lot of dedicated work is required to bridge these differences. Obstetrical haemorrhage is the leading cause of maternal deaths in these developing nations especially in India. The most common causes of this fatal haemorrhage are the placental abnormalities which rarely get detected before delivery. Numerous factors have been incremental in the causation of this abnormal placental implantation with resultant complications. The present article is an attempt to review possible predictors of abnormal placental implantation. Also, a genuine attempt has been made to enumerate possible measures to identify the predictors of abnormal placentation during early pregnancy and their suitable prevention and management.

  11. Cerebellar and Brainstem Malformations.

    PubMed

    Poretti, Andrea; Boltshauser, Eugen; Huisman, Thierry A G M

    2016-08-01

    The frequency and importance of the evaluation of the posterior fossa have increased significantly over the past 20 years owing to advances in neuroimaging. Conventional and advanced neuroimaging techniques allow detailed evaluation of the complex anatomic structures within the posterior fossa. A wide spectrum of cerebellar and brainstem malformations has been shown. Familiarity with the spectrum of cerebellar and brainstem malformations and their well-defined diagnostic criteria is crucial for optimal therapy, an accurate prognosis, and correct genetic counseling. This article discusses cerebellar and brainstem malformations, with emphasis on neuroimaging findings (including diagnostic criteria), neurologic presentation, systemic involvement, prognosis, and recurrence. PMID:27423798

  12. Developmental vitamin D deficiency causes abnormal brain development.

    PubMed

    Eyles, D W; Feron, F; Cui, X; Kesby, J P; Harms, L H; Ko, P; McGrath, J J; Burne, T H J

    2009-12-01

    There is now clear evidence that vitamin D is involved in brain development. Our group is interested in environmental factors that shape brain development and how this may be relevant to neuropsychiatric diseases including schizophrenia. The origins of schizophrenia are considered developmental. We hypothesised that developmental vitamin D (DVD) deficiency may be the plausible neurobiological explanation for several important epidemiological correlates of schizophrenia namely: (1) the excess winter/spring birth rate, (2) increased incidence of the disease in 2nd generation Afro-Caribbean migrants and (3) increased urban birth rate. Moreover we have published two pieces of direct epidemiological support for this hypothesis in patients. In order to establish the "Biological Plausibility" of this hypothesis we have developed an animal model to study the effect of DVD deficiency on brain development. We do this by removing vitamin D from the diet of female rats prior to breeding. At birth we return all dams to a vitamin D containing diet. Using this procedure we impose a transient, gestational vitamin D deficiency, while maintaining normal calcium levels throughout. The brains of offspring from DVD-deficient dams are characterised by (1) a mild distortion in brain shape, (2) increased lateral ventricle volumes, (3) reduced differentiation and (4) diminished expression of neurotrophic factors. As adults, the alterations in ventricular volume persist and alterations in brain gene and protein expression emerge. Adult DVD-deficient rats also display behavioural sensitivity to agents that induce psychosis (the NMDA antagonist MK-801) and have impairments in attentional processing. In this review we summarise the literature addressing the function of vitamin D on neuronal and non-neuronal cells as well as in vivo results from DVD-deficient animals. Our conclusions from these data are that vitamin D is a plausible biological risk factor for neuropsychiatric disorders and that

  13. Environmental Enteropathy: Elusive but Significant Subclinical Abnormalities in Developing Countries.

    PubMed

    Watanabe, Koji; Petri, William A

    2016-08-01

    Environmental enteropathy/Environmental enteric dysfunction (EE/EED) is a chronic disease of small intestine characterized by gut inflammation and barrier disruption, malabsorption and systemic inflammation in the absence of diarrhea. It is predominantly diseases of children in low income countries and is hypothesized to be caused by continuous exposure to fecally contaminated food, water and fomites. It had not been recognized as a priority health issue because it does not cause overt symptoms and was seen in apparently healthy individuals. However, there is a growing concern of EE/EED because of its impact on longitudinal public health issues, such as growth faltering, oral vaccine low efficacy and poor neurocognitive development. Recent works have provided important clues to unravel its complex pathogenesis, and suggest possible strategies for controlling EE/EED. However, effective diagnostic methods and interventions remain unsettled. Here, we review the existing literature, especially about its pathogenesis, and discuss a solution for children living in the developing world.

  14. Environmental Enteropathy: Elusive but Significant Subclinical Abnormalities in Developing Countries.

    PubMed

    Watanabe, Koji; Petri, William A

    2016-08-01

    Environmental enteropathy/Environmental enteric dysfunction (EE/EED) is a chronic disease of small intestine characterized by gut inflammation and barrier disruption, malabsorption and systemic inflammation in the absence of diarrhea. It is predominantly diseases of children in low income countries and is hypothesized to be caused by continuous exposure to fecally contaminated food, water and fomites. It had not been recognized as a priority health issue because it does not cause overt symptoms and was seen in apparently healthy individuals. However, there is a growing concern of EE/EED because of its impact on longitudinal public health issues, such as growth faltering, oral vaccine low efficacy and poor neurocognitive development. Recent works have provided important clues to unravel its complex pathogenesis, and suggest possible strategies for controlling EE/EED. However, effective diagnostic methods and interventions remain unsettled. Here, we review the existing literature, especially about its pathogenesis, and discuss a solution for children living in the developing world. PMID:27495791

  15. Transgenic mice overexpressing reticulon 3 develop neuritic abnormalities

    PubMed Central

    Hu, Xiangyou; Shi, Qi; Zhou, Xiangdong; He, Wanxia; Yi, Hong; Yin, Xinghua; Gearing, Marla; Levey, Allan; Yan, Riqiang

    2007-01-01

    Dystrophic neurites are swollen dendrites or axons recognizable near amyloid plaques as a part of important pathological feature of Alzheimer's disease (AD). We report herein that reticulon 3 (RTN3) is accumulated in a distinct population of dystrophic neurites named as RTN3 immunoreactive dystrophic neurites (RIDNs). The occurrence of RIDNs is concomitant with the formation of high-molecular-weight RTN3 aggregates in brains of AD cases and mice expressing mutant APP. Ultrastructural analysis confirms accumulation of RTN3-containing aggregates in RIDNs. It appears that the protein level of RTN3 governs the formation of RIDNs because transgenic mice expressing RTN3 will develop RIDNs, initially in the hippocampal CA1 region, and later in other hippocampal and cortical regions. Importantly, we show that the presence of dystrophic neurites in Tg-RTN3 mice causes impairments in spatial learning and memory, as well as synaptic plasticity, implying that RIDNs potentially contribute to AD cognitive dysfunction. Together, we demonstrate that aggregation of RTN3 contributes to AD pathogenesis by inducing neuritic dystrophy. Inhibition of RTN3 aggregation is likely a therapeutic approach for reducing neuritic dystrophy. PMID:17476306

  16. Cerebellar ataxia as the presenting manifestation of Lyme disease.

    PubMed

    Arav-Boger, Ravit; Crawford, Thomas; Steere, Allen C; Halsey, Neal A

    2002-04-01

    A 7-year-old boy from suburban Baltimore who presented with cerebellar ataxia and headaches was found by magnetic resonance imaging to have multiple cerebellar enhancing lesions. He had no history of tick exposure. He was initially treated with steroids for presumptive postinfectious encephalitis. Lyme disease was diagnosed 10 weeks later after arthritis developed. Testing of the cerebrospinal fluid obtained at the time cerebellar ataxia was diagnosed revealed intrathecal antibody production to Borrelia burgdorferi. Treatment with intravenous antibiotics led to rapid resolution of persistent cerebellar findings.

  17. Immune activation during cerebellar dysfunction following Plasmodium falciparum malaria.

    PubMed

    de Silva, H J; Hoang, P; Dalton, H; de Silva, N R; Jewell, D P; Peiris, J B

    1992-01-01

    Evidence for immune activation was investigated in 12 patients with a rare syndrome of self-limiting, delayed onset cerebellar dysfunction following an attack of falciparum malaria which occurred 18-26 d previously. Concentrations of tumour necrosis factor, interleukin 6 and interleukin 2 were all significantly higher in serum samples of patients during cerebellar ataxia than in recovery sera and in the sera of 8 patients who did not develop delayed cerebellar dysfunction following an attack of falciparum malaria. Cytokine concentrations in the cerebrospinal fluid were also significantly higher in ataxic patients than in controls. These findings suggest that immunological mechanisms may play a role in delayed cerebellar dysfunction following falciparum malaria.

  18. Regulation of Tlx3 by Pax6 is required for the restricted expression of Chrnα3 in Cerebellar Granule Neuron progenitors during development

    PubMed Central

    Divya, Thulasi Sheela; Lalitha, Soundararajan; Parvathy, Surendran; Subashini, Chandramohan; Sanalkumar, Rajendran; Dhanesh, Sivadasan Bindu; Rasheed, Vazhanthodi Abdul; Divya, Mundackal Sivaraman; Tole, Shubha; James, Jackson

    2016-01-01

    Homeobox gene Tlx3 is known to promote glutamatergic differentiation and is expressed in post-mitotic neurons of CNS. Contrary to this here, we discovered that Tlx3 is expressed in the proliferating progenitors of the external granule layer in the cerebellum, and examined factors that regulate this expression. Using Pax6−/−Sey mouse model and molecular interaction studies we demonstrate Pax6 is a key activator of Tlx3 specifically in cerebellum, and induces its expression starting at embryonic day (E)15. By Postnatal day (PN)7, Tlx3 is expressed in a highly restricted manner in the cerebellar granule neurons of the posterior cerebellar lobes, where it is required for the restricted expression of nicotinic cholinergic receptor-α3 subunit (Chrnα3) and other genes involved in formation of synaptic connections and neuronal migration. These results demonstrate a novel role for Tlx3 and indicate that Pax6-Tlx3 expression and interaction is part of a region specific regulatory network in cerebellum and its deregulation during development could possibly lead to Autistic spectral disorders (ASD). PMID:27452274

  19. Parvovirus associated cerebellar hypoplasia and hydrocephalus in day-old broiler chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cerebellar hypoplasia and hydrocephalus were detected in day-old broiler chickens. Brains of chickens evaluated at necropsy appeared to be abnormal; some were disfigured and cerebellae appeared to be smaller than normal. Histopathologic examination of brains revealed cerebellar folia that were sho...

  20. A Brief History of the Development of Abnormal Psychology: A Training Guide. Final Report.

    ERIC Educational Resources Information Center

    Phelps, William R.

    Presented for practitioners is a history of the development of abnormal psychology. Areas covered include the following: Early medical concepts, ideas carried over from literature, early treatment of the mentally ill, development of the psychological viewpoint, Freud's psychoanalytic theory, Jung's analytic theory, the individual psychology of…

  1. Aprosencephaly and cerebellar dysgenesis in SIBS

    SciTech Connect

    Florell, S.R.; Townsend, J.J.; Klatt, E.C.

    1996-06-28

    Aprosencephaly is a rare, lethal malformation sequence of the central nervous system that has been attributed to a postneuralation encephaloclastic process. We describe autopsy findings consistent with aprosencephaly in 2 fetuses conceived from a consanguineous mating (first cousins). Both showed anecephalic manifestations; however, the crania were intact, with fused sutures. The neuropathologic findings were essentially identical. Each fetus had complete absence of the telecephalon and pyramidal tracts, rudimentary diencephalic and mesencephalic structures, primitive cerebellar hemispheres, posterolateral clusters of primitive neural cells in the medullas suggesting an abnormality of neural migration, a normally-formed spinal cord, and retinal dysplasia within normally-formed globes. In addition, both fetuses manifested a peculiar perivascular mesenchymal proliferation seen only within the central nervous system. The similarity of these cases, coupled with parental consanguinity, suggests a primary malformation in brain development due to the homozygous representation of a mutant allele. We hypothesize that these patients may represent a defect in a gene important in brain development, the nature of which has yet to be elucidated. 26 refs., 4 figs., 4 tabs.

  2. Expression of zebrafish ROR alpha gene in cerebellar-like structures.

    PubMed

    Katsuyama, Yu; Oomiya, Yoshihiro; Dekimoto, Hideyuki; Motooka, Eriko; Takano, Ai; Kikkawa, Satoshi; Hibi, Masahiko; Terashima, Toshio

    2007-09-01

    Mouse genetic studies have identified several genes involved in cerebellar development. The mouse mutants staggerer and lurcher are functionally deficient for the retinoid-related orphan receptor alpha (ROR alpha) and glutamate receptor delta2 (Grid2) genes, respectively, and they show similar functional and developmental abnormalities in the cerebellum. Here, we report the cloning and expression pattern of zebrafish ROR alpha orthologues rora1 and rora2, and compare their expression pattern with that of grid2. Expression of rora1 and rora2 is initiated at late gastrula and pharyngula stages, respectively. Both rora1 and rora2 are spatially expressed in the retina and tectum. Expression of rora2 was further observed in the cerebellum, as reported for mammalian ROR alpha. In the adult brain, rora2 and grid2 are coexpressed in brain regions, designated as cerebellar-like structures. These observations suggest an evolutionarily conserved function of ROR alpha orthologues in the vertebrate brain.

  3. Disorders of sexual development and abnormal early development in domestic food-producing mammals: the role of chromosome abnormalities, environment and stress factors.

    PubMed

    Favetta, L A; Villagómez, D A F; Iannuzzi, L; Di Meo, G; Webb, A; Crain, S; King, W A

    2012-01-01

    The management of disorders of sexual development (DSD) in humans and domestic animals has been the subject of intense interest for decades. The association between abnormal chromosome constitutions and DSDs in domestic animals has been recorded since the beginnings of conventional cytogenetic analysis. Deviated karyotypes consisting of abnormal sex chromosome sets and/or the coexistence of cells with different sex chromosome constitutions in an individual seem to be the main causes of anomalies of sex determination and sex differentiation. In recent years, a growing interest has developed around the environmental insults, such as endocrine-disrupting compounds (EDC) and heat stressors, which affect fertility, early embryonic development and, in some instances, directly the sex ratio and/or the development of 1 specific sex versus the other. A variety of chemical compounds present in the environment at low doses has been shown to have major effects on the reproductive functions in human and domestic animals following prolonged exposure. In this review, we present an overview of congenital/chromosomal factors that are responsible for the DSDs and link them and the lack of proper embryonic development to environmental factors that are becoming a major global concern.

  4. Abnormal Development of Thalamic Microstructure in Premature Neonates with Congenital Heart Disease

    PubMed Central

    Paquette, Lisa B.; Votava-Smith, Jodie K.; Ceschin, Rafael; Nagasunder, Arabhi C.; Jackson, Hollie A.; Blüml, Stefan; Wisnowski, Jessica L.; Panigrahy, Ashok

    2015-01-01

    Background and Purpose Preterm birth is associated with alteration in cortico-thalamic development, which underlies poor neurodevelopmental outcomes. Our hypothesis was that preterm neonates with CHD would demonstrate abnormal thalamic microstructure when compared to critically ill neonates without CHD. A secondary aim was to identify any association between thalamic microstructural abnormalities and peri-operative clinical variables. Material and Methods We compared thalamic DTI measurements in 21 preterm neonates with CHD to two cohorts of neonates without CHD: 28 term and 27 preterm neonates, identified from the same neonatal intensive care unit. Comparison was made with three other selected white matter regions using ROI manual based measurements. Correlation was made with post-conceptional age and peri-operative clinical variables. Results In preterm neonates with CHD, there were age-related differences in thalamic diffusivity (axial and radial) compared to the preterm and term non-CHD group, in contrast to no differences in anisotropy. Contrary to our hypothesis, abnormal thalamic and optic radiation microstructure was most strongly associated with an elevated first arterial blood gas pO2 and elevated pre-operative arterial blood gas pH (p<0.05). Conclusion Age-related thalamic microstructural abnormalities were observed in preterm neonates with CHD. Perinatal hyperoxemia and increased peri-operative serum pH was associated with abnormal thalamic microstructure in preterm neonates with CHD. This study emphasizes the vulnerability of thalamo-cortical development in the preterm neonate with CHD. PMID:25608695

  5. Association of Traditional Cardiovascular Risk Factors With Development of Major and Minor Electrocardiographic Abnormalities: A Systematic Review.

    PubMed

    Healy, Caroline F; Lloyd-Jones, Donald M

    2016-01-01

    Electrocardiographic (ECG) abnormalities are prevalent in middle aged and are associated with risk of adverse cardiovascular events. It is unclear whether and to what extent traditional risk factors are associated with the development of ECG abnormalities. To determine whether traditional cardiovascular risk factors are associated with the presence or development of ECG abnormalities, we performed a systematic review of the English-language literature for cross-sectional and prospective studies examining associations between traditional cardiovascular risk factors and ECG abnormalities, including major and minor ECG abnormalities, isolated nonspecific ST-segment and T-wave abnormalities, other ST-segment and T-wave abnormalities, QT interval, Q waves, and QRS duration. Of the 202 papers initially identified, 19 were eligible for inclusion. We examined data analyzing risk factor associations with ECG abnormalities in individuals free of cardiovascular disease. For composite major or minor ECG abnormalities, black race, older age, higher blood pressure, use of antihypertensive medications, higher body mass index, diabetes, smoking, and evidence of left ventricular hypertrophy or higher left ventricular mass are the factors most commonly associated with prevalence and incidence. Risk factor associations differ somewhat according to types of specific ECG abnormalities. Because major and minor ECG abnormalities have important and independent prognostic significance, understanding the groups at risk for their development may inform prevention strategies focused on modifiable risk factors to reduce the burden of ECG abnormalities, which may in turn promote CVD prevention. PMID:27054606

  6. Increase in cerebellar neurotrophin-3 and oxidative stress markers in autism.

    PubMed

    Sajdel-Sulkowska, Elizabeth M; Xu, Ming; Koibuchi, Noriyuki

    2009-09-01

    Autism is a neurodevelopmental disorder characterized by social and language deficits, ritualistic-repetitive behaviors and disturbance in motor functions. Data of imaging, head circumference studies, and Purkinje cell analysis suggest impaired brain growth and development. Both genetic predisposition and environmental triggers have been implicated in the etiology of autism, but the underlying cause remains unknown. Recently, we have reported an increase in 3-nitrotyrosine (3-NT), a marker of oxidative stress damage to proteins in autistic cerebella. In the present study, we further explored oxidative damage in the autistic cerebellum by measuring 8-hydroxydeoxyguanosine (8-OH-dG), a marker of DNA modification, in a subset of cases analyzed for 3-NT. We also explored the hypothesis that oxidative damage in autism is associated with altered expression of brain neurotrophins critical for normal brain growth and differentiation. The content of 8-OH-dG in cerebellar DNA isolated by the proteinase K method was measured using an enzyme-linked immunosorbent assay (ELISA); neurotrophin-3 (NT-3) levels in cerebellar homogenates were measured using NT-3 ELISA. Cerebellar 8-OH-dG showed trend towards higher levels with the increase of 63.4% observed in autism. Analysis of cerebellar NT-3 showed a significant (p = 0.034) increase (40.3%) in autism. Furthermore, there was a significant positive correlation between cerebellar NT-3 and 3-NT (r = 0.83; p = 0.0408). These data provide the first quantitative measure of brain NT-3 and show its increase in the autistic brain. Altered levels of brain NT-3 are likely to contribute to autistic pathology not only by affecting brain axonal targeting and synapse formation but also by further exacerbating oxidative stress and possibly contributing to Purkinje cell abnormalities.

  7. Cerebellar learning mechanisms

    PubMed Central

    Freeman, John H.

    2014-01-01

    The mechanisms underlying cerebellar learning are reviewed with an emphasis on old arguments and new perspectives on eyeblink conditioning. Eyeblink conditioning has been used for decades a model system for elucidating cerebellar learning mechanisms. The standard model of the mechanisms underlying eyeblink conditioning is that there two synaptic plasticity processes within the cerebellum that are necessary for acquisition of the conditioned response: 1) long-term depression (LTD) at parallel fiber-Purkinje cell synapses and 2) long-term potentiation (LTP) at mossy fiber-interpositus nucleus synapses. Additional Purkinje cell plasticity mechanisms may also contribute to eyeblink conditioning including LTP, excitability, and entrainment of deep nucleus activity. Recent analyses of the sensory input pathways necessary for eyeblink conditioning indicate that the cerebellum regulates its inputs to facilitate learning and maintain plasticity. Cerebellar learning during eyeblink conditioning is therefore a dynamic interactive process which maximizes responding to significant stimuli and suppresses responding to irrelevant or redundant stimuli. PMID:25289586

  8. Orthostatic hypotension in acute cerebellar infarction.

    PubMed

    Kim, Hyun-Ah; Lee, Hyung

    2016-01-01

    To investigate the frequency and pattern of orthostatic hypotension (OH) associated with acute isolated cerebellar infarction, and to identify the cerebellar structure(s) potentially responsible for OH, 29 patients (mean age 60.0) with acute isolated cerebellar infarction performed a standard battery of autonomic function tests including the head up tilt test using Finapres for recording of the beat-to-beat BP response during the acute period. Cerebellar infarction related OH was defined as fall in BP (>20 mmHg systolic BP) on tilting in patients without any disease(s) that could potentially cause autonomic dysfunction, or in patients who had a potential cause of autonomic dysfunction, but showed the absence of OH during a follow-up test. The severity and distribution of autonomic dysfunction were measured by the composite autonomic severity score (CASS). Nine patients (31 %) had OH (range 24-53 mmHg) on tilting during the acute period. Most patients (7/9) had a remarkable decrement in systolic BP immediately upon tilting, but OH rapidly normalized. Mean of maximal decrease in systolic BP during head up tilt test was 37.0 mmHg. The OH group showed mild autonomic dysfunctions (CASS, 3.7) with adrenergic sympathetic dysfunction appearing as the most common abnormality. Lesion subtraction analyses revealed that damage to the medial part of the superior semilunar lobule (Crus I) and tonsil was more frequent in OH group compared to non-OH group. Cerebellar infarction may cause a brief episode of OH. The medial part of the superior semilunar lobule and tonsil may participate in regulating the early BP response during orthostasis. PMID:26530504

  9. The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development.

    PubMed Central

    Goedert, M; Jakes, R; Crowther, R A; Six, J; Lübke, U; Vandermeeren, M; Cras, P; Trojanowski, J Q; Lee, V M

    1993-01-01

    Tau is a neuronal phosphoprotein whose expression is developmentally regulated. A single tau isoform is expressed in fetal human brain but six isoforms are expressed in adult brain, with the fetal isoform corresponding to the shortest of the adult isoforms. Phosphorylation of tau is also developmentally regulated, as fetal tau is phosphorylated at more sites than adult tau. In Alzheimer disease, the six adult tau isoforms become abnormally phosphorylated and form the paired helical filament, the major fibrous component of the characteristic neurofibrillary lesions. We show here that Ser-202 (in the numbering of the longest human brain tau isoform) is a phosphorylation site that distinguishes fetal from adult tau and we identify it as one of the abnormal phosphorylation sites in Alzheimer disease. The abnormal phosphorylation of tau at Ser-202 in Alzheimer disease thus recapitulates normal phosphorylation during development. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8506352

  10. Understanding normal and abnormal development of the Wolffian/epididymal duct by using transgenic mice

    PubMed Central

    Murashima, Aki; Xu, Bingfang; Hinton, Barry T

    2015-01-01

    The development of the Wolffian/epididymal duct is crucial for proper function and, therefore, male fertility. The development of the epididymis is complex; the initial stages form as a transient embryonic kidney; then the mesonephros is formed, which in turn undergoes extensive morphogenesis under the influence of androgens and growth factors. Thus, understanding of its full development requires a wide and multidisciplinary view. This review focuses on mouse models that display abnormalities of the Wolffian duct and mesonephric development, the importance of these mouse models toward understanding male reproductive tract development, and how these models contribute to our understanding of clinical abnormalities in humans such as congenital anomalies of the kidney and urinary tract (CAKUT). PMID:26112482

  11. Understanding normal and abnormal development of the Wolffian/epididymal duct by using transgenic mice.

    PubMed

    Murashima, Aki; Xu, Bingfang; Hinton, Barry T

    2015-01-01

    The development of the Wolffian/epididymal duct is crucial for proper function and, therefore, male fertility. The development of the epididymis is complex; the initial stages form as a transient embryonic kidney; then the mesonephros is formed, which in turn undergoes extensive morphogenesis under the influence of androgens and growth factors. Thus, understanding of its full development requires a wide and multidisciplinary view. This review focuses on mouse models that display abnormalities of the Wolffian duct and mesonephric development, the importance of these mouse models toward understanding male reproductive tract development, and how these models contribute to our understanding of clinical abnormalities in humans such as congenital anomalies of the kidney and urinary tract (CAKUT). PMID:26112482

  12. Locomotor patterns in cerebellar ataxia.

    PubMed

    Martino, G; Ivanenko, Y P; Serrao, M; Ranavolo, A; d'Avella, A; Draicchio, F; Conte, C; Casali, C; Lacquaniti, F

    2014-12-01

    Several studies have demonstrated how cerebellar ataxia (CA) affects gait, resulting in deficits in multijoint coordination and stability. Nevertheless, how lesions of cerebellum influence the locomotor muscle pattern generation is still unclear. To better understand the effects of CA on locomotor output, here we investigated the idiosyncratic features of the spatiotemporal structure of leg muscle activity and impairments in the biomechanics of CA gait. To this end, we recorded the electromyographic (EMG) activity of 12 unilateral lower limb muscles and analyzed kinematic and kinetic parameters of 19 ataxic patients and 20 age-matched healthy subjects during overground walking. Neuromuscular control of gait in CA was characterized by a considerable widening of EMG bursts and significant temporal shifts in the center of activity due to overall enhanced muscle activation between late swing and mid-stance. Patients also demonstrated significant changes in the intersegmental coordination, an abnormal transient in the vertical ground reaction force and instability of limb loading at heel strike. The observed abnormalities in EMG patterns and foot loading correlated with the severity of pathology [International Cooperative Ataxia Rating Scale (ICARS), a clinical ataxia scale] and the changes in the biomechanical output. The findings provide new insights into the physiological role of cerebellum in optimizing the duration of muscle activity bursts and the control of appropriate foot loading during locomotion.

  13. Chromosome Abnormalities

    MedlinePlus

    ... decade, newer techniques have been developed that allow scientists and doctors to screen for chromosomal abnormalities without using a microscope. These newer methods compare the patient's DNA to a normal DNA ...

  14. Cognitive, linguistic and affective disturbances following a right superior cerebellar artery infarction: a case study.

    PubMed

    Mariën, Peter; Baillieux, Hanne; De Smet, Hyo Jung; Engelborghs, Sebastiaan; Wilssens, Ineke; Paquier, Philippe; De Deyn, Peter P

    2009-04-01

    The cerebellar cognitive affective syndrome (CCAS) is a neurobehavioral syndrome that may develop after congenital and acquired cerebellar lesions. The syndrome consists of deficits in executive functioning, spatial cognition, visual-spatial memory and language and also involves personality and behavioral changes. We describe a 58-year-old right-handed man who in addition to affective disturbances presented with a unique combination of cognitive and linguistic deficits following an ischemic infarction in the vascular territory of the right superior cerebellar artery (SCA). Neurocognitive and neurolinguistic examinations were performed in the acute phase (10 days post-onset) and lesion phase (four weeks post-onset) of the stroke. A Tc-99m-ECD SPECT study was performed five weeks after the stroke. Acute phase data revealed a generalized cognitive decline and mild transcortical sensory aphasia. In the lesion phase, the neurobehavioral tableau was dominated by executive dysfunctions, disrupted divided attention, disturbed visual-spatial organization and behavioral abnormalities. Neurolinguistic investigations disclosed visual dyslexia and surface dysgraphia. Reading of words and visual lexical decision tasks of words and nonwords were severely defective and predominantly characterized by visual errors. In addition, writing irregular and ambiguous words resulted in regularization errors (phonologically plausible errors based on phoneme-grapheme correspondence rules). In the absence of any structural damage in the supratentorial brain regions, a quantified SPECT study showed a relative hypoperfusion in the right cerebellar hemisphere and the left medial frontal lobe. CCAS is for the first time reported in association with visual dyslexia and surface dysgraphia. We hypothesize that the cognitive and linguistic deficits might result from functional disruption of the cerebellar-encephalic pathways, connecting the cerebellum to the frontal supratentorial areas which subserve

  15. Molecular markers of neuronal progenitors in the embryonic cerebellar anlage.

    PubMed

    Morales, Daniver; Hatten, Mary E

    2006-11-22

    The cerebellum, like the cerebrum, includes a nuclear structure and an overlying cortical structure. Experiments in the past decade have expanded knowledge beyond the traditional function of the cerebellum to include critical roles in motor learning and memory and sensory discrimination. The initial steps in cerebellar development depend on inductive signaling involving FGF and Wnt proteins produced at the mesencephalic/metencephalic boundary. To address the issue of how individual cerebellar cell fates within the cerebellar territory are specified, we examined the expression of transcription factors, including mammalian homologues of LIM homeodomain-containing proteins, basic helix-loop-helix proteins, and three amino acid loop-containing proteins. The results of these studies show that combinatorial codes of transcription factors define precursors of the cerebellar nuclei, and both Purkinje cells and granule neurons of the cerebellar cortex. Examination of gene expression patterns in several hundred lines of Egfp-BAC (bacterial artificial chromosome) transgenic mice in the GENSAT Project revealed numerous genes with restricted expression in cerebellar progenitor populations, including genes specific for cerebellar nuclear precursors and Purkinje cell precursors. In addition, we identified patterns of gene expression that link granule and Purkinje cells to their precerebellar nuclei. These results identify molecular pathways that offer new insights on the development of the nuclear and cortical structures of the cerebellum, as well as components of the cerebellar circuitry.

  16. A Cerebellar Framework for Predictive Coding and Homeostatic Regulation in Depressive Disorder.

    PubMed

    Schutter, Dennis J L G

    2016-02-01

    Depressive disorder is associated with abnormalities in the processing of reward and punishment signals and disturbances in homeostatic regulation. These abnormalities are proposed to impair error minimization routines for reducing uncertainty. Several lines of research point towards a role of the cerebellum in reward- and punishment-related predictive coding and homeostatic regulatory function in depressive disorder. Available functional and anatomical evidence suggests that in addition to the cortico-limbic networks, the cerebellum is part of the dysfunctional brain circuit in depressive disorder as well. It is proposed that impaired cerebellar function contributes to abnormalities in predictive coding and homeostatic dysregulation in depressive disorder. Further research on the role of the cerebellum in depressive disorder may further extend our knowledge on the functional and neural mechanisms of depressive disorder and development of novel antidepressant treatments strategies targeting the cerebellum.

  17. Metronidazole-Induced Cerebellar Toxicity

    PubMed Central

    Agarwal, Amit; Kanekar, Sangam; Sabat, Shyam; Thamburaj, Krishnamurthy

    2016-01-01

    Metronidazole is a very common antibacterial and antiprotozoal with wide usage across the globe, including the least developed countries. It is generally well-tolerated with a low incidence of serious side-effects. Neurological toxicity is fairly common with this drug, however majority of these are peripheral neuropathy with very few cases of central nervous toxicity reported. We report the imaging findings in two patients with cerebellar dysfunction after Metronidazole usage. Signal changes in the dentate and red nucleus were seen on magnetic resonance imaging in these patients. Most of the cases reported in literature reported similar findings, suggesting high predilection for the dentate nucleus in metronidazole induced encephalopathy. PMID:27127600

  18. Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia.

    PubMed

    Ridler, Khanum; Veijola, Juha M; Tanskanen, Päivikki; Miettunen, Jouko; Chitnis, Xavier; Suckling, John; Murray, Graham K; Haapea, Marianne; Jones, Peter B; Isohanni, Matti K; Bullmore, Edward T

    2006-10-17

    Delineating longitudinal relationships between early developmental markers, adult cognitive function, and adult brain structure could clarify the pathogenesis of neurodevelopmental disorders such as schizophrenia. We aimed to identify brain structural correlates of infant motor development (IMD) and adult executive function in nonpsychotic adults and to test for abnormal associations between these measures in people with schizophrenia. Representative samples of nonpsychotic adults (n = 93) and people with schizophrenia (n = 49) were drawn from the Northern Finland 1966 general population birth cohort. IMD was prospectively assessed at age 1 year; executive function testing and MRI were completed at age 33-35 years. We found that earlier motor development in infancy was correlated with superior executive function in nonpsychotic subjects. Earlier motor development was also normally associated with increased gray matter density in adult premotor cortex, striatum, and cerebellum and increased white matter density in frontal and parietal lobes. Adult executive function was normally associated with increased gray matter density in a fronto-cerebellar system that partially overlapped, but was not identical to, the gray matter regions normally associated with IMD. People with schizophrenia had relatively delayed IMD and impaired adult executive function in adulthood. Furthermore, they demonstrated no normative associations between fronto-cerebellar structure, IMD, or executive function. We conclude that frontal cortico-cerebellar systems correlated with adult executive function are anatomically related to systems associated with normal infant motor development. Disruption of this anatomical system may underlie both the early developmental and adult cognitive abnormalities in schizophrenia.

  19. The physiological basis of therapies for cerebellar ataxias

    PubMed Central

    Mitoma, Hiroshi; Manto, Mario

    2016-01-01

    Cerebellar ataxias represent a group of heterogeneous disorders impacting on activities of daily living and quality of life. Various therapies have been proposed to improve symptoms in cerebellar ataxias. This review examines the physiological background of the various treatments currently administered worldwide. We analyze the mechanisms of action of drugs with a focus on aminopyridines and other antiataxic medications, of noninvasive cerebellar stimulation, and of motor rehabilitation. Considering the cerebellum as a controller, we propose the novel concept of ‘restorable stage’. Because of its unique anatomical architecture and its diffuse connectivity in particular with the cerebral cortex, keeping in mind the anatomophysiology of the cerebellar circuitry is a necessary step to understand the rationale of therapies of cerebellar ataxias and develop novel therapeutic tools. PMID:27582895

  20. The physiological basis of therapies for cerebellar ataxias.

    PubMed

    Mitoma, Hiroshi; Manto, Mario

    2016-09-01

    Cerebellar ataxias represent a group of heterogeneous disorders impacting on activities of daily living and quality of life. Various therapies have been proposed to improve symptoms in cerebellar ataxias. This review examines the physiological background of the various treatments currently administered worldwide. We analyze the mechanisms of action of drugs with a focus on aminopyridines and other antiataxic medications, of noninvasive cerebellar stimulation, and of motor rehabilitation. Considering the cerebellum as a controller, we propose the novel concept of 'restorable stage'. Because of its unique anatomical architecture and its diffuse connectivity in particular with the cerebral cortex, keeping in mind the anatomophysiology of the cerebellar circuitry is a necessary step to understand the rationale of therapies of cerebellar ataxias and develop novel therapeutic tools. PMID:27582895

  1. Obsessive-Compulsive Symptoms in an Adolescent Appearing after Cerebellar Vermian Mass Resection

    PubMed Central

    Sathe, Harshal; Karia, Sagar; Shah, Nilesh

    2016-01-01

    Obsessive compulsive symptoms have been reported in frontal lobe tumours and basal ganglia lesions. We report herewith a case of an adolescent who had a vermian cystic mass for which he underwent excision surgery. Three months postsurgery family members noticed that he started with repeated hand washing and abnormal walking pattern. Also, he developed bedwetting in sleep at night. He was given clinical diagnosis of Obsessive-Compulsive Disorder (OCD) and Nocturnal enuresis following a cerebellar mass removal which improved with fluoxetine and impiramine respectively. PMID:27437334

  2. Obsessive-Compulsive Symptoms in an Adolescent Appearing after Cerebellar Vermian Mass Resection.

    PubMed

    Sathe, Harshal; Karia, Sagar; De Sousa, Avinash; Shah, Nilesh

    2016-05-01

    Obsessive compulsive symptoms have been reported in frontal lobe tumours and basal ganglia lesions. We report herewith a case of an adolescent who had a vermian cystic mass for which he underwent excision surgery. Three months postsurgery family members noticed that he started with repeated hand washing and abnormal walking pattern. Also, he developed bedwetting in sleep at night. He was given clinical diagnosis of Obsessive-Compulsive Disorder (OCD) and Nocturnal enuresis following a cerebellar mass removal which improved with fluoxetine and impiramine respectively. PMID:27437334

  3. Cranial index of children with normal and abnormal brain development in Sokoto, Nigeria: A comparative study

    PubMed Central

    Musa, Muhammad Awwal; Zagga, Abdullahi Daudu; Danfulani, Mohammed; Tadros, Aziz Abdo; Ahmed, Hamid

    2014-01-01

    Background: Abnormal brain development due to neurodevelopmental disorders in children has always been an important concern, but yet has to be considered as a significant public health problem, especially in the low- and middle-income countries including Nigeria. Aims: The aim of this study is to determine whether abnormal brain development in the form of neurodevelopmental disorders causes any deviation in the cranial index of affected children. Materials and Methods: This is a comparative study on the head length, head width, and cranial index of 112 children (72 males and 40 females) diagnosed with at least one abnormal problem in brain development, in the form of a neurodevelopmental disorder (NDD), in comparison with that of 218 normal growing children without any form of NDD (121 males and 97 females), aged 0-18 years old seen at the Usmanu Danfodiyo University Teaching Hospital, Sokoto, over a period of six months, June to December, 2012. The head length and head width of the children was measured using standard anatomical landmarks and cranial index calculated. The data obtained was entered into the Microsoft excel worksheet and analyzed using SPSS version 17. Results: The mean Cephalic Index for normal growing children with normal brain development was 79.82 ± 3.35 and that of the children with abnormal brain development was 77.78 ± 2.95 and the difference between the two groups was not statistically significant (P > 0.05). Conclusion: It can be deduced from this present study that the cranial index does not change in children with neurodevelopmental disorders. PMID:24966551

  4. mTOR signaling and its roles in normal and abnormal brain development

    PubMed Central

    Takei, Nobuyuki; Nawa, Hiroyuki

    2014-01-01

    Target of rapamycin (TOR) was first identified in yeast as a target molecule of rapamycin, an anti-fugal and immunosuppressant macrolide compound. In mammals, its orthologue is called mammalian TOR (mTOR). mTOR is a serine/threonine kinase that converges different extracellular stimuli, such as nutrients and growth factors, and diverges into several biochemical reactions, including translation, autophagy, transcription, and lipid synthesis among others. These biochemical reactions govern cell growth and cause cells to attain an anabolic state. Thus, the disruption of mTOR signaling is implicated in a wide array of diseases such as cancer, diabetes, and obesity. In the central nervous system, the mTOR signaling cascade is activated by nutrients, neurotrophic factors, and neurotransmitters that enhances protein (and possibly lipid) synthesis and suppresses autophagy. These processes contribute to normal neuronal growth by promoting their differentiation, neurite elongation and branching, and synaptic formation during development. Therefore, disruption of mTOR signaling may cause neuronal degeneration and abnormal neural development. While reduced mTOR signaling is associated with neurodegeneration, excess activation of mTOR signaling causes abnormal development of neurons and glia, leading to brain malformation. In this review, we first introduce the current state of molecular knowledge of mTOR complexes and signaling in general. We then describe mTOR activation in neurons, which leads to translational enhancement, and finally discuss the link between mTOR and normal/abnormal neuronal growth during development. PMID:24795562

  5. Abnormal visual experience during development alters the early stages of visual-tactile integration.

    PubMed

    Niechwiej-Szwedo, Ewa; Chin, Jessica; Wolfe, Paul J; Popovich, Christina; Staines, W Richard

    2016-05-01

    Visual experience during the critical periods in early postnatal life is necessary for the normal development of the visual system. Disruption of visual input during this period results in amblyopia, which is associated with reduced activation of the striate and extrastriate cortices. It is well known that visual input converges with other sensory signals and exerts a significant influence on cortical processing in multiple association areas. Recent work in healthy adults has also shown that task-relevant visual input can modulate neural excitability at very early stages of information processing in the primary somatosensory cortex. Here we used electroencephalography to investigate visual-tactile interactions in adults with abnormal binocular vision due to amblyopia and strabismus. Results showed three main findings. First, in comparison to a visually normal control group, participants with abnormal vision had a significantly lower amplitude of the P50 somatosensory event related potential (ERP) when visual and tactile stimuli were presented concurrently. Second, the amplitude of the P100 somatosensory ERP was significantly greater in participants with abnormal vision. These results indicate that task relevant visual input does not significantly influence the excitability of the primary somatosensory cortex, instead, the excitability of the secondary somatosensory cortex is increased. Third, participants with abnormal vision had a higher amplitude of the P1 visual ERP when a tactile stimulus was presented concurrently. Importantly, these results were not modulated by viewing condition, which indicates that the impact of amblyopia on crossmodal interactions is not simply related to the reduced visual acuity as it was evident when viewing with the unaffected eye and binocularly. These results indicate that the consequences of abnormal visual experience on neurophysiological processing extend beyond the primary and secondary visual areas to other modality

  6. Cerebellar ataxia as a possible complication of babesiosis in two dogs.

    PubMed

    Jacobson, L S

    1994-09-01

    A 6-month-old Miniature Doberman Pinscher was presented with inappetance and cerebellar signs. Babesia canis organisms were found on a capillary bloodsmear. The cerebellar signs resolved rapidly following treatment with diminazene aceturate. A 7-month-old Siberian Husky developed cerebellar signs, blindness and quadriparesis 9 d after presentation with clinical signs typical of uncomplicated canine babesiosis. The dog responded favourably to treatment with prednisolone. Both acute and delayed cerebellar ataxia have been associated with malaria in humans. The clinical signs shown by these dogs were similar to those reported for malaria in humans. Cerebellar ataxia should be considered a possible complication of canine babesiosis.

  7. Movement Disorders Following Cerebrovascular Lesions in Cerebellar Circuits.

    PubMed

    Choi, Seong-Min

    2016-05-01

    Cerebellar circuitry is important to controlling and modifying motor activity. It conducts the coordination and correction of errors in muscle contractions during active movements. Therefore, cerebrovascular lesions of the cerebellum or its pathways can cause diverse movement disorders, such as action tremor, Holmes' tremor, palatal tremor, asterixis, and dystonia. The pathophysiology of abnormal movements after stroke remains poorly understood. However, due to the current advances in functional neuroimaging, it has recently been described as changes in functional brain networks. This review describes the clinical features and pathophysiological mechanisms in different types of movement disorders following cerebrovascular lesions in the cerebellar circuits. PMID:27240809

  8. Movement Disorders Following Cerebrovascular Lesions in Cerebellar Circuits

    PubMed Central

    Choi, Seong-Min

    2016-01-01

    Cerebellar circuitry is important to controlling and modifying motor activity. It conducts the coordination and correction of errors in muscle contractions during active movements. Therefore, cerebrovascular lesions of the cerebellum or its pathways can cause diverse movement disorders, such as action tremor, Holmes’ tremor, palatal tremor, asterixis, and dystonia. The pathophysiology of abnormal movements after stroke remains poorly understood. However, due to the current advances in functional neuroimaging, it has recently been described as changes in functional brain networks. This review describes the clinical features and pathophysiological mechanisms in different types of movement disorders following cerebrovascular lesions in the cerebellar circuits. PMID:27240809

  9. Cytogenetic studies of 1232 patients with different sexual development abnormalities from the Sultanate of Oman.

    PubMed

    Al-Alawi, Intisar; Goud, Tadakal Mallana; Al-Harasi, Salma; Rajab, Anna

    2016-02-01

    The aim of this study was to evaluate cytogenetic findings in Omani patients who had been referred for suspicion of sex chromosome abnormalities that resulted in different clinical disorders. Furthermore, it sought to examine the frequency of chromosomal anomalies in these patients and to compare the obtained results with those reported elsewhere. Cytogenetic analysis was performed on 1232 cases with variant characteristics of sexual development disorders who had been referred to the cytogenetic department, National Genetic Centre, Ministry of Health, from different hospitals in the Sultanate of Oman between 1999 and 2014. The karyotype results demonstrated chromosomal anomalies in 24.2% of the cases, where 67.5% of abnormalities were identified in referral females, whereas only 32.6% were in referral males. Of all sex chromosome anomalies detected, Turner syndrome was the most frequent (38.2%) followed by Klinefelter syndrome (24.9%) and XY phenotypic females (16%). XXX syndrome and XX phenotypic males represented 6.8% and 3.8% of all sex chromosome anomalies, respectively. Cytogenetic analysis of patients referred with various clinical suspicions of chromosomal abnormalities revealed a high rate of chromosomal anomalies. This is the first broad cytogenetic study reporting combined frequencies of sex chromosome anomalies in sex development disorders in Oman. PMID:26706459

  10. Transcranial magnetic stimulation in patients with cerebellar stroke.

    PubMed

    Cruz-Martínez, A; Arpa, J

    1997-01-01

    Conduction time of the central motor pathways (CMCT) by transcranial magnetic stimulation (TMS) was performed within the first two weeks in 7 patients with isolated hemicerebellar lesions after stroke. Cerebellar infarcts were small (< 2 cm in diameter) in 5 patients and no brainstem structure was involved in CT studies. The threshold (3 cases) and CMCT (4 cases) were abnormal or asymmetric by stimulation of the motor cortex contralateral to the impaired hemicerebellum. The follow-up study in 2 patients revealed electrophysiological improvement closely related to clinical cerebellar recovery rate. CMCT was significantly longer by cortex stimulation contralateral to the impaired hemicerebellum than by ipsilateral stimulation. Prolonged CMCT was significantly correlated with the rated severity of cerebellar signs. Increased threshold may be due to depressed facilitating action of the deep cerebellar nuclei on contralateral motor cortex. Abnormal CMCT might result in reduced size and increased dispersion of the efferent volleys. Recovery of electrophysiological results could represent in part true potentially reversible functional deficit. Whichever the pathophysiological mechanisms involved, our results demonstrate that the cerebellum dysfunction plays a role in the abnormalities of CMCT elicited by TMS.

  11. Effect of edaravone on acute brainstem-cerebellar infarction with vertigo and sudden hearing loss.

    PubMed

    Inoue, Yuta; Yabe, Takao; Okada, Kazunari; Nakamura, Yuka

    2014-06-01

    We report 2 cases with acute brainstem and brainstem-cerebellar infarction showed improvement of their signs and symptoms after administration of edaravone. Case 1, a 74-year-old woman who experienced sudden vertigo, also had dysarthria and left hemiplegia. Magnetic resonance imaging (MRI) showed an abnormal region in the right ventrolateral medulla oblongata. The patient's vertigo and hemiplegia improved completely after treatment. Case 2, a 50-year-old man who experienced sudden vertigo and sensorineural hearing loss (SNHL), developed dysarthria after admission. MRI revealed acute infarction in the right cerebellar hemisphere. Magnetic resonance angiography revealed dissection of the basilar artery and occlusion of the right anterior inferior cerebellar artery. The patient's vertigo and hearing remarkably improved. We have described 2 patients whose early symptoms were vertigo and sudden SNHL, but who were later shown to have ischemic lesions of the central nervous system. Edaravone is neuroprotective drug with free radical-scavenging actions. Free radicals in the ear are responsible for ischemic damage. Edaravone, a free radical scavenger, may be useful in the treatment of vertigo and SNHL.

  12. A homozygous deletion in GRID2 causes a human phenotype with cerebellar ataxia and atrophy.

    PubMed

    Utine, G Eda; Haliloğlu, Göknur; Salanci, Bilge; Çetinkaya, Arda; Kiper, P Özlem; Alanay, Yasemin; Aktas, Dilek; Boduroğlu, Koray; Alikaşifoğlu, Mehmet

    2013-07-01

    GRID2 is a member of the ionotropic glutamate receptor family of excitatory neurotransmitter receptors. GRID2 encodes the glutamate receptor subunit delta-2, selectively expressed in cerebellar Purkinje cells. The phenotype associated with loss of GRID2 function was described only in mice until now, characterized by different degrees of cerebellar ataxia and usually relatively mild abnormalities of the cerebellum. This work describes for the first time the human phenotype associated with homozygous partial deletion of GRID2 in 3 children in one large consanguineous Turkish family. Homozygous deletion of exons 3 and 4 of GRID2 (94 153 589-94 298 037 bp) in the proband and similarly affected cousins, and heterozygous deletions in parental DNA were shown using Affymetrix® 6.0 single-nucleotide polymorphism array, confirmed by real-time polymerase chain reaction. The phenotype includes nystagmus, hypotonia with marked developmental delay in gross motor skills in early infancy followed by a static encephalopathy course with development of cerebellar ataxia, oculomotor apraxia, and pyramidal tract involvement.

  13. [Abnormal psychosocial development and legal responsibility--results of psychopathometric studies].

    PubMed

    Littmann, E; Friemert, K; Szewczyk, H

    1989-05-01

    The introduction (1968) of the legal concept of Grave Abnormal Development of the Personality Amounting to a Disorder into the penal code, made possible criminal deculpation on the basis of psychosocial maldevelopment. On the basis of an intelligence- and personality-diagnostic test-battery (Psychopathometry), the findings obtained in the examination of a sample of culprits on probation under this legal provision, has been compared with a control group homogeneous in respect of the significant parameters. Psychopathometric methods can and should reasonably supplement expertises of this culprits with defective psychosocial development.

  14. A toolbox to visually explore cerebellar shape changes in cerebellar disease and dysfunction

    NASA Astrophysics Data System (ADS)

    Abulnaga, S. Mazdak; Yang, Zhen; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M.; Onyike, Chiadi U.; Ying, Sarah H.; Prince, Jerry L.

    2016-03-01

    The cerebellum plays an important role in motor control and is also involved in cognitive processes. Cerebellar function is specialized by location, although the exact topographic functional relationship is not fully understood. The spinocerebellar ataxias are a group of neurodegenerative diseases that cause regional atrophy in the cerebellum, yielding distinct motor and cognitive problems. The ability to study the region-specific atrophy patterns can provide insight into the problem of relating cerebellar function to location. In an effort to study these structural change patterns, we developed a toolbox in MATLAB to provide researchers a unique way to visually explore the correlation between cerebellar lobule shape changes and function loss, with a rich set of visualization and analysis modules. In this paper, we outline the functions and highlight the utility of the toolbox. The toolbox takes as input landmark shape representations of subjects' cerebellar substructures. A principal component analysis is used for dimension reduction. Following this, a linear discriminant analysis and a regression analysis can be performed to find the discriminant direction associated with a specific disease type, or the regression line of a specific functional measure can be generated. The characteristic structural change pattern of a disease type or of a functional score is visualized by sampling points on the discriminant or regression line. The sampled points are used to reconstruct synthetic cerebellar lobule shapes. We showed a few case studies highlighting the utility of the toolbox and we compare the analysis results with the literature.

  15. Loss of γ-tubulin, GCP-WD/NEDD1 and CDK5RAP2 from the Centrosome of Neurons in Developing Mouse Cerebral and Cerebellar Cortex

    PubMed Central

    Yonezawa, Satoshi; Shigematsu, Momoko; Hirata, Kazuto; Hayashi, Kensuke

    2015-01-01

    It has been recently reported that the centrosome of neurons does not have microtubule nucleating activity. Microtubule nucleation requires γ-tubulin as well as its recruiting proteins, GCP-WD/NEDD1 and CDK5RAP2 that anchor γ-tubulin to the centrosome. Change in the localization of these proteins during in vivo development of brain, however, has not been well examined. In this study we investigate the localization of γ-tubulin, GCP-WD and CDK5RAP2 in developing cerebral and cerebellar cortex with immunofluorescence. We found that γ-tubulin and its recruiting proteins were localized at centrosomes of immature neurons, while they were lost at centrosomes in mature neurons. This indicated that the loss of microtubule nucleating activity at the centrosome of neurons is due to the loss of γ-tubulin-recruiting proteins from the centrosome. RT-PCR analysis revealed that these proteins are still expressed after birth, suggesting that they have a role in microtubule generation in cell body and dendrites of mature neurons. Microtubule regrowth experiments on cultured mature neurons showed that microtubules are nucleated not at the centrosome but within dendrites. These data indicated the translocation of microtubule-organizing activity from the centrosome to dendrites during maturation of neurons, which would explain the mixed polarity of microtubules in dendrites. PMID:26633906

  16. Loss of γ-tubulin, GCP-WD/NEDD1 and CDK5RAP2 from the Centrosome of Neurons in Developing Mouse Cerebral and Cerebellar Cortex.

    PubMed

    Yonezawa, Satoshi; Shigematsu, Momoko; Hirata, Kazuto; Hayashi, Kensuke

    2015-10-29

    It has been recently reported that the centrosome of neurons does not have microtubule nucleating activity. Microtubule nucleation requires γ-tubulin as well as its recruiting proteins, GCP-WD/NEDD1 and CDK5RAP2 that anchor γ-tubulin to the centrosome. Change in the localization of these proteins during in vivo development of brain, however, has not been well examined. In this study we investigate the localization of γ-tubulin, GCP-WD and CDK5RAP2 in developing cerebral and cerebellar cortex with immunofluorescence. We found that γ-tubulin and its recruiting proteins were localized at centrosomes of immature neurons, while they were lost at centrosomes in mature neurons. This indicated that the loss of microtubule nucleating activity at the centrosome of neurons is due to the loss of γ-tubulin-recruiting proteins from the centrosome. RT-PCR analysis revealed that these proteins are still expressed after birth, suggesting that they have a role in microtubule generation in cell body and dendrites of mature neurons. Microtubule regrowth experiments on cultured mature neurons showed that microtubules are nucleated not at the centrosome but within dendrites. These data indicated the translocation of microtubule-organizing activity from the centrosome to dendrites during maturation of neurons, which would explain the mixed polarity of microtubules in dendrites. PMID:26633906

  17. Unilateral cerebellar and brain stem hypoplasia in a child with a postnatal diagnosis of dissecting aneurysm in basilar artery.

    PubMed

    Akkas-Yazici, Sinem; Benbir, Gulcin; Kocer, Naci; Yalcinkaya, Cengiz

    2014-12-01

    Cerebellum is highly vulnerable in the prenatal period. Increasing experience with fetal imaging studies has demonstrated that unilateral cerebellar hypoplasia (UCH) is mainly prenatally acquired, representing disruption rather than a true malformation. Here, we report the case of a 17-month-old boy presented with a sudden onset of abnormal eye movements, who was diagnosed during routine fetal screening with UCH and brain stem hypoplasia and suffered from cerebral palsy; however, no posterior arterial system pathology was detected on cranial magnetic resonance images at that time. Following this acute event, diagnostic neuroradiological interventions revealed a dissecting aneurysm with a saccular component in midbasilar arterial segment and hypoplastic left posterior cerebral artery, which may support the ischemic disruptive mechanism in the development of prenatally detected UCH in this child. The pathogenetic mechanisms for cerebellar disruption are certainly multifactorial in origin, although ischemic arterial etiologies were often undervalued.

  18. The development of hepatic stellate cells in normal and abnormal human fetuses – an immunohistochemical study

    PubMed Central

    Loo, Christine K C; Pereira, Tamara N; Pozniak, Katarzyna N; Ramsing, Mette; Vogel, Ida; Ramm, Grant A

    2015-01-01

    The precise embryological origin and development of hepatic stellate cells is not established. Animal studies and observations on human fetuses suggest that they derive from posterior mesodermal cells that migrate via the septum transversum and developing diaphragm to form submesothelial cells beneath the liver capsule, which give rise to mesenchymal cells including hepatic stellate cells. However, it is unclear if these are similar to hepatic stellate cells in adults or if this is the only source of stellate cells. We have studied hepatic stellate cells by immunohistochemistry, in developing human liver from autopsies of fetuses with and without malformations and growth restriction, using cellular Retinol Binding Protein-1 (cRBP-1), Glial Fibrillary Acidic Protein (GFAP), and α-Smooth Muscle Actin (αSMA) antibodies, to identify factors that influence their development. We found that hepatic stellate cells expressing cRBP-1 are present from the end of the first trimester of gestation and reduce in density throughout gestation. They appear abnormally formed and variably reduced in number in fetuses with abnormal mesothelial Wilms Tumor 1 (WT1) function, diaphragmatic hernia and in ectopic liver nodules without mesothelium. Stellate cells showed similarities to intravascular cells and their presence in a fetus with diaphragm agenesis suggests they may be derived from circulating stem cells. Our observations suggest circulating stem cells as well as mesothelium can give rise to hepatic stellate cells, and that they require normal mesothelial function for their development. PMID:26265759

  19. [Cerebellar cognitive affective syndrome secondary to a cerebellar tumour].

    PubMed

    Domínguez-Carral, J; Carreras-Sáez, I; García-Peñas, J J; Fournier-Del Castillo, C; Villalobos-Reales, J

    2015-01-01

    Cerebellar cognitive affective syndrome is characterized by disturbances of executive function, impaired spatial cognition, linguistic difficulties, and personality change. The case of an 11 year old boy is presented, with behavior problems, learning difficulties and social interaction problems. In the physical examination he had poor visual contact, immature behavior, reduced expressive language and global motor disability with gait dyspraxia, with no defined cerebellar motor signs. In the neuropsychological evaluation he has a full scale overall intellectual quotient of 84, with signs of cerebellar cognitive affective syndrome. A tumour affecting inferior cerebellar vermis was observed in the magnetic resonance imaging, which had not significantly grown during 5 years of follow up. The cerebellum participates in controlling cognitive and affective functions. Cerebellar pathology must be considered in the differential diagnosis of children with cognitive or learning disorder with associated behavioral and emotional components. PMID:24954915

  20. [Cerebellar cognitive affective syndrome secondary to a cerebellar tumour].

    PubMed

    Domínguez-Carral, J; Carreras-Sáez, I; García-Peñas, J J; Fournier-Del Castillo, C; Villalobos-Reales, J

    2015-01-01

    Cerebellar cognitive affective syndrome is characterized by disturbances of executive function, impaired spatial cognition, linguistic difficulties, and personality change. The case of an 11 year old boy is presented, with behavior problems, learning difficulties and social interaction problems. In the physical examination he had poor visual contact, immature behavior, reduced expressive language and global motor disability with gait dyspraxia, with no defined cerebellar motor signs. In the neuropsychological evaluation he has a full scale overall intellectual quotient of 84, with signs of cerebellar cognitive affective syndrome. A tumour affecting inferior cerebellar vermis was observed in the magnetic resonance imaging, which had not significantly grown during 5 years of follow up. The cerebellum participates in controlling cognitive and affective functions. Cerebellar pathology must be considered in the differential diagnosis of children with cognitive or learning disorder with associated behavioral and emotional components.

  1. A mechanical model predicts morphological abnormalities in the developing human brain

    NASA Astrophysics Data System (ADS)

    Budday, Silvia; Raybaud, Charles; Kuhl, Ellen

    2014-07-01

    The developing human brain remains one of the few unsolved mysteries of science. Advancements in developmental biology, neuroscience, and medical imaging have brought us closer than ever to understand brain development in health and disease. However, the precise role of mechanics throughout this process remains underestimated and poorly understood. Here we show that mechanical stretch plays a crucial role in brain development. Using the nonlinear field theories of mechanics supplemented by the theory of finite growth, we model the human brain as a living system with a morphogenetically growing outer surface and a stretch-driven growing inner core. This approach seamlessly integrates the two popular but competing hypotheses for cortical folding: axonal tension and differential growth. We calibrate our model using magnetic resonance images from very preterm neonates. Our model predicts that deviations in cortical growth and thickness induce morphological abnormalities. Using the gyrification index, the ratio between the total and exposed surface area, we demonstrate that these abnormalities agree with the classical pathologies of lissencephaly and polymicrogyria. Understanding the mechanisms of cortical folding in the developing human brain has direct implications in the diagnostics and treatment of neurological disorders, including epilepsy, schizophrenia, and autism.

  2. A mechanical model predicts morphological abnormalities in the developing human brain

    PubMed Central

    Budday, Silvia; Raybaud, Charles; Kuhl, Ellen

    2014-01-01

    The developing human brain remains one of the few unsolved mysteries of science. Advancements in developmental biology, neuroscience, and medical imaging have brought us closer than ever to understand brain development in health and disease. However, the precise role of mechanics throughout this process remains underestimated and poorly understood. Here we show that mechanical stretch plays a crucial role in brain development. Using the nonlinear field theories of mechanics supplemented by the theory of finite growth, we model the human brain as a living system with a morphogenetically growing outer surface and a stretch-driven growing inner core. This approach seamlessly integrates the two popular but competing hypotheses for cortical folding: axonal tension and differential growth. We calibrate our model using magnetic resonance images from very preterm neonates. Our model predicts that deviations in cortical growth and thickness induce morphological abnormalities. Using the gyrification index, the ratio between the total and exposed surface area, we demonstrate that these abnormalities agree with the classical pathologies of lissencephaly and polymicrogyria. Understanding the mechanisms of cortical folding in the developing human brain has direct implications in the diagnostics and treatment of neurological disorders, including epilepsy, schizophrenia, and autism. PMID:25008163

  3. Posterior fossa syndrome after cerebellar stroke.

    PubMed

    Mariën, Peter; Verslegers, Lieven; Moens, Maarten; Dua, Guido; Herregods, Piet; Verhoeven, Jo

    2013-10-01

    Posterior fossa syndrome (PFS) due to vascular etiology is rare in children and adults. To the best of our knowledge, PFS due to cerebellar stroke has only been reported in patients who also underwent surgical treatment of the underlying vascular cause. We report longitudinal clinical, neurocognitive and neuroradiological findings in a 71-year-old right-handed patient who developed PFS following a right cerebellar haemorrhage that was not surgically evacuated. During follow-up, functional neuroimaging was conducted by means of quantified Tc-99m-ECD SPECT studies. After a 10-day period of akinetic mutism, the clinical picture developed into cerebellar cognitive affective syndrome (CCAS) with reversion to a previously learnt accent, consistent with neurogenic foreign accent syndrome (FAS). No psychometric evidence for dementia was found. Quantified Tc-99m-ECD SPECT studies consistently disclosed perfusional deficits in the anatomoclinically suspected but structurally intact bilateral prefrontal brain regions. Since no surgical treatment of the cerebellar haematoma was performed, this case report is presumably the first description of pure, "non-surgical vascular PFS". In addition, reversion to a previously learnt accent which represents a subtype of FAS has never been reported after cerebellar damage. The combination of this unique constellation of poststroke neurobehavioural changes reflected on SPECT shows that the cerebellum is crucially implicated in the modulation of neurocognitive and affective processes. A decrease of excitatory impulses from the lesioned cerebellum to the structurally intact supratentorial network subserving cognitive, behavioural and affective processes constitutes the likely pathophysiological mechanism underlying PFS and CCAS in this patient. PMID:23575947

  4. Somatosensory temporal discrimination threshold is increased in patients with cerebellar atrophy.

    PubMed

    Manganelli, Fiore; Dubbioso, Raffaele; Pisciotta, Chiara; Antenora, Antonella; Nolano, Maria; De Michele, Giuseppe; Filla, Alessandro; Berardelli, Alfredo; Santoro, Lucio

    2013-08-01

    Processing of time in the millisecond range seems to depend on cerebellar function and it can be assessed by using the somatosensory temporal discrimination threshold testing. No studies have yet investigated this temporal discrimination task in patients with cerebellar atrophy. Eleven patients with degenerative cerebellar ataxia and 11 controls underwent somatosensory temporal discrimination threshold evaluation. The degree of cerebellar dysfunction was measured by the International Cooperative Ataxia Rating Scale. Somatosensory temporal discrimination threshold was higher in patients compared to controls for each stimulated site (hand, neck, and eye). Age, disease duration, and International Cooperative Ataxia Rating Scale scores were not correlated to somatosensory temporal discrimination threshold. Somatosensory temporal discrimination threshold is abnormal in patients with cerebellar atrophy. These findings suggest that the cerebellum plays a role in modulating the somatosensory temporal discrimination threshold and confirm the role of cerebellum in the processing of time in the millisecond range.

  5. Past, Present and Future Therapeutics for Cerebellar Ataxias

    PubMed Central

    Marmolino, D; Manto, M

    2010-01-01

    Cerebellar ataxias are a group of disabling neurological disorders. Patients exhibit a cerebellar syndrome and can also present with extra-cerebellar deficits, namely pigmentary retinopathy, extrapyramidal movement disorders, pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioural symptoms), and peripheral neuropathy. Recently, deficits in cognitive operations have been unraveled. Cerebellar ataxias are heterogeneous both at the phenotypic and genotypic point of view. Therapeutical trials performed during these last 4 decades have failed in most cases, in particular because drugs were not targeting a deleterious pathway, but were given to counteract putative defects in neurotransmission. The identification of the causative mutations of many hereditary ataxias, the development of relevant animal models and the recent identifications of the molecular mechanisms underlying ataxias are impacting on the development of new drugs. We provide an overview of the pharmacological treatments currently used in the clinical practice and we discuss the drugs under development. PMID:20808545

  6. Cr (VI) induced oxidative stress and toxicity in cultured cerebellar granule neurons at different stages of development and protective effect of Rosmarinic acid.

    PubMed

    Dashti, Abolfazl; Soodi, Maliheh; Amani, Nahid

    2016-03-01

    Chromium (Cr) is a widespread metal ion in the workplace, industrial effluent, and water. The toxicity of chromium (VI) on various organs including the liver, kidneys, and lung were studied, but little is known about neurotoxicity. In this study, neurotoxic effects of Cr (VI) have been investigated by cultured cerebellar granule neurons (CGNs). Immature and mature neurons were exposed to different concentrations of potassium dichromate for 24 h and cytotoxicity was measured by MTT assay. In addition, immature neurons were exposed for 5 days as regards cytotoxic effect in development stages. The reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and the protective effect of Rosmarinic acid on mature and immature neurons exposed to potassium dichromate, were measured. Furthermore, lipid peroxidation, glutathione peroxidase (GPx), and acetylcholinesterase activity in mature neurons were assessed following exposure to potassium dichromate. The results indicate that toxicity of Cr (VI) dependent on maturation steps. Cr (VI) was less toxic for immature neurons. Also, Cr (VI) induced MMP reduction and ROS production in both immature and mature neurons. In Cr (VI) treated neurons, increased lipid peroxidation and GPx activity but not acetylcholinesterase activity was observed. Interestingly, Rosmarinic acid, as a natural antioxidant, could protect mature but not immature neurons against Cr (VI) induced toxicity. Our findings revealed vulnerability of mature neurons to Cr (VI) induced toxicity and oxidative stress.

  7. Transcriptome Analysis for Abnormal Spike Development of the Wheat Mutant dms

    PubMed Central

    Zhu, Xin-Xin; Li, Qiao-Yun; Shen, Chun-Cai; Duan, Zong-Biao; Yu, Dong-Yan; Niu, Ji-Shan; Ni, Yong-Jing; Jiang, Yu-Mei

    2016-01-01

    Background Wheat (Triticum aestivum L.) spike development is the foundation for grain yield. We obtained a novel wheat mutant, dms, characterized as dwarf, multi-pistil and sterility. Although the genetic changes are not clear, the heredity of traits suggests that a recessive gene locus controls the two traits of multi-pistil and sterility in self-pollinating populations of the medium plants (M), such that the dwarf genotype (D) and tall genotype (T) in the progeny of the mutant are ideal lines for studies regarding wheat spike development. The objective of this study was to explore the molecular basis for spike abnormalities of dwarf genotype. Results Four unigene libraries were assembled by sequencing the mRNAs of the super-bulked differentiating spikes and stem tips of the D and T plants. Using integrative analysis, we identified 419 genes highly expressed in spikes, including nine typical homeotic genes of the MADS-box family and the genes TaAP2, TaFL and TaDL. We also identified 143 genes that were significantly different between young spikes of T and D, and 26 genes that were putatively involved in spike differentiation. The result showed that the expression levels of TaAP1-2, TaAP2, and other genes involved in the majority of biological processes such as transcription, translation, cell division, photosynthesis, carbohydrate transport and metabolism, and energy production and conversion were significantly lower in D than in T. Conclusions We identified a set of genes related to wheat floral organ differentiation, including typical homeotic genes. Our results showed that the major causal factors resulting in the spike abnormalities of dms were the lower expression homeotic genes, hormonal imbalance, repressed biological processes, and deficiency of construction materials and energy. We performed a series of studies on the homeotic genes, however the other three causal factors for spike abnormal phenotype of dms need further study. PMID:26982202

  8. Treatable causes of cerebellar ataxia.

    PubMed

    Ramirez-Zamora, Adolfo; Zeigler, Warren; Desai, Neeja; Biller, José

    2015-04-15

    The cerebellar ataxia syndromes are a heterogeneous group of disorders clinically characterized by the presence of cerebellar dysfunction. Initial assessment of patients with progressive cerebellar ataxia is complex because of an extensive list of potential diagnoses. A detailed history and comprehensive examination are required for an accurate diagnosis and hierarchical diagnostic investigations. Although no cure exists for most of these conditions, a small group of metabolic, hereditary, inflammatory, and immune-mediated etiologies of cerebellar ataxia are amenable to disease-modifying, targeted therapies. Over the past years, disease-specific treatments have emerged. Thus, clinicians must become familiar with these disorders because maximal therapeutic benefit is only possible when done early. In this article, we review disorders in which cerebellar ataxia is a prominent clinical feature requiring targeted treatments along with specific management recommendations.

  9. Cerebellar circuitry as a neuronal machine.

    PubMed

    Ito, Masao

    2006-01-01

    Shortly after John Eccles completed his studies of synaptic inhibition in the spinal cord, for which he was awarded the 1963 Nobel Prize in physiology/medicine, he opened another chapter of neuroscience with his work on the cerebellum. From 1963 to 1967, Eccles and his colleagues in Canberra successfully dissected the complex neuronal circuitry in the cerebellar cortex. In the 1967 monograph, "The Cerebellum as a Neuronal Machine", he, in collaboration with Masao Ito and Janos Szentágothai, presented blue-print-like wiring diagrams of the cerebellar neuronal circuitry. These stimulated worldwide discussions and experimentation on the potential operational mechanisms of the circuitry and spurred theoreticians to develop relevant network models of the machinelike function of the cerebellum. In following decades, the neuronal machine concept of the cerebellum was strengthened by additional knowledge of the modular organization of its structure and memory mechanism, the latter in the form of synaptic plasticity, in particular, long-term depression. Moreover, several types of motor control were established as model systems representing learning mechanisms of the cerebellum. More recently, both the quantitative preciseness of cerebellar analyses and overall knowledge about the cerebellum have advanced considerably at the cellular and molecular levels of analysis. Cerebellar circuitry now includes Lugaro cells and unipolar brush cells as additional unique elements. Other new revelations include the operation of the complex glomerulus structure, intricate signal transduction for synaptic plasticity, silent synapses, irregularity of spike discharges, temporal fidelity of synaptic activation, rhythm generators, a Golgi cell clock circuit, and sensory or motor representation by mossy fibers and climbing fibers. Furthermore, it has become evident that the cerebellum has cognitive functions, and probably also emotion, as well as better-known motor and autonomic functions

  10. Preadolescent and adolescent endocrinology: physiology and physiopathology. II. Hormonal changes during abnormal pubertal development.

    PubMed

    Sizonenko, P C

    1978-08-01

    Based on the knowledge of the physiology of regulation of gonadotropins and gonadal steroids, basal levels of these hormones might be indicative of the etiologic factors of abnormal pubertal development. In addition, stimulatory tests may help in the diagnosis of such conditions. It is interesting that the pubertal maturation of the adrenal cortex is independent of the hypothalamic-pituitary-gonadal axis. The role of the adrenal cortex for the pubertal development remains questionable: adrenal androgens are low in isosexual precocious puberty, low in delayed adolescence, and normal in hyper- or hypogonadotropic hypogonadism. The importance of this role is doubled in congenital virilizing adrenal hyperplasia. When the disease is untreated, although adrenal androgens in excess advance bone age and hypothalamic maturation, girls remain prepubertal. When the therapeutic control is good, normal puberty occurs. The action of the adrenal androgens on growth and puberty remains to be determined.

  11. The character of abnormalities found in eye development of quail embruos exposed under space flight conditions

    NASA Astrophysics Data System (ADS)

    Grigoryan, E.; Dadheva, O.; Polinskaya, V.; Guryeva, T.

    The avian embryonic eye is used as a model system for studies on the environmental effects on central nervous system development. Here we present results of qualitative investigation of the eye development in quail embryos incubated in micro-"g" environment. In this study we used eyes of Japanese quail (Coturnix coturnix Japonica) embryos "flown" onboard biosatellite Kosmos-1129 and on Mir station within the framework of Mir-NASA Program. Eyes obtained from embryos ranging in age from 3-12 days (E3-E12) were prepared histologically and compared with those of the synchronous and laboratory gound controls. Ther most careful consideration was given to finding and analysis of eye developmental abnormalities. Then they were compared with those already described by experimental teratology for birds and mammals. At the stage of the "eye cup" (E3) we found the case of invalid formation of the inner retina. The latter was represented by disorganized neuroblasts occupying whole posterior chamber of the eye. On the 7th day of quail eye development, at the period of cellular growth activation some cases of small eyes with many folds of overgrowing neural and pigmented retinal layers were detected. In retinal folds of these eyes the normal layering was disturbed as well as the formation of aqueous body and pecten oculi. At this time point the changes were also found in the anterior part of the eye. The peculiarities came out of the bigger width of the cornea and separation of its layers, but were found in synchronous control as well. Few embryos of E10 had also eyes with the abnormities described for E7 but this time they were more vivid because of the completion of eye tissue differentiation. At the stage E12 we found the case evaluated as microphthalmia attending by overgrowth of anterior pigmented tissues - iris and ciliary body attached with the cornea. Most, but not all, of abnormalities we found in eye morphogeneses belonged to the birds "flown" aboard Kosmos- 1129 and

  12. The abnormal distribution of development: policies for southern women and children.

    PubMed

    Burman, E

    1995-03-01

    This paper offers a feminist critique of the relationships between gender and development by exploring the intersections between three sets of debates: firstly, the relations between interventions for women and for children through the anomalous position accorded to 'the girl child' in aid and development policies; secondly, the relations between psychological and economic models of development; and thirdly, the gendered and geographical allocation of attributes and opportunities. Drawing on analyses of the 'psychological complex' the author suggests that the cultural resources that inform developmental psychological models are highly cultural and class-specific (white, middle class, of the northern hemisphere), giving rise to a globalization of development that is reinscribed within international aid and development policies. In homogenizing difference to its norms, this globalization paradoxically reproduces the north-south opposition as an expression of cultural and political imperialism. While northern children 'develop', dominant discourses of children of the South are preoccupied with 'survival'. By such means the cultural hegemony of a unitary psychology remains intact. This paper discusses the 'abnormal distribution' of development to draw attention to the ways cultural and gender inequalities flow from the norms and generalized descriptions central to the current practice of developmental psychology and to urge that this is an important site of intervention for feminists addressing gender and development issues.

  13. The abnormal distribution of development: policies for southern women and children.

    PubMed

    Burman, E

    1995-03-01

    This paper offers a feminist critique of the relationships between gender and development by exploring the intersections between three sets of debates: firstly, the relations between interventions for women and for children through the anomalous position accorded to 'the girl child' in aid and development policies; secondly, the relations between psychological and economic models of development; and thirdly, the gendered and geographical allocation of attributes and opportunities. Drawing on analyses of the 'psychological complex' the author suggests that the cultural resources that inform developmental psychological models are highly cultural and class-specific (white, middle class, of the northern hemisphere), giving rise to a globalization of development that is reinscribed within international aid and development policies. In homogenizing difference to its norms, this globalization paradoxically reproduces the north-south opposition as an expression of cultural and political imperialism. While northern children 'develop', dominant discourses of children of the South are preoccupied with 'survival'. By such means the cultural hegemony of a unitary psychology remains intact. This paper discusses the 'abnormal distribution' of development to draw attention to the ways cultural and gender inequalities flow from the norms and generalized descriptions central to the current practice of developmental psychology and to urge that this is an important site of intervention for feminists addressing gender and development issues. PMID:12319980

  14. Tuberous sclerosis complex suppression in cerebellar development and medulloblastoma: separate regulation of mTOR activity and p27Kip1 localization

    PubMed Central

    Bhatia, Bobby; Northcott, Paul A.; Hambardzumyan, Dolores; Govindarajan, Baskaran; Brat, Daniel J.; Arbiser, Jack L.; Holland, Eric C.; Taylor, Michael D.; Kenney, Anna Marie

    2009-01-01

    During development, proliferation of cerebellar granule neuron precursors (CGNPs), candidate cells-of-origin for the pediatric brain tumor medulloblastoma, requires signaling by Sonic hedgehog (Shh) and insulin-like growth factor (IGF), whose pathways are also implicated in medulloblastoma. One of the consequences of IGF signaling is inactivation of the mTOR-suppressing Tuberous Sclerosis Complex (TSC), comprised of TSC1 and TSC2, leading to increased mRNA translation. We show that mice in which TSC function is impaired display increased mTOR pathway activation, enhanced CGNP proliferation, GSK-3α/β inactivation, and cytoplasmic localization of the cyclin-dependent kinase (cdk) inhibitor p27Kip1, which has been proposed to cause its inactivation or gain of oncogenic functions. We observed the same characteristics in wild-type primary cultures of CGNPs in which TSC1 and/or TSC2 were knocked down, and in mouse medulloblastomas induced by ectopic Shh pathway activation. Moreover, Shh-induced mouse medulloblastomas manifested Akt-mediated TSC2 inactivation, and the mutant TSC2 allele synergized with aberrant Shh signaling to increase medulloblastoma incidence in mice. Driving exogenous TSC2 expression in Shh-induced medulloblastoma cells corrected p27Kip1 localization and reduced proliferation. GSK-3α/β inactivation in the tumors in vivo and in primary CGNP cultures was mTOR-dependent, whereas p27Kip1 cytoplasmic localization was regulated upstream of mTOR, by TSC2. These results indicate that a balance between Shh mitogenic signaling and TSC function regulating new protein synthesis and cdk inhibition is essential for normal development and prevention of tumor formation or expansion. PMID:19738049

  15. Abnormal Mammary Development in 129:STAT1-Null Mice is Stroma-Dependent.

    PubMed

    Chen, Jane Q; Mori, Hidetoshi; Cardiff, Robert D; Trott, Josephine F; Hovey, Russell C; Hubbard, Neil E; Engelberg, Jesse A; Tepper, Clifford G; Willis, Brandon J; Khan, Imran H; Ravindran, Resmi K; Chan, Szeman R; Schreiber, Robert D; Borowsky, Alexander D

    2015-01-01

    Female 129:Stat1-null mice (129S6/SvEvTac-Stat1(tm1Rds) homozygous) uniquely develop estrogen-receptor (ER)-positive mammary tumors. Herein we report that the mammary glands (MG) of these mice have altered growth and development with abnormal terminal end buds alongside defective branching morphogenesis and ductal elongation. We also find that the 129:Stat1-null mammary fat pad (MFP) fails to sustain the growth of 129S6/SvEv wild-type and Stat1-null epithelium. These abnormalities are partially reversed by elevated serum progesterone and prolactin whereas transplantation of wild-type bone marrow into 129:Stat1-null mice does not reverse the MG developmental defects. Medium conditioned by 129:Stat1-null epithelium-cleared MFP does not stimulate epithelial proliferation, whereas it is stimulated by medium conditioned by epithelium-cleared MFP from either wild-type or 129:Stat1-null females having elevated progesterone and prolactin. Microarrays and multiplexed cytokine assays reveal that the MG of 129:Stat1-null mice has lower levels of growth factors that have been implicated in normal MG growth and development. Transplanted 129:Stat1-null tumors and their isolated cells also grow slower in 129:Stat1-null MG compared to wild-type recipient MG. These studies demonstrate that growth of normal and neoplastic 129:Stat1-null epithelium is dependent on the hormonal milieu and on factors from the mammary stroma such as cytokines. While the individual or combined effects of these factors remains to be resolved, our data supports the role of STAT1 in maintaining a tumor-suppressive MG microenvironment.

  16. Imaging Spectrum of Cerebellar Pathologies: A Pictorial Essay

    PubMed Central

    Arora, Richa

    2015-01-01

    Summary The cerebellum is a crucial structure of hindbrain which helps in maintaining motor tone, posture, gait and also coordinates skilled voluntary movements including eye movements. Cerebellar abnormalities have different spectrum, presenting symptoms and prognosis as compared to supratentorial structures and brainstem. This article intends to review the various pathological processes involving the cerebellum along with their imaging features on MR, which are must to know for all radiologists, neurologists and neurosurgeons for their prompt diagnosis and management. PMID:25806100

  17. Automated cerebellar lobule segmentation with application to cerebellar structural analysis in cerebellar disease.

    PubMed

    Yang, Zhen; Ye, Chuyang; Bogovic, John A; Carass, Aaron; Jedynak, Bruno M; Ying, Sarah H; Prince, Jerry L

    2016-02-15

    The cerebellum plays an important role in both motor control and cognitive function. Cerebellar function is topographically organized and diseases that affect specific parts of the cerebellum are associated with specific patterns of symptoms. Accordingly, delineation and quantification of cerebellar sub-regions from magnetic resonance images are important in the study of cerebellar atrophy and associated functional losses. This paper describes an automated cerebellar lobule segmentation method based on a graph cut segmentation framework. Results from multi-atlas labeling and tissue classification contribute to the region terms in the graph cut energy function and boundary classification contributes to the boundary term in the energy function. A cerebellar parcellation is achieved by minimizing the energy function using the α-expansion technique. The proposed method was evaluated using a leave-one-out cross-validation on 15 subjects including both healthy controls and patients with cerebellar diseases. Based on reported Dice coefficients, the proposed method outperforms two state-of-the-art methods. The proposed method was then applied to 77 subjects to study the region-specific cerebellar structural differences in three spinocerebellar ataxia (SCA) genetic subtypes. Quantitative analysis of the lobule volumes shows distinct patterns of volume changes associated with different SCA subtypes consistent with known patterns of atrophy in these genetic subtypes. PMID:26408861

  18. Kruppel-Like Factor 4 Regulates Granule Cell Pax6 Expression and Cell Proliferation in Early Cerebellar Development

    PubMed Central

    Zhang, Peter; Ha, Thomas; Larouche, Matt; Swanson, Douglas; Goldowitz, Dan

    2015-01-01

    Kruppel-like factor 4 (Klf4) is a transcription factor that regulates many important cellular processes in stem cell biology, cancer, and development. We used histological and molecular methods to study the expression of Klf4 in embryonic development of the normal and Klf4 knockout cerebellum. We find that Klf4 is expressed strongly in early granule cell progenitor development but tails-off considerably by the end of embryonic development. Klf4 is also co-expressed with Pax6 in these cells. In the Klf4-null mouse, which is perinatal lethal, Klf4 positively regulates Pax6 expression and regulates the proliferation of neuronal progenitors in the rhombic lip, external granular layer and the neuroepithelium. This paper is the first to describe a role for Klf4 in the cerebellum and provides insight into this gene’s function in neuronal development. PMID:26226504

  19. Apert and Crouzon syndromes-Cognitive development, brain abnormalities, and molecular aspects.

    PubMed

    Fernandes, Marilyse B L; Maximino, Luciana P; Perosa, Gimol B; Abramides, Dagma V M; Passos-Bueno, Maria Rita; Yacubian-Fernandes, Adriano

    2016-06-01

    Apert and Crouzon are the most common craniosynostosis syndromes associated with mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. We conducted a study to examine the molecular biology, brain abnormalities, and cognitive development of individuals with these syndromes. A retrospective longitudinal review of 14 patients with Apert and Crouzon syndromes seen at the outpatient Craniofacial Surgery Hospital for Rehabilitation of Craniofacial Anomalies in Brazil from January 1999 through August 2010 was performed. Patients between 11 and 36 years of age (mean 18.29 ± 5.80), received cognitive evaluations, cerebral magnetic resonance imaging, and molecular DNA analyses. Eight patients with Apert syndrome (AS) had full scale intelligence quotients (FSIQs) that ranged from 47 to 108 (mean 76.9 ± 20.2), and structural brain abnormalities were identified in five of eight patients. Six patients presented with a gain-of-function mutation (p.Ser252Trp) in FGFR2 and FSIQs in those patients ranged from 47 to78 (mean 67.2 ± 10.7). One patient with a gain-of-function mutation (p.Pro253Arg) had a FSIQ of 108 and another patient with an atypical splice mutation (940-2A →G) had a FSIQ of 104. Six patients with Crouzon syndrome had with mutations in exons IIIa and IIIc of FGFR2 and their FSIQs ranged from 82 to 102 (mean 93.5 ± 6.7). These reveal that molecular aspects are another factor that can be considered in studies of global and cognitive development of patients with Apert and Crouzon syndrome (CS). © 2016 Wiley Periodicals, Inc. PMID:27028366

  20. Expression of LPP3 in Bergmann glia is required for proper cerebellar sphingosine-1-phosphate metabolism/signaling and development

    PubMed Central

    López-Juárez, Alejandro; Morales-Lázaro, Sara; Sánchez-Sánchez, Roberto; Sunkara, Manjula; Lomelí, Hilda; Velasco, Iván; Morris, Andrew J.; Escalante-Alcalde, Diana

    2011-01-01

    Bioactive lipids serve as intracellular and extracellular mediators in cell signaling in normal and pathological conditions. Here we describe that an important regulator of some of these lipids, the lipid phosphate phosphatase-3 (LPP3), is abundantly expressed in specific plasma membrane domains of Bergmann glia (BG), a specialized type of astrocyte with key roles in cerebellum development and physiology. Mice selectively lacking expression of LPP3/Ppap2b in the nervous system are viable and fertile but exhibit defects in postnatal cerebellum development and modifications in the cytoarchitecture and arrangement of BG with a mild non-progressive motor coordination defect. Lipid and gene profiling studies in combination with pharmacological treatments suggest that most of these effects are associated with alterations in sphingosine-1-phosphate (S1P) metabolism and signaling. Altogether our data indicate that LPP3 participates in several aspects of neuron-glia communication required for proper cerebellum development. PMID:21319224

  1. Expression of LPP3 in Bergmann glia is required for proper cerebellar sphingosine-1-phosphate metabolism/signaling and development.

    PubMed

    López-Juárez, Alejandro; Morales-Lázaro, Sara; Sánchez-Sánchez, Roberto; Sunkara, Manjula; Lomelí, Hilda; Velasco, Iván; Morris, Andrew J; Escalante-Alcalde, Diana

    2011-04-01

    Bioactive lipids serve as intracellular and extracellular mediators in cell signaling in normal and pathological conditions. Here we describe that an important regulator of some of these lipids, the lipid phosphate phosphatase-3 (LPP3), is abundantly expressed in specific plasma membrane domains of Bergmann glia (BG), a specialized type of astrocyte with key roles in cerebellum development and physiology. Mice selectively lacking expression of LPP3/Ppap2b in the nervous system are viable and fertile but exhibit defects in postnatal cerebellum development and modifications in the cytoarchitecture and arrangement of BG with a mild non-progressive motor coordination defect. Lipid and gene profiling studies in combination with pharmacological treatments suggest that most of these effects are associated with alterations in sphingosine-1-phosphate (S1P) metabolism and signaling. Altogether our data indicate that LPP3 participates in several aspects of neuron-glia communication required for proper cerebellum development.

  2. Isolated cerebellar involvement in vitamin B12 deficiency: a case report.

    PubMed

    Chakrabarty, Biswaroop; Dubey, Rachana; Gulati, Sheffali; Yoganathan, Sangeetha; Kumar, Ajay; Kumar, Atin

    2014-11-01

    Deficiency of vitamin B12 causes megaloblastic anemia and nervous system demyelination. Structures affected in the nervous system include spinal cord, cranial and peripheral nerves, and brain white matter. A 9-year-old boy presented with knuckle hyperpigmentation and oral ulcers for 3 years, pallor and easy fatigability for 6 months, gait abnormalities for 3 months, and abnormal speech and behavioral abnormalities for 3 days. On examination, he had physical signs of megaloblastic anemia, mood swings with intermittent hallucinations, and features of cerebellar impairment. Blood investigations revealed megaloblastic anemia, and pernicious anemia was ruled out. Brain magnetic resonance imaging (MRI) revealed bilateral cerebellar signal changes. He received treatment for vitamin B12 deficiency and appropriate nutritional counseling. Three months later, he showed significant clinical and radiologic resolution. To our knowledge, isolated cerebellar involvement as the sole neurologic manifestation of vitamin B12 deficiency has not been described previously in children. PMID:24346315

  3. Speech prosody in cerebellar ataxia

    NASA Astrophysics Data System (ADS)

    Casper, Maureen

    The present study sought an acoustic signature for the speech disturbance recognized in cerebellar degeneration. Magnetic resonance imaging was used for a radiological rating of cerebellar involvement in six cerebellar ataxic dysarthric speakers. Acoustic measures of the [pap] syllables in contrastive prosodic conditions and of normal vs. brain-damaged patients were used to further our understanding both of the speech degeneration that accompanies cerebellar pathology and of speech motor control and movement in general. Pair-wise comparisons of the prosodic conditions within the normal group showed statistically significant differences for four prosodic contrasts. For three of the four contrasts analyzed, the normal speakers showed both longer durations and higher formant and fundamental frequency values in the more prominent first condition of the contrast. The acoustic measures of the normal prosodic contrast values were then used as a model to measure the degree of speech deterioration for individual cerebellar subjects. This estimate of speech deterioration as determined by individual differences between cerebellar and normal subjects' acoustic values of the four prosodic contrasts was used in correlation analyses with MRI ratings. Moderate correlations between speech deterioration and cerebellar atrophy were found in the measures of syllable duration and f0. A strong negative correlation was found for F1. Moreover, the normal model presented by these acoustic data allows for a description of the flexibility of task- oriented behavior in normal speech motor control. These data challenge spatio-temporal theory which explains movement as an artifact of time wherein longer durations predict more extreme movements and give further evidence for gestural internal dynamics of movement in which time emerges from articulatory events rather than dictating those events. This model provides a sensitive index of cerebellar pathology with quantitative acoustic

  4. Congenital Hydrocephalus and Abnormal Subcommissural Organ Development in Sox3 Transgenic Mice

    PubMed Central

    Lee, Kristie; Tan, Jacqueline; Morris, Michael B.; Rizzoti, Karine; Hughes, James; Cheah, Pike See; Felquer, Fernando; Liu, Xuan; Piltz, Sandra; Lovell-Badge, Robin; Thomas, Paul Q.

    2012-01-01

    Congenital hydrocephalus (CH) is a life-threatening medical condition in which excessive accumulation of CSF leads to ventricular expansion and increased intracranial pressure. Stenosis (blockage) of the Sylvian aqueduct (Aq; the narrow passageway that connects the third and fourth ventricles) is a common form of CH in humans, although the genetic basis of this condition is unknown. Mouse models of CH indicate that Aq stenosis is associated with abnormal development of the subcommmissural organ (SCO) a small secretory organ located at the dorsal midline of the caudal diencephalon. Glycoproteins secreted by the SCO generate Reissner's fibre (RF), a thread-like structure that descends into the Aq and is thought to maintain its patency. However, despite the importance of SCO function in CSF homeostasis, the genetic program that controls SCO development is poorly understood. Here, we show that the X-linked transcription factor SOX3 is expressed in the murine SCO throughout its development and in the mature organ. Importantly, overexpression of Sox3 in the dorsal diencephalic midline of transgenic mice induces CH via a dose-dependent mechanism. Histological, gene expression and cellular proliferation studies indicate that Sox3 overexpression disrupts the development of the SCO primordium through inhibition of diencephalic roof plate identity without inducing programmed cell death. This study provides further evidence that SCO function is essential for the prevention of hydrocephalus and indicates that overexpression of Sox3 in the dorsal midline alters progenitor cell differentiation in a dose-dependent manner. PMID:22291885

  5. Maternal Postsecondary Education Associated With Improved Cerebellar Growth After Preterm Birth.

    PubMed

    Stiver, Mikaela L; Kamino, Daphne; Guo, Ting; Thompson, Angela; Duerden, Emma G; Taylor, Margot J; Tam, Emily W Y

    2015-10-01

    The preterm cerebellum is vulnerable to impaired development impacting long-term outcome. Preterm newborns (<32 weeks) underwent serial magnetic resonance imaging (MRI) scans. The association between parental education and cerebellar volume at each time point was assessed, adjusting for age at scan. In 26 infants, cerebellar volumes at term (P = .001), but not birth (P = .4), were associated with 2-year volumes. For 1 cm(3) smaller cerebellar volume (4% total volume) at term, the cerebellum was 3.18 cm(3) smaller (3% total volume) by 2 years. Maternal postsecondary education was not associated with cerebellar volume at term (P = .16). Maternal postsecondary education was a significant confounder in the relationship between term and 2-year cerebellar volumes (P = .016), with higher education associated with improved volumes by 2 years. Although preterm birth has been found to be associated with smaller cerebellar volumes at term, maternal postsecondary education is associated with improved growth detectable by 2 years.

  6. An Evo-Devo Approach to Thyroid Hormones in Cerebral and Cerebellar Cortical Development: Etiological Implications for Autism

    PubMed Central

    Berbel, Pere; Navarro, Daniela; Román, Gustavo C.

    2014-01-01

    The morphological alterations of cortical lamination observed in mouse models of developmental hypothyroidism prompted the recognition that these experimental changes resembled the brain lesions of children with autism; this led to recent studies showing that maternal thyroid hormone deficiency increases fourfold the risk of autism spectrum disorders (ASD), offering for the first time the possibility of prevention of some forms of ASD. For ethical reasons, the role of thyroid hormones on brain development is currently studied using animal models, usually mice and rats. Although mammals have in common many basic developmental principles regulating brain development, as well as fundamental basic mechanisms that are controlled by similar metabolic pathway activated genes, there are also important differences. For instance, the rodent cerebral cortex is basically a primary cortex, whereas the primary sensory areas in humans account for a very small surface in the cerebral cortex when compared to the associative and frontal areas that are more extensive. Associative and frontal areas in humans are involved in many neurological disorders, including ASD, attention deficit-hyperactive disorder, and dyslexia, among others. Therefore, an evo-devo approach to neocortical evolution among species is fundamental to understand not only the role of thyroid hormones and environmental thyroid disruptors on evolution, development, and organization of the cerebral cortex in mammals but also their role in neurological diseases associated to thyroid dysfunction. PMID:25250016

  7. An evo-devo approach to thyroid hormones in cerebral and cerebellar cortical development: etiological implications for autism.

    PubMed

    Berbel, Pere; Navarro, Daniela; Román, Gustavo C

    2014-01-01

    The morphological alterations of cortical lamination observed in mouse models of developmental hypothyroidism prompted the recognition that these experimental changes resembled the brain lesions of children with autism; this led to recent studies showing that maternal thyroid hormone deficiency increases fourfold the risk of autism spectrum disorders (ASD), offering for the first time the possibility of prevention of some forms of ASD. For ethical reasons, the role of thyroid hormones on brain development is currently studied using animal models, usually mice and rats. Although mammals have in common many basic developmental principles regulating brain development, as well as fundamental basic mechanisms that are controlled by similar metabolic pathway activated genes, there are also important differences. For instance, the rodent cerebral cortex is basically a primary cortex, whereas the primary sensory areas in humans account for a very small surface in the cerebral cortex when compared to the associative and frontal areas that are more extensive. Associative and frontal areas in humans are involved in many neurological disorders, including ASD, attention deficit-hyperactive disorder, and dyslexia, among others. Therefore, an evo-devo approach to neocortical evolution among species is fundamental to understand not only the role of thyroid hormones and environmental thyroid disruptors on evolution, development, and organization of the cerebral cortex in mammals but also their role in neurological diseases associated to thyroid dysfunction.

  8. The mysterious microcircuitry of the cerebellar nuclei

    PubMed Central

    Uusisaari, Marylka; De Schutter, Erik

    2011-01-01

    Abstract The microcircuitry of cerebellar cortex and, in particular, the physiology of its main element, the Purkinje neuron, has been extensively investigated and described. However, activity in Purkinje neurons, either as single cells or populations, does not directly mediate the cerebellar effects on the motor effector systems. Rather, the result of the entire cerebellar cortical computation is passed to the relatively small cerebellar nuclei that act as the final, integrative processing unit in the cerebellar circuitry. The nuclei ultimately control the temporal and spatial features of the cerebellar output. Given this key role, it is striking that the internal organization and the connectivity with afferent and efferent pathways in the cerebellar nuclei are rather poorly known. In the present review, we discuss some of the many critical shortcomings in the understanding of cerebellar nuclei microcircuitry: the extent of convergence and divergence of the cerebellar cortical pathway to the various cerebellar nuclei neurons and subareas, the possible (lack of) conservation of the finely-divided topographical organization in the cerebellar cortex at the level of the nuclei, as well as the absence of knowledge of the synaptic circuitry within the cerebellar nuclei. All these issues are important for predicting the pattern-extraction and encoding capabilities of the cerebellar nuclei and, until resolved, theories and models of cerebellar motor control and learning may err considerably. PMID:21521761

  9. Timing Tasks Synchronize Cerebellar and Frontal Ramping Activity and Theta Oscillations: Implications for Cerebellar Stimulation in Diseases of Impaired Cognition

    PubMed Central

    Parker, Krystal L.

    2016-01-01

    Timing is a fundamental and highly conserved mammalian capability, yet the underlying neural mechanisms are widely debated. Ramping activity of single neurons that gradually increase or decrease activity to encode the passage of time has been speculated to predict a behaviorally relevant temporal event. Cue-evoked low-frequency activity has also been implicated in temporal processing. Ramping activity and low-frequency oscillations occur throughout the brain and could indicate a network-based approach to timing. Temporal processing requires cognitive mechanisms of working memory, attention, and reasoning, which are dysfunctional in neuropsychiatric disease. Therefore, timing tasks could be used to probe cognition in animals with disease phenotypes. The medial frontal cortex and cerebellum are involved in cognition. Cerebellar stimulation has been shown to influence medial frontal activity and improve cognition in schizophrenia. However, the mechanism underlying the efficacy of cerebellar stimulation is unknown. Here, we discuss how timing tasks can be used to probe cerebellar interactions with the frontal cortex and the therapeutic potential of cerebellar stimulation. The goal of this theory and hypothesis manuscript is threefold. First, we will summarize evidence indicating that in addition to motor learning, timing tasks involve cognitive processes that are present within both the cerebellum and medial frontal cortex. Second, we propose methodologies to investigate the connections between these areas in patients with Parkinson’s disease, autism, and schizophrenia. Lastly, we hypothesize that cerebellar transcranial stimulation may rescue medial frontal ramping activity, theta oscillations, and timing abnormalities, thereby restoring executive function in diseases of impaired cognition. This hypothesis could inspire the use of timing tasks as biomarkers for neuronal and cognitive abnormalities in neuropsychiatric disease and promote the therapeutic potential of

  10. Abnormal Development of Tapetum and Microspores Induced by Chemical Hybridization Agent SQ-1 in Wheat

    PubMed Central

    Wang, Shuping; Zhang, Gaisheng; Song, Qilu; Zhang, Yingxin; Li, Zheng; Guo, Jialin; Niu, Na; Ma, Shoucai; Wang, Junwei

    2015-01-01

    Chemical hybridization agent (CHA)-induced male sterility is an important tool in crop heterosis. To demonstrate that CHA-SQ-1-induced male sterility is associated with abnormal tapetal and microspore development, the cytology of CHA-SQ-1-treated plant anthers at various developmental stages was studied by light microscopy, scanning and transmission electron microscopy, in situ terminal deoxynucleotidyl transferasemediated dUTP nick end-labelling (TUNEL) assay and DAPI staining. The results indicated that the SQ-1-treated plants underwent premature tapetal programmed cell death (PCD), which was initiated at the early-uninucleate stage of microspore development and continued until the tapetal cells were completely degraded; the process of microspore development was then blocked. Microspores with low-viability (fluorescein diacetate staining) were aborted. The study suggests that premature tapetal PCD is the main cause of pollen abortion. Furthermore, it determines the starting period and a key factor in CHA-SQ-1-induced male sterility at the cell level, and provides cytological evidence to further study the mechanism between PCD and male sterility. PMID:25803723

  11. Abnormal development of tapetum and microspores induced by chemical hybridization agent SQ-1 in wheat.

    PubMed

    Wang, Shuping; Zhang, Gaisheng; Song, Qilu; Zhang, Yingxin; Li, Zheng; Guo, Jialin; Niu, Na; Ma, Shoucai; Wang, Junwei

    2015-01-01

    Chemical hybridization agent (CHA)-induced male sterility is an important tool in crop heterosis. To demonstrate that CHA-SQ-1-induced male sterility is associated with abnormal tapetal and microspore development, the cytology of CHA-SQ-1-treated plant anthers at various developmental stages was studied by light microscopy, scanning and transmission electron microscopy, in situ terminal deoxynucleotidyl transferasemediated dUTP nick end-labelling (TUNEL) assay and DAPI staining. The results indicated that the SQ-1-treated plants underwent premature tapetal programmed cell death (PCD), which was initiated at the early-uninucleate stage of microspore development and continued until the tapetal cells were completely degraded; the process of microspore development was then blocked. Microspores with low-viability (fluorescein diacetate staining) were aborted. The study suggests that premature tapetal PCD is the main cause of pollen abortion. Furthermore, it determines the starting period and a key factor in CHA-SQ-1-induced male sterility at the cell level, and provides cytological evidence to further study the mechanism between PCD and male sterility.

  12. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function

    PubMed Central

    Margolis, Kara Gross; Li, Zhishan; Stevanovic, Korey; Saurman, Virginia; Anderson, George M.; Snyder, Isaac; Blakely, Randy D.; Gershon, Michael D.

    2016-01-01

    Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4–mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation. PMID:27111230

  13. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function.

    PubMed

    Margolis, Kara Gross; Li, Zhishan; Stevanovic, Korey; Saurman, Virginia; Israelyan, Narek; Anderson, George M; Snyder, Isaac; Veenstra-VanderWeele, Jeremy; Blakely, Randy D; Gershon, Michael D

    2016-06-01

    Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4-mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation. PMID:27111230

  14. The microvasculature of the human cerebellar meninges.

    PubMed

    Nonaka, Hiroko; Akima, Michiko; Hatori, Tsutomu; Nagayama, Tadashi; Zhang, Zean; Ihara, Fumie

    2002-12-01

    The vascular architecture of the human cerebellar meninges was investigated. The surface meninges were poor in vasculature. In the sulci, the meninges were highly vascular but had few capillaries. The venous blood vessels gave long side branches at right angles to the parent vessels in a cruciform pattern, running horizontally along the cerebellar sulci. They were situated at the origin of the secondary or tertiary sulci. Anastomoses between these horizontal branches gave a crosshatched appearance. Short branches often extended to the bases of the sulci, terminating in T-shaped bifurcations with numerous tiny branches, like the roots of a tree. The arteries ran perpendicular to venous branches which were parallel to each other exclusively along the sagittal plane. These arteries bifurcated to straddle the horizontally running veins at the origin of the secondary or tertiary sulci. They gave off many small branches like teeth of a fork from each artery in the secondary or tertiary sulci after they bifurcated to straddle the venous branches and penetrated the cerebellar cortex at the bases of sulci. These fork-like ramifications in the bases of the sulci were most likely responsible for the ready development of pronounced ischemic state. They might also play an important role in the occurrence of ischemic damage at the bases of sulci in cases of severe generalized ischemia.

  15. Ultrastructural and cellular basis for the development of abnormal myocardial mechanics during the transition from hypertension to heart failure.

    PubMed

    Shah, Sanjiv J; Aistrup, Gary L; Gupta, Deepak K; O'Toole, Matthew J; Nahhas, Amanda F; Schuster, Daniel; Chirayil, Nimi; Bassi, Nikhil; Ramakrishna, Satvik; Beussink, Lauren; Misener, Sol; Kane, Bonnie; Wang, David; Randolph, Blake; Ito, Aiko; Wu, Megan; Akintilo, Lisa; Mongkolrattanothai, Thitipong; Reddy, Mahendra; Kumar, Manvinder; Arora, Rishi; Ng, Jason; Wasserstrom, J Andrew

    2014-01-01

    Although the development of abnormal myocardial mechanics represents a key step during the transition from hypertension to overt heart failure (HF), the underlying ultrastructural and cellular basis of abnormal myocardial mechanics remains unclear. We therefore investigated how changes in transverse (T)-tubule organization and the resulting altered intracellular Ca(2+) cycling in large cell populations underlie the development of abnormal myocardial mechanics in a model of chronic hypertension. Hearts from spontaneously hypertensive rats (SHRs; n = 72) were studied at different ages and stages of hypertensive heart disease and early HF and were compared with age-matched control (Wistar-Kyoto) rats (n = 34). Echocardiography, including tissue Doppler and speckle-tracking analysis, was performed just before euthanization, after which T-tubule organization and Ca(2+) transients were studied using confocal microscopy. In SHRs, abnormalities in myocardial mechanics occurred early in response to hypertension, before the development of overt systolic dysfunction and HF. Reduced longitudinal, circumferential, and radial strain as well as reduced tissue Doppler early diastolic tissue velocities occurred in concert with T-tubule disorganization and impaired Ca(2+) cycling, all of which preceded the development of cardiac fibrosis. The time to peak of intracellular Ca(2+) transients was slowed due to T-tubule disruption, providing a link between declining cell ultrastructure and abnormal myocardial mechanics. In conclusion, subclinical abnormalities in myocardial mechanics occur early in response to hypertension and coincide with the development of T-tubule disorganization and impaired intracellular Ca(2+) cycling. These changes occur before the development of significant cardiac fibrosis and precede the development of overt cardiac dysfunction and HF.

  16. Prenatal ketamine exposure causes abnormal development of prefrontal cortex in rat

    PubMed Central

    Zhao, Tianyun; Li, Chuanxiang; Wei, Wei; Zhang, Haixing; Ma, Daqing; Song, Xingrong; Zhou, Libing

    2016-01-01

    Ketamine is commonly used for anesthesia and as a recreational drug. In pregnant users, a potential neurotoxicity in offspring has been noted. Our previous work demonstrated that ketamine exposure of pregnant rats induces affective disorders and cognitive impairments in offspring. As the prefrontal cortex (PFC) is critically involved in emotional and cognitive processes, here we studied whether maternal ketamine exposure influences the development of the PFC in offspring. Pregnant rats on gestational day 14 were treated with ketamine at a sedative dose for 2 hrs, and pups were studied at postnatal day 0 (P0) or P30. We found that maternal ketamine exposure resulted in cell apoptosis and neuronal loss in fetal brain. Upon ketamine exposure in utero, PFC neurons at P30 showed more dendritic branching, while cultured neurons from P0 PFC extended shorter neurites than controls. In addition, maternal ketamine exposure postponed the switch of NR2B/2A expression, and perturbed pre- and postsynaptic protein expression in the PFC. These data suggest that prenatal ketamine exposure impairs neuronal development of the PFC, which may be associated with abnormal behavior in offsprings. PMID:27226073

  17. Over-expression of thymosin beta 4 promotes abnormal tooth development and stimulation of hair growth.

    PubMed

    Cha, Hee-Jae; Philp, Deborah; Lee, Soo-Hyun; Moon, Hye-Sung; Kleinman, Hynda K; Nakamura, Takashi

    2010-01-01

    Thymosin beta 4 has multi-functional roles in cell physiology. It accelerates wound healing, hair growth and angiogenesis, and increases laminin-5 expression in corneal epithelium. Furthermore, thymosin beta 4 stimulates tumor growth and metastasis by induction of cell migration and vascular endothelial growth factor-mediated angiogenesis. Using a construct on the skin-specific keratin-5 promoter, we have developed thymosin beta 4 over-expressing transgenic mice to further study its functional roles. Thymosin beta 4 in adult skin and in embryonic stages of the transgenic mouse was analyzed by both Western blot and immunohistochemistry. The over-expression of thymosin beta 4 was observed especially around hair follicles and in the teeth in the transgenic mice. We examined the phenotype of the thymosin beta 4 over-expressing mice. Hair growth was accelerated. In addition, the transgenic mice had abnormally-shaped white teeth and dull incisors. We found that the expression of laminin-5 was up-regulated in the skin of the transgenic mice. We conclude that thymosin beta 4 has an important physiological role in hair growth and in tooth development.

  18. Neural tube defects and abnormal brain development in F52-deficient mice.

    PubMed Central

    Wu, M; Chen, D F; Sasaoka, T; Tonegawa, S

    1996-01-01

    F52 is a myristoylated, alanine-rich substrate for protein kinase C. We have generated F52-deficient mice by the gene targeting technique. These mutant mice manifest severe neural tube defects that are not associated with other complex malformations, a phenotype reminiscent of common human neural tube defects. The neural tube defects observed include both exencephaly and spina bifida, and the phenotype exhibits partial penetrance with about 60% of homozygous embryos developing neural tube defects. Exencephaly is the prominent type of defect and leads to high prenatal lethality. Neural tube defects are observed in a smaller percentage of heterozygous embryos (about 10%). Abnormal brain development and tail formation occur in homozygous mutants and are likely to be secondary to the neural tube defects. Disruption of F52 in mice therefore identifies a gene whose mutation results in isolated neural tube defects and may provide an animal model for common human neural tube defects. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8700893

  19. Facial Metrics in Children with Corticotrophin-Producing Pituitary Adenomas Suggest Abnormalities in Midface Development

    PubMed Central

    Keil, Margaret F.; Stratakis, Constantine A.

    2011-01-01

    Background Tumors of the hypothalamic-pituitary unit have been linked to genetic syndromes that are associated with midfacial abnormalities. Aim We hypothesized that mutations of genes that affect the development of the face (and consequently of the anterior pituitary) may be present in children with ACTH-producing pituitary adenomas, and if this is true then facial measurements would be different from those predicted by parental features. Methods We studied 20 children with cortico-tropinomas and a control group and their parents. All facial measurements were expressed according to standard deviation scores. Results Significant differences were seen between the children with pituitary adenomas and their parents for vertical facial height measures: nasal length (p <0.001), lower facial height (p <0.03) and overall facial height (p <0.01). Conclusion We conclude that some of the indices of midline craniofacial development, in particular those affecting the vertical axis, are different in children with corticotroph adenomas producing ACTH. PMID:19344074

  20. Caytaxin Deficiency Disrupts Signaling Pathways in Cerebellar Cortex

    PubMed Central

    Xiao, Jianfeng; Gong, Suzhen; LeDoux, Mark S.

    2007-01-01

    The genetically dystonic (dt) rat, an autosomal recessive model of generalized dystonia, harbors an insertional mutation in Atcay. As a result, dt rats are deficient in Atcay transcript and the neuronally-restricted protein caytaxin. Previous electrophysiological and biochemical studies have defined olivocerebellar pathways, particularly the climbing fiber projection to Purkinje cells, as a site of significant functional abnormality in dt rats. In normal rats, Atcay transcript is abundantly expressed in the granular and Purkinje cell layers of cerebellar cortex. To better understand the consequences of caytaxin deficiency in cerebellar cortex, differential gene expression was examined in dt rats and their normal littermates. Data from oligonucleotide microarrays and quantitative real-time RT-PCR (QRT-PCR) identified phosphatidylinositol signaling pathways, calcium homeostasis, and extracellular matrix interactions as domains of cellular dysfunction in dt rats. In dt rats, genes encoding the corticotropin-releasing hormone receptor 1 (CRH-R1, Crhr1) and calcium-transporting plasma membrane ATPase 4 (PMCA4, Atp2b4) showed the greatest up-regulation with QRT-PCR. Immunocytochemical experiments demonstrated that CRH-R1, CRH, and PMCA4 were up-regulated in cerebellar cortex of mutant rats. Along with previous electrophysiological and pharmacological studies, our data indicate that caytaxin plays a critical role in the molecular response of Purkinje cells to climbing fiber input. Caytaxin may also contribute to maturational events in cerebellar cortex. PMID:17092653

  1. A Cerebellar Neuroprosthetic System: Computational Architecture and in vivo Test

    PubMed Central

    Herreros, Ivan; Giovannucci, Andrea; Taub, Aryeh H.; Hogri, Roni; Magal, Ari; Bamford, Sim; Prueckl, Robert; Verschure, Paul F. M. J.

    2014-01-01

    Emulating the input–output functions performed by a brain structure opens the possibility for developing neuroprosthetic systems that replace damaged neuronal circuits. Here, we demonstrate the feasibility of this approach by replacing the cerebellar circuit responsible for the acquisition and extinction of motor memories. Specifically, we show that a rat can undergo acquisition, retention, and extinction of the eye-blink reflex even though the biological circuit responsible for this task has been chemically inactivated via anesthesia. This is achieved by first developing a computational model of the cerebellar microcircuit involved in the acquisition of conditioned reflexes and training it with synthetic data generated based on physiological recordings. Secondly, the cerebellar model is interfaced with the brain of an anesthetized rat, connecting the model’s inputs and outputs to afferent and efferent cerebellar structures. As a result, we show that the anesthetized rat, equipped with our neuroprosthetic system, can be classically conditioned to the acquisition of an eye-blink response. However, non-stationarities in the recorded biological signals limit the performance of the cerebellar model. Thus, we introduce an updated cerebellar model and validate it with physiological recordings showing that learning becomes stable and reliable. The resulting system represents an important step toward replacing lost functions of the central nervous system via neuroprosthetics, obtained by integrating a synthetic circuit with the afferent and efferent pathways of a damaged brain region. These results also embody an early example of science-based medicine, where on the one hand the neuroprosthetic system directly validates a theory of cerebellar learning that informed the design of the system, and on the other one it takes a step toward the development of neuro-prostheses that could recover lost learning functions in animals and, in the longer term, humans. PMID:25152887

  2. Looking at Cerebellar Malformations through Text-Mined Interactomes of Mice and Humans

    PubMed Central

    Iossifov, Ivan; Rodriguez-Esteban, Raul; Mayzus, Ilya; Millen, Kathleen J.; Rzhetsky, Andrey

    2009-01-01

    We have generated and made publicly available two very large networks of molecular interactions: 49,493 mouse-specific and 52,518 human-specific interactions. These networks were generated through automated analysis of 368,331 full-text research articles and 8,039,972 article abstracts from the PubMed database, using the GeneWays system. Our networks cover a wide spectrum of molecular interactions, such as bind, phosphorylate, glycosylate, and activate; 207 of these interaction types occur more than 1,000 times in our unfiltered, multi-species data set. Because mouse and human genes are linked through an orthological relationship, human and mouse networks are amenable to straightforward, joint computational analysis. Using our newly generated networks and known associations between mouse genes and cerebellar malformation phenotypes, we predicted a number of new associations between genes and five cerebellar phenotypes (small cerebellum, absent cerebellum, cerebellar degeneration, abnormal foliation, and abnormal vermis). Using a battery of statistical tests, we showed that genes that are associated with cerebellar phenotypes tend to form compact network clusters. Further, we observed that cerebellar malformation phenotypes tend to be associated with highly connected genes. This tendency was stronger for developmental phenotypes and weaker for cerebellar degeneration. PMID:19893633

  3. Lateralized cognitive deficits in children following cerebellar lesions.

    PubMed

    Scott, R B; Stoodley, C J; Anslow, P; Paul, C; Stein, J F; Sugden, E M; Mitchell, C D

    2001-10-01

    The aim of this preliminary study was to examine the developing cognitive profiles of children with cerebellar tumours in a consecutive series of clinical patients. MRI and longitudinal intellectual profiles were obtained on seven children (two females, five males; mean age 3 years at diagnosis; mean age 7 years at first assessment). Tumours in three of the children were astrocytomas; of the remaining tumours, two were medulloblastomas, one low-grade glioma, and one ependymoma. In right-handed children, we observed an association between greater damage to right cerebellar structures and a plateauing in verbal and/or literacy skills. In contrast, greater damage to left cerebellar structures was associated with delayed or impaired non-verbal/spatial skills. Long-term cognitive development of the children studied tentatively supports a role for the cerebellum in learning/development. These findings suggest that lateralized cerebellar damage may selectively impair the development of cognitive functions subserved by the contralateral cerebral hemisphere and, in addition, that all children with cerebellar lesions in early childhood should routinely undergo long-term monitoring of their intellectual development. PMID:11665825

  4. Glutamate dysfunction associated with developmental cerebellar damage: Relevance to autism spectrum disorders

    PubMed Central

    McKimm, Erik J.; Corkill, Beau; Goldowitz, Dan; Albritton, Lorraine M.; Homayouni, Ramin; Blaha, Charles D.; Mittleman, Guy

    2014-01-01

    Neural abnormalities commonly associated with autism spectrum disorders include prefrontal cortex (PFC) dysfunction and cerebellar pathology in the form of Purkinje cell loss and cerebellar hypoplasia. It has been reported that loss of cerebellar Purkinje cells results in aberrant dopamine neurotransmission in the PFC which occurs via dysregulation of multisynaptic efferents from the cerebellum to the PFC. Using a mouse model we investigated the possibility that developmental cerebellar Purkinje cell loss could disrupt glutamatergic cerebellar projections to the PFC that ultimately modulate DA release. We measured glutamate release evoked by local electrical stimulation using fixed potential amperometry in combination with glutamate selective enzyme-based recording probes in urethane anesthetized Lurcher mutant and wildtype mice. Target sites included the medio-dorsal and ventro-lateral thalamic nuclei, reticulo-tegmental nuclei, pedunculopontine nuclei, and ventral tegmental area. With the exception of the ventral tegmental area, results indicated that in comparison to wildtype mice, evoked glutamate release was reduced in Lurcher mutants by between 9% to 72% at all stimulated sites. These results are consistent with the notion that developmental loss of cerebellar Purkinje cells drives reductions in evoked glutamate release in cerebellar efferent pathways that ultimately influence PFC dopamine release. Possible mechanisms whereby reductions in glutamate release could occur are discussed. PMID:24307139

  5. [Cerebellar infarctions and their mechanisms].

    PubMed

    Amarenco, P

    1993-01-01

    Cerebellar infarcts have been neglected for a long time and are now shown well by CT and especially MRI. Some infarcts involve the full territory supplied by a cerebellar artery. They are frequently complicated by edema with brain stem compression and supratentorial hydrocephalus, requiring at times emergency surgery, and are often accompanied by other medullary, medial pontine, mesencephalic, thalamic and occipital infarcts. On the other hand, partial territory infarcts are usually confined to the cerebellum and have a benign outcome with total recovery or minimal disability. They are more common than full territory infarcts. However, clinical presentations are similar to those full territory infarcts, differing mainly by the lack of drowsiness or unconsciousness. The main symptoms are vertigo, headache, vomiting, unsteadiness of gait and dysarthria. Signs include ipsilateral limb dysmetria, ipsilateral axial lateropulsion, ataxia and dysarthria. Vertigo is more severe and rotary in posterior inferior cerebellar artery territory infarcts, whereas dysarthria and ataxia are prominent in superior cerebellar artery territory infarcts. A few brain stem signs are sometimes added. In these territorial cerebellar infarcts, cardioembolism is the most common cause. Atherosclerotic occlusion comes next, involving the intracranial part of the vertebral artery and, less frequently, the lower basilar artery, both locations inaccessible to surgery. Other causes are artery to artery embolism from a vertebral artery origin stenosis, or the aortic arch, in situ intracranial branch atherosclerotic occlusion, and vertebral artery dissection. Border zone cerebellar infarcts occur in one third of the cases. They are small cortical or deep infarcts. They have the same symptoms and signs as territorial infarcts except for more frequent postural symptoms occurring over days, weeks or months after the ischemic event. The infarcts mainly have a thromboembolic mechanism, and sometimes have a

  6. Repeated intermittent alcohol exposure during the third trimester-equivalent increases expression of the GABA(A) receptor δ subunit in cerebellar granule neurons and delays motor development in rats.

    PubMed

    Diaz, Marvin R; Vollmer, Cyndel C; Zamudio-Bulcock, Paula A; Vollmer, William; Blomquist, Samantha L; Morton, Russell A; Everett, Julie C; Zurek, Agnieszka A; Yu, Jieying; Orser, Beverley A; Valenzuela, C Fernando

    2014-04-01

    Exposure to ethanol (EtOH) during fetal development can lead to long-lasting alterations, including deficits in fine motor skills and motor learning. Studies suggest that these are, in part, a consequence of cerebellar damage. Cerebellar granule neurons (CGNs) are the gateway of information into the cerebellar cortex. Functionally, CGNs are heavily regulated by phasic and tonic GABAergic inhibition from Golgi cell interneurons; however, the effect of EtOH exposure on the development of GABAergic transmission in immature CGNs has not been investigated. To model EtOH exposure during the 3rd trimester-equivalent of human pregnancy, neonatal pups were exposed intermittently to high levels of vaporized EtOH from postnatal day (P) 2 to P12. This exposure gradually increased pup serum EtOH concentrations (SECs) to ∼60 mM (∼0.28 g/dl) during the 4 h of exposure. EtOH levels gradually decreased to baseline 8 h after the end of exposure. Surprisingly, basal tonic and phasic GABAergic currents in CGNs were not significantly affected by postnatal alcohol exposure (PAE). However, PAE increased δ subunit expression at P28 as detected by immunohistochemical and western blot analyses. Also, electrophysiological studies with an agonist that is highly selective for δ-containing GABA(A) receptors, 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THIP), showed an increase in THIP-induced tonic current. Behavioral studies of PAE rats did not reveal any deficits in motor coordination, except for a delay in the acquisition of the mid-air righting reflex that was apparent at P15 to P18. These findings demonstrate that repeated intermittent exposure to high levels of EtOH during the equivalent of the last trimester of human pregnancy has significant but relatively subtle effects on motor coordination and GABAergic transmission in CGNs in rats.

  7. Purkinje cell and cerebellar effects following developmental exposure to PCBs and/or MeHg.

    PubMed

    Roegge, Cindy S; Morris, John R; Villareal, Sherilyn; Wang, Victor C; Powers, Brian E; Klintsova, Anna Y; Greenough, William T; Pessah, Isaac N; Schantz, Susan L

    2006-01-01

    We recently reported that rats exposed to PCBs and MeHg during development were impaired on the rotating rod, a test of balance and coordination that is often indicative of cerebellar damage. In addition, developmental PCB exposure is known to dramatically reduce circulating thyroid hormone concentrations, which may have a negative impact on cerebellar development. Therefore, we investigated the effects of combined PCB and MeHg exposure on Purkinje cells and the cerebellum. The serum and brains from littermates of the animals tested on the rotating rod were collected at weaning, and we also collected brains from the adult animals at the end of motor testing. Four groups were studied: 1) vehicle controls, 2) PCBs only (Aroclor 1254, 6 mg/kg/d, oral), 3) MeHg only (0.5 ppm, in dams' drinking water), and 4) PCB+MeHg (at the same doses as in individual toxicant exposures). Female Long-Evans rats were exposed beginning 4 weeks prior to breeding with an unexposed male and continuing until postnatal day (PND) 16. There was a significant reduction in serum T4 and T3 concentrations in the PCB and PCB+MeHg pups on PND21. Golgi-impregnated Purkinje cells were examined in PND21 brains, but there were no significant exposure-related effects on primary dendrite length, branching area, or structural abnormalities. However, all three male exposure groups had a marginally significant increase in Purkinje cell height, which may suggest a subtle thyromimetic effect in the cerebellum. Cresyl-violet stained sections from the adult brains showed no exposure-related effects within paramedian lobule in Purkinje cell number, total lobule volume or layer volumes (molecular, granule cell and white matter layers). Evidence is provided for the dysregulation of expression of cerebellar ryanodine receptor (RyR) isoforms in PCB-exposed brains, and this could contribute to the rotating rod deficit by changing critical aspects of intracellular calcium signaling within the cerebellum.

  8. Cerebellar granule cell migration and the effects of alcohol.

    PubMed

    Jiang, Yulan; Kumada, Tatsuro; Cameron, D Bryant; Komuro, Hitoshi

    2008-01-01

    In the developing brain the majority of neurons migrate from their birthplace to their final destination. This active movement is essential for the formation of cortical layers and nuclei. The impairment of migration does not affect the viability of neurons but often results in abnormal differentiation. The proper migration of neurons requires the orchestrated activities of multiple cellular and molecular events, such as pathway selection, the activation of specific receptors and channels, and the assembly and disassembly of cytoskeletal components. The migration of neurons is very vulnerable to exposure to environmental toxins, such as alcohol. In this article, we will focus on recent developments in the migration of cerebellar granule cells. First, we will describe when, where and how granule cells migrate through different cortical layers to reach their final destination. Second, we will present how internal programs control the sequential changes in granule cell migration. Third, we will review the roles of external guidance cues and transmembrane signals in granule cell migration. Finally, we will reveal mechanisms by which alcohol exposure impairs granule cell migration. PMID:18075250

  9. Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development.

    PubMed

    Fukami, Maki; Homma, Keiko; Hasegawa, Tomonobu; Ogata, Tsutomu

    2013-04-01

    We review the current knowledge about the "backdoor" pathway for the biosynthesis of dihydrotestosterone (DHT). While DHT is produced from cholesterol through the conventional "frontdoor" pathway via testosterone, recent studies have provided compelling evidence for the presence of an alternative "backdoor" pathway to DHT without testosterone intermediacy. This backdoor pathway is known to exist in the tammar wallaby pouch young testis and the immature mouse testis, and has been suggested to be present in the human as well. Indeed, molecular analysis has identified pathologic mutations of genes involved in the backdoor pathway in genetic male patients with undermasculinized external genitalia, and urine steroid profile analysis has argued for the relevance of the activated backdoor pathway to abnormal virilization in genetic females with cytochrome P450 oxidoreductase deficiency and 21-hydroxylase deficiency. It is likely that the backdoor pathway is primarily operating in the fetal testis in a physiological condition to produce a sufficient amount of DHT for male sex development, and that the backdoor pathway is driven with a possible interaction between fetal and permanent adrenals in pathologic conditions with increased 17-hydroxyprogesterone levels. These findings provide novel insights into androgen biosynthesis in both physiological and pathological conditions. PMID:23073980

  10. Abnormalities in synaptic dynamics during development in a mouse model of spinocerebellar ataxia type 1

    PubMed Central

    Hatanaka, Yusuke; Watase, Kei; Wada, Keiji; Nagai, Yoshitaka

    2015-01-01

    Late-onset neurodegenerative diseases are characterized by neurological symptoms and progressive neuronal death. Accumulating evidence suggests that neuronal dysfunction, rather than neuronal death, causes the symptoms of neurodegenerative diseases. However, the mechanisms underlying the dysfunction that occurs prior to cell death remain unclear. To investigate the synaptic basis of this dysfunction, we employed in vivo two-photon imaging to analyse excitatory postsynaptic dendritic protrusions. We used Sca1154Q/2Q mice, an established knock-in mouse model of the polyglutamine disease spinocerebellar ataxia type 1 (SCA1), which replicates human SCA1 features including ataxia, cognitive impairment, and neuronal death. We found that Sca1154Q/2Q mice exhibited greater synaptic instability than controls, without synaptic loss, in the cerebral cortex, where obvious neuronal death is not observed, even before the onset of distinct symptoms. Interestingly, this abnormal synaptic instability was evident in Sca1154Q/2Q mice from the synaptic developmental stage, and persisted into adulthood. Expression of synaptic scaffolding proteins was also lower in Sca1154Q/2Q mice than controls before synaptic maturation. As symptoms progressed, synaptic loss became evident. These results indicate that aberrant synaptic instability, accompanied by decreased expression of scaffolding proteins during synaptic development, is a very early pathology that precedes distinct neurological symptoms and neuronal cell death in SCA1. PMID:26531852

  11. Abnormal germling development by brown rust and powdery mildew on cer barley mutants.

    PubMed

    Rubiales, D; Ramirez, M C; Carver, T L; Niks, R E

    2001-01-01

    The barley leaf rust fungus forms appressoria over host leaf stomata and penetrates via the stomatal pore. High levels of avoidance to leaf rust fungi have been described in some wild accessions of Hordeum species where a prominent wax layer on the stomata inhibits triggering of fungal appressorium differentiation. Leaf rust avoidance has not yet been found in H. vulgare. Since cuticular leaf waxes are implicated in the avoidance trait, we screened 27 eceriferum (cer) mutant lines of H. vulgare for avoidance to barley leaf rust. These mutations affect leaf waxes. Reduction in numbers of germ tubes forming appressoria over stomata was found in some lines, but the greatest reduction (ca 30%) was less than previously found in wild barley spp. or in an accession of H. chilense used here as a check. In one line (cer-zh654), avoidance was due to a combination of factors. Firstly, fewer germ tubes oriented towards stomata and so failed to contact them. Secondly, some germ tubes that encountered stomata did not form appressoria but over-grew them. In this line, therefore, the fungus tended to fail both to locate and to respond to stomata. The appressoria of barley powdery mildew form on leaf epidermal cells that they penetrate directly. On certain cer lines, a proportion of germlings of the barley powdery mildew fungus developed abnormally, suggesting that germlings failed to recognise and/or respond to the leaf surface waxes on these mutants.

  12. Abnormalities in synaptic dynamics during development in a mouse model of spinocerebellar ataxia type 1.

    PubMed

    Hatanaka, Yusuke; Watase, Kei; Wada, Keiji; Nagai, Yoshitaka

    2015-11-04

    Late-onset neurodegenerative diseases are characterized by neurological symptoms and progressive neuronal death. Accumulating evidence suggests that neuronal dysfunction, rather than neuronal death, causes the symptoms of neurodegenerative diseases. However, the mechanisms underlying the dysfunction that occurs prior to cell death remain unclear. To investigate the synaptic basis of this dysfunction, we employed in vivo two-photon imaging to analyse excitatory postsynaptic dendritic protrusions. We used Sca1(154Q/2Q) mice, an established knock-in mouse model of the polyglutamine disease spinocerebellar ataxia type 1 (SCA1), which replicates human SCA1 features including ataxia, cognitive impairment, and neuronal death. We found that Sca1(154Q/2Q) mice exhibited greater synaptic instability than controls, without synaptic loss, in the cerebral cortex, where obvious neuronal death is not observed, even before the onset of distinct symptoms. Interestingly, this abnormal synaptic instability was evident in Sca1(154Q/2Q) mice from the synaptic developmental stage, and persisted into adulthood. Expression of synaptic scaffolding proteins was also lower in Sca1(154Q/2Q) mice than controls before synaptic maturation. As symptoms progressed, synaptic loss became evident. These results indicate that aberrant synaptic instability, accompanied by decreased expression of scaffolding proteins during synaptic development, is a very early pathology that precedes distinct neurological symptoms and neuronal cell death in SCA1.

  13. A New Mouse Allele of Glutamate Receptor Delta 2 with Cerebellar Atrophy and Progressive Ataxia

    PubMed Central

    Miyoshi, Yuka; Yoshioka, Yoshichika; Suzuki, Kinuko; Miyazaki, Taisuke; Koura, Minako; Saigoh, Kazumasa; Kajimura, Naoko; Monobe, Yoko; Kusunoki, Susumu; Matsuda, Junichiro; Watanabe, Masahiko; Hayasaka, Naoto

    2014-01-01

    Spinocerebellar degenerations (SCDs) are a large class of sporadic or hereditary neurodegenerative disorders characterized by progressive motion defects and degenerative changes in the cerebellum and other parts of the CNS. Here we report the identification and establishment from a C57BL/6J mouse colony of a novel mouse line developing spontaneous progressive ataxia, which we refer to as ts3. Frequency of the phenotypic expression was consistent with an autosomal recessive Mendelian trait of inheritance, suggesting that a single gene mutation is responsible for the ataxic phenotype of this line. The onset of ataxia was observed at about three weeks of age, which slowly progressed until the hind limbs became entirely paralyzed in many cases. Micro-MRI study revealed significant cerebellar atrophy in all the ataxic mice, although individual variations were observed. Detailed histological analyses demonstrated significant atrophy of the anterior folia with reduced granule cells (GC) and abnormal morphology of cerebellar Purkinje cells (PC). Study by ultra-high voltage electron microscopy (UHVEM) further indicated aberrant morphology of PC dendrites and their spines, suggesting both morphological and functional abnormalities of the PC in the mutants. Immunohistochemical studies also revealed defects in parallel fiber (PF)–PC synapse formation and abnormal distal extension of climbing fibers (CF). Based on the phenotypic similarities of the ts3 mutant with other known ataxic mutants, we performed immunohistological analyses and found that expression levels of two genes and their products, glutamate receptor delta2 (grid2) and its ligand, cerebellin1 (Cbln1), are significantly reduced or undetectable. Finally, we sequenced the candidate genes and detected a large deletion in the coding region of the grid2 gene. Our present study suggests that ts3 is a new allele of the grid2 gene, which causes similar but different phenotypes as compared to other grid2 mutants. PMID

  14. A new mouse allele of glutamate receptor delta 2 with cerebellar atrophy and progressive ataxia.

    PubMed

    Miyoshi, Yuka; Yoshioka, Yoshichika; Suzuki, Kinuko; Miyazaki, Taisuke; Koura, Minako; Saigoh, Kazumasa; Kajimura, Naoko; Monobe, Yoko; Kusunoki, Susumu; Matsuda, Junichiro; Watanabe, Masahiko; Hayasaka, Naoto

    2014-01-01

    Spinocerebellar degenerations (SCDs) are a large class of sporadic or hereditary neurodegenerative disorders characterized by progressive motion defects and degenerative changes in the cerebellum and other parts of the CNS. Here we report the identification and establishment from a C57BL/6J mouse colony of a novel mouse line developing spontaneous progressive ataxia, which we refer to as ts3. Frequency of the phenotypic expression was consistent with an autosomal recessive Mendelian trait of inheritance, suggesting that a single gene mutation is responsible for the ataxic phenotype of this line. The onset of ataxia was observed at about three weeks of age, which slowly progressed until the hind limbs became entirely paralyzed in many cases. Micro-MRI study revealed significant cerebellar atrophy in all the ataxic mice, although individual variations were observed. Detailed histological analyses demonstrated significant atrophy of the anterior folia with reduced granule cells (GC) and abnormal morphology of cerebellar Purkinje cells (PC). Study by ultra-high voltage electron microscopy (UHVEM) further indicated aberrant morphology of PC dendrites and their spines, suggesting both morphological and functional abnormalities of the PC in the mutants. Immunohistochemical studies also revealed defects in parallel fiber (PF)-PC synapse formation and abnormal distal extension of climbing fibers (CF). Based on the phenotypic similarities of the ts3 mutant with other known ataxic mutants, we performed immunohistological analyses and found that expression levels of two genes and their products, glutamate receptor delta2 (grid2) and its ligand, cerebellin1 (Cbln1), are significantly reduced or undetectable. Finally, we sequenced the candidate genes and detected a large deletion in the coding region of the grid2 gene. Our present study suggests that ts3 is a new allele of the grid2 gene, which causes similar but different phenotypes as compared to other grid2 mutants.

  15. Ataxia, dysmetria, tremor. Cerebellar diseases.

    PubMed

    Kornegay, J N

    1991-09-01

    Diseases affecting the cerebellum typically cause ataxia, coupled with dysmetria and tremor. Dysmetria is a condition in which there is improper measuring of distance in muscular acts; hypermetria is overreaching (overstepping) and hypometria is underreaching (understepping). Tremor refers to an involuntary, rhythmic, oscillatory movement of a body part. The tremor of cerebellar disease typically is exaggerated by goal-oriented movements (intention tremor). Cerebellar lesions also often cause loss of the menace response, despite the presence of normal vision. The anatomic basis for this phenomenon is obscure. The principal disease affecting the cerebellum in cats is cerebellar hypoplasia due to in utero infection with the panleukopenia virus. This disease will be discussed here. Neurologic signs of cerebellar involvement also may be seen in association with those diseases that affect the CNS multifocally. In these cats, there may be additional signs indicating involvement of other anatomic areas or the cerebellar deficits may occur alone (see discussion of multifocal diseases in Multiple Neurologic Deficits: Inflammatory Diseases [page 426] and Multiple Neurologic Deficits: Noninfectious Diseases [page 440]). PMID:1802262

  16. Speech prosody in cerebellar ataxia.

    PubMed

    Casper, Maureen A; Raphael, Lawrence J; Harris, Katherine S; Geibel, Jennifer M

    2007-01-01

    Persons with cerebellar ataxia exhibit changes in physical coordination and speech and voice production. Previously, these alterations of speech and voice production were described primarily via perceptual coordinates. In this study, the spatial-temporal properties of syllable production were examined in 12 speakers, six of whom were healthy speakers and six with ataxia. The speaking task was designed to elicit six different prosodic conditions and four contrastive prosodic events. Distinct prosodic patterns were elicited by the examiner for cerebellar patients and healthy speakers. These utterances were digitally recorded and analysed acoustically and statistically. The healthy speakers showed statistically significant differences among all four prosodic contrasts. The normal model described by the prosodic contrasts provided a sensitive index of cerebellar pathology with quantitative acoustic analyses. A significant interaction between subject groups and prosodic conditions revealed a compromised prosody in cerebellar patients. Significant differences were found for durational parameters, F0 and formant frequencies. The cerebellar speakers demonstrated different patterns of syllable lengthening and syllable reduction from that of the healthy speakers. PMID:17613097

  17. Ataxias and Cerebellar or Spinocerebellar Degeneration

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Ataxias and Cerebellar or Spinocerebellar Degeneration Information Page Synonym(s): ... Publications and Information Publicaciones en Español What are Ataxias and Cerebellar or Spinocerebellar Degeneration? Ataxia often occurs ...

  18. MRI volumetry of the vermis and the cerebellar hemispheres in men with schizophrenia.

    PubMed

    Joyal, Christian C; Pennanen, Corina; Tiihonen, Eila; Laakso, Mikko P; Tiihonen, Jari; Aronen, Hannu J

    2004-07-30

    An association between cerebellar abnormalities and different manifestations of schizophrenia is increasingly hypothesized, either at the motor (anterior vermis), affective/psychotic (posterior vermis), or cognitive (cerebellar hemispheres) level. However, morphometric and volumetric cerebellar measurements have yielded highly divergent results. The main goal of this study was to use magnetic resonance imaging (MRI) to separately estimate the volumes of the entire vermis, the cerebellar hemispheres and three midsaggital vermian areas among 38 men with schizophrenia and 26 healthy men. Compared with the control group, persons with schizophrenia had significantly smaller volumes of the whole vermis, but not of the cerebellar hemispheres, a difference that approached significance when only the patients without a comorbid diagnosis of alcohol abuse/dependence were considered. Significant anomalies of the posterior vermian areas (lobules VI and VII) were detected in both subgroups of patients, while abnormalities of the anterior vermis (lobules I-V) were observed only among patients with a dual diagnosis of alcoholism. No difference emerged between the groups at the inferior vermian level (lobules VIII-X). Overall, these findings corroborate the hypothesized association between schizophrenia and specific posterior vermian anomalies, which might not necessarily be the consequence of alcohol abuse. However, the suggestion that schizophrenia is related to abnormal volumes of the lateral cerebellum is not supported.

  19. The genetics of cerebellar malformations.

    PubMed

    Aldinger, Kimberly A; Doherty, Dan

    2016-10-01

    The cerebellum has long been recognized for its role in motor co-ordination, but it is also increasingly appreciated for its role in complex cognitive behavior. Historically, the cerebellum has been overwhelmingly understudied compared to the neocortex in both humans and model organisms. However, this tide is changing as advances in neuroimaging, neuropathology, and neurogenetics have led to clinical classification and gene identification for numerous developmental disorders that impact cerebellar structure and function associated with significant overall neurodevelopmental dysfunction. Given the broad range in prognosis and associated medical and neurodevelopmental concerns accompanying cerebellar malformations, a working knowledge of these disorders and their causes is critical for obstetricians, perinatologists, and neonatologists. Here we present an update on the genetic causes for cerebellar malformations that can be recognized by neuroimaging and clinical characteristics during the prenatal and postnatal periods. PMID:27160001

  20. Seeking a unified framework for cerebellar function and dysfunction: from circuit operations to cognition

    PubMed Central

    D'Angelo, Egidio; Casali, Stefano

    2013-01-01

    Following the fundamental recognition of its involvement in sensory-motor coordination and learning, the cerebellum is now also believed to take part in the processing of cognition and emotion. This hypothesis is recurrent in numerous papers reporting anatomical and functional observations, and it requires an explanation. We argue that a similar circuit structure in all cerebellar areas may carry out various operations using a common computational scheme. On the basis of a broad review of anatomical data, it is conceivable that the different roles of the cerebellum lie in the specific connectivity of the cerebellar modules, with motor, cognitive, and emotional functions (at least partially) segregated into different cerebro-cerebellar loops. We here develop a conceptual and operational framework based on multiple interconnected levels (a meta-levels hypothesis): from cellular/molecular to network mechanisms leading to generation of computational primitives, thence to high-level cognitive/emotional processing, and finally to the sphere of mental function and dysfunction. The main concept explored is that of intimate interplay between timing and learning (reminiscent of the “timing and learning machine” capabilities long attributed to the cerebellum), which reverberates from cellular to circuit mechanisms. Subsequently, integration within large-scale brain loops could generate the disparate cognitive/emotional and mental functions in which the cerebellum has been implicated. We propose, therefore, that the cerebellum operates as a general-purpose co-processor, whose effects depend on the specific brain centers to which individual modules are connected. Abnormal functioning in these loops could eventually contribute to the pathogenesis of major brain pathologies including not just ataxia but also dyslexia, autism, schizophrenia, and depression. PMID:23335884

  1. Ultrastructural pathology of human peritumoural oedematous cerebellar cortex.

    PubMed

    Castejón, O J

    2016-01-01

    Cerebellar cortical biopsies of the peritumoural region of seven patients with cerebellar haemangioma, mesencephalic meningioma, cerebellopontine astrocytoma, cerebellopontine meningioma, and medulloblastoma of cerebellar vermis were examined by means of conventional transmission electron microscopy. Granule cells showed oedematous cytoplasm and mitochondria. Swollen Golgi cells exhibited lipofuscin granules and intranuclear inclusions. Both neuron cell types displayed swollen dendritic digits synapsing with afferent mossy fibre endings. Degenerated myelinated axons corresponding to afferent mossy and climbing fibres and efferent Purkinje cell axons were observed at the granular layer. Dense and clear ischaemic Purkinje cells established degenerated synapses with swollen parallel fibre synaptic varicosities. Degenerated Purkinje cell recurrent axonal collaterals were found at the molecular layer. Swollen and clear Bergmann glial cell cytoplasm was observed closely applied to the oedematous clear and dark Purkinje cell body, dendritic trunk, secondary and tertiary dendritic branches. Swollen climbing fibre endings featured by numerous microtubules and neurofilaments, and a decreased number of synaptic vesicles were observed making degenerated axo-spinodendritic synapses with clear and swollen dendritic spines from Purkinje, Golgi, basket and stellate cell dendrites. Swollen stellate neurons showed oedematous mitochondria. Lipofuscin-rich astrocytes and reactive phagocytic astrocytes were observed. The latter appeared engulfing haematogenous proteinaceous oedema fluid. All cerebellar neurons showed stress endoplasmic reticulum dysfunction featured by focal dilated cisterns and detachment of associated ribosomes. Myelin sheath degeneration was related with oligodendrocyte degenerating hydropic changes. The peritumoural ischaemic cerebellar nerve and glial cell abnormalities were related with neurobehavioral changes, tremor, nystagmus, dismetry and gait disturbance

  2. Aberrant cerebellar connectivity in motor and association networks in schizophrenia

    PubMed Central

    Shinn, Ann K.; Baker, Justin T.; Lewandowski, Kathryn E.; Öngür, Dost; Cohen, Bruce M.

    2015-01-01

    Schizophrenia is a devastating illness characterized by disturbances in multiple domains. The cerebellum is involved in both motor and non-motor functions, and the “cognitive dysmetria” and “dysmetria of thought” models propose that abnormalities of the cerebellum may contribute to schizophrenia signs and symptoms. The cerebellum and cerebral cortex are reciprocally connected via a modular, closed-loop network architecture, but few schizophrenia neuroimaging studies have taken into account the topographical and functional heterogeneity of the cerebellum. In this study, using a previously defined 17-network cerebral cortical parcellation system as the basis for our functional connectivity seeds, we systematically investigated connectivity abnormalities within the cerebellum of 44 schizophrenia patients and 28 healthy control participants. We found selective alterations in cerebro-cerebellar functional connectivity. Specifically, schizophrenia patients showed decreased cerebro-cerebellar functional connectivity in higher level association networks (ventral attention, salience, control, and default mode networks) relative to healthy control participants. Schizophrenia patients also showed increased cerebro-cerebellar connectivity in somatomotor and default mode networks, with the latter showing no overlap with the regions found to be hypoconnected within the same default mode network. Finally, we found evidence to suggest that somatomotor and default mode networks may be inappropriately linked in schizophrenia. The relationship of these dysconnectivities to schizophrenia symptoms, such as neurological soft signs and altered sense of agency, is discussed. We conclude that the cerebellum ought to be considered for analysis in all future studies of network abnormalities in SZ, and further suggest the cerebellum as a potential target for further elucidation, and possibly treatment, of the underlying mechanisms and network abnormalities producing symptoms of

  3. Diphenylarsinic Acid Induced Activation of Cultured Rat Cerebellar Astrocytes: Phosphorylation of Mitogen-Activated Protein Kinases, Upregulation of Transcription Factors, and Release of Brain-Active Cytokines.

    PubMed

    Negishi, Takayuki; Matsumoto, Mami; Kojima, Mikiya; Asai, Ryota; Kanehira, Tomoko; Sakaguchi, Fumika; Takahata, Kazuaki; Arakaki, Rina; Aoyama, Yohei; Yoshida, Hikari; Yoshida, Kenji; Yukawa, Kazunori; Tashiro, Tomoko; Hirano, Seishiro

    2016-03-01

    Diphenylarsinic acid (DPAA) was detected as the primary compound responsible for the arsenic poisoning that occurred in Kamisu, Ibaraki, Japan, where people using water from a well that was contaminated with a high level of arsenic developed neurological (mostly cerebellar) symptoms and dysregulation of regional cerebral blood flow. To understand the underlying molecular mechanism of DPAA-induced cerebellar symptoms, we focused on astrocytes, which have a brain-protective function. Incubation with 10 µM DPAA for 96 h promoted cell proliferation, increased the expression of antioxidative stress proteins (heme oxygenase-1 and heat shock protein 70), and induced the release of cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6). Furthermore, DPAA overpoweringly increased the phosphorylation of three major mitogen-activated protein kinases (MAPKs) (ERK1/2, p38MAPK, and SAPK/JNK), which indicated MAPK activation, and subsequently induced expression and/or phosphorylation of transcription factors (Nrf2, CREB, c-Jun, and c-Fos) in cultured rat cerebellar astrocytes. Structure-activity relationship analyses of DPAA and other related pentavalent organic arsenicals revealed that DPAA at 10 µM activated astrocytes most effective among organic arsenicals tested at the same dose. These results suggest that in a cerebellum exposed to DPAA, abnormal activation of the MAPK-transcription factor pathway and irregular secretion of these neuroactive, glioactive, and/or vasoactive cytokines in astrocytes can be the direct/indirect cause of functional abnormalities in surrounding neurons, glial cells, and vascular cells: This in turn might lead to the onset of cerebellar symptoms and disruption of cerebral blood flow. PMID:26645585

  4. Cerebellar Plasticity and Motor Learning Deficits in a Copy Number Variation Mouse Model of Autism

    PubMed Central

    Piochon, Claire; Kloth, Alexander D; Grasselli, Giorgio; Titley, Heather K; Nakayama, Hisako; Hashimoto, Kouichi; Wan, Vivian; Simmons, Dana H; Eissa, Tahra; Nakatani, Jin; Cherskov, Adriana; Miyazaki, Taisuke; Watanabe, Masahiko; Takumi, Toru; Kano, Masanobu; Wang, Samuel S-H; Hansel, Christian

    2014-01-01

    A common feature of autism spectrum disorder (ASD) is the impairment of motor control and learning, occurring in a majority of children with autism, consistent with perturbation in cerebellar function. Here we report alterations in motor behavior and cerebellar synaptic plasticity in a mouse model (patDp/+) for the human 15q11-13 duplication, one of the most frequently observed genetic aberrations in autism. These mice show ASD-resembling social behavior deficits. We find that in patDp/+ mice delay eyeblink conditioning—a form of cerebellum-dependent motor learning—is impaired, and observe deregulation of a putative cellular mechanism for motor learning, long-term depression (LTD) at parallel fiber-Purkinje cell synapses. Moreover, developmental elimination of surplus climbing fibers—a model for activity-dependent synaptic pruning—is impaired. These findings point to deficits in synaptic plasticity and pruning as potential causes for motor problems and abnormal circuit development in autism. PMID:25418414

  5. Bilateral cerebellar activation in unilaterally challenged essential tremor

    PubMed Central

    Broersma, Marja; van der Stouwe, Anna M.M.; Buijink, Arthur W.G.; de Jong, Bauke M.; Groot, Paul F.C.; Speelman, Johannes D.; Tijssen, Marina A.J.; van Rootselaar, Anne-Fleur; Maurits, Natasha M.

    2015-01-01

    Background Essential tremor (ET) is one of the most common hyperkinetic movement disorders. Previous research into the pathophysiology of ET suggested underlying cerebellar abnormalities. Objective In this study, we added electromyography as an index of tremor intensity to functional Magnetic Resonance Imaging (EMG-fMRI) to study a group of ET patients selected according to strict criteria to achieve maximal homogeneity. With this approach we expected to improve upon the localization of the bilateral cerebellar abnormalities found in earlier fMRI studies. Methods We included 21 propranolol sensitive patients, who were not using other tremor medication, with a definite diagnosis of ET defined by the Tremor Investigation Group. Simultaneous EMG-fMRI recordings were performed while patients were off tremor medication. Patients performed unilateral right hand and arm extension, inducing tremor, alternated with relaxation (rest). Twenty-one healthy, age- and sex-matched participants mimicked tremor during right arm extension. EMG power variability at the individual tremor frequency as a measure of tremor intensity variability was used as a regressor, mathematically independent of the block regressor, in the general linear model used for fMRI analysis, to find specific tremor-related activations. Results Block-related activations were found in the classical upper-limb motor network, both for ET patients and healthy participants in motor, premotor and supplementary motor areas. In ET patients, we found tremor-related activations bilaterally in the cerebellum: in left lobules V, VI, VIIb and IX and in right lobules V, VI, VIIIa and b, and in the brainstem. In healthy controls we found simulated tremor-related activations in right cerebellar lobule V. Conclusions Our results expand on previous findings of bilateral cerebellar involvement in ET. We have identified specific areas in the bilateral somatomotor regions of the cerebellum: lobules V, VI and VIII. PMID:26909321

  6. Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred

    PubMed Central

    Gulsuner, Suleyman; Tekinay, Ayse Begum; Doerschner, Katja; Boyaci, Huseyin; Bilguvar, Kaya; Unal, Hilal; Ors, Aslihan; Onat, O. Emre; Atalar, Ergin; Basak, A. Nazli; Topaloglu, Haluk; Kansu, Tulay; Tan, Meliha; Tan, Uner; Gunel, Murat; Ozcelik, Tayfun

    2011-01-01

    The biological basis for the development of the cerebro-cerebellar structures required for posture and gait in humans is poorly understood. We investigated a large consanguineous family from Turkey exhibiting an extremely rare phenotype associated with quadrupedal locomotion, mental retardation, and cerebro-cerebellar hypoplasia, linked to a 7.1-Mb region of homozygosity on chromosome 17p13.1–13.3. Diffusion weighted imaging and fiber tractography of the patients' brains revealed morphological abnormalities in the cerebellum and corpus callosum, in particular atrophy of superior, middle, and inferior peduncles of the cerebellum. Structural magnetic resonance imaging showed additional morphometric abnormalities in several cortical areas, including the corpus callosum, precentral gyrus, and Brodmann areas BA6, BA44, and BA45. Targeted sequencing of the entire homozygous region in three affected individuals and two obligate carriers uncovered a private missense mutation, WDR81 p.P856L, which cosegregated with the condition in the extended family. The mutation lies in a highly conserved region of WDR81, flanked by an N-terminal BEACH domain and C-terminal WD40 beta-propeller domains. WDR81 is predicted to be a transmembrane protein. It is highly expressed in the cerebellum and corpus callosum, in particular in the Purkinje cell layer of the cerebellum. WDR81 represents the third gene, after VLDLR and CA8, implicated in quadrupedal locomotion in humans. PMID:21885617

  7. Speech Prosody in Cerebellar Ataxia

    ERIC Educational Resources Information Center

    Casper, Maureen A.; Raphael, Lawrence J.; Harris, Katherine S.; Geibel, Jennifer M.

    2007-01-01

    Persons with cerebellar ataxia exhibit changes in physical coordination and speech and voice production. Previously, these alterations of speech and voice production were described primarily via perceptual coordinates. In this study, the spatial-temporal properties of syllable production were examined in 12 speakers, six of whom were healthy…

  8. Linking oscillations in cerebellar circuits

    PubMed Central

    Courtemanche, Richard; Robinson, Jennifer C.; Aponte, Daniel I.

    2013-01-01

    In many neuroscience fields, the study of local and global rhythmicity has been receiving increasing attention. These network influences could directly impact on how neuronal groups interact together, organizing for different contexts. The cerebellar cortex harbors a variety of such local circuit rhythms, from the rhythms in the cerebellar cortex per se, or those dictated from important afferents. We present here certain cerebellar oscillatory phenomena that have been recorded in rodents and primates. Those take place in a range of frequencies: from the more known oscillations in the 4–25 Hz band, such as the olivocerebellar oscillatory activity and the granule cell layer oscillations, to the more recently reported slow (<1 Hz oscillations), and the fast (>150 Hz) activity in the Purkinje cell layer. Many of these oscillations appear spontaneously in the circuits, and are modulated by behavioral imperatives. We review here how those oscillations are recorded, some of their modulatory mechanisms, and also identify some of the cerebellar nodes where they could interact. A particular emphasis has been placed on how these oscillations could be modulated by movement and certain neuropathological manifestations. Many of those oscillations could have a definite impact on the way information is processed in the cerebellum and how it interacts with other structures in a variety of contexts. PMID:23908606

  9. Behavioral effects of neonatal lesions on the cerebellar system.

    PubMed

    Lalonde, Robert; Strazielle, Catherine

    2015-06-01

    Several rodent models with spontaneous mutations causing cerebellar pathology are impaired in motor functions during the neonatal period, including Grid2(Lc), Rora(sg), Dab1(scm), Girk2(Wv), Lmx1a(dr-sst), Myo5a(dn), Inpp4a(wbl), and Cacna1a(rol) mice as well as shaker and dystonic rats. Deficits are also evident in murine null mutants such as Zic1, Fgfr1/FgFr2, and Xpa/Ercc8. Behavioral deficits are time-dependent following X-irradiated- or aspiration-induced lesions of the cerebellum in rats. In addition, motor functions are deficient after lesions in cerebellar-related pathways. As in animal subjects, sensorimotor disturbances have been described in children with cerebellar lesions. These results underline the importance of the cerebellum and its connections in the development of motor functions.

  10. Studying Cerebellar Circuits by Remote Control of Selected Neuronal Types with GABAA Receptors

    PubMed Central

    Wisden, William; Murray, Andrew J.; McClure, Christina; Wulff, Peer

    2009-01-01

    Although GABAA receptor-mediated inhibition of cerebellar Purkinje cells by molecular layer interneurons (MLIs) has been studied intensely at the cellular level, it has remained unclear how this inhibition regulates cerebellum-dependent behaviour. We have implemented two complementary approaches to investigate the function of the MLI-Purkinje cell synapse on the behavioural level. In the first approach we permanently disrupted inhibitory fast synaptic transmission at the synapse by genetically removing the postsynaptic GABAA receptors from Purkinje cells (PC-Δγ2 mice). We found that chronic disruption of the MLI-Purkinje cell synapse strongly impaired cerebellar learning of the vestibular occular reflex (VOR), presumably by disrupting the temporal patterns of Purkinje cell activity. However, in PC-Δγ2 mice the baseline VOR reflex was only mildly affected; indeed PC-Δγ2 mice show no ataxia or gait abnormalities, suggesting that MLI control of Purkinje cell activity is either not involved in ongoing motor tasks or that the system compensates for its loss. To investigate the latter possibility we developed an alternative genetic technique; we made the MLI-Purkinje cell synapse selectively sensitive to rapid manipulation with the GABAA receptor modulator zolpidem (PC-γ2-swap mice). Minutes after intraperitoneal zolpidem injection, these PC-γ2-swap mice developed severe motor abnormalities, revealing a substantial contribution of the MLI-Purkinje cell synapses to real time motor control. The cell-type selective permanent knockout of synaptic GABAergic input and the fast reversible modulation of GABAergic input at the same synapse illustrate how pursuing both strategies gives a fuller view. PMID:20076763

  11. Middle cerebellar peduncles: Magnetic resonance imaging and pathophysiologic correlate

    PubMed Central

    Morales, Humberto; Tomsick, Thomas

    2015-01-01

    We describe common and less common diseases that can cause magnetic resonance signal abnormalities of middle cerebellar peduncles (MCP), offering a systematic approach correlating imaging findings with clinical clues and pathologic mechanisms. Myelin abnormalities, different types of edema or neurodegenerative processes, can cause areas of abnormal T2 signal, variable enhancement, and patterns of diffusivity of MCP. Pathologies such as demyelinating disorders or certain neurodegenerative entities (e.g., multiple system atrophy or fragile X-associated tremor-ataxia syndrome) appear to have predilection for MCP. Careful evaluation of concomitant imaging findings in the brain or brainstem; and focused correlation with key clinical findings such as immunosuppression for progressive multifocal leukoencephalopahty; hypertension, post-transplant status or high dose chemotherapy for posterior reversible encephalopathy; electrolyte disorders for myelinolysis or suspected toxic-drug related encephalopathy; would yield an appropriate and accurate differential diagnosis in the majority of cases. PMID:26751508

  12. Amygdala Modulation of Cerebellar Learning

    PubMed Central

    Farley, Sean J.; Radley, Jason J.

    2016-01-01

    Previous studies showed that amygdala lesions or inactivation slow the acquisition rate of cerebellum-dependent eyeblink conditioning, a type of associative motor learning. The current study was designed to determine the behavioral nature of amygdala–cerebellum interactions, to identify the neural pathways underlying amygdala–cerebellum interactions, and to examine how the amygdala influences cerebellar learning mechanisms in rats. Pharmacological inactivation of the central amygdala (CeA) severely impaired acquisition and retention of eyeblink conditioning, indicating that the amygdala continues to interact with the cerebellum after conditioning is consolidated (Experiment 1). CeA inactivation also substantially reduced stimulus-evoked and learning-related neuronal activity in the cerebellar anterior interpositus nucleus during acquisition and retention of eyeblink conditioning (Experiment 2). A very small proportion of cerebellar neurons responded to the conditioned stimulus (CS) during CeA inactivation. Finally, retrograde and anterograde tracing experiments identified the basilar pontine nucleus at the confluence of outputs from CeA that may support amygdala modulation of CS input to the cerebellum (Experiment 3). Together, these results highlight a role for the CeA in the gating of CS-related input to the cerebellum during motor learning that is maintained even after the conditioned response is well learned. SIGNIFICANCE STATEMENT The current study is the first to demonstrate that the amygdala modulates sensory-evoked and learning-related neuronal activity within the cerebellum during acquisition and retention of associative learning. The findings suggest a model of amygdala–cerebellum interactions in which the amygdala gates conditioned stimulus inputs to the cerebellum through a direct projection from the medial central nucleus to the basilar pontine nucleus. Amygdala gating of sensory input to the cerebellum may be an attention-like mechanism that

  13. Paraneoplastic cerebellar degeneration as a marker of endometrial cancer recurrence.

    PubMed

    Lie, Geoffrey; Morley, Thomas; Chowdhury, Muhammad

    2016-01-01

    An 84-year-old woman developed a cerebellar syndrome having undergone a total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometrial cancer 1 year previously. She was found to be anti-Yo antibody positive and was diagnosed with paraneoplastic cerebellar degeneration (PCD). A subsequent positron emission tomography scan and lymph node biopsy identified recurrence of her endometrial cancer. This case illustrates how PCD can be an indicator of cancer recurrence, underlines the significance of PCD as a prompt to search for underlying malignancy, and highlights the difficulties PCD poses to the clinician in terms of diagnosis and management.

  14. Sex differences in abnormal white matter development associated with conduct disorder in children.

    PubMed

    Decety, Jean; Yoder, Keith J; Lahey, Benjamin B

    2015-08-30

    Associations between white matter pathway abnormalities and antisocial personality disorder in adults are well replicated, and there is some evidence for an association of white matter abnormalities with conduct disorder (CD) in adolescents. In this study, white matter maturation using diffusion tensor imaging (DTI) was examined in 110 children aged 10.0 ± 0.8 years selected to vary widely in their numbers of CD symptoms. The results replicated age-related increases in fractional anisotropy (FA) found in previous studies. There was not a significant association between the number of CD symptoms and FA, but CD symptoms were found to be significantly associated with greater axial and radial diffusivity in a broad range of white matter tracts, particularly in girls. In complementary analyses, there were similar significant differences in axial and radial diffusivity between children who met diagnostic criteria for CD and healthy children with no symptoms of CD, particularly in girls. Brain structural abnormalities may contribute to the emergence of CD in childhood, perhaps playing a greater role in girls.

  15. Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult

    PubMed Central

    Carreira, Vinicius S.; Fan, Yunxia; Kurita, Hisaka; Wang, Qin; Ko, Chia-I; Naticchioni, Mindi; Jiang, Min; Koch, Sheryl; Zhang, Xiang; Biesiada, Jacek; Medvedovic, Mario; Xia, Ying; Rubinstein, Jack; Puga, Alvaro

    2015-01-01

    The Developmental Origins of Health and Disease (DOHaD) Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr-/- and in utero TCDD-exposed Ahr+/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr-/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease. PMID:26555816

  16. Ischemia-Induced Autophagy Contributes to Neurodegeneration in Cerebellar Purkinje Cells in the Developing Rat Brain and in Primary Cortical Neurons In Vitro

    PubMed Central

    Au, Alicia K.; Chen, Yaming; Du, Lina; Smith, Craig M.; Manole, Mioara D.; Baltagi, Sirine A.; Chu, Charleen T.; Aneja, Rajesh K.; Bayır, Hülya; Kochanek, Patrick M.; Clark, Robert S. B.

    2015-01-01

    Increased autophagy/mitophagy is thought to contribute to cerebellar dysfunction in Purkinje cell degeneration mice. Intriguingly, cerebellar Purkinje cells are highly vulnerable to hypoxia-ischemia (HI), related at least in part to their high metabolic activity. Whether or not excessive or supraphysiologic autophagy plays a role in Purkinje cell susceptibility to HI is unknown. Accordingly, we evaluated the role of autophagy in the cerebellum after global ischemia produced by asphyxial cardiac arrest in postnatal day (PND) 16–18 rats, using siRNA-targeted inhibition of Atg7, necessary for microtubule-associated protein light chain 3-II (LC3-II) and Atg12-Atg5 complex formation. Two days before a 9 min asphyxial cardiac arrest or sham surgery, Atg7 or control siRNA was injected intracisternally to target the cerebellum. Treatment with Atg7 siRNA: 1) reduced Atg7 protein expression in the cerebellum by 56%; 2) prevented the typical ischemia-induced formation of LC3-II in the cerebellum 24 h after asphyxial cardiac arrest; 3) improved performance on the beam-balance apparatus on days 1–5; and 4) increased calbindin-labeled Purkinje cell survival assessed on day 14. Improved Purkinje cell survival was more consistent in female vs. male rats, and improved beam-balance performance was only seen in female rats. Similar responses to Atg7 siRNA i.e. reduced autophagy and neurodegeneration vs. control siRNA were seen when exposing sex-segregated green fluorescent protein-LC3 tagged mouse primary cortical neurons to oxygen glucose deprivation in vitro. Thus, inhibition of autophagy after global ischemia in PND 16–18 rats leads to increased survival of Purkinje cells and improved motor performance in a sex-dependent manner. PMID:26071643

  17. Cerebellar substrates for error correction in motor conditioning.

    PubMed

    Gluck, M A; Allen, M T; Myers, C E; Thompson, R F

    2001-11-01

    The authors evaluate a mapping of Rescorla and Wagner's (1972) behavioral model of classical conditioning onto the cerebellar substrates for motor reflex learning and illustrate how the limitations of the Rescorla-Wagner model are just as useful as its successes for guiding the development of new psychobiological theories of learning. They postulate that the inhibitory pathway that returns conditioned response information from the cerebellar interpositus nucleus back to the inferior olive is the neural basis for the error correction learning proposed by Rescorla and Wagner (Gluck, Myers, & Thompson, 1994; Thompson, 1986). The authors' cerebellar model expects that behavioral processes described by the Rescorla-Wagner model will be localized within the cerebellum and related brain stem structures, whereas behavioral processes beyond the scope of the Rescorla-Wagner model will depend on extracerebellar structures such as the hippocampus and related cortical regions. Simulations presented here support both implications. Several novel implications of the authors' cerebellar error-correcting model are described including a recent empirical study by Kim, Krupa, and Thompson (1998), who verified that suppressing the putative error correction pathway should interfere with the Kamin (1969) blocking effect, a behavioral manifestation of error correction learning. The authors also discuss the model's implications for understanding the limits of cerebellar contributions to associative learning and how this informs our understanding of hippocampal function in conditioning. This leads to a more integrative view of the neural substrates of conditioning in which the authors' real-time circuit-level model of the cerebellum can be viewed as a generalization of the long-term memory module of Gluck and Myers' (1993) trial-level theory of cerebellar-hippocampal interaction in motor conditioning. PMID:11726240

  18. Cerebellar substrates for error correction in motor conditioning.

    PubMed

    Gluck, M A; Allen, M T; Myers, C E; Thompson, R F

    2001-11-01

    The authors evaluate a mapping of Rescorla and Wagner's (1972) behavioral model of classical conditioning onto the cerebellar substrates for motor reflex learning and illustrate how the limitations of the Rescorla-Wagner model are just as useful as its successes for guiding the development of new psychobiological theories of learning. They postulate that the inhibitory pathway that returns conditioned response information from the cerebellar interpositus nucleus back to the inferior olive is the neural basis for the error correction learning proposed by Rescorla and Wagner (Gluck, Myers, & Thompson, 1994; Thompson, 1986). The authors' cerebellar model expects that behavioral processes described by the Rescorla-Wagner model will be localized within the cerebellum and related brain stem structures, whereas behavioral processes beyond the scope of the Rescorla-Wagner model will depend on extracerebellar structures such as the hippocampus and related cortical regions. Simulations presented here support both implications. Several novel implications of the authors' cerebellar error-correcting model are described including a recent empirical study by Kim, Krupa, and Thompson (1998), who verified that suppressing the putative error correction pathway should interfere with the Kamin (1969) blocking effect, a behavioral manifestation of error correction learning. The authors also discuss the model's implications for understanding the limits of cerebellar contributions to associative learning and how this informs our understanding of hippocampal function in conditioning. This leads to a more integrative view of the neural substrates of conditioning in which the authors' real-time circuit-level model of the cerebellum can be viewed as a generalization of the long-term memory module of Gluck and Myers' (1993) trial-level theory of cerebellar-hippocampal interaction in motor conditioning.

  19. Cerebellar ependymal cyst in a dog.

    PubMed

    Wyss-Fluehmann, G; Konar, M; Jaggy, A; Vandevelde, M; Oevermann, A

    2008-11-01

    An 11-week-old, male, Staffordshire Bull Terrier had a history of generalized ataxia and falling since birth. The neurologic findings suggested a localization in the cerebellum. Magnetic resonance imaging of the brain was performed. In all sequences the area of the cerebellum was almost replaced by fluid isointense to cerebrospinal fluid. A complete necropsy was performed after euthanasia. Histologically, the lesion was characterized by extensive loss of cerebellar tissue in both hemispheres and vermis. Toward the surface of the cerebellar defect, the cavity was confined by ruptured and folded membranes consisting of a layer of glial fibrillary acidic (GFAP)-positive glial cells covered multifocally by epithelial cells. Some of these cells bore apical cilia and were cytokeratin and GFAP negative, supporting their ependymal origin. The histopathologic features of our case are consistent with the diagnosis of an ependymal cyst. Its glial and ependymal nature as demonstrated by histopathologic and immunohistochemical examination differs from arachnoid cysts, which have also been reported in dogs. The origin of these cysts remains controversial, but it has been suggested that they develop during embryogenesis subsequent to sequestration of developing neuroectoderm. We speculate that the cyst could have been the result of a pre- or perinatal, possibly traumatic, insult because hemorrhage, and tissue destruction had occurred. To our knowledge, this is the first description of an ependymal cyst in the veterinary literature.

  20. Impaired Cerebellar-Dependent Eyeblink Conditioning in First-Degree Relatives of Individuals With Schizophrenia

    PubMed Central

    Bolbecker, Amanda R.; Kent, Jerillyn S.; Petersen, Isaac T.; Klaunig, Mallory J.; Forsyth, Jennifer K.; Howell, Josselyn M.; Westfall, Daniel R.; O’Donnell, Brian F.; Hetrick, William P.

    2014-01-01

    Consistent with reports of cerebellar structural, functional, and neurochemical anomalies in schizophrenia, robust cerebellar-dependent delay eyeblink conditioning (dEBC) deficits have been observed in the disorder. Impaired dEBC is also present in schizotypal personality disorder, an intermediate phenotype of schizophrenia. The present work sought to determine whether dEBC deficits exist in nonpsychotic first-degree relatives of individuals with schizophrenia. A single-cue tone dEBC paradigm consisting of 10 blocks with 10 trials each (9 paired and 1 unpaired trials) was used to examine the functional integrity of cerebellar circuitry in schizophrenia participants, individuals with a first-degree relative diagnosed with schizophrenia, and healthy controls with no first-degree relatives diagnosed with schizophrenia. The conditioned stimulus (a 400ms tone) coterminated with the unconditioned stimulus (a 50ms air puff to the left eye) on paired trials. One relative and 2 healthy controls were removed from further analysis due to declining conditioned response rates, leaving 18 schizophrenia participants, 17 first-degree relatives, and 16 healthy controls. Electromyographic data were subsequently analyzed using growth curve models in hierarchical linear regression. Acquisition of dEBC conditioned responses was significantly impaired in schizophrenia and first-degree relative groups compared with controls. This finding that cerebellar-mediated associative learning deficits are present in first-degree relatives of individuals with schizophrenia provides evidence that dEBC abnormalities in schizophrenia may not be due to medication or course of illness effects. Instead, the present results are consistent with models of schizophrenia positing cerebellar-cortical circuit abnormalities and suggest that cerebellar abnormalities represent a risk marker for the disorder. PMID:23962891

  1. Impaired cerebellar-dependent eyeblink conditioning in first-degree relatives of individuals with schizophrenia.

    PubMed

    Bolbecker, Amanda R; Kent, Jerillyn S; Petersen, Isaac T; Klaunig, Mallory J; Forsyth, Jennifer K; Howell, Josselyn M; Westfall, Daniel R; O'Donnell, Brian F; Hetrick, William P

    2014-09-01

    Consistent with reports of cerebellar structural, functional, and neurochemical anomalies in schizophrenia, robust cerebellar-dependent delay eyeblink conditioning (dEBC) deficits have been observed in the disorder. Impaired dEBC is also present in schizotypal personality disorder, an intermediate phenotype of schizophrenia. The present work sought to determine whether dEBC deficits exist in nonpsychotic first-degree relatives of individuals with schizophrenia. A single-cue tone dEBC paradigm consisting of 10 blocks with 10 trials each (9 paired and 1 unpaired trials) was used to examine the functional integrity of cerebellar circuitry in schizophrenia participants, individuals with a first-degree relative diagnosed with schizophrenia, and healthy controls with no first-degree relatives diagnosed with schizophrenia. The conditioned stimulus (a 400ms tone) coterminated with the unconditioned stimulus (a 50ms air puff to the left eye) on paired trials. One relative and 2 healthy controls were removed from further analysis due to declining conditioned response rates, leaving 18 schizophrenia participants, 17 first-degree relatives, and 16 healthy controls. Electromyographic data were subsequently analyzed using growth curve models in hierarchical linear regression. Acquisition of dEBC conditioned responses was significantly impaired in schizophrenia and first-degree relative groups compared with controls. This finding that cerebellar-mediated associative learning deficits are present in first-degree relatives of individuals with schizophrenia provides evidence that dEBC abnormalities in schizophrenia may not be due to medication or course of illness effects. Instead, the present results are consistent with models of schizophrenia positing cerebellar-cortical circuit abnormalities and suggest that cerebellar abnormalities represent a risk marker for the disorder.

  2. Neurodevelopmental Outcomes in Children with Cerebellar Malformations: A Systematic Review

    ERIC Educational Resources Information Center

    Bolduc, Marie-Eve; Limperopoulos, Catherine

    2009-01-01

    Cerebellar malformations are increasingly diagnosed in the fetal period. Consequently, their consideration requires stressful and often critical decisions from both clinicians and families. This has resulted in an emergent need to understand better the impact of these early life lesions on child development. We performed a comprehensive literature…

  3. Cerebellar gray matter and lobular volumes correlate with core autism symptoms

    PubMed Central

    D'Mello, Anila M.; Crocetti, Deana; Mostofsky, Stewart H.; Stoodley, Catherine J.

    2015-01-01

    Neuroanatomical differences in the cerebellum are among the most consistent findings in autism spectrum disorder (ASD), but little is known about the relationship between cerebellar dysfunction and core ASD symptoms. The newly-emerging existence of cerebellar sensorimotor and cognitive subregions provides a new framework for interpreting the functional significance of cerebellar findings in ASD. Here we use two complementary analyses — whole-brain voxel-based morphometry (VBM) and the SUIT cerebellar atlas — to investigate cerebellar regional gray matter (GM) and volumetric lobular measurements in 35 children with ASD and 35 typically-developing (TD) children (mean age 10.4 ± 1.6 years; range 8–13 years). To examine the relationships between cerebellar structure and core ASD symptoms, correlations were calculated between scores on the Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview (ADI) and the VBM and volumetric data. Both VBM and the SUIT analyses revealed reduced GM in ASD children in cerebellar lobule VII (Crus I/II). The degree of regional and lobular gray matter reductions in different cerebellar subregions correlated with the severity of symptoms in social interaction, communication, and repetitive behaviors. Structural differences and behavioral correlations converged on right cerebellar Crus I/II, a region which shows structural and functional connectivity with fronto-parietal and default mode networks. These results emphasize the importance of the location within the cerebellum to the potential functional impact of structural differences in ASD, and suggest that GM differences in cerebellar right Crus I/II are associated with the core ASD profile. PMID:25844317

  4. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  5. Altered structure of cortical sulci in gilles de la Tourette syndrome: Further support for abnormal brain development.

    PubMed

    Muellner, Julia; Delmaire, Christine; Valabrégue, Romain; Schüpbach, Michael; Mangin, Jean-François; Vidailhet, Marie; Lehéricy, Stéphane; Hartmann, Andreas; Worbe, Yulia

    2015-04-15

    Gilles de la Tourette syndrome is a neurodevelopmental disorder characterized by the presence of motor and vocal tics. We hypothesized that patients with this syndrome would present an aberrant pattern of cortical formation, which could potentially reflect global alterations of brain development. Using 3 Tesla structural neuroimaging, we compared sulcal depth, opening, and length and thickness of sulcal gray matter in 52 adult patients and 52 matched controls. Cortical sulci were automatically reconstructed and identified over the whole brain, using BrainVisa software. We focused on frontal, parietal, and temporal cortical regions, in which abnormal structure and functional activity were identified in previous neuroimaging studies. Partial correlation analysis with age, sex, and treatment as covariables of noninterest was performed amongst relevant clinical and neuroimaging variables in patients. Patients with Gilles de la Tourette syndrome showed lower depth and reduced thickness of gray matter in the pre- and post-central as well as superior, inferior, and internal frontal sulci. In patients with associated obsessive-compulsive disorder, additional structural changes were found in temporal, insular, and olfactory sulci. Crucially, severity of tics and of obsessive-compulsive disorder measured by Yale Global Tic severity scale and Yale-Brown Obsessive-Compulsive scale, respectively, correlated with structural sulcal changes in sensorimotor, temporal, dorsolateral prefrontal, and middle cingulate cortical areas. Patients with Gilles de la Tourette syndrome displayed an abnormal structural pattern of cortical sulci, which correlated with severity of clinical symptoms. Our results provide further evidence of abnormal brain development in GTS.

  6. The pleiotropic ABNORMAL FLOWER AND DWARF1 affects plant height, floral development and grain yield in rice

    PubMed Central

    Ren, Deyong; Rao, Yuchun; Wu, Liwen; Xu, Qiankun; Li, Zizhuang; Yu, Haiping; Zhang, Yu; Leng, Yujia; Hu, Jiang; Zhu, Li; Gao, Zhenyu; Dong, Guojun; Zhang, Guangheng; Guo, Longbiao

    2016-01-01

    Abstract Moderate plant height and successful establishment of reproductive organs play pivotal roles in rice grain production. The molecular mechanism that controls the two aspects remains unclear in rice. In the present study, we characterized a rice gene, ABNORMAL FLOWER AND DWARF1 (AFD1) that determined plant height, floral development and grain yield. The afd1 mutant showed variable defects including the dwarfism, long panicle, low seed setting and reduced grain yield. In addition, abnormal floral organs were also observed in the afd1 mutant including slender and thick hulls, and hull‐like lodicules. AFD1 encoded a DUF640 domain protein and was expressed in all tested tissues and organs. Subcellular localization showed AFD1‐green fluorescent fusion protein (GFP) was localized in the nucleus. Meantime, our results suggested that AFD1 regulated the expression of cell division and expansion related genes. PMID:26486996

  7. Development of a sintering methodology through abnormal glow discharge for manufacturing metal matrix composites

    NASA Astrophysics Data System (ADS)

    Pérez, S.; Pineda, Y.; Sarmiento, A.; López, A.

    2016-02-01

    In this study, a sintering methodology is presented by using abnormal glow discharge to metal matrix composites (MMC), consisting of 316 steel, reinforced with titanium carbide (TiC). The wear behaviour of these compounds was evaluated according to the standard ASTM G 99 in a tribometer pin-on-disk. The effect of the percentage of reinforcement (3, 6, and 9%), with 40 minutes of mixing in the planetary mill is analysed, using compaction pressure of 700MPa and sintering temperature of 1,100°C±5°C, gaseous atmosphere of H2 - N2, and sintering time of 30 minutes. As a result of the research, it shows that the best behaviour against wear is obtained when the MMC contains 6% TiC. Under this parameter the lowest percentage of pores and the lowest coefficient of friction are achieved, ensuring that the incorporation of ceramic particles (TiC) in 316 austenitic steel matrix significantly improves the wear resistance. Also, it is shown that it is possible to sinter such materials using the abnormal glow discharge, being a novel and effective method in which the working temperature is reached in a short time.

  8. Acute hydrocephalus following cerebellar infarct

    PubMed Central

    Epstein, Elliot; Naqvi, Huma

    2010-01-01

    A 59-year-old man was admitted with a diagnosis of acute cerebellar infarct. The next day his level of consciousness deteriorated (Glasgow Coma Score 5) and repeat computed tomography (CT) brain scan showed subtle signs of hydrocephalus. Following neurosurgical intervention, he recovered and is now walking with a frame and assistance. The CT changes of hydrocephalus were subtle and difficult to spot. Recognition of these signs of hydrocephalus and prompt neurosurgical intervention were lifesaving. PMID:22355298

  9. Visuomotor learning in cerebellar patients.

    PubMed

    Timmann, D; Shimansky, Y; Larson, P S; Wunderlich, D A; Stelmach, G E; Bloedel, J R

    1996-11-01

    The aim of the present study was to demonstrate that patients with pathology affecting substantial regions of the cerebellum can improve their performance in a series of two-dimensional tracing tasks, thus supporting the view that this type of motor behavior can be acquired even when the integrity of this structure is compromised. Eight patients with chronic, isolated cerebellar lesions and eight age- and sex-matched healthy controls were tested. Three patients had mild, five had moderate upper limb ataxia. The experiment was divided into two parts. In the first, subjects traced an irregularly shaped outline over 20 consecutive trials ('Trace 1' task). Next, subjects were asked to redraw the object without any underlying template as a guide ('Memory 1' task). In the second part of the study, subjects were asked to trace a different, irregularly shaped outline over 20 consecutive trials ('Trace 2' task). Next, they were required to redraw it by memory with its axis rotated 90 degrees ('Memory 2' task). In each of the memory tasks the template was placed over the drawn image after each trial and shown to the subjects. The error of performance was determined by calculating three different measurements, each focused on different aspects of the task. Based on these measurements, the cerebellar patients showed improvement in both memory tasks. In the 'Memory 1' task the calculated error decreased significantly for the patients with mild ataxia. In the 'Memory 2' task all cerebellar patients improved their performance substantially enough to reduce significantly the magnitude of all three error measurements. The experiments demonstrate that patients with cerebellar lesions are capable of improving substantially their performance of a complex motor task involving the recall of memorized shapes and the visuomotor control of a tracing movement.

  10. Mitotic Events in Cerebellar Granule Progenitor Cells that Expand Cerebellar Surface Area Are Critical for Normal Cerebellar Cortical Lamination in Mice

    PubMed Central

    Chang, Joshua C.; Leung, Mark; Gokozan, Hamza Numan; Gygli, Patrick Edwin; Catacutan, Fay Patsy; Czeisler, Catherine; Otero, José Javier

    2015-01-01

    Late embryonic and postnatal cerebellar folial surface area expansion promotes cerebellar cortical cytoarchitectural lamination. We developed a streamlined sampling scheme to generate unbiased estimates of murine cerebellar surface area and volume using stereological principles. We demonstrate that during the proliferative phase of the external granule layer (EGL) and folial surface area expansion, EGL thickness does not change and thus is a topological proxy for progenitor self-renewal. The topological constraints indicate that during proliferative phases, migration out of the EGL is balanced by self-renewal. Progenitor self-renewal must, therefore, include mitotic events yielding either 2 cells in the same layer to increase surface area (β-events) and mitotic events yielding 2 cells, with 1 cell in a superficial layer and 1 cell in a deeper layer (α-events). As the cerebellum grows, therefore, β-events lie upstream of α-events. Using a mathematical model constrained by the measurements of volume and surface area, we could quantify inter-mitotic times for β-events on a per-cell basis in post-natal mouse cerebellum. Furthermore, we found that loss of CCNA2, which decreases EGL proliferation and secondarily induces cerebellar cortical dyslamination, shows preserved α-type events. Thus, CCNA2-null cerebellar granule progenitor cells are capable of self-renewal of the EGL stem cell niche; this is concordant with prior findings of extensive apoptosis in CCNA2-null mice. Similar methodologies may provide another layer of depth to the interpretation of results from stereological studies. PMID:25668568

  11. Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1

    PubMed Central

    Kim, Edward; Wang, Yuan; Kim, Sun-Jung; Bornhorst, Miriam; Jecrois, Emmanuelle S; Anthony, Todd E; Wang, Chenran; Li, Yi E; Guan, Jun-Lin; Murphy, Geoffrey G; Zhu, Yuan

    2014-01-01

    Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities. DOI: http://dx.doi.org/10.7554/eLife.05151.001 PMID:25535838

  12. Remote cerebellar hemorrhage following supratentorial cerebrovascular surgery.

    PubMed

    Smith, Ross; Kebriaei, Meysam; Gard, Andrew; Thorell, William; Surdell, Daniel

    2014-04-01

    Three patients with remote cerebellar hemorrhage following supratentorial cerebrovascular surgery are presented. Remote cerebellar hemorrhage is a rare surgical complication that is most often associated with aneurysm clipping or temporal lobectomies. Bleeding occurs on the superior cerebellar cortex and is believed to be venous in origin. The precise pathogenesis of remote cerebellar hemorrhage has yet to be fully elucidated but is generally considered to be a consequence of intraoperative cerebrospinal fluid loss causing caudal displacement of the cerebellum with resultant stretching of the supracerebellar veins. This case series will hopefully shed further light on the incidence, presentation, workup, and treatment of this particular complication of supratentorial surgery. PMID:24238635

  13. Multiple large and small cerebellar infarcts

    PubMed Central

    Canaple, S.; Bogousslavsky, J.

    1999-01-01

    To assess the clinical, topographical, and aetiological features of multiple cerebellar infarcts,18 patients (16.5% of patients with cerebellar infarction) were collected from a prospective acute stroke registry, using a standard investigation protocol including MRI and magnetic resonance angiography. Infarcts in the posterior inferior cerebellar artery (PICA)+superior cerebellar artery (SCA) territory were most common (9/18; 50%), followed by PICA+anterior inferior cerebellar artery (AICA)+SCA territory infarcts (6/18; 33%). One patient had bilateral AICA infarcts. No infarct involved the PICA+AICA combined territory. Other infarcts in the posterior circulation were present in half of the patients and the clinical presentation largely depended on them. Large artery disease was the main aetiology. Our findings emphasised the common occurrence of very small multiple cerebellar infarcts (<2 cm diameter).These very small multiple cerebellar infarcts may occur with (13 patients/18; 72%) or without (3/18; 22%) territorial cerebellar infarcts. Unlike previous series, they could not all be considered junctional infarcts (between two main cerebellar artery territories: 51/91), but also small territorial infarcts (40/91). It is suggested that these very small territorial infarcts may be endzone infarcts, due to the involvement of small distal arterial branches. It is possible that some very small territorial infarcts may be due to a microembolic process, but this hypothesis needs pathological confirmation.

 PMID:10329747

  14. Modeling abnormal early development with induced pluripotent stem cells from aneuploid syndromes.

    PubMed

    Li, Wen; Wang, Xianming; Fan, Wenxia; Zhao, Ping; Chan, Yau-Chi; Chen, Shen; Zhang, Shiqiang; Guo, Xiangpeng; Zhang, Ya; Li, Yanhua; Cai, Jinglei; Qin, Dajiang; Li, Xingyan; Yang, Jiayin; Peng, Tianran; Zychlinski, Daniela; Hoffmann, Dirk; Zhang, Ruosi; Deng, Kang; Ng, Kwong-Man; Menten, Bjorn; Zhong, Mei; Wu, Jiayan; Li, Zhiyuan; Chen, Yonglong; Schambach, Axel; Tse, Hung-Fat; Pei, Duanqing; Esteban, Miguel A

    2012-01-01

    Many human diseases share a developmental origin that manifests during childhood or maturity. Aneuploid syndromes are caused by supernumerary or reduced number of chromosomes and represent an extreme example of developmental disease, as they have devastating consequences before and after birth. Investigating how alterations in gene dosage drive these conditions is relevant because it might help treat some clinical aspects. It may also provide explanations as to how quantitative differences in gene expression determine phenotypic diversity and disease susceptibility among natural populations. Here, we aimed to produce induced pluripotent stem cell (iPSC) lines that can be used to improve our understanding of aneuploid syndromes. We have generated iPSCs from monosomy X [Turner syndrome (TS)], trisomy 8 (Warkany syndrome 2), trisomy 13 (Patau syndrome) and partial trisomy 11;22 (Emanuel syndrome), using either skin fibroblasts from affected individuals or amniocytes from antenatal diagnostic tests. These cell lines stably maintain the karyotype of the donors and behave like embryonic stem cells in all tested assays. TS iPSCs were used for further studies including global gene expression analysis and tissue-specific directed differentiation. Multiple clones displayed lower levels of the pseudoautosomal genes ASMTL and PPP2R3B than the controls. Moreover, they could be transformed into neural-like, hepatocyte-like and heart-like cells, but displayed insufficient up-regulation of the pseudoautosomal placental gene CSF2RA during embryoid body formation. These data support that abnormal organogenesis and early lethality in TS are not caused by a tissue-specific differentiation blockade, but rather involves other abnormalities including impaired placentation.

  15. Tract Profiles of the Cerebellar White Matter Pathways in Children and Adolescents.

    PubMed

    Leitner, Yael; Travis, Katherine E; Ben-Shachar, Michal; Yeom, Kristen W; Feldman, Heidi M

    2015-12-01

    Intact development of cerebellar connectivity is essential for healthy neuromotor and neurocognitive development. To date, limited knowledge about the microstructural properties of the cerebellar peduncles, the major white matter tracts of the cerebellum, is available for children and adolescents. Such information would be useful as a comparison for studies of normal development, clinical conditions, or associations of cerebellar structures with cognitive and motor functions. The goal of the present study was to evaluate the variability in diffusion measures of the cerebellar peduncles within individuals and within a normative sample of healthy children. Participants were 19 healthy children and adolescents, aged 9-17 years, mean age 13.0 ± 2.3. We analyzed diffusion magnetic resonance imaging (dMRI) data with deterministic tractography. We generated tract profiles for each of the cerebellar peduncles by extracting four diffusion properties (fractional anisotropy (FA) and mean, radial, and axial diffusivity) at 30 equidistant points along each tract. We were able to identify the middle cerebellar peduncle and the bilateral inferior and superior cerebellar peduncles in all participants. The results showed that within each of the peduncles, the diffusion properties varied along the trajectory of the tracts. However, the tracts showed consistent patterns of variation across individuals; the coefficient of variation for FA across individual profiles was low (≤20%) for each tract. We observed no systematic variation of the diffusion properties with age. These cerebellar tract profiles of the cerebellar peduncles can serve as a reference for future studies of children across the age range and for children and adolescents with clinical conditions that affect the cerebellum.

  16. Skeletal development and abnormalities of the vertebral column and of the fins in hatchery-reared turbot Scophthalmus maximus.

    PubMed

    Tong, X H; Liu, Q H; Xu, S H; Ma, D Y; Xiao, Z Z; Xiao, Y S; Li, J

    2012-03-01

    To describe the skeletal development and abnormalities in turbot Scophthalmus maximus, samples were collected every day from hatching to 60 days after hatching (DAH). A whole-mount cartilage and bone-staining technique was used. Vertebral ontogeny started with the formation of anterior haemal arches at 5·1 mm standard length (L(S) ) c. 11 DAH, and was completed by the full attainment of parapophyses at 16·9 mm L(S) c. 31 DAH. Vertebral centra started to develop at 6·3 mm L(S) c. 16 DAH and ossification in all centra was visible at 11·0 mm L(S) c. 25 DAH. The caudal fin appeared at 5·1 mm L(S) c. 11 DAH and ossification was visible at 20·6 mm L(S) c. 37 DAH. The onset of dorsal and anal fin elements appeared at 5·8 mm L(S) c. 15 DAH and 6·3 mm L(S) c. 16 DAH, respectively. Ossifications of both dorsal fin and anal fin were visible at 20·6 mm L(S) c. 37 DAH. The pectorals were the only fins present before first feeding, their ossifications were completed at 23·5 mm L(S) c. 48 DAH. Pelvic fins began forming at 7·2 mm L(S) c. 19 DAH and calcification of the whole structure was visible at 19·8 mm L(S) c. 36 DAH. In the present study, 24 types of skeletal abnormalities were observed. About 51% of individuals presented skeletal abnormalities, and the highest occurrence was found in the haemal region of the vertebral column. As for each developmental stage, the most common abnormalities were in the dorsal fin during early metamorphic period (stage 2), vertebral fusion during climax metamorphosis (stage 3) and caudal fin abnormality during both late-metamorphic period (stage 4) and post-metamorphic period (stage 5). Such research will be useful for early detection of skeletal malformations during different growth periods of reared S. maximus.

  17. Craniofacial Abnormalities

    MedlinePlus

    ... of the skull and face. Craniofacial abnormalities are birth defects of the face or head. Some, like cleft ... palate, are among the most common of all birth defects. Others are very rare. Most of them affect ...

  18. Walking abnormalities

    MedlinePlus

    ... include: Arthritis of the leg or foot joints Conversion disorder (a psychological disorder) Foot problems (such as a ... injuries. For an abnormal gait that occurs with conversion disorder, counseling and support from family members are strongly ...

  19. Nail abnormalities

    MedlinePlus

    Beau's lines; Fingernail abnormalities; Spoon nails; Onycholysis; Leukonychia; Koilonychia; Brittle nails ... Just like the skin, the fingernails tell a lot about your health: ... the fingernail. These lines can occur after illness, injury to ...

  20. Neonatal diabetes mellitus and cerebellar hypoplasia/agenesis: report of a new recessive syndrome

    PubMed Central

    Hoveyda, N.; Shield, J.; Garrett, C.; Chong, W; Beardsall, K.; Bentsi-Enchill, E.; Mallya, H.; Thompson, M.

    1999-01-01

    Classical neonatal diabetes mellitus is defined as hyperglycaemia occurring within the first six weeks of life in term infants. Cerebellar agenesis is rare. We report three cases of neonatal diabetes mellitus, cerebellar hypoplasia/agenesis, and dysmorphism occurring within a highly consanguineous family. This constellation of abnormalities has not previously been described. Two of these cases are sisters and the third case is a female first cousin. The pattern of inheritance suggests this is a previously undescribed autosomal recessive disorder. Prenatal diagnosis of the condition in this family was possible by demonstration of the absence of the cerebellum and severe IUGR.


Keywords: cerebellar agenesis/hypoplasia; neonatal diabetes mellitus; dysmorphic features; autosomal recessive PMID:10507728

  1. Milder progressive cerebellar atrophy caused by biallelic SEPSECS mutations.

    PubMed

    Iwama, Kazuhiro; Sasaki, Masayuki; Hirabayashi, Shinichi; Ohba, Chihiro; Iwabuchi, Emi; Miyatake, Satoko; Nakashima, Mitsuko; Miyake, Noriko; Ito, Shuichi; Saitsu, Hirotomo; Matsumoto, Naomichi

    2016-06-01

    Cerebellar atrophy is recognized in various types of childhood neurological disorders with clinical and genetic heterogeneity. Genetic analyses such as whole exome sequencing are useful for elucidating the genetic basis of these conditions. Pathological recessive mutations in Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase (SEPSECS) have been reported in a total of 11 patients with pontocerebellar hypoplasia type 2, progressive cerebellocerebral atrophy or progressive encephalopathy, yet detailed clinical features are limited to only four patients. We identified two new families with progressive cerebellar atrophy, and by whole exome sequencing detected biallelic SEPSECS mutations: c.356A>G (p.Asn119Ser) and c.77delG (p.Arg26Profs*42) in family 1, and c.356A>G (p.Asn119Ser) and c.467G>A (p.Arg156Gln) in family 2. Their development was slightly delayed regardless of normal brain magnetic resonance imaging (MRI) in infancy. The progression of clinical symptoms in these families is evidently slower than in previously reported cases, and the cerebellar atrophy milder by brain MRI, indicating that SEPSECS mutations are also involved in milder late-onset cerebellar atrophy. PMID:26888482

  2. Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells.

    PubMed

    Muguruma, Keiko; Nishiyama, Ayaka; Kawakami, Hideshi; Hashimoto, Kouichi; Sasai, Yoshiki

    2015-02-01

    During cerebellar development, the main portion of the cerebellar plate neuroepithelium gives birth to Purkinje cells and interneurons, whereas the rhombic lip, the germinal zone at its dorsal edge, generates granule cells and cerebellar nuclei neurons. However, it remains elusive how these components cooperate to form the intricate cerebellar structure. Here, we found that a polarized cerebellar structure self-organizes in 3D human embryonic stem cell (ESC) culture. The self-organized neuroepithelium differentiates into electrophysiologically functional Purkinje cells. The addition of fibroblast growth factor 19 (FGF19) promotes spontaneous generation of dorsoventrally polarized neural-tube-like structures at the level of the cerebellum. Furthermore, addition of SDF1 and FGF19 promotes the generation of a continuous cerebellar plate neuroepithelium with rhombic-lip-like structure at one end and a three-layer cytoarchitecture similar to the embryonic cerebellum. Thus, human-ESC-derived cerebellar progenitors exhibit substantial self-organizing potential for generating a polarized structure reminiscent of the early human cerebellum at the first trimester. PMID:25640179

  3. Fluoro-jade identification of cerebellar granule cell and purkinje cell death in the alpha1A calcium ion channel mutant mouse, leaner.

    PubMed

    Frank, T C; Nunley, M C; Sons, H D; Ramon, R; Abbott, L C

    2003-01-01

    Cell death is a critical component of normal nervous system development; too little or too much results in abnormal development and function of the nervous system. The leaner mouse exhibits excessive, abnormal cerebellar granule cell and Purkinje cell death during postnatal development, which is a consequence of a mutated calcium ion channel subunit, alpha(1A). Previous studies have shown that leaner cerebellar Purkinje cells die in a specific pattern that appears to be influenced by functional and anatomical boundaries of the cerebellum. However, the mechanism of Purkinje cell death and the specific timing of the spatial pattern of cell death remain unclear. By double labeling both leaner and wild-type cerebella with Fluoro-Jade and terminal deoxynucleotide transferase-mediated, deoxyuridine triphosphate nick-end labeling or Fluoro-Jade and tyrosine hydroxylase immunohistochemistry we demonstrated that the relatively new stain, Fluoro-Jade, will label neurons that are dying secondary to a genetic mutation. Then, by staining leaner and wild-type cerebella between postnatal days 20 and 80 with Fluoro-Jade, we were able to show that Purkinje cell death begins at approximately postnatal day 25, peaks in the vermis about postnatal day 40 and in the hemispheres at postnatal day 50 and persists at a low level at postnatal day 80. In addition, we showed that there is a significant difference in the amount of cerebellar Purkinje cell death between rostral and caudal divisions of the leaner cerebellum, and that there is little to no Purkinje cell death in the wild type cerebellum at the ages we examined. This is the first report of the use of Fluoro-Jade to identify dying neurons in a genetic model for neuronal cell death. By using Fluoro-Jade, we have specifically defined the temporospatial pattern of postnatal Purkinje cell death in the leaner mouse. This information can be used to gain insight into the dynamic mechanisms controlling Purkinje cell death in the leaner

  4. Abnormal gene expression in cerebellum of Npc1-/- mice during postnatal development

    PubMed Central

    Liao, Guanghong; Wen, Zhining; Irizarry, Kristopher; Huang, Ying; Mitsouras, Katherine; Darmani, Mariam; Leon, Terry; Shi, Leming; Bi, Xiaoning

    2010-01-01

    Niemann-Pick Type C disease is an autosomal recessive neurodegenerative disorder with abnormal lipid storage as the major cellular pathologic hallmark. Genetic analyses have identified mutations in NPC1 gene in the great majority of cases, while mutations in NPC2 account for the remainders. Yet, little is known regarding the cellular mechanisms responsible for NPC pathogenesis, especially for neurodegeneration, which is the usual cause of death. To identify critical steps that could account for the pathological manifestations of the disease in one of the most affected brain structures, we performed global gene expression analysis in the cerebellum from three-week old Npc1+/+ and Npc1-/- mice with two different microarray platforms (Agilent and Illumina). Differentially-expressed genes identified by both microarray platforms were then subjected to KEGG pathway analysis. Expression of genes in six pathways was significantly altered in Npc1-/- mice; functionally, these signaling pathways belong to the following three categories: 1) steroid and terpenoid biosynthesis, 2) immune response, and 3) cell adhesion/motility. In addition, the expression of several proteins involved in lipid transport was significantly altered in Npc1-/- mice. Our results provide novel molecular insight regarding the mechanisms of pathogenesis in NPC disease and reveal potential new therapeutic targets. PMID:20153740

  5. Microbial community structure and function during abnormal curve development of substrate-induced respiration measurements.

    PubMed

    Bartling, Johanna; Kotzerke, Anja; Mai, Maike; Esperschütz, Jürgen; Buegger, Franz; Schloter, Michael; Wilke, Berndt-Michael

    2009-12-01

    Soil respiration measurements are an established method to test the abundance, activity and vitality of the soil microorganisms. However, abnormal progressions of soil respiration curves impede a clear interpretation of the data. The aim of this study was to investigate the changes in the microbial structure during the formation of phenomena like double peaks and terraces by analysis of the PLFA composition (phospholipid fatty acid composition). Moreover, 13C labeled glucose was used as substrate; therefore it was possible to measure delta13C values both within the PLFA fraction as well as within the carbon dioxide evolved during respiration. As contaminants trinitrotoluene, cycloheximide, and hexadecane were used. The results showed that the appearance of double peaks was mainly related to the growth of fungi with the marker 18:2delta9,12 due to a toxic effect of trinitrotoluene and cycloheximide. In contrast, the phenomenon of terrace formation was related to the utilization of hexadecane as a carbon source mainly by bacteria.

  6. Sexual dimorphism of the cerebellar vermis in schizophrenia.

    PubMed

    Womer, Fay Y; Tang, Yanqing; Harms, Michael P; Bai, Chuan; Chang, Miao; Jiang, Xiaowei; Wei, Shengnan; Wang, Fei; Barch, Deanna M

    2016-10-01

    Converging lines of evidence implicate structural and functional abnormalities in the cerebellum in schizophrenia (SCZ). The cerebellar vermis is of particular interest given its association with clinical symptoms and cognitive deficits in SCZ and its known connections with cortical regions such as the prefrontal cortex. Prior neuroimaging studies have shown structural and functional abnormalities in the vermis in SCZ. In this study, we examined the cerebellar vermis in 50 individuals with SCZ and 54 healthy controls (HC) using a quantitative volumetric approach. All participants underwent high-resolution structural magnetic resonance imaging (MRI). The vermis was manually traced for each participant, and vermis volumes were computed using semiautomated methods. Volumes for total vermis and vermis subregions (anterior and posterior vermis) were analyzed in the SCZ and HC groups. Significant diagnosis-by-sex interaction effects were found in total vermis and vermis subregion analyses. These effects appeared to be driven by significantly decreased posterior vermis volumes in males with SCZ. Exploratory analyses did not reveal significant effects of clinical variables (FEP status, illness duration, and BPRS total score and subscores) on vermis volumes. The findings herein highlight the presence of neural sex differences in SCZ and the need for considering sex-related factors in studying the disorder. PMID:27401530

  7. The Philadelphia Neurodevelopmental Cohort: A publicly available resource for the study of normal and abnormal brain development in youth.

    PubMed

    Satterthwaite, Theodore D; Connolly, John J; Ruparel, Kosha; Calkins, Monica E; Jackson, Chad; Elliott, Mark A; Roalf, David R; Ryan Hopsona, Karthik Prabhakaran; Behr, Meckenzie; Qiu, Haijun; Mentch, Frank D; Chiavacci, Rosetta; Sleiman, Patrick M A; Gur, Ruben C; Hakonarson, Hakon; Gur, Raquel E

    2016-01-01

    The Philadelphia Neurodevelopmental Cohort (PNC) is a large-scale study of child development that combines neuroimaging, diverse clinical and cognitive phenotypes, and genomics. Data from this rich resource is now publicly available through the Database of Genotypes and Phenotypes (dbGaP). Here we focus on the data from the PNC that is available through dbGaP and describe how users can access this data, which is evolving to be a significant resource for the broader neuroscience community for studies of normal and abnormal neurodevelopment.

  8. Abnormal P-selectin localization during megakaryocyte development determines thrombosis in the gata1low model of myelofibrosis.

    PubMed

    Zetterberg, Eva; Verrucci, Maria; Martelli, Fabrizio; Zingariello, Maria; Sancillo, Laura; D'Amore, Emanuela; Rana, Rosa Alba; Migliaccio, Anna Rita

    2014-01-01

    Patients with primary myelofibrosis have increased risk for bleeding and thrombosis. It is debated whether propensity to thrombosis is due to increased numbers of platelet microparticles and/or to pathological platelet-neutrophil interactions. Platelet neutrophil interactions are mediated by P-selectin and even though the megakaryocytes of myelofibrosis patients express normal levels of P-selectin, it remains abnormally localized to the demarcation membrane system rather than being assembled into the α-granules in platelets. Mice carrying the hypomorphic Gata1(low) mutation express the same megakaryocyte abnormalities presented by primary myelofibrosis patients, including abnormal P-selectin localization to the DMS and develop with age myelofibrosis, a disease that closely resembles human primary myelofibrosis. Whether these mice would also develop thrombosis has not been investigated as yet. The aim of this study was to determine whether Gata1(low) mice would develop thrombosis with age and, in this case, the role played by P-selectin in the development of the trait. To this aim, Gata1(low) mice were crossed with P-sel(null) mice according to standard genetic protocols and Gata1(low)P-sel(wt), Gata1(low)P-sel(null) and Gata1(WT)P-sel(null) or Gata1(wt)P-sel(wt) (as controls) littermates obtained. It was shown that platelet counts, but not hematocrit, are reduced in Gata1(low) mice. Moreover, platelet microparticles are reduced in Gata1(low) mice and P-selectin positive platelet microparticles were not found. To determine the phenotypic implications of the different mutations, bleeding time was estimated by a tail cut procedure. Mutant mice were sacrificed and presence of thrombosis was determined by immunohistological staining of organs. Gata1(low) mice with or without the P-selectin null trait had a prolonged bleeding time compared to wild type mice. However, in Gata1(low) mice significantly higher frequency of thrombotic events was seen in adult and old Gata1

  9. Crossed Cerebellar Diaschisis in Status Epilepticus.

    PubMed

    Miyazaki, Daigo; Fukushima, Kazuhiro; Nakahara, Asa; Kodaira, Minori; Mochizuki, Katsunori; Kaneko, Kikuko; Kaneko, Tomoki; Sekijima, Yoshiki; Ikeda, Shu-Ichi

    2016-01-01

    Crossed cerebellar diaschisis (CCD) is an interesting phenomenon which classically refers to the depressed blood flow and metabolism affecting one cerebellar hemisphere after a contralateral hemispheric infarction. However, CCD can also be caused by a prolonged seizure. We herein report a case of CCD due to status epilepticus in a patient who showed unique magnetic resonance imaging findings.

  10. Learning of Sensory Sequences in Cerebellar Patients

    ERIC Educational Resources Information Center

    Frings, Markus; Boenisch, Raoul; Gerwig, Marcus; Diener, Hans-Christoph; Timmann, Dagmar

    2004-01-01

    A possible role of the cerebellum in detecting and recognizing event sequences has been proposed. The present study sought to determine whether patients with cerebellar lesions are impaired in the acquisition and discrimination of sequences of sensory stimuli of different modalities. A group of 26 cerebellar patients and 26 controls matched for…

  11. Diphenylarsinic acid increased the synthesis and release of neuroactive and vasoactive peptides in rat cerebellar astrocytes.

    PubMed

    Negishi, Takayuki; Takahashi, Masaki; Matsunaga, Yuki; Hirano, Seishiro; Tashiro, Tomoko

    2012-06-01

    An incident of poisoning occurred in Japan in 2003 when high-level contamination with arsenic, mainly diphenylarsinic acid (DPAA), was found in well water. People using this water particularly experienced cerebellar symptoms. In the present study, we investigated the adverse effects of DPAA on the cerebellum in vitro and in vivo to understand the biological mechanisms that cause cerebellar symptoms. Comprehensive gene expression analyses in primary cultured ratcerebellar cells exposed to 10 μM DPAA for 24 hours indicated significant alterations in the mRNA expression of genes encoding antioxidative stress proteins (heme oxigenase 1 and heat shock protein72) and neuroactive and vasoactive peptides (neuropeptide Y, adrenomedullin, monocyte chemoattractant protein 1, and fibroblast growth factor 2). Further analyses of proteins revealed that cultured cerebellar astrocytes expressed these antioxidative stress proteins and peptides in response to exposure to DPAA. In addition, these adverseeffects were also observed in the cerebellum exposed in vivo to DPAA (100 mg/L) for 21 days. These results suggested that cerebellarastrocytes irregularly secrete neuroactive and vasoactive peptidesagainst DPAA-induced oxidative stress, which leads to abnormal neural functions and disrupted cerebellar autoregulation dynamics and results in the onset of cerebellar symptoms.

  12. Effects of two weeks of cerebellar theta burst stimulation in cervical dystonia patients.

    PubMed

    Koch, Giacomo; Porcacchia, Paolo; Ponzo, Viviana; Carrillo, Fatima; Cáceres-Redondo, María Teresa; Brusa, Livia; Desiato, Maria Teresa; Arciprete, Flavio; Di Lorenzo, Francesco; Pisani, Antonio; Caltagirone, Carlo; Palomar, Francisco J; Mir, Pablo

    2014-01-01

    Dystonia is generally regarded as a disorder of the basal ganglia and their efferent connections to the thalamus and brainstem, but an important role of cerebellar-thalamo-cortical (CTC) circuits in the pathophysiology of dystonia has been invoked. Here in a sham controlled trial, we tested the effects of two-weeks of cerebellar continuous theta burst stimulation (cTBS) in a sample of cervical dystonia (CD) patients. Clinical evaluations were performed by administering the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). We used TMS to measure the inhibitory connectivity between the cerebellum and the contralateral motor cortex (cerebellar brain inhibition [CBI]), and the excitability of the contralateral primary motor cortex assessing intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (CSP). Paired associative stimulation (PAS) was tested to evaluate the level and the topographical specificity of cortical plasticity, which is abnormally enhanced and non-focal in CD patients. Two weeks of cerebellar stimulation resulted in a small but significant clinical improvement as measured by the TWSTRS of approximately 15%. Cerebellar stimulation modified the CBI circuits and reduced the heterotopic PAS potentiation, leading to a normal pattern of topographic specific induced plasticity. These data provide novel evidence CTC circuits could be a potential target to partially control some dystonic symptoms in patients with cervical dystonia. PMID:24881805

  13. DLX4 is associated with orofacial clefting and abnormal jaw development

    PubMed Central

    Wu, Di; Mandal, Shyamali; Choi, Alex; Anderson, August; Prochazkova, Michaela; Perry, Hazel; Gil-Da-Silva-Lopes, Vera L.; Lao, Richard; Wan, Eunice; Tang, Paul Ling-Fung; Kwok, Pui-yan; Klein, Ophir; Zhuan, Bian; Slavotinek, Anne M.

    2015-01-01

    Cleft lip and/or palate (CL/P) are common structural birth defects in humans. We used exome sequencing to study a patient with bilateral CL/P and identified a single nucleotide deletion in the patient and her similarly affected son—c.546_546delG, predicting p.Gln183Argfs*57 in the Distal-less 4 (DLX4) gene. The sequence variant was absent from databases, predicted to be deleterious and was verified by Sanger sequencing. In mammals, there are three Dlx homeobox clusters with closely located gene pairs (Dlx1/Dlx2, Dlx3/Dlx4, Dlx5/Dlx6). In situ hybridization showed that Dlx4 was expressed in the mesenchyme of the murine palatal shelves at E12.5, prior to palate closure. Wild-type human DLX4, but not mutant DLX4_c.546delG, could activate two murine Dlx conserved regulatory elements, implying that the mutation caused haploinsufficiency. We showed that reduced DLX4 expression after short interfering RNA treatment in a human cell line resulted in significant up-regulation of DLX3, DLX5 and DLX6, with reduced expression of DLX2 and significant up-regulation of BMP4, although the increased BMP4 expression was demonstrated only in HeLa cells. We used antisense morpholino oligonucleotides to target the orthologous Danio rerio gene, dlx4b, and found reduced cranial size and abnormal cartilaginous elements. We sequenced DLX4 in 155 patients with non-syndromic CL/P and CP, but observed no sequence variants. From the published literature, Dlx1/Dlx2 double homozygous null mice and Dlx5 homozygous null mice both have clefts of the secondary palate. This first finding of a DLX4 mutation in a family with CL/P establishes DLX4 as a potential cause of human clefts. PMID:25954033

  14. Cerebellar hemangioblastoma manifesting as hearing disturbance.

    PubMed

    Amano, Toshiyuki; Tokunaga, So; Shono, Tadahisa; Mizoguchi, Masahiro; Matsumoto, Kenichi; Yoshida, Fumiaki; Sasaki, Tomio

    2009-09-01

    A 49-year-old man presented with a rare case of cerebellar hemangioblastoma manifesting as only hearing disturbance. He had suffered from hearing difficulty in the right ear for a few months. Magnetic resonance imaging revealed a cystic mass lesion with an internal fluid level and surrounding flow voids in the right cerebellopontine (CP) angle. Cerebral angiography disclosed a vascular-rich tumor fed by both the superior cerebellar and anterior inferior cerebellar arteries. En bloc resection of the tumor was planned under a preoperative diagnosis of cerebellar hemangioblastoma. The tumor protruded into the CP cistern and compressed cranial nerve VIII. The feeding arteries were meticulously coagulated and the tumor was successfully removed. The histological diagnosis was hemangioblastoma. After the operation, the patient's hearing acuity improved dramatically. Cerebellar hemangioblastoma should be considered in the differential diagnosis of CP angle tumors associated with hearing disturbance.

  15. Automated MRI Cerebellar Size Measurements Using Active Appearance Modeling

    PubMed Central

    Price, Mathew; Cardenas, Valerie A.; Fein, George

    2014-01-01

    Although the human cerebellum has been increasingly identified as an important hub that shows potential for helping in the diagnosis of a large spectrum of disorders, such as alcoholism, autism, and fetal alcohol spectrum disorder, the high costs associated with manual segmentation, and low availability of reliable automated cerebellar segmentation tools, has resulted in a limited focus on cerebellar measurement in human neuroimaging studies. We present here the CATK (Cerebellar Analysis Toolkit), which is based on the Bayesian framework implemented in FMRIB’s FIRST. This approach involves training Active Appearance Models (AAM) using hand-delineated examples. CATK can currently delineate the cerebellar hemispheres and three vermal groups (lobules I–V, VI–VII, and VIII–X). Linear registration with the low-resolution MNI152 template is used to provide initial alignment, and Point Distribution Models (PDM) are parameterized using stellar sampling. The Bayesian approach models the relationship between shape and texture through computation of conditionals in the training set. Our method varies from the FIRST framework in that initial fitting is driven by 1D intensity profile matching, and the conditional likelihood function is subsequently used to refine fitting. The method was developed using T1-weighted images from 63 subjects that were imaged and manually labeled: 43 subjects were scanned once and were used for training models, and 20 subjects were imaged twice (with manual labeling applied to both runs) and used to assess reliability and validity. Intraclass correlation analysis shows that CATK is highly reliable (average test-retest ICCs of 0.96), and offers excellent agreement with the gold standard (average validity ICC of 0.87 against manual labels). Comparisons against an alternative atlas-based approach, SUIT (Spatially Unbiased Infratentorial Template), that registers images with a high-resolution template of the cerebellum, show that our AAM

  16. Long lasting cerebellar alterations after perinatal asphyxia in rats.

    PubMed

    Campanille, Verónica; Saraceno, G Ezequiel; Rivière, Stéphanie; Logica, Tamara; Kölliker, Rodolfo; Capani, Francisco; Castilla, Rocío

    2015-07-01

    The developing brain may be particularly vulnerable to injury before, at and after birth. Among possible insults, hypoxia suffered as a consequence of perinatal asphyxia (PA) exhibits the highest incidence levels and the cerebellar circuitry appears to be particularly susceptible, as the cellular makeup and the quantity of inputs change quickly during days and weeks following birth. In this work, we have used a murine model to induce severe global PA in rats at the time of birth. Short-term cerebellar alterations within this PA model have been previously reported but whether such alterations remain in adulthood has not been conclusively determined yet. For this reason, and given the crucial cerebellar role in determining connectivity patterns in the brain, the aim of our work is to unveil long-term cerebellum histomorphology following a PA insult. Morphological and cytological neuronal changes and glial reaction in the cerebellar cortex were analyzed at postnatal 120 (P120) following injury performed at birth. As compared to control, PA animals exhibited: (1) an increase in molecular and granular thickness, both presenting lower cellular density; (2) a disarrayed Purkinje cell layer presenting a higher number of anomalous calbindin-stained cells. (3) focal swelling and marked fragmentation of microtubule-associated protein 2 (MAP-2) in Purkinje cell dendrites and, (4) an increase in glial fibrillary acidic protein (GFAP) expression in Bergmann cells and the granular layer. In conclusion, we demonstrate that PA produces long-term damage in cellular histomorphology in rat cerebellar cortex which could be involved in the pathogenesis of cognitive deficits observed in both animals and humans.

  17. GDNF-induced cerebellar toxicity: A brief review.

    PubMed

    Luz, Matthias; Mohr, Erich; Fibiger, H Christian

    2016-01-01

    Recombinant-methionyl human glial cell line-derived neurotrophic factor (GDNF) is known for its neurorestorative and neuroprotective effects in rodent and primate models of Parkinson's disease (PD). When administered locally into the putamen of Parkinsonian subjects, early clinical studies showed its potential promise as a disease-modifying agent. However, the development of GDNF for the treatment of PD has been significantly clouded by findings of cerebellar toxicity after continuous intraputamenal high-dose administration in a 6-month treatment/3-month recovery toxicology study in rhesus monkeys. Specifically, multifocal cerebellar Purkinje cell loss affecting 1-21% of the cerebellar cortex was observed in 4 of 15 (26.7%; 95% confidence interval [CI]: 10.5-52.4%) animals treated at the highest dose level tested (3000μg/month). No cerebellar toxicity was observed at lower doses (450 and 900μg/month) in the same study, or at similar or higher doses (up to 10,000μg/month) in subchronic or chronic toxicology studies testing intermittent intracerebroventricular administration. While seemingly associated with the use of GDNF, the pathogenesis of the cerebellar lesions has not been fully understood to date. This review integrates available information to evaluate potential pathogenic mechanisms and provide a consolidated assessment of the findings. While other explanations are considered, the existing evidence is most consistent with the hypothesis that leakage of GDNF into cerebrospinal fluid during chronic infusions into the putamen down-regulates GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF generates the observed lesions. The implications of these findings for clinical studies with GDNF are discussed.

  18. L1 modulates PKD1 phosphorylation in cerebellar granule neurons.

    PubMed

    Chen, Shuang-xi; Hu, Cheng-liang; Liao, Yong-hong; Zhao, Wei-jiang

    2015-01-01

    The neural cell adhesion molecule L1 (L1CAM) is crucial for the development of the nervous system, with an essential role in regulating multiple cellular activities. Protein kinase D1 (PKD1) serves as a key kinase given its diverse array of functions within the cell. Here, we investigated various aspects of the functional relationship between L1 and phosphorylated PKD1 (pPKD1) in cerebellar granule neurons. To study the relationship between L1 and PKD1 phosphorylation, human cerebellar tissue microarrays were subject to immunofluorescence staining. We observed a positive correlation between L1 protein levels and PKD1 phosphorylation. In addition, L1 also co-localized with pPKD1. To analyze the regulatory role of L1 on PKD1 phosphorylation, primary mouse cerebellar granule neurons were treated with various concentrations of rL1 for 48 h. Using Western blot, we revealed that L1 significantly increased PKD1 phosphorylation compared with vehicle control, with the maximal effect observed at 5 nM. ERK1/2 phosphorylation was significantly increased by 2.5 nM and 10nM L1, with no apparent change in SRC phosphorylation. However, SRC expression was markedly reduced by 10nM rL1. AKT1 expression and phosphorylation levels were significantly increased by rL1, with the maximal effect observed at 2.5 and 5 nM, respectively. Our combined data revealed a positive relationship between L1 and pPKD1 in both cultured cerebellar neurons and human cerebellar tissue, suggesting that L1 functions in the modulation of PKD1 phosphorylation. PMID:25445362

  19. Adaptive Robotic Control Driven by a Versatile Spiking Cerebellar Network

    PubMed Central

    Casellato, Claudia; Antonietti, Alberto; Garrido, Jesus A.; Carrillo, Richard R.; Luque, Niceto R.; Ros, Eduardo; Pedrocchi, Alessandra; D'Angelo, Egidio

    2014-01-01

    The cerebellum is involved in a large number of different neural processes, especially in associative learning and in fine motor control. To develop a comprehensive theory of sensorimotor learning and control, it is crucial to determine the neural basis of coding and plasticity embedded into the cerebellar neural circuit and how they are translated into behavioral outcomes in learning paradigms. Learning has to be inferred from the interaction of an embodied system with its real environment, and the same cerebellar principles derived from cell physiology have to be able to drive a variety of tasks of different nature, calling for complex timing and movement patterns. We have coupled a realistic cerebellar spiking neural network (SNN) with a real robot and challenged it in multiple diverse sensorimotor tasks. Encoding and decoding strategies based on neuronal firing rates were applied. Adaptive motor control protocols with acquisition and extinction phases have been designed and tested, including an associative Pavlovian task (Eye blinking classical conditioning), a vestibulo-ocular task and a perturbed arm reaching task operating in closed-loop. The SNN processed in real-time mossy fiber inputs as arbitrary contextual signals, irrespective of whether they conveyed a tone, a vestibular stimulus or the position of a limb. A bidirectional long-term plasticity rule implemented at parallel fibers-Purkinje cell synapses modulated the output activity in the deep cerebellar nuclei. In all tasks, the neurorobot learned to adjust timing and gain of the motor responses by tuning its output discharge. It succeeded in reproducing how human biological systems acquire, extinguish and express knowledge of a noisy and changing world. By varying stimuli and perturbations patterns, real-time control robustness and generalizability were validated. The implicit spiking dynamics of the cerebellar model fulfill timing, prediction and learning functions. PMID:25390365

  20. Adaptive robotic control driven by a versatile spiking cerebellar network.

    PubMed

    Casellato, Claudia; Antonietti, Alberto; Garrido, Jesus A; Carrillo, Richard R; Luque, Niceto R; Ros, Eduardo; Pedrocchi, Alessandra; D'Angelo, Egidio

    2014-01-01

    The cerebellum is involved in a large number of different neural processes, especially in associative learning and in fine motor control. To develop a comprehensive theory of sensorimotor learning and control, it is crucial to determine the neural basis of coding and plasticity embedded into the cerebellar neural circuit and how they are translated into behavioral outcomes in learning paradigms. Learning has to be inferred from the interaction of an embodied system with its real environment, and the same cerebellar principles derived from cell physiology have to be able to drive a variety of tasks of different nature, calling for complex timing and movement patterns. We have coupled a realistic cerebellar spiking neural network (SNN) with a real robot and challenged it in multiple diverse sensorimotor tasks. Encoding and decoding strategies based on neuronal firing rates were applied. Adaptive motor control protocols with acquisition and extinction phases have been designed and tested, including an associative Pavlovian task (Eye blinking classical conditioning), a vestibulo-ocular task and a perturbed arm reaching task operating in closed-loop. The SNN processed in real-time mossy fiber inputs as arbitrary contextual signals, irrespective of whether they conveyed a tone, a vestibular stimulus or the position of a limb. A bidirectional long-term plasticity rule implemented at parallel fibers-Purkinje cell synapses modulated the output activity in the deep cerebellar nuclei. In all tasks, the neurorobot learned to adjust timing and gain of the motor responses by tuning its output discharge. It succeeded in reproducing how human biological systems acquire, extinguish and express knowledge of a noisy and changing world. By varying stimuli and perturbations patterns, real-time control robustness and generalizability were validated. The implicit spiking dynamics of the cerebellar model fulfill timing, prediction and learning functions. PMID:25390365

  1. A panel of free fatty acid ratios to predict the development of metabolic abnormalities in healthy obese individuals

    PubMed Central

    Zhao, Linjing; Ni, Yan; Ma, Xiaojing; Zhao, Aihua; Bao, Yuqian; Liu, Jiajian; Chen, Tianlu; Xie, Guoxiang; Panee, Jun; Su, Mingming; Yu, Herbert; Wang, Congrong; Hu, Cheng; Jia, Weiping; Jia, Wei

    2016-01-01

    Increasing evidences support that metabolically healthy obese (MHO) is a transient state. However, little is known about the early markers associated with the development of metabolic abnormalities in MHO individuals. Serum free fatty acids (FFAs) profile is highlighted in its association with obesity-related insulin resistance, type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). To examine the association of endogenous fatty acid metabolism with future development of metabolic abnormalities in MHO individuals, we retrospectively analyzed 24 [product FFA]/[precursor FFA] ratios in fasting sera and clinical data from 481 individuals who participated in three independent studies, including 131 metabolic healthy subjects who completed the 10-year longitudinal Shanghai Diabetes Study (SHDS), 312 subjects cross-sectionally sampled from the Shanghai Obesity Study (SHOS), and 38 subjects who completed an 8-week very low carbohydrate diet (VLCD) intervention study. Results showed that higher baseline level of oleic acid/stearic acid (OA/SA), and lower levels of stearic acid/palmitic acid (SA/PA) and arachidonic acid/dihomo-γ-linolenic acid (AA/DGLA) ratios were associated with higher rate of MHO to MUO conversion in the longitudinal SHDS. Further, the finding was validated in the cross-sectional and interventional studies. This panel of FFA ratios could be used for identification and early intervention of at-risk obese individuals. PMID:27344992

  2. A panel of free fatty acid ratios to predict the development of metabolic abnormalities in healthy obese individuals.

    PubMed

    Zhao, Linjing; Ni, Yan; Ma, Xiaojing; Zhao, Aihua; Bao, Yuqian; Liu, Jiajian; Chen, Tianlu; Xie, Guoxiang; Panee, Jun; Su, Mingming; Yu, Herbert; Wang, Congrong; Hu, Cheng; Jia, Weiping; Jia, Wei

    2016-01-01

    Increasing evidences support that metabolically healthy obese (MHO) is a transient state. However, little is known about the early markers associated with the development of metabolic abnormalities in MHO individuals. Serum free fatty acids (FFAs) profile is highlighted in its association with obesity-related insulin resistance, type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). To examine the association of endogenous fatty acid metabolism with future development of metabolic abnormalities in MHO individuals, we retrospectively analyzed 24 [product FFA]/[precursor FFA] ratios in fasting sera and clinical data from 481 individuals who participated in three independent studies, including 131 metabolic healthy subjects who completed the 10-year longitudinal Shanghai Diabetes Study (SHDS), 312 subjects cross-sectionally sampled from the Shanghai Obesity Study (SHOS), and 38 subjects who completed an 8-week very low carbohydrate diet (VLCD) intervention study. Results showed that higher baseline level of oleic acid/stearic acid (OA/SA), and lower levels of stearic acid/palmitic acid (SA/PA) and arachidonic acid/dihomo-γ-linolenic acid (AA/DGLA) ratios were associated with higher rate of MHO to MUO conversion in the longitudinal SHDS. Further, the finding was validated in the cross-sectional and interventional studies. This panel of FFA ratios could be used for identification and early intervention of at-risk obese individuals. PMID:27344992

  3. Cerebellar Transcranial Direct Current Stimulation (ctDCS): A Novel Approach to Understanding Cerebellar Function in Health and Disease.

    PubMed

    Grimaldi, Giuliana; Argyropoulos, Georgios P; Bastian, Amy; Cortes, Mar; Davis, Nicholas J; Edwards, Dylan J; Ferrucci, Roberta; Fregni, Felipe; Galea, Joseph M; Hamada, Masahi; Manto, Mario; Miall, R Chris; Morales-Quezada, Leon; Pope, Paul A; Priori, Alberto; Rothwell, John; Tomlinson, S Paul; Celnik, Pablo

    2016-02-01

    The cerebellum is critical for both motor and cognitive control. Dysfunction of the cerebellum is a component of multiple neurological disorders. In recent years, interventions have been developed that aim to excite or inhibit the activity and function of the human cerebellum. Transcranial direct current stimulation of the cerebellum (ctDCS) promises to be a powerful tool for the modulation of cerebellar excitability. This technique has gained popularity in recent years as it can be used to investigate human cerebellar function, is easily delivered, is well tolerated, and has not shown serious adverse effects. Importantly, the ability of ctDCS to modify behavior makes it an interesting approach with a potential therapeutic role for neurological patients. Through both electrical and non-electrical effects (vascular, metabolic) ctDCS is thought to modify the activity of the cerebellum and alter the output from cerebellar nuclei. Physiological studies have shown a polarity-specific effect on the modulation of cerebellar-motor cortex connectivity, likely via cerebellar-thalamocortical pathways. Modeling studies that have assessed commonly used electrode montages have shown that the ctDCS-generated electric field reaches the human cerebellum with little diffusion to neighboring structures. The posterior and inferior parts of the cerebellum (i.e., lobules VI-VIII) seem particularly susceptible to modulation by ctDCS. Numerous studies have shown to date that ctDCS can modulate motor learning, and affect cognitive and emotional processes. Importantly, this intervention has a good safety profile; similar to when applied over cerebral areas. Thus, investigations have begun exploring ctDCS as a viable intervention for patients with neurological conditions. PMID:25406224

  4. Developmental Cerebellar Cognitive Affective Syndrome in Ex-preterm Survivors Following Cerebellar Injury

    PubMed Central

    Brossard-Racine, Marie; du Plessis, Adre J.; Limperopoulos, Catherine

    2015-01-01

    Cerebellar injury is increasingly recognized as an important complication of very preterm birth. However, the neurodevelopmental consequences of early life cerebellar injury in prematurely born infants have not been well elucidated. We performed a literature search of studies published between 1997 and 2014 describing neurodevelopmental outcomes of preterm infants following direct cerebellar injury or indirect cerebellar injury/underdevelopment. Available data suggests that both direct and indirect mechanisms of cerebellar injury appear to stunt cerebellar growth and adversely affect neurodevelopment. This review also provides important insights into the highly integrated cerebral-cerebellar structural and functional correlates. Finally, this review highlights that early life impairment of cerebellar growth extends far beyond motor impairments and plays a critical, previously underrecognized role in the long-term cognitive, behavioral, and social deficits associated with brain injury among premature infants. These data point to a developmental form of the cerebellar cognitive affective syndrome previously described in adults. Longitudinal prospective studies using serial advanced magnetic resonance imaging techniques are needed to better delineate the full extent of the role of prematurity-related cerebellar injury and topography in the genesis of cognitive, social-behavioral dysfunction. PMID:25241880

  5. Abnormal pressures as hydrodynamic phenomena

    USGS Publications Warehouse

    Neuzil, C.E.

    1995-01-01

    So-called abnormal pressures, subsurface fluid pressures significantly higher or lower than hydrostatic, have excited speculation about their origin since subsurface exploration first encountered them. Two distinct conceptual models for abnormal pressures have gained currency among earth scientists. The static model sees abnormal pressures generally as relict features preserved by a virtual absence of fluid flow over geologic time. The hydrodynamic model instead envisions abnormal pressures as phenomena in which flow usually plays an important role. This paper develops the theoretical framework for abnormal pressures as hydrodynamic phenomena, shows that it explains the manifold occurrences of abnormal pressures, and examines the implications of this approach. -from Author

  6. Abnormal Development of the Femoral Head Epiphysis in an Infant with no Developmental Dysplasia of the Hip Apparent on Ultrasonography

    PubMed Central

    Atalar, Hakan; Gunay, Cuneyd; Aytekin, Mahmut Nedim

    2014-01-01

    Introduction: In the investigation of hip development in newborns and infants, ultrasonography and radiography are widely used, but their optimal roles in this setting remain controversial. Case Report: Here we describe an 8.5-month-old infant who had undergone hip radiography at a primary care facility and was referred to our hospital to be evaluated for developmental dysplasia of the hip. Ultrasonography showed no developmental dysplasia of the hip according to standard criteria, but developmental retardation of the femoral head was apparent on the radiograph. Conclusion: This patient's findings demonstrate that abnormalities in femoral head epiphysis development can go undetected during routine ultrasonographic evaluations for developmental dysplasia of the hip. PMID:27298982

  7. Steroid abnormalities and the developing brain: Declarative memory for emotionally arousing and neutral material in children with congenital adrenal hyperplasia

    PubMed Central

    Maheu, Françoise S.; Merke, Deborah P.; Schroth, Elizabeth A.; Keil, Margaret F.; Hardin, Julie; Poeth, Kaitlin; Pine, Daniel S.; Ernst, Monique

    2008-01-01

    Summary Steroid hormones modulate memory in animals and human adults. Little is known on the developmental effect of these hormones on the neural networks underlying memory. Using Congenital Adrenal Hyperplasia (CAH) as a naturalistic model of early steroid abnormalities, this study examines the consequences of CAH on memory and its neural correlates for emotionally arousing and neutral material in children. Seventeen patients with CAH and 17 age- and sex-matched healthy children (ages 12 to 14 years) completed the study. Subjects were presented positive, negative and neutral pictures. Memory recall occurred about 30 minutes after viewing the pictures. Children with CAH showed memory deficits for negative pictures compared to healthy children (p < 0.01). There were no group differences on memory performance for either positive or neutral pictures (p’s >0.1). In patients, 24h urinary-free cortisol levels (reflecting glucocorticoid replacement therapy) and testosterone levels were not associated with memory performance. These findings suggest that early steroid imbalances affect memory for negative material in children with CAH. Such memory impairments may result from abnormal brain organization and function following hormonal dysfunction during critical periods of development. PMID:18162329

  8. Abnormal development of sensory-motor, visual temporal and parahippocampal cortex in children with learning disabilities and borderline intellectual functioning

    PubMed Central

    Baglio, Francesca; Cabinio, Monia; Ricci, Cristian; Baglio, Gisella; Lipari, Susanna; Griffanti, Ludovica; Preti, Maria G.; Nemni, Raffaello; Clerici, Mario; Zanette, Michela; Blasi, Valeria

    2014-01-01

    Borderline intellectual functioning (BIF) is a condition characterized by an intelligence quotient (IQ) between 70 and 85. BIF children present with cognitive, motor, social, and adaptive limitations that result in learning disabilities and are more likely to develop psychiatric disorders later in life. The aim of this study was to investigate brain morphometry and its relation to IQ level in BIF children. Thirteen children with BIF and 14 age- and sex-matched typically developing (TD) children were enrolled. All children underwent a full IQ assessment (WISC-III scale) and a magnetic resonance (MR) examination including conventional sequences to assess brain structural abnormalities and high resolution 3D images for voxel-based morphometry analysis. To investigate to what extent the group influenced gray matter (GM) volumes, both univariate and multivariate generalized linear model analysis of variance were used, and the varimax factor analysis was used to explore variable correlations and clusters among subjects. Results showed that BIF children, compared to controls have increased regional GM volume in bilateral sensorimotor and right posterior temporal cortices and decreased GM volume in the right parahippocampal gyrus. GM volumes were highly correlated with IQ indices. The present work is a case study of a group of BIF children showing that BIF is associated with abnormal cortical development in brain areas that have a pivotal role in motor, learning, and behavioral processes. Our findings, although allowing for little generalization to the general population, contribute to the very limited knowledge in this field. Future longitudinal MR studies will be useful in verifying whether cortical features can be modified over time even in association with rehabilitative intervention. PMID:25360097

  9. Auditory Processing in Infancy: Do Early Abnormalities Predict Disorders of Language and Cognitive Development?

    ERIC Educational Resources Information Center

    Guzzetta, Francesco; Conti, Guido; Mercuri, Eugenio

    2011-01-01

    Increasing attention has been devoted to the maturation of sensory processing in the first year of life. While the development of cortical visual function has been thoroughly studied, much less information is available on auditory processing and its early disorders. The aim of this paper is to provide an overview of the assessment techniques for…

  10. Increased variability in finger position occurs throughout overarm throws made by cerebellar and unskilled subjects.

    PubMed

    Timmann, D; Citron, R; Watts, S; Hore, J

    2001-12-01

    We investigated the ability of cerebellar patients and unskilled subjects to control finger grip position and the amplitude of finger opening during a multijoint overarm throw. This situation is of interest because the appropriate finger control requires predicting the magnitude of back forces from the ball on the finger throughout the throw and generating the appropriate level and rate of change of finger flexor torque to oppose the back force. Cerebellar patients, matched controls, and unskilled subjects threw tennis balls and tennis-sized balls of different weights. In all cases angular positions of five arm segments in three dimension were recorded at 1,000 Hz with the search-coil technique as subjects threw from a seated position. When the hand was stationary, cerebellar patients showed a normal ability to grip the ball and open the fingers and drop the ball. In contrast, in overarm throws where a back force occurred on the fingers, cerebellar patients showed an abnormally large variability in amplitude of the change in finger position when gripping, in amplitude of finger opening, and in amplitude of the change in finger position 10 ms after ball release. This was not due to more trial-to-trial variation in throwing speed. When throwing balls of increasing weights, both controls and cerebellar patients had increasing finger flexions after ball release that indicated that, on average, both scaled finger force in proportion to ball weight during the throw. Unlike skilled controls, cerebellar patients showed a small (<20 degrees ) increase in the amplitude of finger opening with balls of increasing weight. However, neither the increase in variability of finger position nor the increase in finger amplitude with balls of increasing weight were unique cerebellar signs because both were observed to various degrees in unskilled throwers. It is concluded that in the absence of either normal cerebellar function or skill, the central neural activity that controls finger

  11. Pediatric Neurocutaneous Syndromes with Cerebellar Involvement.

    PubMed

    Bosemani, Thangamadhan; Huisman, Thierry A G M; Poretti, Andrea

    2016-08-01

    Neurocutaneous syndromes encompasses a broad group of genetic disorders with different clinical, genetic, and pathologic features that share developmental lesions of the skin as well as central and peripheral nervous system. Cerebellar involvement has been shown in numerous types of neurocutaneous syndrome. It may help or be needed for the diagnosis and to explain the cognitive and behavioral phenotype of affected children. This article describes various types of neurocutaneous syndrome with cerebellar involvement. For each neurocutaneous disease or syndrome, clinical features, genetic, neuroimaging findings, and the potential role of the cerebellar involvement is discussed. PMID:27423801

  12. Abnormal development of glomerular endothelial and mesangial cells in mice with targeted disruption of the lama3 gene.

    PubMed

    Abrass, C K; Berfield, A K; Ryan, M C; Carter, W G; Hansen, K M

    2006-09-01

    Mice with targeted disruption of the lama3 gene, which encodes the alpha3 chain of laminin-5 (alpha3beta3gamma2, 332), develop a blistering skin disease similar to junctional epidermolysis bullosa in humans. These animals also develop abnormalities in glomerulogenesis. In both wild-type and mutant animals (lama3(-/-)), podocytes secrete glomerular basement membrane and develop foot processes. Endothelial cells migrate into this scaffolding and secrete a layer of basement membrane that fuses with the one formed by the podocyte. In lama3(-/-) animals, glomerular maturation arrests at this stage. Endothelial cells do not attenuate, develop fenestrae, or form typical lumens, and mesangial cells (MCs) were not identified. LN alpha3 subunit (LAMA3) protein was identified in the basement membrane adjacent to glomerular endothelial cells (GEnCs) in normal rats and mice. In developing rat glomeruli, the LAMA3 subunit was first detectable in the early capillary loop stage, which corresponds to the stage at which maturation arrest was observed in the mutant mice. Lama3 mRNA and protein were identified in isolated rat and mouse glomeruli and cultured rat GEnCs, but not MC. These data document expression of LAMA3 in glomeruli and support a critical role for it in GEnC differentiation. Furthermore, LAMA3 chain expression and/or another product of endothelial cells are required for MC migration into the developing glomerulus. PMID:16850021

  13. Overexpression of the CmACS-3 gene in melon causes abnormal pollen development.

    PubMed

    Zhang, H; Luan, F

    2015-09-08

    Sexual diversity expressed by the Curcurbitaceae family is a primary example of developmental plasticity in plants. Most melon genotypes are andromonoecious, where an initial phase of male flowers is followed by a mixture of bisexual and male flowers. Over-expression of the CmACS-3 gene in melon plants showed an increased number of flower buds, and increased femaleness as demonstrated by a larger number bisexual buds. Transformation of CmACS-3 in melons showed earlier development of and an increased number of bisexual buds that matured to anthesis but also increased the rate of development of the bisexual buds to maturity. Field studies showed that CmACS-3-overexpressing melons had earlier mature bisexual flowers, earlier fruit set, and an increased number of fruits set on closely spaced nodes on the main stem.

  14. Overexpression of the CmACS-3 gene in melon causes abnormal pollen development.

    PubMed

    Zhang, H; Luan, F

    2015-01-01

    Sexual diversity expressed by the Curcurbitaceae family is a primary example of developmental plasticity in plants. Most melon genotypes are andromonoecious, where an initial phase of male flowers is followed by a mixture of bisexual and male flowers. Over-expression of the CmACS-3 gene in melon plants showed an increased number of flower buds, and increased femaleness as demonstrated by a larger number bisexual buds. Transformation of CmACS-3 in melons showed earlier development of and an increased number of bisexual buds that matured to anthesis but also increased the rate of development of the bisexual buds to maturity. Field studies showed that CmACS-3-overexpressing melons had earlier mature bisexual flowers, earlier fruit set, and an increased number of fruits set on closely spaced nodes on the main stem. PMID:26400274

  15. A mouse model for eukaryotic translation initiation factor 2B-leucodystrophy reveals abnormal development of brain white matter.

    PubMed

    Geva, Michal; Cabilly, Yuval; Assaf, Yaniv; Mindroul, Nina; Marom, Liraz; Raini, Gali; Pinchasi, Dalia; Elroy-Stein, Orna

    2010-08-01

    Eukaryotic translation initiation factor 2B is a major housekeeping complex that governs the rate of global protein synthesis under normal and stress conditions. Mutations in any of its five subunits lead to leucoencephalopathy with vanishing white matter, an inherited chronic-progressive fatal brain disease with unknown aetiology, which is among the most prevalent childhood white matter disorders. We generated the first animal model for the disease by introducing a point mutation into the mouse Eif2b5 gene locus, leading to R132H replacement corresponding to the clinically significant human R136H mutation in the catalytic subunit. In contrast to human patients, mice homozygous for the mutant Eif2b5 allele (Eif2b5(R132H/R132H) mice) enable multiple analyses under a defined genetic background during the pre-symptomatic stages and during recovery from a defined brain insult. Time-course magnetic resonance imaging revealed for the first time the delayed development of the brain white matter due to the mutation. Electron microscopy demonstrated a higher proportion of small-calibre nerve fibres. Immunohistochemistry detected an abnormal abundance of oligodendrocytes and astrocytes in the brain of younger animals, as well as an abnormal level of major myelin proteins. Most importantly, mutant mice failed to recover from cuprizone-induced demyelination, reflecting an increased sensitivity to brain insults. The anomalous development of white matter in Eif2b5(R132H/R132H) mice underscores the importance of tight translational control to normal myelin formation and maintenance.

  16. Hind brain agenesis a rare imaging findings in cerebro cerebellar lissencephalic syndrome.

    PubMed

    Mundaganur, Praveen M; Solwalkar, Pradeep; Nimbal, Vishal

    2014-01-01

    A case report of cerebro cerebellar lissencephaly shows complete agenesis of cerebellum and brainstem which is rare imaging finding of group lissencephaly (type I lissencephaly). Though agenesis of cerebellum and brainstem were included in literature, in most of the cases we saw a hypoplasia or atrophy of cerebellum in lissencephaly syndrome. The CT scan findings of this patient shows features of lissencephaly with complete agenesis of brain stem and cerebellum associated with multiple congenital abnormalities.

  17. A theory of cerebellar cortex.

    PubMed

    Marr, D

    1969-06-01

    1. A detailed theory of cerebellar cortex is proposed whose consequence is that the cerebellum learns to perform motor skills. Two forms of input-output relation are described, both consistent with the cortical theory. One is suitable for learning movements (actions), and the other for learning to maintain posture and balance (maintenance reflexes).2. It is known that the cells of the inferior olive and the cerebellar Purkinje cells have a special one-to-one relationship induced by the climbing fibre input. For learning actions, it is assumed that:(a) each olivary cell responds to a cerebral instruction for an elemental movement. Any action has a defining representation in terms of elemental movements, and this representation has a neural expression as a sequence of firing patterns in the inferior olive; and(b) in the correct state of the nervous system, a Purkinje cell can initiate the elemental movement to which its corresponding olivary cell responds.3. Whenever an olivary cell fires, it sends an impulse (via the climbing fibre input) to its corresponding Purkinje cell. This Purkinje cell is also exposed (via the mossy fibre input) to information about the context in which its olivary cell fired; and it is shown how, during rehearsal of an action, each Purkinje cell can learn to recognize such contexts. Later, when the action has been learnt, occurrence of the context alone is enough to fire the Purkinje cell, which then causes the next elemental movement. The action thus progresses as it did during rehearsal.4. It is shown that an interpretation of cerebellar cortex as a structure which allows each Purkinje cell to learn a number of contexts is consistent both with the distributions of the various types of cell, and with their known excitatory or inhibitory natures. It is demonstrated that the mossy fibre-granule cell arrangement provides the required pattern discrimination capability.5. The following predictions are made.(a) The synapses from parallel fibres

  18. Annual Research Review: Growth connectomics – the organization and reorganization of brain networks during normal and abnormal development

    PubMed Central

    Vértes, Petra E; Bullmore, Edward T

    2015-01-01

    Background We first give a brief introduction to graph theoretical analysis and its application to the study of brain network topology or connectomics. Within this framework, we review the existing empirical data on developmental changes in brain network organization across a range of experimental modalities (including structural and functional MRI, diffusion tensor imaging, magnetoencephalography and electroencephalography in humans). Synthesis We discuss preliminary evidence and current hypotheses for how the emergence of network properties correlates with concomitant cognitive and behavioural changes associated with development. We highlight some of the technical and conceptual challenges to be addressed by future developments in this rapidly moving field. Given the parallels previously discovered between neural systems across species and over a range of spatial scales, we also review some recent advances in developmental network studies at the cellular scale. We highlight the opportunities presented by such studies and how they may complement neuroimaging in advancing our understanding of brain development. Finally, we note that many brain and mind disorders are thought to be neurodevelopmental in origin and that charting the trajectory of brain network changes associated with healthy development also sets the stage for understanding abnormal network development. Conclusions We therefore briefly review the clinical relevance of network metrics as potential diagnostic markers and some recent efforts in computational modelling of brain networks which might contribute to a more mechanistic understanding of neurodevelopmental disorders in future. PMID:25441756

  19. A mitochondrial DNA sequence is associated with abnormal pollen development in cytoplasmic male sterile bean plants.

    PubMed Central

    Johns, C; Lu, M; Lyznik, A; Mackenzie, S

    1992-01-01

    Cytoplasmic male sterility (CMS) in common bean is associated with the presence of a 3-kb unique mitochondrial sequence designated pvs. The pvs sequence encodes at least two open reading frames (297 and 720 bp in length) with portions derived from the chloroplast genome. Fertility restoration by the nuclear restorer gene Fr results in the loss of this transcriptionally active unique region. We examined the effect of CMS (pvs present) and fertility restoration by Fr (pvs absent) on the pattern of pollen development in bean. In the CMS line, pollen aborted in the tetrad stage late in microgametogenesis. Microspores maintained cytoplasmic connections throughout pollen development, indicating aberrant or incomplete cytokinesis. Pollen-specific events associated with pollen abortion and fertility restoration imply that a gametophytic factor or event may be involved in CMS. In situ hybridization experiments suggested that significant reduction or complete loss of the mitochondrial sterility-associated sequence occurred in fertile pollen of F2 populations segregating for fertility. These observations support a model of fertility restoration by the loss of a mitochondrial DNA sequence prior to or during microsporogenesis/gametogenesis. PMID:1498602

  20. P53 functional abnormality in mesenchymal stem cells promotes osteosarcoma development

    PubMed Central

    Velletri, T; Xie, N; Wang, Y; Huang, Y; Yang, Q; Chen, X; Chen, Q; Shou, P; Gan, Y; Cao, G; Melino, G; Shi, Y

    2016-01-01

    It has been shown that p53 has a critical role in the differentiation and functionality of various multipotent progenitor cells. P53 mutations can lead to genome instability and subsequent functional alterations and aberrant transformation of mesenchymal stem cells (MSCs). The significance of p53 in safeguarding our body from developing osteosarcoma (OS) is well recognized. During bone remodeling, p53 has a key role in negatively regulating key factors orchestrating the early stages of osteogenic differentiation of MSCs. Interestingly, changes in the p53 status can compromise bone homeostasis and affect the tumor microenvironment. This review aims to provide a unique opportunity to study the p53 function in MSCs and OS. In the context of loss of function of p53, we provide a model for two sources of OS: MSCs as progenitor cells of osteoblasts and bone tumor microenvironment components. Standing at the bone remodeling point of view, in this review we will first explain the determinant function of p53 in OS development. We will then summarize the role of p53 in monitoring MSC fidelity and in regulating MSC differentiation programs during osteogenesis. Finally, we will discuss the importance of loss of p53 function in tissue microenvironment. We expect that the information provided herein could lead to better understanding and treatment of OS. PMID:26775693

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

    PubMed

    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.

  2. A rare saccade velocity profile in Stiff-Person Syndrome with cerebellar degeneration.

    PubMed

    Zivotofsky, Ari Z; Siman-Tov, Tali; Gadoth, Natan; Gordon, Carlos R

    2006-06-01

    Stiff-Person Syndrome (SPS) is an immune-mediated disorder of the central nervous system characterized by muscle rigidity, episodic muscle spasms, and high titers of antibodies against glutamic acid decarboxylase (GAD). The presence of cerebellar ataxia in SPS is extremely rare, but occurs. Clinical observations of ocular motor abnormalities have been noted in a few SPS patients. The purpose of this study is to provide a detailed quantitative documentation of ocular motor abnormalities in a patient with SPS and progressive cerebellar signs. Detailed clinical assessment of a woman with SPS and precise eye movement recordings using the magnetic search coil technique was performed. In addition to other ocular motor abnormalities that included longer latencies for saccades, downbeat nystagmus, and loss of downward smooth pursuit, a rare saccade velocity profile consisting of multi-component saccades was observed. We postulate that these ocular motor findings are related to impairment of GABAergic neurotransmission because antibodies to glutamic acid decarboxylase (GAD-Abs) have been implicated in the pathogenesis of both SPS and some cases of cerebellar ataxia. In addition, this unusual saccadic velocity profile may have important implications for modeling the saccadic system and furthering a complete understanding of saccade generation. PMID:16725126

  3. Developing and testing a multi-probe resonance electrical impedance spectroscopy system for detecting breast abnormalities

    NASA Astrophysics Data System (ADS)

    Gur, David; Zheng, Bin; Dhurjaty, Sreeram; Wolfe, Gene; Fradin, Mary; Weil, Richard; Sumkin, Jules; Zuley, Margarita

    2009-02-01

    In our previous study, we reported on the development and preliminary testing of a prototype resonance electrical impedance spectroscopy (REIS) system with a pair of probes. Although our pilot study on 150 young women ranging from 30 to 50 years old indicated the feasibility of using REIS output sweep signals to classify between the women who had negative examinations and those who would ultimately be recommended for biopsy, the detection sensitivity was relatively low. To improve performance when using REIS technology, we recently developed a new multi-probe based REIS system. The system consists of a sensor module box that can be easily lifted along a vertical support device to fit women of different height. Two user selectable breast placement "cups" with different curvatures are included in the system. Seven probes are mounted on each of the cups on opposing sides of the sensor box. By rotating the sensor box, the technologist can select the detection sensor cup that better fits the breast size of the woman being examined. One probe is mounted in the cup center for direct contact with the nipple and the other six probes are uniformly distributed along an outside circle to enable contact with six points on the outer and inner breast skin surfaces. The outer probes are located at a distance of 60mm away from the center (nipple) probe. The system automatically monitors the quality of the contact between the breast surface and each of the seven probes and data acquisition can only be initiated when adequate contact is confirmed. The measurement time for each breast is approximately 15 seconds during which time the system records 121 REIS signal sweep outputs generated from 200 KHz to 800 KHz at 5 KHz increments for all preselected probe pairs. Currently we are measuring 6 pairs between the center probe and each of six probes located on the outer circle as well as two pairs between probe pairs on the outer circle. This new REIS system has been installed in our

  4. Neural tube opening and abnormal extraembryonic membrane development in SEC23A deficient mice

    PubMed Central

    Zhu, Min; Tao, Jiayi; Vasievich, Matthew P.; Wei, Wei; Zhu, Guojing; Khoriaty, Rami N.; Zhang, Bin

    2015-01-01

    COPII (coat protein complex-II) vesicles transport proteins from the endoplasmic reticulum (ER) to the Golgi. Higher eukaryotes have two or more paralogs of most COPII components. Here we characterize mice deficient for SEC23A and studied interactions of Sec23a null allele with the previously reported Sec23b null allele. SEC23A deficiency leads to mid-embryonic lethality associated with defective development of extraembryonic membranes and neural tube opening in midbrain. Secretion defects of multiple collagen types are observed in different connective tissues, suggesting that collagens are primarily transported in SEC23A-containing vesicles in these cells. Other extracellular matrix proteins, such as fibronectin, are not affected by SEC23A deficiency. Intracellular accumulation of unsecreted proteins leads to strong induction of the unfolded protein response in collagen-producing cells. No collagen secretion defects are observed in SEC23B deficient embryos. We report that E-cadherin is a cargo that accumulates in acini of SEC23B deficient pancreas and salivary glands. Compensatory increase of one paralog is observed in the absence of the second paralog. Haploinsufficiency of the remaining Sec23 paralog on top of homozygous inactivation of the first paralog leads to earlier lethality of embryos. Our results suggest that mammalian SEC23A and SEC23B transport overlapping yet distinct spectra of cargo in vivo. PMID:26494538

  5. Zebrafish embryos exposed to alcohol undergo abnormal development of motor neurons and muscle fibers.

    PubMed

    Sylvain, Nicole J; Brewster, Daniel L; Ali, Declan W

    2010-01-01

    Children exposed to alcohol in utero have significantly delayed gross and fine motor skills, as well as deficiencies in reflex development. The reasons that underlie the motor deficits caused by ethanol (EtOH) exposure remain to be fully elucidated. The present study was undertaken to investigate the effects of embryonic alcohol exposure (1.5%, 2% and 2.5% EtOH) on motor neuron and muscle fiber morphology in 3 days post fertilization (dpf) larval zebrafish. EtOH treated fish exhibited morphological deformities and fewer bouts of swimming in response to touch, compared with untreated fish. Immunolabelling with anti-acetylated tubulin indicated that fish exposed to 2.5% EtOH had significantly higher rates of motor neuron axon defects. Immunolabelling of primary and secondary motor neurons, using znp-1 and zn-8, revealed that fish exposed to 2% and 2.5% EtOH exhibited significantly higher rates of primary and secondary motor neuron axon defects compared to controls. Examination of red and white muscle fibers revealed that fish exposed to EtOH had significantly smaller fibers compared with controls. These findings indicate that motor neuron and muscle fiber morphology is affected by early alcohol exposure in zebrafish embryos, and that this may be related to deficits in locomotion. PMID:20211721

  6. Roles of retinoic acid signaling in normal and abnormal development of the palate and tongue.

    PubMed

    Okano, Junko; Udagawa, Jun; Shiota, Kohei

    2014-05-01

    Palatogenesis involves various developmental events such as growth, elevation, elongation and fusion of opposing palatal shelves. Extrinsic factors such as mouth opening and subsequent tongue withdrawal are also needed for the horizontal elevation of palate shelves. Failure of any of these steps can lead to cleft palate, one of the most common birth defects in humans. It has been shown that retinoic acid (RA) plays important roles during palate development, but excess RA causes cleft palate in fetuses of both rodents and humans. Thus, the coordinated regulation of retinoid metabolism is essential for normal palatogenesis. The endogenous RA level is determined by the balance of RA-synthesizing (retinaldehyde dehydrogenases: RALDHs) and RA-degrading enzymes (CYP26s). Cyp26b1 is a key player in normal palatogenesis. In this review, we discuss recent progress in the study of the pathogenesis of RA-induced cleft palate, with special reference to the regulation of endogenous RA levels by RA-degrading enzymes.

  7. Role of abnormal lipid metabolism in development, progression, diagnosis and therapy of pancreatic cancer

    PubMed Central

    Swierczynski, Julian; Hebanowska, Areta; Sledzinski, Tomasz

    2014-01-01

    There is growing evidence that metabolic alterations play an important role in cancer development and progression. The metabolism of cancer cells is reprogrammed in order to support their rapid proliferation. Elevated fatty acid synthesis is one of the most important aberrations of cancer cell metabolism. An enhancement of fatty acids synthesis is required both for carcinogenesis and cancer cell survival, as inhibition of key lipogenic enzymes slows down the growth of tumor cells and impairs their survival. Based on the data that serum fatty acid synthase (FASN), also known as oncoantigen 519, is elevated in patients with certain types of cancer, its serum level was proposed as a marker of neoplasia. This review aims to demonstrate the changes in lipid metabolism and other metabolic processes associated with lipid metabolism in pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic neoplasm, characterized by high mortality. We also addressed the influence of some oncogenic factors and tumor suppressors on pancreatic cancer cell metabolism. Additionally the review discusses the potential role of elevated lipid synthesis in diagnosis and treatment of pancreatic cancer. In particular, FASN is a viable candidate for indicator of pathologic state, marker of neoplasia, as well as, pharmacological treatment target in pancreatic cancer. Recent research showed that, in addition to lipogenesis, certain cancer cells can use fatty acids from circulation, derived from diet (chylomicrons), synthesized in liver, or released from adipose tissue for their growth. Thus, the interactions between de novo lipogenesis and uptake of fatty acids from circulation by PDAC cells require further investigation. PMID:24605027

  8. Abnormal etioplast development in barley seedlings infected with BSMV by seed transmission.

    PubMed

    Harsányi, Anett; Böddi, Béla; Bóka, Károly; Almási, Asztéria; Gáborjányi, Richard

    2002-01-01

    The effect of barley stripe mosaic hordeivirus (BSMV) was studied on the ultrastructure of etioplasts, protochlorophyllide forms and the greening process of barley (Hordeum vulgare cv. Pannónia) plants infected by seed transmission. The leaves of 7- to 11-day-old etiolated seedlings were examined by transmission electron microscopy, fluorescence and absorption spectroscopy. The etioplasts of infected seedlings contained smaller prolamellar bodies with less regular membrane structure, while prothylakoid content was higher than in the control. The protochlorophyllide content of virus-infected seedlings was reduced to 74% of the control. In the 77 K fluorescence spectra the relative amount of 655 nm emitting photoactive protochlorophyllide form decreased, and the amount of the 645 and 633 nm emitting forms increased in the infected leaves. A characteristic effect was observed in the process of the Shibata-shift: 40 min delay was observed in the infected leaves. The results of this work proved that BSMV infection delays or inhibits plastid development and the formation of photosynthetic apparatus. PMID:11982946

  9. Global resting-state fMRI analysis identifies frontal cortex, striatal, and cerebellar dysconnectivity in obsessive-compulsive disorder

    PubMed Central

    Anticevic, Alan; Hu, Sien; Zhang, Sheng; Savic, Aleksandar; Billingslea, Eileen; Wasylink, Suzanne; Repovs, Grega; Cole, Michael W.; Bednarski, Sarah; Krystal, John H.; Bloch, Michael H.; Li, Chiang-shan R.; Pittenger, Christopher

    2013-01-01

    Background Obsessive-compulsive disorder (OCD) is associated with regional hyperactivity in cortico-striatal circuits. However, the large-scale patterns of abnormal neural connectivity remain uncharacterized. Resting-state functional connectivity (rs-fcMRI) studies have shown altered connectivity within the implicated circuitry, but they have used seed-driven approaches wherein a circuit of interest is defined a priori. This limits their ability to identify network abnormalities beyond the prevailing framework. This limitation is particularly problematic within the prefrontal cortex (PFC), which is large and heterogeneous and where a priori specification of seeds is therefore difficult. A hypothesis-neutral data-driven approach to the analysis of connectivity is vital. Method We analyzed rs-fcMRI data collected at 3T in 27 OCD patients and 66 matched controls using a recently developed data-driven global brain connectivity (GBC) method, both within the PFC and across the whole brain. Results We found clusters of decreased connectivity in the left lateral PFC in both whole-brain and PFC-restricted analyses. Increased GBC was found in the right putamen and left cerebellar cortex. Within ROIs in the basal ganglia and thalamus, we identified increased GBC in dorsal striatum and anterior thalamus, which was reduced in patients on medication. The ventral striatum/nucleus accumbens exhibited decreased global connectivity, but increased connectivity specifically with the ventral anterior cingulate cortex in subjects with OCD. Conclusion These findings identify previously uncharacterized PFC and basal ganglia dysconnectivity in OCD and reveal differentially altered GBC in dorsal and ventral striatum. Results highlight complex disturbances in PFC networks, which could contribute to disrupted cortical-striatal-cerebellar circuits in OCD. PMID:24314349

  10. A dynamical system view of cerebellar function

    NASA Astrophysics Data System (ADS)

    Keeler, James D.

    1990-06-01

    First some previous theories of cerebellar function are reviewed, and deficiencies in how they map onto the neurophysiological structure are pointed out. I hypothesize that the cerebellar cortex builds an internal model, or prediction, of the dynamics of the animal. A class of algorithms for doing prediction based on local reconstruction of attractors are described, and it is shown how this class maps very well onto the structure of the cerebellar cortex. I hypothesize that the climbing fibers multiplex between different trajectories corresponding to different modes of operation. Then the vestibulo-ocular reflex is examined, and experiments to test the proposed model are suggested. The purpose of the presentation here is twofold: (1) To enlighten physiologists to the mathematics of a class of prediction algorithms that map well onto cerebellar architecture. (2) To enlighten dynamical system theorists to the physiological and anatomical details of the cerebellum.

  11. Deficiency in DGCR8-dependent canonical microRNAs causes infertility due to multiple abnormalities during uterine development in mice.

    PubMed

    Kim, Yeon Sun; Kim, Hye-Ryun; Kim, Hyongbum; Yang, Seung Chel; Park, Mira; Yoon, Jung Ah; Lim, Hyunjung J; Hong, Seok-Ho; DeMayo, Francesco J; Lydon, John P; Choi, Youngsok; Lee, Dong Ryul; Song, Haengseok

    2016-01-01

    DGCR8 is an RNA-binding protein that interacts with DROSHA to produce pre-microRNA in the nucleus, while DICER generates not only mature microRNA, but also endogenous small interfering RNAs in the cytoplasm. Here, we produced Dgcr8 conditional knock-out mice using progesterone receptor (PR)-Cre (Dgcr8(d/d)) and demonstrated that canonical microRNAs dependent on the DROSHA-DGCR8 complex are required for uterine development as well as female fertility in mice. Adult Dgcr8(d/d) females neither underwent regular reproductive cycles nor produced pups, whereas administration of exogenous gonadotropins induced normal ovulation in these mice. Interestingly, immune cells associated with acute inflammation aberrantly infiltrated into reproductive organs of pregnant Dgcr8(d/d) mice. Regarding uterine development, multiple uterine abnormalities were noticeable at 4 weeks of age when PR is significantly increased, and the severity of these deformities increased over time. Gland formation and myometrial layers were significantly reduced, and the stromal cell compartment did not expand and became atrophic during uterine development in these mice. These results were consistent with aberrantly reduced stromal cell proliferation and completely failed decidualization. Collectively, we suggest that DGCR8-dependent canonical microRNAs are essential for uterine development and physiological processes such as proper immune modulation, reproductive cycle, and steroid hormone responsiveness in mice. PMID:26833131

  12. Deficiency in DGCR8-dependent canonical microRNAs causes infertility due to multiple abnormalities during uterine development in mice

    PubMed Central

    Kim, Yeon Sun; Kim, Hye-Ryun; Kim, Hyongbum; Yang, Seung Chel; Park, Mira; Yoon, Jung Ah; Lim, Hyunjung J.; Hong, Seok-Ho; DeMayo, Francesco J.; Lydon, John P.; Choi, Youngsok; Lee, Dong Ryul; Song, Haengseok

    2016-01-01

    DGCR8 is an RNA-binding protein that interacts with DROSHA to produce pre-microRNA in the nucleus, while DICER generates not only mature microRNA, but also endogenous small interfering RNAs in the cytoplasm. Here, we produced Dgcr8 conditional knock-out mice using progesterone receptor (PR)-Cre (Dgcr8d/d) and demonstrated that canonical microRNAs dependent on the DROSHA-DGCR8 complex are required for uterine development as well as female fertility in mice. Adult Dgcr8d/d females neither underwent regular reproductive cycles nor produced pups, whereas administration of exogenous gonadotropins induced normal ovulation in these mice. Interestingly, immune cells associated with acute inflammation aberrantly infiltrated into reproductive organs of pregnant Dgcr8d/d mice. Regarding uterine development, multiple uterine abnormalities were noticeable at 4 weeks of age when PR is significantly increased, and the severity of these deformities increased over time. Gland formation and myometrial layers were significantly reduced, and the stromal cell compartment did not expand and became atrophic during uterine development in these mice. These results were consistent with aberrantly reduced stromal cell proliferation and completely failed decidualization. Collectively, we suggest that DGCR8-dependent canonical microRNAs are essential for uterine development and physiological processes such as proper immune modulation, reproductive cycle, and steroid hormone responsiveness in mice. PMID:26833131

  13. Cerebellar Cognitive Affective Syndrome Presented as Severe Borderline Personality Disorder

    PubMed Central

    Pesic, Danilo; Peljto, Amir; Lukic, Biljana; Milovanovic, Maja; Svetozarevic, Snezana; Lecic Tosevski, Dusica

    2014-01-01

    An increasing number of findings confirm the significance of cerebellum in affecting regulation and early learning. Most consistent findings refer to association of congenital vermis anomalies with deficits in nonmotor functions of cerebellum. In this paper we presented a young woman who was treated since sixteen years of age for polysubstance abuse, affective instability, and self-harming who was later diagnosed with borderline personality disorder. Since the neurological and neuropsychological reports pointed to signs of cerebellar dysfunction and dysexecutive syndrome, we performed magnetic resonance imaging of brain which demonstrated partially developed vermis and rhombencephalosynapsis. These findings match the description of cerebellar cognitive affective syndrome and show an overlap with clinical manifestations of borderline personality disorder. PMID:24715924

  14. R6/2 Huntington’s disease Mice Develop Early and Progressive Abnormal Brain Metabolism and Seizures

    PubMed Central

    Cepeda-Prado, E; Popp, S; Khan, U; Stefanov, D; Rodriguez, J; Menalled, L; Dow-Edwards, D; Small, SA; Moreno, H

    2012-01-01

    A hallmark feature of Huntington's disease pathology is the atrophy of brain regions including, but not limited to, the striatum. Though MRI studies have identified structural CNS changes in several HD mouse models, the functional consequences of HD pathology during the progression of the disease have yet to be investigated using in vivo functional magnetic resonance imaging (fMRI). To address this issue, we first established the structural and functional MRI phenotype of juvenile HD mouse model R6/2 at early and advanced stages of disease. Significantly higher fMRI-signals (relative cerebral blood volumes-rCBV) and atrophy were observed in both age groups in specific brain regions. Next, fMRI results were correlated with electrophysiological analysis, which showed abnormal increases in neuronal activity in affected brain regions- thus identifying a mechanism accounting for the abnormal fMRI findings. [14C] deoxyglucose (2DG) maps to investigate patterns of glucose utilization were also generated. An interesting mismatch between increases in rCBV and decreases in glucose uptake was observed. Finally, we evaluated the sensitivity of this mouse line to audiogenic seizures early in the disease course. We found that R6/2 mice had an increased susceptibility to develop seizures. Together, these findings identified seizure activity in R6/2 mice, and show that neuroimaging measures sensitive to oxygen metabolism can be used as in vivo biomarkers, preceding the onset of an overt behavioral phenotype. Since fMRI-rCBV can also be obtained in patients, we propose that it may serve as a translational tool to evaluate therapeutic responses in humans and HD mouse models. PMID:22573668

  15. Knockdown of zebrafish Lgi1a results in abnormal development, brain defects and a seizure-like behavioral phenotype

    PubMed Central

    Teng, Yong; Xie, Xiayang; Walker, Steven; Rempala, Grzegorz; Kozlowski, David J.; Mumm, Jeff S.; Cowell, John K.

    2010-01-01

    Epilepsy is a common disorder, typified by recurrent seizures with underlying neurological disorders or disease. Approximately one-third of patients are unresponsive to currently available therapies. Thus, a deeper understanding of the genetics and etiology of epilepsy is needed to advance the development of new therapies. Previously, treatment of zebrafish with epilepsy-inducing pharmacological agents was shown to result in a seizure-like phenotype, suggesting that fish provide a tractable model to understand the function of epilepsy-predisposing genes. Here, we report the first model of genetically linked epilepsy in zebrafish and provide an initial characterization of the behavioral and neurological phenotypes associated with morpholino (MO) knockdown of leucine-rich, glioma-inactivated 1a (lgi1a) expression. Mutations in the LGI1 gene in humans have been shown to predispose to a subtype of autosomal dominant epilepsy. Low-dose Lgi1a MO knockdown fish (morphants) appear morphologically normal but are sensitized to epilepsy-inducing drugs. High-dose Lgi1a morphants have morphological defects which persist into adult stages that are typified by smaller brains and eyes and abnormalities in tail shape, and display hyperactive swimming behaviors. Increased apoptosis was observed throughout the central nervous system of high-dose morphant fish, accounting for the size reduction of neural tissues. These observations demonstrate that zebrafish can be exploited to dissect the embryonic function(s) of genes known to predispose to seizure-like behavior in humans, and offer potential insight into the relationship between developmental neurobiological abnormalities and seizure. PMID:20819949

  16. Cerebellar ataxias: β-III spectrin's interactions suggest common pathogenic pathways.

    PubMed

    Perkins, Emma; Suminaite, Daumante; Jackson, Mandy

    2016-08-15

    Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of disorders all characterised by postural abnormalities, motor deficits and cerebellar degeneration. Animal and in vitro models have revealed β-III spectrin, a cytoskeletal protein present throughout the soma and dendritic tree of cerebellar Purkinje cells, to be required for the maintenance of dendritic architecture and for the trafficking and/or stabilisation of several membrane proteins: ankyrin-R, cell adhesion molecules, metabotropic glutamate receptor-1 (mGluR1), voltage-gated sodium channels (Nav ) and glutamate transporters. This scaffold of interactions connects β-III spectrin to a wide variety of proteins implicated in the pathology of many SCAs. Heterozygous mutations in the gene encoding β-III spectrin (SPTBN2) underlie SCA type-5 whereas homozygous mutations cause spectrin associated autosomal recessive ataxia type-1 (SPARCA1), an infantile form of ataxia with cognitive impairment. Loss-of β-III spectrin function appears to underpin cerebellar dysfunction and degeneration in both diseases resulting in thinner dendrites, excessive dendritic protrusion with loss of planarity, reduced resurgent sodium currents and abnormal glutamatergic neurotransmission. The initial physiological consequences are a decrease in spontaneous activity and excessive excitation, likely to be offsetting each other, but eventually hyperexcitability gives rise to dark cell degeneration and reduced cerebellar output. Similar molecular mechanisms have been implicated for SCA1, 2, 3, 7, 13, 14, 19, 22, 27 and 28, highlighting alterations to intrinsic Purkinje cell activity, dendritic architecture and glutamatergic transmission as possible common mechanisms downstream of various loss-of-function primary genetic defects. A key question for future research is whether similar mechanisms underlie progressive cerebellar decline in normal ageing. PMID:26821241

  17. Global dysrhythmia of cerebro-basal ganglia-cerebellar networks underlies motor tics following striatal disinhibition.

    PubMed

    McCairn, Kevin W; Iriki, Atsushi; Isoda, Masaki

    2013-01-01

    Motor tics, a cardinal symptom of Tourette syndrome (TS), are hypothesized to arise from abnormalities within cerebro-basal ganglia circuits. Yet noninvasive neuroimaging of TS has previously identified robust activation in the cerebellum. To date, electrophysiological properties of cerebellar activation and its role in basal ganglia-mediated tic expression remain unknown. We performed multisite, multielectrode recordings of single-unit activity and local field potentials from the cerebellum, basal ganglia, and primary motor cortex using a pharmacologic monkey model of motor tics/TS. Following microinjections of bicuculline into the sensorimotor putamen, periodic tics occurred predominantly in the orofacial region, and a sizable number of cerebellar neurons showed phasic changes in activity associated with tic episodes. Specifically, 64% of the recorded cerebellar cortex neurons exhibited increases in activity, and 85% of the dentate nucleus neurons displayed excitatory, inhibitory, or multiphasic responses. Critically, abnormal discharges of cerebellar cortex neurons and excitatory-type dentate neurons mostly preceded behavioral tic onset, indicating their central origins. Latencies of pathological activity in the cerebellum and primary motor cortex substantially overlapped, suggesting that aberrant signals may be traveling along divergent pathways to these structures from the basal ganglia. Furthermore, the occurrence of tic movement was most closely associated with local field potential spikes in the cerebellum and primary motor cortex, implying that these structures may function as a gate to release overt tic movements. These findings indicate that tic-generating networks in basal ganglia mediated tic disorders extend beyond classical cerebro-basal ganglia circuits, leading to global network dysrhythmia including cerebellar circuits.

  18. Cerebellar ataxias: β‐III spectrin's interactions suggest common pathogenic pathways

    PubMed Central

    Perkins, Emma; Suminaite, Daumante

    2016-01-01

    Abstract Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of disorders all characterised by postural abnormalities, motor deficits and cerebellar degeneration. Animal and in vitro models have revealed β‐III spectrin, a cytoskeletal protein present throughout the soma and dendritic tree of cerebellar Purkinje cells, to be required for the maintenance of dendritic architecture and for the trafficking and/or stabilisation of several membrane proteins: ankyrin‐R, cell adhesion molecules, metabotropic glutamate receptor‐1 (mGluR1), voltage‐gated sodium channels (Nav) and glutamate transporters. This scaffold of interactions connects β‐III spectrin to a wide variety of proteins implicated in the pathology of many SCAs. Heterozygous mutations in the gene encoding β‐III spectrin (SPTBN2) underlie SCA type‐5 whereas homozygous mutations cause spectrin associated autosomal recessive ataxia type‐1 (SPARCA1), an infantile form of ataxia with cognitive impairment. Loss‐of β‐III spectrin function appears to underpin cerebellar dysfunction and degeneration in both diseases resulting in thinner dendrites, excessive dendritic protrusion with loss of planarity, reduced resurgent sodium currents and abnormal glutamatergic neurotransmission. The initial physiological consequences are a decrease in spontaneous activity and excessive excitation, likely to be offsetting each other, but eventually hyperexcitability gives rise to dark cell degeneration and reduced cerebellar output. Similar molecular mechanisms have been implicated for SCA1, 2, 3, 7, 13, 14, 19, 22, 27 and 28, highlighting alterations to intrinsic Purkinje cell activity, dendritic architecture and glutamatergic transmission as possible common mechanisms downstream of various loss‐of‐function primary genetic defects. A key question for future research is whether similar mechanisms underlie progressive cerebellar decline in normal ageing. PMID:26821241

  19. Cerebellar-Dependent Eyeblink Conditioning Deficits in Schizophrenia Spectrum Disorders

    PubMed Central

    Forsyth, Jennifer K.; Bolbecker, Amanda R.; Mehta, Crystal S.; Klaunig, Mallory J.; Steinmetz, Joseph E.; O'Donnell, Brian F.; Hetrick, William P.

    2012-01-01

    Accumulating evidence suggests that abnormalities in neural circuitry and timing associated with the cerebellum may play a role in the pathophysiology of schizophrenia. Schizotypal personality disorder (SPD) may be genetically linked to schizophrenia, but individuals with SPD are freer from potential research confounds and may therefore offer insight into psychophysiological correlates of schizophrenia. The present study employed a delay eyeblink conditioning (EBC) procedure to examine cerebellar-dependent learning in schizophrenia, SPD, and healthy control subjects (n = 18 per group) who were matched for age and gender. The conditioned stimulus was a 400-ms tone that coterminated with a 50 ms unconditioned stimulus air puff. Cognitive performance on the Picture Completion, Digit Symbol Coding, Similarities, and Digit Span subscales of the Wechsler Adult Intelligence Scale—Third Edition was also investigated. The schizophrenia and SPD groups demonstrated robust EBC impairment relative to the control subjects; they had significantly fewer conditioned responses (CRs), as well as smaller CR amplitudes. Schizophrenia subjects showed cognitive impairment across subscales compared with SPD and control subjects; SPD subjects showed intermediate performance to schizophrenia and control subjects and performed significantly worse than controls on Picture Completion. Impaired EBC was significantly related to decreased processing speed in schizophrenia spectrum subjects. These findings support the role of altered cortico-cerebellar-thalamic-cortical circuitry in the pathophysiology of schizophrenia spectrum disorders. PMID:21148238

  20. Cerebellar involvement of Griscelli syndrome type 2

    PubMed Central

    Işikay, Sedat

    2014-01-01

    Griscelli syndrome type 2 is characterised by partial albinism and primary immunodeficiency. We present a case of a 3-year-old girl diagnosed with cerebellar involvement of Griscelli syndrome type 2. Neurological complications may accompany Griscelli syndrome, however, to the best of my knowledge there are only a few case reports of cerebellar involvement of Griscelli syndrome type 2 in the literature. PMID:25315806

  1. Hedgehog regulates cerebellar progenitor cell and medulloblastoma apoptosis.

    PubMed

    Noguchi, Kevin Kiyoshi; Cabrera, Omar Hoseá; Swiney, Brant S; Salinas-Contreras, Patricia; Smith, Julie Kathryn; Farber, Nuri B

    2015-11-01

    The external granule layer (EGL) is a proliferative region that produces over 90% of the neurons in the cerebellum but can also malignantly transform into a cerebellar tumor called the medulloblastoma (the most common malignant brain tumor in children). Current dogma considers Hedgehog stimulation a potent proliferative signal for EGL neural progenitor cells (NPCs) and medulloblastomas. However, the Hedgehog pathway also acts as a survival signal in the neural tube where it regulates dorsoventral patterning by controlling NPC apoptosis. Here we show that Hedgehog stimulation is also a potent survival signal in the EGL and medulloblastomas that produces a massive apoptotic response within hours of signal loss in mice. This toxicity can be produced by numerous Hedgehog antagonists (vismodegib, cyclopamine, and jervine) and is Bax/Bak dependent but p53 independent. Finally, since glucocorticoids can also induce EGL and medulloblastoma apoptosis, we show that Hedgehog's effects on apoptosis can occur independent of glucocorticoid stimulation. This effect may play a major role in cerebellar development by directing where EGL proliferation occurs thereby morphologically sculpting growth. It may also be a previously unknown major therapeutic effect of Hedgehog antagonists during medulloblastoma therapy. Results are discussed in terms of their implications for both cerebellar development and medulloblastoma treatment. PMID:26319366

  2. Mutations in PTF1A cause pancreatic and cerebellar agenesis.

    PubMed

    Sellick, Gabrielle S; Barker, Karen T; Stolte-Dijkstra, Irene; Fleischmann, Christina; Coleman, Richard J; Garrett, Christine; Gloyn, Anna L; Edghill, Emma L; Hattersley, Andrew T; Wellauer, Peter K; Goodwin, Graham; Houlston, Richard S

    2004-12-01

    Individuals with permanent neonatal diabetes mellitus usually present within the first three months of life and require insulin treatment. We recently identified a locus on chromosome 10p13-p12.1 involved in permanent neonatal diabetes mellitus associated with pancreatic and cerebellar agenesis in a genome-wide linkage search of a consanguineous Pakistani family. Here we report the further linkage analysis of this family and a second family of Northern European descent segregating an identical phenotype. Positional cloning identified the mutations 705insG and C886T in the gene PTF1A, encoding pancreas transcription factor 1alpha, as disease-causing sequence changes. Both mutations cause truncation of the expressed PTF1A protein C-terminal to the basic-helix-loop-helix domain. Reporter-gene studies using a minimal PTF1A deletion mutant indicate that the deleted region defines a new domain that is crucial for the function of this protein. PTF1A is known to have a role in mammalian pancreatic development, and the clinical phenotype of the affected individuals implicated the protein as a key regulator of cerebellar neurogenesis. The essential role of PTF1A in normal cerebellar development was confirmed by detailed neuropathological analysis of Ptf1a(-/-) mice. PMID:15543146

  3. Silencing abnormal wing disc gene of the Asian citrus psyllid, Diaphorina citri disrupts adult wing development and increases nymph mortality.

    PubMed

    El-Shesheny, Ibrahim; Hajeri, Subhas; El-Hawary, Ibrahim; Gowda, Siddarame; Killiny, Nabil

    2013-01-01

    Huanglongbing (HLB) causes considerable economic losses to citrus industries worldwide. Its management depends on controlling of the Asian citrus Psyllid (ACP), the vector of the bacterium, Candidatus Liberibacter asiaticus (CLas), the causal agent of HLB. Silencing genes by RNA interference (RNAi) is a promising tool to explore gene functions as well as control pests. In the current study, abnormal wing disc (awd) gene associated with wing development in insects is used to interfere with the flight of psyllids. Our study showed that transcription of awd is development-dependent and the highest level was found in the last instar (5(th)) of the nymphal stage. Micro-application (topical application) of dsRNA to 5(th) instar of nymphs caused significant nymphal mortality and adult wing-malformation. These adverse effects in ACP were positively correlated with the amounts of dsRNA used. A qRT-PCR analysis confirmed the dsRNA-mediated transcriptional down-regulation of the awd gene. Significant down-regulation was required to induce a wing-malformed phenotype. No effect was found when dsRNA-gfp was used, indicating the specific effect of dsRNA-awd. Our findings suggest a role for awd in ACP wing development and metamorphosis. awd could serve as a potential target for insect management either via direct application of dsRNA or by producing transgenic plants expressing dsRNA-awd. These strategies will help to mitigate HLB by controlling ACP.

  4. Electron beam irradiation induces abnormal development and the stabilization of p53 protein of American serpentine leafminer, Liriomyza trifolii (Burgess)

    NASA Astrophysics Data System (ADS)

    Koo, Hyun-Na; Yun, Seung-Hwan; Yoon, Changmann; Kim, Gil-Hah

    2012-01-01

    The American serpentine leafminer fly, Liriomyza trifolii (Burgess), is one of the most destructive polyphagous pests worldwide. In this study, we determined electron beam doses for inhibition of normal development of the leaf miner and investigated the effect of electron beam irradiation on DNA damage and p53 stability. Eggs (0-24 h old), larvae (2nd instar), puparia (0-24 h old after pupariation) and adults (24 h after emergence) were irradiated with increasing doses of electron beam irradiation (six levels between 30 and 200 Gy). At 150 Gy, the number of adults that developed from irradiated eggs, larvae and puparia was lower than in the untreated control. Fecundity and egg hatchability decreased depending on the doses applied. Reciprocal crosses between irradiated and unirradiated flies demonstrated that males were more radiotolerant than females. Adult longevity was not affected in all stages. The levels of DNA damage in L. trifolii adults were evaluated using the alkaline comet assay. Our results indicate that electron beam irradiation increased levels of DNA damage in a dose-dependent manner. Moreover, low doses of electron beam irradiation led to the rapid appearance of p53 protein within 6 h; however, it decreased after exposure to high doses (150 Gy and 200 Gy). These results suggest that electron beam irradiation induced not only abnormal development and reproduction but also p53 stability caused by DNA damage in L. trifolii. We conclude that a minimum dose of 150 Gy should be sufficient for female sterilization of L. trifolii.

  5. Can Signal Abnormalities Detected with MR Imaging in Knee Articular Cartilage Be Used to Predict Development of Morphologic Cartilage Defects? 48-Month Data from the Osteoarthritis Initiative.

    PubMed

    Schwaiger, Benedikt J; Gersing, Alexandra S; Mbapte Wamba, John; Nevitt, Michael C; McCulloch, Charles E; Link, Thomas M

    2016-10-01

    Purpose To determine the incidence with which morphologic articular cartilage defects develop over 48 months in cartilage with signal abnormalities at baseline magnetic resonance (MR) imaging in comparison with the incidence in articular cartilage without signal abnormalities at baseline. Materials and Methods The institutional review boards of all participating centers approved this HIPAA-compliant study. Right knees of 90 subjects from the Osteoarthritis Initiative (mean age, 55 years ± 8 [standard deviation]; 51% women) with cartilage signal abnormalities but without morphologic cartilage defects at 3.0-T MR imaging and without radiographic osteoarthritis (Kellgren-Lawrence score, 0-1) were frequency matched for age, sex, Kellgren-Lawrence score, and body mass index with right knees in 90 subjects without any signal abnormalities or morphologic defects in the articular cartilage (mean age, 54 years ± 5; 51% women). Individual signal abnormalities (n = 126) on intermediate-weighted fast spin-echo MR images were categorized into four subgrades: subgrade A, hypointense; subgrade B, inhomogeneous; subgrade C, hyperintense; and subgrade D, hyperintense with swelling. The development of morphologic articular cartilage defects (Whole-Organ MR Imaging Score ≥2) at 48 months was analyzed on a compartment level and was compared between groups by using generalized estimating equation logistic regression models. Results Cartilage signal abnormalities were more frequent in the patellofemoral joint than in the tibiofemoral joint (59.5% vs 39.5%). Subgrade A was seen more frequently than were subgrades C and D (36% vs 22%). Incidence of morphologic cartilage defects at 48 months was 57% in cartilage with baseline signal abnormalities, while only 4% of compartments without baseline signal abnormalities developed morphologic defects at 48 months (all compartments combined and each compartment separately, P < .01). The development of morphologic defects was not significantly

  6. Prenatal exposure to sodium valproate alters androgen receptor expression in the developing cerebellum in a region and age specific manner in male and female rats.

    PubMed

    Perez-Pouchoulen, Miguel; Miquel, Marta; Saft, Paul; Brug, Brenda; Toledo, Rebeca; Hernandez, Maria Elena; Manzo, Jorge

    2016-10-01

    Valproic acid (VPA) is an anti-epileptic drug with teratogenicity activity that has been related to autism. In rodents, exposure to VPA in utero leads to brain abnormalities similar than those reported in the autistic brain. Particularly, VPA reduces the number of Purkinje neurons in the rat cerebellum parallel to cerebellar abnormalities found in autism. Thus, we injected pregnant females on embryonic day 12 either with VPA (600mg/kg, i.p.) or 0.9% saline solution and obtained the cerebellum from their offspring at different postnatal time points. Testosterone has been linked to autism and plays an important role during brain development. Therefore, we identified and analyzed the androgen receptor (AR) by immunohistochemistry and densitometry, respectively. We found VPA decreases AR density in the superficial Purkinje layer only in cerebellar lobule 8 at PN7, but increased it at PN14 compared to control in males. In females, VPA decreased AR density in the superficial Purkinje layer in cerebellar lobule 6 at PN14, but increased it in lobule 9 at the same time point. No differences were found in the deep Purkinje layer of any cerebellar lobule in terms of AR density neither in males nor females. We additionally found a particular AR density decreasing in both superficial and deep regions across development in the majority of cerebellar lobules in males, but in all cerebellar lobules in females. Thus, our results indicate that VPA disrupts the AR ontogeny in the developing cerebellum in an age and region specific manner in male and female rats. Future epigenetic studies including the evaluation of histone deacetylases (HDAC's) might shed light these results as HDAC's are expressed by Purkinje neurons, interact with the AR and are VPA targets. This work contributes to the understanding of the cerebellar development and it might help to understand the role of the cerebellum in neurodevelopmental disorders such as autism.

  7. Frequency and patterns of abnormality detected by iodine-123 amine emission CT after cerebral infarction

    SciTech Connect

    Brott, T.G.; Gelfand, M.J.; Williams, C.C.; Spilker, J.A.; Hertzberg, V.S.

    1986-03-01

    Single photon emission computed tomography (SPECT) was performed in 31 patients with cerebral infarction and 13 who had had transient ischemic attacks, using iodine-123-labeled N,N,N'-trimethyl-N'-(2-hydroxyl-3-methyl-5-iodobenzyl)-1,3-propanediamin e (I-123-HIPDM) as the radiopharmaceutical. SPECT scans were compared with computed tomographic (CT) scans. SPECT was as sensitive as CT in detecting cerebral infarction (94% vs. 84%). The abnormalities were larger on the SPECT scans than on the CT scans in 19 cases, equal in seven, and smaller in five (SPECT abnormalities greater than or equal to CT abnormalities in 86% of cases). Fifteen of 30 patients with hemispheric infarction had decreased perfusion (decreased uptake of I-123-HIPDM) to the cerebellar hemisphere contralateral to the cerebral hemisphere involved by the infarction (crossed cerebellar diaschisis). Nine of these 15 patients had major motor deficits, while only one of the 15 without crossed cerebellar diaschisis had a major motor deficit.

  8. Morphological abnormalities during early-life development of the estuarine mummichog, Fundulus heteroclitus, as an indicator of androgenic and anti-androgenic endocrine disruption.

    PubMed

    Boudreau, Monica; Courtenay, Simon C; Maclatchy, Deborah L; Bérubé, Céline H; Hewitt, L Mark; Van Der Kraak, Glen J

    2005-03-01

    We tested the hypothesis that gross morphological abnormalities are a sensitive indicator of exposure to waterborne androgenic and anti-androgenic compounds during embryonic, larval and juvenile stages of development in the common estuarine killifish, the mummichog (Fundulus heteroclitus; Pisces: Cyprinodontidae). Static exposures with daily renewal were carried out with 10-100,000 ng/L of the androgen agonist, 17alpha-methyltestosterone (MT), or the androgen antagonist, cyproterone acetate (CA), for 60 days post-fertilization (PF) in duplicate exposures. Measured concentrations were 78.4-155.8% of nominal concentrations for MT and 13.5-168.1% for CA. No dose-related or consistent effects of MT or CA were observed before hatch. In 60 days PF juveniles, incidence of skeletal abnormalities (scoliosis, lordosis, head, facial and fin), soft tissue abnormality (anal swelling) and hemorrhaging were significantly increased by MT but only at high concentrations (> or =1000 ng/L). The 10,000 and 100,000 ng/L concentrations of MT produced a wider range of abnormalities than 1000ng/L. Over 90% of fish exposed to 10,000 or 100,000 ng/L were abnormal with an average of over 3.5 abnormalities per fish. CA did not increase the incidence of any type of abnormality. Survival of juveniles to the end of the exposure was reduced by MT at concentrations of 1000 ng/L and greater in the first experiment and at concentrations of 10,000 ng/L and greater in the second experiment. Juvenile length was reduced by high concentrations of MT (> or =10,000 ng/L) in the first experiment and by most concentrations in the second experiment. We conclude that morphological abnormalities in early-life stages of mummichogs are not a sensitive indicator of exposure to androgenic or anti-androgenic waterborne EDSs at environmentally relevant concentrations.

  9. [Genetic nature of abnormal larval development in the progeny of l(1)ts403(sbr10) females of Drosophila melanogaster].

    PubMed

    Pugacheva, O M; Mamon, L A

    2005-01-01

    In Drosophila melanogaster the small bristles (sbr) gene is vital and evolutionary conservative and controls nuclear export of mRNA. Sbr mutant alleles had a broad pleiotropic effect. High frequency of abnormal larva dying (up to 18 %) at the first instar stage in progeny of heat shock (37 degrees C, 1 h) treated mutant females is one of the most interesting l(l)ts403(sbr10) allele effects. Abnormal larvae display characteristic phenotype that involves the Malpighian tubules defect. Using interphase FISH method (fluorescence in situ hybridization), we showed that abnormal larvae had monosomy on chromosomes 2 and 3. DNA content in neuroblast interphase nuclei of abnormal larvae is 2.1 times less than in normal larvae. We suggest that abnormal larvae could be full or mosaic haploids that appeared as a result of maternal genome loss during fertilization or the mitotic division. Larvae with the same abnormalities appear in a progeny of females with different genotypes mating with males carrying compound chromosomes 2 or 3. FISH analysis showed that such larvae had monosomy only on a chromosome that is compound in paternal strain. Thus, monosomy on large autosomes may cause aspecial phenotype of abnormal larvae in D. melanogaster.

  10. Altered corticomotor-cerebellar integrity in young ataxia telangiectasia patients.

    PubMed

    Sahama, Ishani; Sinclair, Kate; Fiori, Simona; Pannek, Kerstin; Lavin, Martin; Rose, Stephen

    2014-09-01

    Magnetic resonance imaging (MRI) research in identifying altered brain structure and function in ataxia-telangiectasia, an autosomal recessive neurodegenerative disorder, is limited. Diffusion-weighted MRI were obtained from 11 ataxia telangiectasia patients (age range, 7-22 years; mean, 12 years) and 11 typically developing age-matched participants (age range, 8-23 years; mean, 13 years). Gray matter volume alterations in patients were compared with those of healthy controls using voxel-based morphometry, whereas tract-based spatial statistics was employed to elucidate white matter microstructure differences between groups. White matter microstructure was probed using quantitative fractional anisotropy and mean diffusivity measures. Reduced gray matter volume in both cerebellar hemispheres and in the precentral-postcentral gyrus in the left cerebral hemisphere was observed in ataxia telangiectasia patients compared with controls (P < 0.05, corrected for multiple comparisons). A significant reduction in fractional anisotropy in the cerebellar hemispheres, anterior/posterior horns of the medulla, cerebral peduncles, and internal capsule white matter, particularly in the left posterior limb of the internal capsule and corona radiata in the left cerebral hemisphere, was observed in patients compared with controls (P < 0.05). Mean diffusivity differences were observed within the left cerebellar hemisphere and the white matter of the superior lobule of the right cerebellar hemisphere (P < 0.05). Cerebellum-localized gray matter changes are seen in young ataxia telangiectasia patients along with white matter tract degeneration projecting from the cerebellum into corticomotor regions. The lack of cortical involvement may reflect early-stage white matter motor pathway degeneration within young patients. PMID:25042086

  11. Blocking Endogenous Leukemia Inhibitory Factor During Placental Development in Mice Leads to Abnormal Placentation and Pregnancy Loss

    PubMed Central

    Winship, Amy; Correia, Jeanne; Krishnan, Tara; Menkhorst, Ellen; Cuman, Carly; Zhang, Jian-Guo; Nicola, Nicos A.; Dimitriadis, Evdokia

    2015-01-01

    The placenta forms the interface between the maternal and fetal circulation and is critical for the establishment of a healthy pregnancy. Specialized trophoblast cells derived from the embryonic trophectoderm play a pivotal role in the establishment of the placenta. Leukemia inhibitory factor (LIF) is one of the predominant cytokines present in the placenta during early pregnancy. LIF has been shown to regulate trophoblast adhesion and invasion in vitro, however its precise role in vivo is unknown. We hypothesized that LIF would be required for normal placental development in mice. LIF and LIFRα were immunolocalized to placental trophoblasts and fetal vessels in mouse implantation sites during mid-gestation. Temporally blocking LIF action during specific periods of placental development via intraperitoneal administration of our specific LIFRα antagonist, PEGLA, resulted in abnormal placental trophoblast and vascular morphology and reduced activated STAT3 but not ERK. Numerous genes regulating angiogenesis and oxidative stress were altered in the placenta in response to LIF inhibition. Pregnancy viability was also significantly compromised in PEGLA treated mice. Our data suggest that LIF plays an important role in placentation in vivo and the maintenance of healthy pregnancy. PMID:26272398

  12. Clinical, neuroradiological and molecular characterization of cerebellar dysplasia with cysts (Poretti-Boltshauser syndrome).

    PubMed

    Micalizzi, Alessia; Poretti, Andrea; Romani, Marta; Ginevrino, Monia; Mazza, Tommaso; Aiello, Chiara; Zanni, Ginevra; Baumgartner, Bastian; Borgatti, Renato; Brockmann, Knut; Camacho, Ana; Cantalupo, Gaetano; Haeusler, Martin; Hikel, Christiane; Klein, Andrea; Mandrile, Giorgia; Mercuri, Eugenio; Rating, Dietz; Romaniello, Romina; Santorelli, Filippo Maria; Schimmel, Mareike; Spaccini, Luigina; Teber, Serap; von Moers, Arpad; Wente, Sarah; Ziegler, Andreas; Zonta, Andrea; Bertini, Enrico; Boltshauser, Eugen; Valente, Enza Maria

    2016-08-01

    Cerebellar dysplasia with cysts and abnormal shape of the fourth ventricle, in the absence of significant supratentorial anomalies and of muscular involvement, defines recessively inherited Poretti-Boltshauser syndrome (PBS). Clinical features comprise non-progressive cerebellar ataxia, intellectual disability of variable degree, language impairment, ocular motor apraxia and frequent occurrence of myopia or retinopathy. Recently, loss-of-function variants in the LAMA1 gene were identified in six probands with PBS. Here we report the detailed clinical, neuroimaging and genetic characterization of 18 PBS patients from 15 unrelated families. Biallelic LAMA1 variants were identified in 14 families (93%). The only non-mutated proband presented atypical clinical and neuroimaging features, challenging the diagnosis of PBS. Sixteen distinct variants were identified, which were all novel. In particular, the frameshift variant c.[2935delA] recurred in six unrelated families on a shared haplotype, suggesting a founder effect. No LAMA1 variants could be detected in 27 probands with different cerebellar dysplasias or non-progressive cerebellar ataxia, confirming the strong correlate between LAMA1 variants and PBS. PMID:26932191

  13. Clinical, neuroradiological and molecular characterization of cerebellar dysplasia with cysts (Poretti-Boltshauser syndrome)

    PubMed Central

    Romani, Marta; Ginevrino, Monia; Mazza, Tommaso; Aiello, Chiara; Zanni, Ginevra; Baumgartner, Bastian; Borgatti, Renato; Brockmann, Knut; Camacho, Ana; Cantalupo, Gaetano; Haeusler, Martin; Hikel, Christiane; Klein, Andrea; Mandrile, Giorgia; Mercuri, Eugenio; Rating, Dietz; Romaniello, Romina; Santorelli, Filippo Maria; Schimmel, Mareike; Spaccini, Luigina; Teber, Serap; von Moers, Arpad; Wente, Sarah; Ziegler, Andreas; Zonta, Andrea; Bertini, Enrico; Boltshauser, Eugen; Valente, Enza Maria

    2016-01-01

    Cerebellar dysplasia with cysts and abnormal shape of the fourth ventricle, in the absence of significant supratentorial anomalies and of muscular involvement, defines recessively inherited Poretti-Boltshauser syndrome (PBS). Clinical features comprise non-progressive cerebellar ataxia, intellectual disability of variable degree, language impairment, ocular motor apraxia and frequent occurrence of myopia or retinopathy. Recently, loss-of-function variants in the LAMA1 gene were identified in six probands with PBS. Here we report the detailed clinical, neuroimaging and genetic characterization of 18 PBS patients from 15 unrelated families. Biallelic LAMA1 variants were identified in 14 families (93%). The only non-mutated proband presented atypical clinical and neuroimaging features, challenging the diagnosis of PBS. Sixteen distinct variants were identified, which were all novel. In particular, the frameshift variant c.[2935delA] recurred in six unrelated families on a shared haplotype, suggesting a founder effect. No LAMA1 variants could be detected in 27 probands with different cerebellar dysplasias or non-progressive cerebellar ataxia, confirming the strong correlate between LAMA1 variants and PBS. PMID:26932191

  14. LXR agonist rescued the deficit in the proliferation of the cerebellar granule cells induced by dexamethasone.

    PubMed

    Bian, Xuting; Zhong, Hongyu; Li, Fen; Cai, Yulong; Li, Xin; Wang, Lian; Fan, Xiaotang

    2016-09-01

    Dexamethasone (DEX) exposure during early postnatal life produces permanent neuromotor and intellectual deficits and stunts cerebellar growth. The liver X receptor (LXR) plays important roles in CNS development. However, the effects of LXR on the DEX-mediated impairment of cerebellar development remain undetermined. Thus, mice were pretreated with LXR agonist TO901317 (TO) and were later exposed to DEX to evaluate its protective effects on DEX-mediated deficit during cerebellar development. The results showed that an acute exposure of DEX on postnatal day 7 resulted in a significant impairment in cerebellar development and decreased the proliferation of granule neuron precursors in the external granule layer of cerebellum. This effect was attenuated by pretreatment with TO. We further found that the decrease in the proliferation caused by DEX occurred via up-regulation of glucocorticoid receptor and p27kip1, which could be partially prevented by LXR agonist pretreatment. Overall, our results suggest that LXR agonist pretreatment could protect against DEX-induced deficits in cerebellar development in postnatal mice and may thus be perspective recruited to counteract such GC side effects. PMID:27369072

  15. Abnormal immune system development and function in schizophrenia helps reconcile diverse findings and suggests new treatment and prevention strategies.

    PubMed

    Anders, Sherry; Kinney, Dennis K

    2015-08-18

    Extensive research implicates disturbed immune function and development in the etiology and pathology of schizophrenia. In addition to reviewing evidence for immunological factors in schizophrenia, this paper discusses how an emerging model of atypical immune function and development helps explain a wide variety of well-established - but puzzling - findings about schizophrenia. A number of theorists have presented hypotheses that early immune system programming, disrupted by pre- and perinatal adversity, often combines with abnormal brain development to produce schizophrenia. The present paper focuses on the hypothesis that disruption of early immune system development produces a latent immune vulnerability that manifests more fully after puberty, when changes in immune function and the thymus leave individuals more susceptible to infections and immune dysfunctions that contribute to schizophrenia. Complementing neurodevelopmental models, this hypothesis integrates findings on many contributing factors to schizophrenia, including prenatal adversity, genes, climate, migration, infections, and stress, among others. It helps explain, for example, why (a) schizophrenia onset is typically delayed until years after prenatal adversity, (b) individual risk factors alone often do not lead to schizophrenia, and (c) schizophrenia prevalence rates actually tend to be higher in economically advantaged countries. Here we discuss how the hypothesis explains 10 key findings, and suggests new, potentially highly cost-effective, strategies for treatment and prevention of schizophrenia. Moreover, while most human research linking immune factors to schizophrenia has been correlational, these strategies provide ethical ways to experimentally test in humans theories about immune function and schizophrenia. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.

  16. Characterization of the skeletal fusion with sterility (sks) mouse showing axial skeleton abnormalities caused by defects of embryonic skeletal development.

    PubMed

    Akiyama, Kouyou; Katayama, Kentaro; Tsuji, Takehito; Kunieda, Tetsuo

    2014-01-01

    The development of the axial skeleton is a complex process, consisting of segmentation and differentiation of somites and ossification of the vertebrae. The autosomal recessive skeletal fusion with sterility (sks) mutation of the mouse causes skeletal malformations due to fusion of the vertebrae and ribs, but the underlying defects of vertebral formation during embryonic development have not yet been elucidated. For the present study, we examined the skeletal phenotypes of sks/sks mice during embryonic development and the chromosomal localization of the sks locus. Multiple defects of the axial skeleton, including fusion of vertebrae and fusion and bifurcation of ribs, were observed in adult and neonatal sks/sks mice. In addition, we also found polydactyly and delayed skull ossification in the sks/sks mice. Morphological defects, including disorganized vertebral arches and fusions and bifurcations of the axial skeletal elements, were observed during embryonic development at embryonic day 12.5 (E12.5) and E14.5. However, no morphological abnormality was observed at E11.5, indicating that defects of the axial skeleton are caused by malformation of the cartilaginous vertebra and ribs at an early developmental stage after formation and segmentation of the somites. By linkage analysis, the sks locus was mapped to an 8-Mb region of chromosome 4 between D4Mit331 and D4Mit199. Since no gene has already been identified as a cause of malformation of the vertebra and ribs in this region, the gene responsible for sks is suggested to be a novel gene essential for the cartilaginous vertebra and ribs.

  17. Gene expression as a sensitive endpoint to evaluate cell differentiation and maturation of the developing central nervous system in primary cultures of rat cerebellar granule cells (CGCs) exposed to pesticides

    SciTech Connect

    Hogberg, Helena T.; Kinsner-Ovaskainen, Agnieszka; Hartung, Thomas; Coecke, Sandra; Bal-Price, Anna K.

    2009-03-15

    The major advantage of primary neuronal cultures for developmental neurotoxicity (DNT) testing is their ability to replicate the crucial stages of neurodevelopment. In our studies using primary culture of cerebellar granule cells (CGCs) we have evaluated whether the gene expression relevant to the most critical developmental processes such as neuronal differentiation (NF-68 and NF-200) and functional maturation (NMDA and GABA{sub A} receptors), proliferation and differentiation of astrocytes (GFAP and S100{beta}) as well as the presence of neural precursor cells (nestin and Sox10) could be used as an endpoint for in vitro DNT. The expression of these genes was assessed after exposure to various pesticides (paraquat parathion, dichlorvos, pentachlorophenol and cycloheximide) that could induce developmental neurotoxicity through different mechanisms. All studied pesticides significantly modified the expression of selected genes, related to the different stages of neuronal and/or glial cell development and maturation. The most significant changes were observed after exposure to paraquat and parathion (i.e. down-regulation of mRNA expression of NF-68 and NF-200, NMDA and GABA{sub A} receptors). Similarly, dichlorvos affected mainly neurons (decreased mRNA expression of NF-68 and GABA{sub A} receptors) whereas cycloheximide had an effect on neurons and astrocytes, as significant decreases in the mRNA expression of both neurofilaments (NF-68 and NF-200) and the astrocyte marker (S100{beta}) were observed. Our results suggest that toxicity induced by pesticides that target multiple pathways of neurodevelopment can be identified by studying expression of genes that are involved in different stages of cell development and maturation, and that gene expression could be used as a sensitive endpoint for initial screening to identify the compounds with the potential to cause developmental neurotoxicity.

  18. Cerebellar Ataxia and Glutamic Acid Decarboxylase Antibodies

    PubMed Central

    Ariño, Helena; Gresa-Arribas, Nuria; Blanco, Yolanda; Martínez-Hernández, Eugenia; Sabater, Lidia; Petit-Pedrol, Mar; Rouco, Idoia; Bataller, Luis; Dalmau, Josep O.; Saiz, Albert; Graus, Francesc

    2016-01-01

    IMPORTANCE Current clinical and immunologic knowledge on cerebellar ataxia (CA) with glutamic acid decarboxylase 65 antibodies (GAD65-Abs) is based on case reports and small series with short-term follow-up data. OBJECTIVE To report the symptoms, additional antibodies, prognostic factors, and long-term outcomes in a cohort of patients with CA and GAD65-Abs. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study and laboratory investigations at a center for autoimmune neurologic disorders among 34 patients with CA and GAD65-Abs, including 25 with long-term follow-up data (median, 5.4 years; interquartile range, 3.1-10.3 years). MAIN OUTCOMES AND MEASURES Analysis of clinicoimmunologic features and predictors of response to immunotherapy. Immunochemistry on rat brain, cultured neurons, and human embryonic kidney cells expressing GAD65, GAD67, α1-subunit of the glycine receptor, and a repertoire of known cell surface autoantigens were used to identify additional antibodies. Twenty-eight patients with stiff person syndrome and GAD65-Abs served as controls. RESULTS The median age of patients was 58 years (range, 33-80 years); 28 of 34 patients (82%) were women. Nine patients (26%) reported episodes of brainstem and cerebellar dysfunction or persistent vertigo several months before developing CA. The clinical presentation was subacute during a period of weeks in 13 patients (38%). Nine patients (26%) had coexisting stiff person syndrome symptoms. Systemic organ-specific autoimmunities (type 1 diabetes mellitus and others) were present in 29 patients (85%). Twenty of 25 patients with long-term follow-up data received immunotherapy (intravenous immunoglobulin in 10 and corticosteroids and intravenous immunoglobulin or other immunosuppressors in 10), and 7 of them (35%) improved. Predictors of clinical response included subacute onset of CA (odds ratio [OR], 0.50; 95% CI, 0.25-0.99; P = .047) and prompt immunotherapy (OR, 0.98; 95% CI, 0.96-0.99; P = .01). Similar

  19. Inhibition of tyrosine kinase receptors by SU6668 promotes abnormal stromal development at the periphery of carcinomas

    PubMed Central

    Farace, P; Galiè, M; Merigo, F; Daducci, A; Calderan, L; Nicolato, E; Degrassi, A; Pesenti, E; Sbarbati, A; Marzola, P

    2009-01-01

    Dynamic contrast-enhanced (albumin-Gd-DTPA) magnetic resonance imaging, performed during 2 weeks of daily administration of an inhibitor of tyrosine kinase receptors (SU6668) in an HT-29 colon carcinoma model, revealed the onset of a hyper-enhancing rim, not observed in untreated tumours. To account for tissue heterogeneity in the quantitative analysis, we segmented tumours into three subunits automatically identified by cluster analysis of the enhancement curves using a k-means algorithm. Transendothelial permeability (Kps) and fractional plasma volume (fPV) were calculated in each subunit. An avascular and necrotic region, an intermediate zone and a well-vascularised periphery were reliably identified. During untreated tumour growth, the identified sub-regions did not substantially change their enhancement pattern. Treatment with SU6668 induced major changes at tumour periphery where a significant increase of Kps and fPV was observed with respect to control tumours. Histology revealed a sub-capsular layer composed of hyper-dense viable tumour cells in the periphery of untreated tumours. The rim of viable neoplastic cells was reduced in treated tumours, and replaced by loose connective tissue characterised by numerous vessels, which explains the observed hyper-enhancement. The present data show a peripheral abnormal development of cancer-associated stroma, indicative of an adaptive response to anti-angiogenic treatment. PMID:19384298

  20. Potential Adverse Effects of Prolonged Sevoflurane Exposure on Developing Monkey Brain: From Abnormal Lipid Metabolism to Neuronal Damage.

    PubMed

    Liu, Fang; Rainosek, Shuo W; Frisch-Daiello, Jessica L; Patterson, Tucker A; Paule, Merle G; Slikker, William; Wang, Cheng; Han, Xianlin

    2015-10-01

    Sevoflurane is a volatile anesthetic that has been widely used in general anesthesia, yet its safety in pediatric use is a public concern. This study sought to evaluate whether prolonged exposure of infant monkeys to a clinically relevant concentration of sevoflurane is associated with any adverse effects on the developing brain. Infant monkeys were exposed to 2.5% sevoflurane for 9 h, and frontal cortical tissues were harvested for DNA microarray, lipidomics, Luminex protein, and histological assays. DNA microarray analysis showed that sevoflurane exposure resulted in a broad identification of differentially expressed genes (DEGs) in the monkey brain. In general, these genes were associated with nervous system development, function, and neural cell viability. Notably, a number of DEGs were closely related to lipid metabolism. Lipidomic analysis demonstrated that critical lipid components, (eg, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol) were significantly downregulated by prolonged exposure of sevoflurane. Luminex protein analysis indicated abnormal levels of cytokines in sevoflurane-exposed brains. Consistently, Fluoro-Jade C staining revealed more degenerating neurons after sevoflurane exposure. These data demonstrate that a clinically relevant concentration of sevoflurane (2.5%) is capable of inducing and maintaining an effective surgical plane of anesthesia in the developing nonhuman primate and that a prolonged exposure of 9 h resulted in profound changes in gene expression, cytokine levels, lipid metabolism, and subsequently, neuronal damage. Generally, sevoflurane-induced neuronal damage was also associated with changes in lipid content, composition, or both; and specific lipid changes could provide insights into the molecular mechanism(s) underlying anesthetic-induced neurotoxicity and may be sensitive biomarkers for the early detection of anesthetic-induced neuronal damage.

  1. Multiple Renal Cyst Development but Not Situs Abnormalities in Transgenic RNAi Mice against Inv::GFP Rescue Gene

    PubMed Central

    Kamijho, Yuki; Shiozaki, Yayoi; Sakurai, Eiki; Hanaoka, Kazunori; Watanabe, Daisuke

    2014-01-01

    In this study we generated RNA interference (RNAi)-mediated gene knockdown transgenic mice (transgenic RNAi mice) against the functional Inv gene. Inv mutant mice show consistently reversed internal organs (situs inversus), multiple renal cysts and neonatal lethality. The Inv::GFP-rescue mice, which introduced the Inv::GFP fusion gene, can rescue inv mutant mice phenotypes. This indicates that the Inv::GFP gene is functional in vivo. To analyze the physiological functions of the Inv gene, and to demonstrate the availability of transgenic RNAi mice, we introduced a short hairpin RNA expression vector against GFP mRNA into Inv::GFP-rescue mice and analyzed the gene silencing effects and Inv functions by examining phenotypes. Transgenic RNAi mice with the Inv::GFP-rescue gene (Inv-KD mice) down-regulated Inv::GFP fusion protein and showed hypomorphic phenotypes of inv mutant mice, such as renal cyst development, but not situs abnormalities or postnatal lethality. This indicates that shRNAi-mediated gene silencing systems that target the tag sequence of the fusion gene work properly in vivo, and suggests that a relatively high level of Inv protein is required for kidney development in contrast to left/right axis determination. Inv::GFP protein was significantly down-regulated in the germ cells of Inv-KD mice testis compared with somatic cells, suggesting the existence of a testicular germ cell-specific enhanced RNAi system that regulates germ cell development. The Inv-KD mouse is useful for studying Inv gene functions in adult tissue that are unable to be analyzed in inv mutant mice showing postnatal lethality. In addition, the shRNA-based gene silencing system against the tag sequence of the fusion gene can be utilized as a new technique to regulate gene expression in either in vitro or in vivo experiments. PMID:24586938

  2. Genetically induced abnormal cranial development in human trisomy 18 with holoprosencephaly: comparisons with the normal tempo of osteogenic-neural development.

    PubMed

    Reid, Shaina N; Ziermann, Janine M; Gondré-Lewis, Marjorie C

    2015-07-01

    Craniofacial malformations are common congenital defects caused by failed midline inductive signals. These midline defects are associated with exposure of the fetus to exogenous teratogens and with inborn genetic errors such as those found in Down, Patau, Edwards' and Smith-Lemli-Opitz syndromes. Yet, there are no studies that analyze contributions of synchronous neurocranial and neural development in these disorders. Here we present the first in-depth analysis of malformations of the basicranium of a holoprosencephalic (HPE) trisomy 18 (T18; Edwards' syndrome) fetus with synophthalmic cyclopia and alobar HPE. With a combination of traditional gross dissection and state-of-the-art computed tomography, we demonstrate the deleterious effects of T18 caused by a translocation at 18p11.31. Bony features included a single developmentally unseparated frontal bone, and complete dual absence of the anterior cranial fossa and ethmoid bone. From a superior view with the calvarium plates removed, there was direct visual access to the orbital foramen and hard palate. Both the eyes and the pituitary gland, normally protected by bony structures, were exposed in the cranial cavity and in direct contact with the brain. The middle cranial fossa was shifted anteriorly, and foramina were either missing or displaced to an abnormal location due to the absence or misplacement of its respective cranial nerve (CN). When CN development was conserved in its induction and placement, the respective foramen developed in its normal location albeit with abnormal gross anatomical features, as seen in the facial nerve (CNVII) and the internal acoustic meatus. More anteriorly localized CNs and their foramina were absent or heavily disrupted compared with posterior ones. The severe malformations exhibited in the cranial fossae, orbital region, pituitary gland and sella turcica highlight the crucial involvement of transcription factors such as TGIF, which is located on chromosome 18 and contributes

  3. Cerebellar modules operate at different frequencies

    PubMed Central

    Zhou, Haibo; Lin, Zhanmin; Voges, Kai; Ju, Chiheng; Gao, Zhenyu; Bosman, Laurens WJ; Ruigrok, Tom JH; Hoebeek, Freek E

    2014-01-01

    Due to the uniform cyto-architecture of the cerebellar cortex, its overall physiological characteristics have traditionally been considered to be homogeneous. In this study, we show in awake mice at rest that spiking activity of Purkinje cells, the sole output cells of the cerebellar cortex, differs between cerebellar modules and correlates with their expression of the glycolytic enzyme aldolase C or zebrin. Simple spike and complex spike frequencies were significantly higher in Purkinje cells located in zebrin-negative than zebrin-positive modules. The difference in simple spike frequency persisted when the synaptic input to, but not intrinsic activity of, Purkinje cells was manipulated. Blocking TRPC3, the effector channel of a cascade of proteins that have zebrin-like distribution patterns, attenuated the simple spike frequency difference. Our results indicate that zebrin-discriminated cerebellar modules operate at different frequencies, which depend on activation of TRPC3, and that this property is relevant for all cerebellar functions. DOI: http://dx.doi.org/10.7554/eLife.02536.001 PMID:24843004

  4. Genetics Home Reference: autosomal recessive cerebellar ataxia type 1

    MedlinePlus

    ... Health Conditions ARCA1 autosomal recessive cerebellar ataxia type 1 Enable Javascript to view the expand/collapse boxes. ... Close All Description Autosomal recessive cerebellar ataxia type 1 ( ARCA1 ) is a condition characterized by progressive problems ...

  5. Neurodevelopmental malformations of the cerebellar vermis in genetically engineered rats

    EPA Science Inventory

    The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformati...

  6. Epiphyseal abnormalities, trabecular bone loss and articular chondrocyte hypertrophy develop in the long bones of postnatal Ext1-deficient mice.

    PubMed

    Sgariglia, Federica; Candela, Maria Elena; Huegel, Julianne; Jacenko, Olena; Koyama, Eiki; Yamaguchi, Yu; Pacifici, Maurizio; Enomoto-Iwamoto, Motomi

    2013-11-01

    Long bones are integral components of the limb skeleton. Recent studies have indicated that embryonic long bone development is altered by mutations in Ext genes and consequent heparan sulfate (HS) deficiency, possibly due to changes in activity and distribution of HS-binding/growth plate-associated signaling proteins. Here we asked whether Ext function is continuously required after birth to sustain growth plate function and long bone growth and organization. Compound transgenic Ext1(f/f);Col2CreERT mice were injected with tamoxifen at postnatal day 5 (P5) to ablate Ext1 in cartilage and monitored over time. The Ext1-deficient mice exhibited growth retardation already by 2weeks post-injection, as did their long bones. Mutant growth plates displayed a severe disorganization of chondrocyte columnar organization, a shortened hypertrophic zone with low expression of collagen X and MMP-13, and reduced primary spongiosa accompanied, however, by increased numbers of TRAP-positive osteoclasts at the chondro-osseous border. The mutant epiphyses were abnormal as well. Formation of a secondary ossification center was significantly delayed but interestingly, hypertrophic-like chondrocytes emerged within articular cartilage, similar to those often seen in osteoarthritic joints. Indeed, the cells displayed a large size and round shape, expressed collagen X and MMP-13 and were surrounded by an abundant Perlecan-rich pericellular matrix not seen in control articular chondrocytes. In addition, ectopic cartilaginous outgrowths developed on the lateral side of mutant growth plates over time that resembled exostotic characteristic of children with Hereditary Multiple Exostoses, a syndrome caused by Ext mutations and HS deficiency. In sum, the data do show that Ext1 is continuously required for postnatal growth and organization of long bones as well as their adjacent joints. Ext1 deficiency elicits defects that can occur in human skeletal conditions including trabecular bone loss

  7. Absence of the lysophosphatidic acid receptor LPA1 results in abnormal bone development and decreased bone mass.

    PubMed

    Gennero, Isabelle; Laurencin-Dalicieux, Sara; Conte-Auriol, Françoise; Briand-Mésange, Fabienne; Laurencin, Danielle; Rue, Jackie; Beton, Nicolas; Malet, Nicole; Mus, Marianne; Tokumura, Akira; Bourin, Philippe; Vico, Laurence; Brunel, Gérard; Oreffo, Richard O C; Chun, Jerold; Salles, Jean Pierre

    2011-09-01

    Lysophosphatidic acid (LPA) is a lipid mediator that acts in paracrine systems via interaction with a subset of G protein-coupled receptors (GPCRs). LPA promotes cell growth and differentiation, and has been shown to be implicated in a variety of developmental and pathophysiological processes. At least 6 LPA GPCRs have been identified to date: LPA1-LPA6. Several studies have suggested that local production of LPA by tissues and cells contributes to paracrine regulation, and a complex interplay between LPA and its receptors, LPA1 and LPA4, is believed to be involved in the regulation of bone cell activity. In particular, LPA1 may activate both osteoblasts and osteoclasts. However, its role has not as yet been examined with regard to the overall status of bone in vivo. We attempted to clarify this role by defining the bone phenotype of LPA1((-/-)) mice. These mice demonstrated significant bone defects and low bone mass, indicating that LPA1 plays an important role in osteogenesis. The LPA1((-/-)) mice also presented growth and sternal and costal abnormalities, which highlights the specific roles of LPA1 during bone development. Microcomputed tomography and histological analysis demonstrated osteoporosis in the trabecular and cortical bone of LPA1((-/-)) mice. Finally, bone marrow mesenchymal progenitors from these mice displayed decreased osteoblastic differentiation. These results suggest that LPA1 strongly influences bone development both qualitatively and quantitatively and that, in vivo, its absence results in decreased osteogenesis with no clear modification of osteoclasis. They open perspectives for a better understanding of the role of the LPA/LPA1 paracrine pathway in bone pathophysiology.

  8. Absence of the lysophosphatidic acid receptor LPA1 results in abnormal bone development and decreased bone mass☆,☆☆

    PubMed Central

    Gennero, Isabelle; Laurencin-Dalicieux, Sara; Conte-Auriol, Françoise; Briand-Mésange, Fabienne; Laurencin, Danielle; Rue, Jackie; Beton, Nicolas; Malet, Nicole; Mus, Marianne; Tokumura, Akira; Bourin, Philippe; Vico, Laurence; Brunel, Gérard; Oreffo, Richard O. C.; Chun, Jerold; Salles, Jean Pierre

    2013-01-01

    Lysophosphatidic acid (LPA) is a lipid mediator that acts in paracrine systems via interaction with a subset of G protein-coupled receptors (GPCRs). LPA promotes cell growth and differentiation, and has been shown to be implicated in a variety of developmental and pathophysiological processes. At least 6 LPA GPCRs have been identified to date: LPA1–LPA6. Several studies have suggested that local production of LPA by tissues and cells contributes to paracrine regulation, and a complex interplay between LPA and its receptors, LPA1 and LPA4, is believed to be involved in the regulation of bone cell activity. In particular, LPA1may activate both osteoblasts and osteoclasts. However, its role has not as yet been examined with regard to the overall status of bone in vivo. We attempted to clarify this role by defining the bone phenotype of LPA1(−/−) mice. These mice demonstrated significant bone defects and low bone mass, indicating that LPA1 plays an important role in osteogenesis. The LPA1(−/−) mice also presented growth and sternal and costal abnormalities, which highlights the specific roles of LPA1 during bone development. Microcomputed tomography and histological analysis demonstrated osteoporosis in the trabecular and cortical bone of LPA1(−/−) mice. Finally, bone marrow mesenchymal progenitors from these mice displayed decreased osteoblastic differentiation. These results suggest that LPA1 strongly influences bone development both qualitatively and quantitatively and that, in vivo, its absence results in decreased osteogenesis with no clear modification of osteoclasis. They open perspectives for a better understanding of the role of the LPA/LPA1 paracrine pathway in bone pathophysiology. PMID:21569876

  9. The trajectory of gray matter development in Broca’s area is abnormal in people who stutter

    PubMed Central

    Beal, Deryk S.; Lerch, Jason P.; Cameron, Brodie; Henderson, Rhaeling; Gracco, Vincent L.; De Nil, Luc F.

    2015-01-01

    The acquisition and mastery of speech-motor control requires years of practice spanning the course of development. People who stutter often perform poorly on speech-motor tasks thereby calling into question their ability to establish the stable neural motor programs required for masterful speech-motor control. There is evidence to support the assertion that these neural motor programs are represented in the posterior part of Broca’s area, specifically the left pars opercularis. Consequently, various theories of stuttering causation posit that the disorder is related to a breakdown in the formation of the neural motor programs for speech early in development and that this breakdown is maintained throughout life. To date, no study has examined the potential neurodevelopmental signatures of the disorder across pediatric and adult populations. The current study aimed to fill this gap in our knowledge. We hypothesized that the developmental trajectory of cortical thickness in people who stutter would differ across the lifespan in the left pars opercularis relative to a group of control participants. We collected structural magnetic resonance images from 116 males (55 people who stutter) ranging in age from 6 to 48 years old. Differences in cortical thickness across ages and between patients and controls were investigated in 30 brain regions previously implicated in speech-motor control. An interaction between age and group was found for the left pars opercularis only. In people who stutter, the pars opercularis did not demonstrate the typical maturational pattern of gradual gray matter thinning with age across the lifespan that we observed in control participants. In contrast, the developmental trajectory of gray matter thickness in other regions of interest within the neural network for speech-motor control was similar for both groups. Our findings indicate that the developmental trajectory of gray matter in left pars opercularis is abnormal in people who stutter

  10. The Relationship between Personality Dimensions and Resiliency to Environmental Stress in Orange-Winged Amazon Parrots (Amazona amazonica), as Indicated by the Development of Abnormal Behaviors

    PubMed Central

    Cussen, Victoria A.; Mench, Joy A.

    2015-01-01

    Parrots are popular companion animals, but are frequently relinquished because of behavioral problems, including abnormal repetitive behaviors like feather damaging behavior and stereotypy. In addition to contributing to pet relinquishment, these behaviors are important as potential indicators of diminished psychological well-being. While abnormal behaviors are common in captive animals, their presence and/or severity varies between animals of the same species that are experiencing the same environmental conditions. Personality differences could contribute to this observed individual variation, as they are known risk factors for stress sensitivity and affective disorders in humans. The goal of this study was to assess the relationship between personality and the development and severity of abnormal behaviors in captive-bred orange-winged Amazon parrots (Amazona amazonica). We monitored between-individual behavioral differences in enrichment-reared parrots of known personality types before, during, and after enrichment deprivation. We predicted that parrots with higher scores for neurotic-like personality traits would be more susceptible to enrichment deprivation and develop more abnormal behaviors. Our results partially supported this hypothesis, but also showed that distinct personality dimensions were related to different forms of abnormal behavior. While neuroticism-like traits were linked to feather damaging behavior, extraversion-like traits were negatively related to stereotypic behavior. More extraverted birds showed resiliency to environmental stress, developing fewer stereotypies during enrichment deprivation and showing lower levels of these behaviors following re-enrichment. Our data, together with the results of the few studies conducted on other species, suggest that, as in humans, certain personality types render individual animals more susceptible or resilient to environmental stress. Further, this susceptibility/resiliency can have a long

  11. The Relationship between Personality Dimensions and Resiliency to Environmental Stress in Orange-Winged Amazon Parrots (Amazona amazonica), as Indicated by the Development of Abnormal Behaviors.

    PubMed

    Cussen, Victoria A; Mench, Joy A

    2015-01-01

    Parrots are popular companion animals, but are frequently relinquished because of behavioral problems, including abnormal repetitive behaviors like feather damaging behavior and stereotypy. In addition to contributing to pet relinquishment, these behaviors are important as potential indicators of diminished psychological well-being. While abnormal behaviors are common in captive animals, their presence and/or severity varies between animals of the same species that are experiencing the same environmental conditions. Personality differences could contribute to this observed individual variation, as they are known risk factors for stress sensitivity and affective disorders in humans. The goal of this study was to assess the relationship between personality and the development and severity of abnormal behaviors in captive-bred orange-winged Amazon parrots (Amazona amazonica). We monitored between-individual behavioral differences in enrichment-reared parrots of known personality types before, during, and after enrichment deprivation. We predicted that parrots with higher scores for neurotic-like personality traits would be more susceptible to enrichment deprivation and develop more abnormal behaviors. Our results partially supported this hypothesis, but also showed that distinct personality dimensions were related to different forms of abnormal behavior. While neuroticism-like traits were linked to feather damaging behavior, extraversion-like traits were negatively related to stereotypic behavior. More extraverted birds showed resiliency to environmental stress, developing fewer stereotypies during enrichment deprivation and showing lower levels of these behaviors following re-enrichment. Our data, together with the results of the few studies conducted on other species, suggest that, as in humans, certain personality types render individual animals more susceptible or resilient to environmental stress. Further, this susceptibility/resiliency can have a long

  12. Cerebellar volume deficits in medication-naïve obsessive compulsive disorder.

    PubMed

    Narayanaswamy, Janardhanan C; Jose, Dania; Kalmady, Sunil V; Agarwal, Sri Mahavir; Venkatasubramanian, Ganesan; Janardhan Reddy, Y C

    2016-08-30

    Even though conventional neurobiological models of obsessive compulsive disorder (OCD) commonly demonstrate abnormalities involving fronto-striatal circuits, there is emerging evidence regarding the role of posterior brain structures such as cerebellum. In this study, we examined the cerebellar regional volume in a large sample of medication-naïve OCD patients compared to matched healthy controls (HC). In 49 medication naïve right handed OCD patients and 39 age and sex matched HC, sub-region wise volume of cerebellum was extracted from the T1 weighted images using Spatially Unbiased Infra tentorial Template (SUIT) toolbox and compared using hypothesis driven, region of interest approach after clinical assessment with standard scales. After controlling for age, sex and ICV, the subjects with OCD had significantly smaller cerebellum compared to HC, especially in the posterior lobe sub-regions - lobule VI and left crus 1. This study gives preliminary evidence for region specific cerebellar volumetric deficits in the pathophysiological of OCD. Regional cerebellar volume deficits conform to the abnormal connectivity of cerebellum to specific cortical regions and it is indicative of involvement of regions outside the conventional fronto-striatal circuitry. This might be important in the context of cognitive deficits seen in OCD. PMID:27454206

  13. Exome sequencing reveals a novel CWF19L1 mutation associated with intellectual disability and cerebellar atrophy.

    PubMed

    Evers, Christina; Kaufmann, Lilian; Seitz, Angelika; Paramasivam, Nagarajan; Granzow, Martin; Karch, Stephanie; Fischer, Christine; Hinderhofer, Katrin; Gdynia, Georg; Elsässer, Michael; Pinkert, Stefan; Schlesner, Matthias; Bartram, Claus R; Moog, Ute

    2016-06-01

    Intellectual disability (ID) with cerebellar ataxia comprises a genetically heterogeneous group of neurodevelopmental disorders. We identified a homozygous frameshift mutation in CWF19L1 (c.467delC; p.(P156Hfs*33)) by a combination of linkage analysis and Whole Exome Sequencing in a consanguineous Turkish family with a 9-year-old boy affected by early onset cerebellar ataxia and mild ID. Serial MRI showed mildly progressive cerebellar atrophy. Absent C19L1 protein expression in lymphoblastoid cell lines strongly suggested that c.467delC is a disease-causing alteration. One further pregnancy of the mother had been terminated at 22 weeks of gestation because of a small cerebellum and agenesis of corpus callosum. The homozygous CWF19L1 variant was also present in the fetus. Postmortem examination of the fetus in addition showed unilateral hexadactyly and vertebral malformations. These features have not been reported and may represent an expansion of the CWF19L1-related phenotypic spectrum, but could also be due to another, possibly autosomal recessive disorder. The exact function of the evolutionarily highly conserved C19L1 protein is unknown. So far, homozygous or compound heterozygous mutations in CWF19L1 have been identified in two Turkish siblings and a Dutch girl, respectively, affected by cerebellar ataxia and ID. A zebrafish model showed that CWF19L1 loss-of-function mutations result in abnormal cerebellar morphology and movement disorders. Our report corroborates that loss-of-function mutations in CWF19Ll lead to early onset cerebellar ataxia and (progressive) cerebellar atrophy. © 2016 Wiley Periodicals, Inc. PMID:27016154

  14. Landmark Based Shape Analysis for Cerebellar Ataxia Classification and Cerebellar Atrophy Pattern Visualization

    PubMed Central

    Yang, Zhen; Abulnaga, S. Mazdak; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M.; Onyike, Chiadi; Ying, Sarah H.; Prince, Jerry L.

    2016-01-01

    Cerebellar dysfunction can lead to a wide range of movement disorders. Studying the cerebellar atrophy pattern associated with different cerebellar disease types can potentially help in diagnosis, prognosis, and treatment planning. In this paper, we present a landmark based shape analysis pipeline to classify healthy control and different ataxia types and to visualize the characteristic cerebellar atrophy patterns associated with different types. A highly informative feature representation of the cerebellar structure is constructed by extracting dense homologous landmarks on the boundary surfaces of cerebellar sub-structures. A diagnosis group classifier based on this representation is built using partial least square dimension reduction and regularized linear discriminant analysis. The characteristic atrophy pattern for an ataxia type is visualized by sampling along the discriminant direction between healthy controls and the ataxia type. Experimental results show that the proposed method can successfully classify healthy controls and different ataxia types. The visualized cerebellar atrophy patterns were consistent with the regional volume decreases observed in previous studies, but the proposed method provides intuitive and detailed understanding about changes of overall size and shape of the cerebellum, as well as that of individual lobules. PMID:27303111

  15. Landmark based shape analysis for cerebellar ataxia classification and cerebellar atrophy pattern visualization

    NASA Astrophysics Data System (ADS)

    Yang, Zhen; Abulnaga, S. Mazdak; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M.; Onyike, Chiadi; Ying, Sarah H.; Prince, Jerry L.

    2016-03-01

    Cerebellar dysfunction can lead to a wide range of movement disorders. Studying the cerebellar atrophy pattern associated with different cerebellar disease types can potentially help in diagnosis, prognosis, and treatment planning. In this paper, we present a landmark based shape analysis pipeline to classify healthy control and different ataxia types and to visualize the characteristic cerebellar atrophy patterns associated with different types. A highly informative feature representation of the cerebellar structure is constructed by extracting dense homologous landmarks on the boundary surfaces of cerebellar sub-structures. A diagnosis group classifier based on this representation is built using partial least square dimension reduction and regularized linear discriminant analysis. The characteristic atrophy pattern for an ataxia type is visualized by sampling along the discriminant direction between healthy controls and the ataxia type. Experimental results show that the proposed method can successfully classify healthy controls and different ataxia types. The visualized cerebellar atrophy patterns were consistent with the regional volume decreases observed in previous studies, but the proposed method provides intuitive and detailed understanding about changes of overall size and shape of the cerebellum, as well as that of individual lobules.

  16. Paraneoplastic cerebellar degeneration with anti-Yo antibodies associated with metastatic uveal melanoma.

    PubMed

    Valpione, Sara; Zoccarato, Marco; Parrozzani, Raffaele; Pigozzo, Jacopo; Giometto, Bruno; Laveder, Francesco; Aliberti, Camillo; Chiarion-Sileni, Vanna

    2013-12-15

    Paraneoplastic cerebellar degeneration (PCD) is characterized by subacute development of pancerebellar dysfunction as a remote effect of a systemic cancer and usually develops in patients affected by gynecological tumors. Uveal melanoma is a very rare disease with a severe prognosis. A 58-year-old man affected by uveal melanoma developed anti-Yo positive paraneoplastic cerebellar degeneration (PCD) 42 months after the initial diagnosis. The onset and worsening of the neurological symptoms were parallel to the course of liver metastasis. To our knowledge this is the first case of PCD in a patient with uveal melanoma. We speculate that the cerebellar degeneration-related protein 2 (CDR2), to which the anti-Yo antibodies are directed, may have been expressed in melanoma cells and conferred proliferative advantage to the disease. PMID:24035275

  17. Mapping cerebellar degeneration in HIV/AIDS.

    PubMed

    Klunder, Andrea D; Chiang, Ming-Chang; Dutton, Rebecca A; Lee, Sharon E; Toga, Arthur W; Lopez, Oscar L; Aizenstein, Howard J; Becker, James T; Thompson, Paul M

    2008-11-19

    Progressive brain atrophy in HIV/AIDS is associated with impaired psychomotor performance, perhaps partly reflecting cerebellar degeneration; yet little is known about how HIV/AIDS affects the cerebellum. We visualized the three-dimensional profile of atrophy in 19 HIV-positive patients (age: 42.9+/-8.3 years) versus 15 healthy controls (age: 38.5+/-12.0 years). We localized consistent patterns of subregional atrophy with an image analysis method that automatically deforms each patient's scan, in three dimensions, to match a reference image. Atrophy was greatest in the posterior cerebellar vermis (14.9% deficit) and correlated with depression severity (P=0.009, corrected), but not with dementia, alcohol/substance abuse, CD4+T-cell counts, or viral load. Profound cerebellar deficits in HIV/AIDS (P=0.007, corrected) were associated with depression, suggesting a surrogate disease marker for antiretroviral trials.

  18. Effective reinforcement learning following cerebellar damage requires a balance between exploration and motor noise.

    PubMed

    Therrien, Amanda S; Wolpert, Daniel M; Bastian, Amy J

    2016-01-01

    Reinforcement and error-based processes are essential for motor learning, with the cerebellum thought to be required only for the error-based mechanism. Here we examined learning and retention of a reaching skill under both processes. Control subjects learned similarly from reinforcement and error-based feedback, but showed much better retention under reinforcement. To apply reinforcement to cerebellar patients, we developed a closed-loop reinforcement schedule in which task difficulty was controlled based on recent performance. This schedule produced substantial learning in cerebellar patients and controls. Cerebellar patients varied in their learning under reinforcement but fully retained what was learned. In contrast, they showed complete lack of retention in error-based learning. We developed a mechanistic model of the reinforcement task and found that learning depended on a balance between exploration variability and motor noise. While the cerebellar and control groups had similar exploration variability, the patients had greater motor noise and hence learned less. Our results suggest that cerebellar damage indirectly impairs reinforcement learning by increasing motor noise, but does not interfere with the reinforcement mechanism itself. Therefore, reinforcement can be used to learn and retain novel skills, but optimal reinforcement learning requires a balance between exploration variability and motor noise.

  19. Over-expression of a grape stilbene synthase gene in tomato induces parthenocarpy and causes abnormal pollen development.

    PubMed

    Ingrosso, Ilaria; Bonsegna, Stefania; De Domenico, Stefania; Laddomada, Barbara; Blando, Federica; Santino, Angelo; Giovinazzo, Giovanna

    2011-10-01

    A novel strategy to induce parthenocarpy in tomato fruits by the induction of resveratrol biosynthesis in flower tissues was exploited. Two transgenic tomato lines were considered: a higher resveratrol-producing (35SS) line, constitutively expressing a grape stilbene synthase cDNA, and a lower resveratrol-producing (LoxS) line, expressing stilbene synthase under a fruit-specific promoter. The expression of the stilbene synthase gene affected flavonoid metabolism in a different manner in the transgenic lines, and in one of these, the 35SS line, resulted in complete male sterility. Resveratrol was synthesised either in 35SS or LoxS tomato flowers, at an even higher extent (about 8-10 times) in the former line. We further investigated whether stilbene synthase expression may have resulted in impaired naringenin accumulation during flower development. In the 35SS flowers, naringenin was significantly impaired by about 50%, probably due to metabolic competition. Conversely, the amount of glycosylated flavonols increased in transgenic flowers, thereby excluding the diminished production of flavonols as a reason for parthenocarpy in tomato. We further investigated whether resveratrol synthesis may have resulted changes to pollen structure. Microscopic observations revealed the presence of few and abnormal flake-like pollen grains in 35SS flowers with no germination capability. Finally, the analysis of coumaric and ferulic acids, the precursors of lignin and sporopollenin biosynthesis, revealed significant depletion of these compounds, therefore suggesting an impairment in structural compounds as a reason for pollen ablation. These overall outcomes, to the best of our knowledge, reveal for the first time the major role displayed by resveratrol synthesis on parthenocarpy in tomato fruits. PMID:21843947

  20. Postural sway and regional cerebellar volume in adults with attention-deficit/hyperactivity disorder

    PubMed Central

    Hove, Michael J.; Zeffiro, Thomas A.; Biederman, Joseph; Li, Zhi; Schmahmann, Jeremy; Valera, Eve M.

    2015-01-01

    Objective Motor abnormalities, including impaired balance and increased postural sway, are commonly reported in children with ADHD, but have yet to be investigated in adults with ADHD. Furthermore, although these abnormalities are thought to stem from cerebellar deficits, evidence for an association between the cerebellum and these motor deficits has yet to be provided for either adults or children with ADHD. Method In this study, we measured postural sway in adults with ADHD and controls, examining the relationship between sway and regional cerebellar gray matter volume. Thirty-two ADHD and 28 control participants completed various standing-posture tasks on a Wii balance board. Results Postural sway was significantly higher for the ADHD group compared to the healthy controls. Higher sway was positively associated with regional gray matter volume in the right posterior cerebellum (lobule VIII/IX). Conclusion These findings show that sway abnormalities commonly reported in children with ADHD are also present in adults, and for the first time show a relationship between postural control atypicalities and the cerebellum in this group. Our findings extend the literature on motor abnormalities in ADHD and contribute to our knowledge of their neural substrate. PMID:26106567

  1. Do sleep abnormalities and misaligned sleep/circadian rhythm patterns represent early clinical characteristics for developing psychosis in high risk populations?

    PubMed

    Zanini, Marcio; Castro, Juliana; Coelho, Fernando Morgadinho; Bittencourt, Lia; Bressan, Rodrigo A; Tufik, Sergio; Brietzke, Elisa

    2013-12-01

    Sleep architecture changes, such as slow-wave sleep (SWS) percentage variations and reductions in latency and density of rapid eye movement (REM), are found in most patients with schizophrenia and are considered to be an important part of the pathophysiology of the disorder. In addition to these sleep parameters changes, disruptions in sleep homeostasis and the sleep/circadian rhythm also occur in these patients. Sleep/circadian rhythm abnormalities negatively affect neocortical plasticity and cognition and often precede the diagnosis of the illness. Thus, it has been suggested that the sleep/circadian rhythm might be involved in the pathophysiology of psychosis. Recent advances in the identification of individuals at a high risk for developing schizophrenia allow us to investigate several neurobiological processes involved in the development of psychosis. In this article, we review the current evidence of the effects of sleep parameter abnormalities, disruptions in sleep homeostasis and misalignments of sleep circadian rhythm on the early stages of schizophrenia. In addition, we discuss the preliminary evidence of sleep and circadian rhythm abnormalities during the prodromal stages of psychosis and propose that these abnormalities can be explored as potential predictors, as an adjunct to clinical diagnosis, of developing a psychotic disorder in at risk populations.

  2. The Cerebellar Mutism Syndrome and Its Relation to Cerebellar Cognitive Function and the Cerebellar Cognitive Affective Disorder

    ERIC Educational Resources Information Center

    Wells, Elizabeth M.; Walsh, Karin S.; Khademian, Zarir P.; Keating, Robert F.; Packer, Roger J.

    2008-01-01

    The postoperative cerebellar mutism syndrome (CMS), consisting of diminished speech output, hypotonia, ataxia, and emotional lability, occurs after surgery in up to 25% of patients with medulloblastoma and occasionally after removal of other posterior fossa tumors. Although the mutism is transient, speech rarely normalizes and the syndrome is…

  3. Non-progressive cerebellar ataxia and previous undetermined acute cerebellar injury: a mysterious clinical condition.

    PubMed

    Pinto, Wladimir Bocca Vieira de Rezende; Pedroso, José Luiz; Souza, Paulo Victor Sgobbi de; Albuquerque, Marcus Vinícius Cristino de; Barsottini, Orlando Graziani Povoas

    2015-10-01

    Cerebellar ataxias represent a wide group of neurological diseases secondary to dysfunctions of cerebellum or its associated pathways, rarely coursing with acute-onset acquired etiologies and chronic non-progressive presentation. We evaluated patients with acquired non-progressive cerebellar ataxia that presented previous acute or subacute onset. Clinical and neuroimaging characterization of adult patients with acquired non-progressive ataxia were performed. Five patients were identified with the phenotype of acquired non-progressive ataxia. Most patients presented with a juvenile to adult-onset acute to subacute appendicular and truncal cerebellar ataxia with mild to moderate cerebellar or olivopontocerebellar atrophy. Establishing the etiology of the acute triggering events of such ataxias is complex. Non-progressive ataxia in adults must be distinguished from hereditary ataxias.

  4. Cerebellar cortical inhibition and classical eyeblink conditioning.

    PubMed

    Bao, Shaowen; Chen, Lu; Kim, Jeansok J; Thompson, Richard F

    2002-02-01

    The cerebellum is considered a brain structure in which memories for learned motor responses (e.g., conditioned eyeblink responses) are stored. Within the cerebellum, however, the relative importance of the cortex and the deep nuclei in motor learning/memory is not entirely clear. In this study, we show that the cerebellar cortex exerts both basal and stimulus-activated inhibition to the deep nuclei. Sequential application of a gamma-aminobutyric acid type A receptor (GABA(A)R) agonist and a noncompetitive GABA(A)R antagonist allows selective blockade of stimulus-activated inhibition. By using the same sequential agonist and antagonist methods in behaving animals, we demonstrate that the conditioned response (CR) expression and timing are completely dissociable and involve different inhibitory inputs; although the basal inhibition modulates CR expression, the conditioned stimulus-activated inhibition is required for the proper timing of the CR. In addition, complete blockade of cerebellar deep nuclear GABA(A)Rs prevents CR acquisition. Together, these results suggest that different aspects of the memories for eyeblink CRs are encoded in the cerebellar cortex and the cerebellar deep nuclei.

  5. Improving cerebellar segmentation with statistical fusion

    NASA Astrophysics Data System (ADS)

    Plassard, Andrew J.; Yang, Zhen; Prince, Jerry L.; Claassen, Daniel O.; Landman, Bennett A.

    2016-03-01

    The cerebellum is a somatotopically organized central component of the central nervous system well known to be involved with motor coordination and increasingly recognized roles in cognition and planning. Recent work in multiatlas labeling has created methods that offer the potential for fully automated 3-D parcellation of the cerebellar lobules and vermis (which are organizationally equivalent to cortical gray matter areas). This work explores the trade offs of using different statistical fusion techniques and post hoc optimizations in two datasets with distinct imaging protocols. We offer a novel fusion technique by extending the ideas of the Selective and Iterative Method for Performance Level Estimation (SIMPLE) to a patch-based performance model. We demonstrate the effectiveness of our algorithm, Non- Local SIMPLE, for segmentation of a mixed population of healthy subjects and patients with severe cerebellar anatomy. Under the first imaging protocol, we show that Non-Local SIMPLE outperforms previous gold-standard segmentation techniques. In the second imaging protocol, we show that Non-Local SIMPLE outperforms previous gold standard techniques but is outperformed by a non-locally weighted vote with the deeper population of atlases available. This work advances the state of the art in open source cerebellar segmentation algorithms and offers the opportunity for routinely including cerebellar segmentation in magnetic resonance imaging studies that acquire whole brain T1-weighted volumes with approximately 1 mm isotropic resolution.

  6. Cerebellar endocannabinoids: retrograde signaling from purkinje cells.

    PubMed

    Marcaggi, Païkan

    2015-06-01

    The cerebellar cortex exhibits a strikingly high expression of type 1 cannabinoid receptor (CB1), the cannabinoid binding protein responsible for the psychoactive effects of marijuana. CB1 is primarily found in presynaptic elements in the molecular layer. While the functional importance of cerebellar CB1 is supported by the effect of gene deletion or exogenous cannabinoids on animal behavior, evidence for a role of endocannabinoids in synaptic signaling is provided by in vitro experiments on superfused acute rodent cerebellar slices. These studies have demonstrated that endocannabinoids can be transiently released by Purkinje cells and signal at synapses in a direction opposite to information transfer (retrograde). Here, following a description of the reported expression pattern of the endocannabinoid system in the cerebellum, I review the accumulated in vitro data, which have addressed the mechanism of retrograde endocannabinoid signaling and identified 2-arachidonoylglycerol as the mediator of this signaling. The mechanisms leading to endocannabinoid release, the effects of CB1 activation, and the associated synaptic plasticity mechanisms are discussed and the remaining unknowns are pointed. Notably, it is argued that the spatial specificity of this signaling and the physiological conditions required for its induction need to be determined in order to understand endocannabinoid function in the cerebellar cortex. PMID:25520276

  7. Inverse Stochastic Resonance in Cerebellar Purkinje Cells.

    PubMed

    Buchin, Anatoly; Rieubland, Sarah; Häusser, Michael; Gutkin, Boris S; Roth, Arnd

    2016-08-01

    Purkinje neurons play an important role in cerebellar computation since their axons are the only projection from the cerebellar cortex to deeper cerebellar structures. They have complex internal dynamics, which allow them to fire spontaneously, display bistability, and also to be involved in network phenomena such as high frequency oscillations and travelling waves. Purkinje cells exhibit type II excitability, which can be revealed by a discontinuity in their f-I curves. We show that this excitability mechanism allows Purkinje cells to be efficiently inhibited by noise of a particular variance, a phenomenon known as inverse stochastic resonance (ISR). While ISR has been described in theoretical models of single neurons, here we provide the first experimental evidence for this effect. We find that an adaptive exponential integrate-and-fire model fitted to the basic Purkinje cell characteristics using a modified dynamic IV method displays ISR and bistability between the resting state and a repetitive activity limit cycle. ISR allows the Purkinje cell to operate in different functional regimes: the all-or-none toggle or the linear filter mode, depending on the variance of the synaptic input. We propose that synaptic noise allows Purkinje cells to quickly switch between these functional regimes. Using mutual information analysis, we demonstrate that ISR can lead to a locally optimal information transfer between the input and output spike train of the Purkinje cell. These results provide the first experimental evidence for ISR and suggest a functional role for ISR in cerebellar information processing. PMID:27541958

  8. Cerebellar Disease in an Adult Cow

    PubMed Central

    Oz, H. H.; Nicholson, S. S.; Al-Bagdadi, F. K.; Zeman, D. H.

    1986-01-01

    This is the report of clinical signs and lesions of a cerebellar disorder in an adult four year old Limousin cow grazing perennial ryegrass (Lolium perenne). The most striking histopathological lesion was a marked paucity of Purkinje cells throughout the cerebellum. ImagesFigure 1.Figure 2. PMID:17422607

  9. Vergence Deficits in Patients with Cerebellar Lesions

    ERIC Educational Resources Information Center

    Sander, T.; Sprenger, A.; Neumann, G.; Machner, B.; Gottschalk, S.; Rambold, H.; Helmchen, C.

    2009-01-01

    The cerebellum is part of the cortico-ponto-cerebellar circuit for conjugate eye movements. Recent animal data suggest an additional role of the cerebellum for the control of binocular alignment and disconjugate, i.e. vergence eye movements. The latter is separated into two different components: fast vergence (to step targets) and slow vergence…

  10. Inverse Stochastic Resonance in Cerebellar Purkinje Cells

    PubMed Central

    Häusser, Michael; Gutkin, Boris S.; Roth, Arnd

    2016-01-01

    Purkinje neurons play an important role in cerebellar computation since their axons are the only projection from the cerebellar cortex to deeper cerebellar structures. They have complex internal dynamics, which allow them to fire spontaneously, display bistability, and also to be involved in network phenomena such as high frequency oscillations and travelling waves. Purkinje cells exhibit type II excitability, which can be revealed by a discontinuity in their f-I curves. We show that this excitability mechanism allows Purkinje cells to be efficiently inhibited by noise of a particular variance, a phenomenon known as inverse stochastic resonance (ISR). While ISR has been described in theoretical models of single neurons, here we provide the first experimental evidence for this effect. We find that an adaptive exponential integrate-and-fire model fitted to the basic Purkinje cell characteristics using a modified dynamic IV method displays ISR and bistability between the resting state and a repetitive activity limit cycle. ISR allows the Purkinje cell to operate in different functional regimes: the all-or-none toggle or the linear filter mode, depending on the variance of the synaptic input. We propose that synaptic noise allows Purkinje cells to quickly switch between these functional regimes. Using mutual information analysis, we demonstrate that ISR can lead to a locally optimal information transfer between the input and output spike train of the Purkinje cell. These results provide the first experimental evidence for ISR and suggest a functional role for ISR in cerebellar information processing. PMID:27541958

  11. New Evidence of Cerebellar and Brainstem Hypoplasia in Autistic Infants, Children and Adolescents: The MR Imaging Study by Hashimoto and Colleagues.

    ERIC Educational Resources Information Center

    Courchesne, Eric

    1995-01-01

    In a study by Toshiaki Hashimoto and colleagues (EC 611 142), 10 infants with developmental delay, poor eye contact, and poor facial expression underwent magnetic resonance brain imaging and were later diagnosed with autism. This offered direct evidence of abnormality of the cerebellar vermis and the brainstem at the beginning stages of behavioral…

  12. The impact of steroid withdrawal on the development of lipid abnormalities and obesity in heart transplant recipients.

    PubMed

    Lake, K D; Reutzel, T J; Pritzker, M R; Jorgensen, C R; Emery, R W

    1993-01-01

    Hyperlipidemia and obesity are common problems after heart transplantation, which may increase the risk of chronic graft atherosclerosis. The intent of this study was to (1) determine the impact of a history of hyperlipidemia on the occurrence of lipid abnormalities after transplantation, (2) compare lipid profiles of those patients being treated with triple-drug immunosuppression versus those patients weaned from prednisone therapy, and (3) identify any factors that would predict which patients are at highest risk for the development of hyperlipidemia after transplantation. Of 89 patients who lived for more than 12 months, 35 patients had a history of hyperlipidemia before heart transplantation (cholesterol level of more than 240 mg/dl; low-density lipoprotein cholesterol level of more than 160 mg/dl). The most dramatic rise in cholesterol level was observed in patients with no history of hyperlipidemia who were treated with triple-drug immunosuppression, in whom a 64% increase occurred versus a 24% increase in patients receiving steroid-free immunosuppression (p < 0.001). In patients with a history of hyperlipidemia, cholesterol level increased by 20% with triple-drug immunosuppression versus 14% with steroid-free immunosuppression (p = 0.613); however, 83% of the patients in the triple-drug group and 92% in the steroid-free group had elevated cholesterol levels. Multiple regression analysis revealed that significant independent and additive (p < 0.00001) contributions with respect to percent change in cholesterol level were evident for (1) a negative history of hyperlipidemia (p = 0.005), (2) triple-drug immunosuppression (p = 0.0021), and (3) female sex (p = 0.0113). A negative history of hyperlipidemia was predictive of the percent change in low-density lipoprotein cholesterol level (p = 0.0049), and triple-drug immunosuppression administration predicted the percent change in high-density lipoprotein cholesterol (p = 0.0119). Patients with a positive history

  13. Optogenetic Manipulation of Cerebellar Purkinje Cell Activity In Vivo

    PubMed Central

    Tsubota, Tadashi; Ohashi, Yohei; Tamura, Keita; Sato, Ayana; Miyashita, Yasushi

    2011-01-01

    Purkinje cells (PCs) are the sole output neurons of the cerebellar cortex. Although their anatomical connections and physiological response properties have been extensively studied, the causal role of their activity in behavioral, cognitive and autonomic functions is still unclear because PC activity cannot be selectively controlled. Here we developed a novel technique using optogenetics for selective and rapidly reversible manipulation of PC activity in vivo. We injected into rat cerebellar cortex lentiviruses expressing either the light-activated cationic channel channelrhodopsin-2 (ChR2) or light-driven chloride pump halorhodopsin (eNpHR) under the control of the PC-specific L7 promoter. Transgene expression was observed in most PCs (ChR2, 92.6%; eNpHR, 95.3%), as determined by immunohistochemical analysis. In vivo electrophysiological recordings showed that all light-responsive PCs in ChR2-transduced rats increased frequency of simple spike in response to blue laser illumination. Similarly, most light-responsive PCs (93.8%) in eNpHR-transduced rats decreased frequency of simple spike in response to orange laser illumination. We then applied these techniques to characterize the roles of rat cerebellar uvula, one of the cardiovascular regulatory regions in the cerebellum, in resting blood pressure (BP) regulation in anesthetized rats. ChR2-mediated photostimulation and eNpHR-mediated photoinhibition of the uvula had opposite effects on resting BP, inducing depressor and pressor responses, respectively. In contrast, manipulation of PC activity within the neighboring lobule VIII had no effect on BP. Blue and orange laser illumination onto PBS-injected lobule IX didn't affect BP, indicating the observed effects on BP were actually due to PC activation and inhibition. These results clearly demonstrate that the optogenetic method we developed here will provide a powerful way to elucidate a causal relationship between local PC activity and functions of the cerebellum

  14. Isolated Hemiataxia and Cerebellar Diaschisis after a Small Dorsolateral Medullary Infarct

    PubMed Central

    Kishi, Masahiko; Sakakibara, Ryuji; Nagao, Takeki; Terada, Hitoshi; Ogawa, Emina

    2009-01-01

    Isolated hemiataxia after a medullary infarct is rare. We describe a case of isolated hemiataxia after a small infarct localized at the ipsilateral dorsolateral medulla. An 83-year-old man developed acute onset of ataxia in the left arm and in both legs. Speech and extraocular movement were normal, and he did not have any other neurological manifestations. Brain MRI showed a small infarct localized at the left dorsolateral medulla, which involved the inferior cerebellar peduncle. 123ECD-SPECT showed hypoperfusion in the left cerebellar hemisphere without clear vascular territory. Neuroimaging findings for our patient suggested the involvement of the inferior cerebellar peduncle that projects to the cerebellum in our patient. PMID:20847835

  15. Cerebellar Transcranial Direct Current Stimulation (ctDCS)

    PubMed Central

    Grimaldi, Giuliana; Argyropoulos, Georgios P.; Bastian, Amy; Cortes, Mar; Davis, Nicholas J.; Edwards, Dylan J.; Ferrucci, Roberta; Fregni, Felipe; Galea, Joseph M.; Hamada, Masahi; Manto, Mario; Miall, R. Chris; Morales-Quezada, Leon; Pope, Paul A.; Priori, Alberto; Rothwell, John; Tomlinson, S. Paul; Celnik, Pablo

    2016-01-01

    The cerebellum is critical for both motor and cognitive control. Dysfunction of the cerebellum is a component of multiple neurological disorders. In recent years, interventions have been developed that aim to excite or inhibit the activity and function of the human cerebellum. Transcranial direct current stimulation of the cerebellum (ctDCS) promises to be a powerful tool for the modulation of cerebellar excitability. This technique has gained popularity in recent years as it can be used to investigate human cerebellar function, is easily delivered, is well tolerated, and has not shown serious adverse effects. Importantly, the ability of ctDCS to modify behavior makes it an interesting approach with a potential therapeutic role for neurological patients. Through both electrical and non-electrical effects (vascular, metabolic) ctDCS is thought to modify the activity of the cerebellum and alter the output from cerebellar nuclei. Physiological studies have shown a polarity-specific effect on the modulation of cerebellar–motor cortex connectivity, likely via cerebellar–thalamocortical pathways. Modeling studies that have assessed commonly used electrode montages have shown that the ctDCS-generated electric field reaches the human cerebellum with little diffusion to neighboring structures. The posterior and inferior parts of the cerebellum (i.e., lobules VI-VIII) seem particularly susceptible to modulation by ctDCS. Numerous studies have shown to date that ctDCS can modulate motor learning, and affect cognitive and emotional processes. Importantly, this intervention has a good safety profile; similar to when applied over cerebral areas. Thus, investigations have begun exploring ctDCS as a viable intervention for patients with neurological conditions. PMID:25406224

  16. MicroRNA-122 Influences the Development of Sperm Abnormalities from Human Induced Pluripotent Stem Cells by Regulating TNP2 Expression

    PubMed Central

    Huang, Yongyi; Liu, Jianjun; Zhao, Yanhui; Jiang, Lizhen; Huang, Qin

    2013-01-01

    Sperm abnormalities are one of the main factors responsible for male infertility; however, their pathogenesis remains unclear. The role of microRNAs in the development of sperm abnormalities in infertile men has not yet been investigated. Here, we used human induced pluripotent stem cells to investigate the influence of miR-122 expression on the differentiation of these cells into spermatozoa-like cells in vitro. After induction, mutant miR-122-transfected cells formed spermatozoa-like cells. Flow cytometry of DNA content revealed a significant increase in the haploid cell population in spermatozoa-like cells derived from mutant miR-122-transfected cells as compared to those derived from miR-122-transfected cells. During induction, TNP2 and protamine mRNA and protein levels were significantly higher in mutant miR-122-transfected cells than in miR-122-transfected cells. High-throughput isobaric tags for relative and absolute quantification were used to identify and quantify the different protein expression levels in miR-122- and mutant miR-122-transfected cells. Among all the proteins analyzed, the expression of lipoproteins, for example, APOB and APOA1, showed the most significant difference between the two groups. This study illustrates that miR-122 expression is associated with abnormal sperm development. MiR-122 may influence spermatozoa-like cells by suppressing TNP2 expression and inhibiting the expression of proteins associated with sperm development. PMID:23327642

  17. A probabilistic atlas of the cerebellar white matter.

    PubMed

    van Baarsen, K M; Kleinnijenhuis, M; Jbabdi, S; Sotiropoulos, S N; Grotenhuis, J A; van Cappellen van Walsum, A M

    2016-01-01

    Imaging of the cerebellar cortex, deep cerebellar nuclei and their connectivity are gaining attraction, due to the important role the cerebellum plays in cognition and motor control. Atlases of the cerebellar cortex and nuclei are used to locate regions of interest in clinical and neuroscience studies. However, the white matter that connects these relay stations is of at least similar functional importance. Damage to these cerebellar white matter tracts may lead to serious language, cognitive and emotional disturbances, although the pathophysiological mechanism behind it is still debated. Differences in white matter integrity between patients and controls might shed light on structure-function correlations. A probabilistic parcellation atlas of the cerebellar white matter would help these studies by facilitating automatic segmentation of the cerebellar peduncles, the localization of lesions and the comparison of white matter integrity between patients and controls. In this work a digital three-dimensional probabilistic atlas of the cerebellar white matter is presented, based on high quality 3T, 1.25mm resolution diffusion MRI data from 90 subjects participating in the Human Connectome Project. The white matter tracts were estimated using probabilistic tractography. Results over 90 subjects were symmetrical and trajectories of superior, middle and inferior cerebellar peduncles resembled the anatomy as known from anatomical studies. This atlas will contribute to a better understanding of cerebellar white matter architecture. It may eventually aid in defining structure-function correlations in patients with cerebellar disorders.

  18. Neuro-Otological Aspects of Cerebellar Stroke Syndrome

    PubMed Central

    2009-01-01

    Cerebellar stroke is a common cause of a vascular vestibular syndrome. Although vertigo ascribed to cerebellar stroke is usually associated with other neurological symptoms or signs, it may mimic acute peripheral vestibulopathy (APV), so called pseudo-APV. The most common pseudo-APV is a cerebellar infarction in the territory of the medial branch of the posterior inferior cerebellar artery (PICA). Recent studies have shown that a normal head impulse result can differentiate acute medial PICA infarction from APV. Therefore, physicians who evaluate stroke patients should be trained to perform and interpret the results of the head impulse test. Cerebellar infarction in the territory of the anterior inferior cerebellar artery (AICA) can produce a unique stroke syndrome in that it is typically accompanied by unilateral hearing loss, which could easily go unnoticed by patients. The low incidence of vertigo associated with infarction involving the superior cerebellar artery distribution may be a useful way of distinguishing it clinically from PICA or AICA cerebellar infarction in patients with acute vertigo and limb ataxia. For the purpose of prompt diagnosis and adequate treatment, it is imperative to recognize the characteristic patterns of the clinical presentation of each cerebellar stroke syndrome. This paper provides a concise review of the key features of cerebellar stroke syndromes from the neuro-otology viewpoint. PMID:19587812

  19. Hereditary lissencephaly and cerebellar hypoplasia in Churra lambs

    PubMed Central

    2013-01-01

    pathological findings of lissencephaly with cerebellar hypoplasia in Churra lambs for which an autosomal recessive inheritance was the most likely cause. Histopathological features observed in the cerebral cortex and hippocampus are consistent with a possible failure in neuronal migration during brain development. This report suggests that lissencephaly should be considered in the differential diagnosis of congenital neurological disease in newborn lambs showing weakness, inability to walk and difficulty sucking. PMID:23938146

  20. Consensus Paper: Roles of the Cerebellum in Motor Control—The Diversity of Ideas on Cerebellar Involvement in Movement

    PubMed Central

    Bower, James M.; Conforto, Adriana Bastos; Delgado-García, José M.; da Guarda, Suzete Nascimento Farias; Gerwig, Marcus; Habas, Christophe; Hagura, Nobuhiro; Ivry, Richard B.; Mariën, Peter; Molinari, Marco; Naito, Eiichi; Nowak, Dennis A.; Ben Taib, Nordeyn Oulad; Pelisson, Denis; Tesche, Claudia D.; Tilikete, Caroline; Timmann, Dagmar

    2015-01-01

    Considerable progress has been made in developing models of cerebellar function in sensorimotor control, as well as in identifying key problems that are the focus of current investigation. In this consensus paper, we discuss the literature on the role of the cerebellar circuitry in motor control, bringing together a range of different viewpoints. The following topics are covered: oculomotor control, classical conditioning (evidence in animals and in humans), cerebellar control of motor speech, control of grip forces, control of voluntary limb movements, timing, sensorimotor synchronization, control of corticomotor excitability, control of movement-related sensory data acquisition, cerebro-cerebellar interaction in visuokinesthetic perception of hand movement, functional neuroimaging studies, and magnetoencephalographic mapping of cortico-cerebellar dynamics. While the field has yet to reach a consensus on the precise role played by the cerebellum in movement control, the literature has witnessed the emergence of broad proposals that address cerebellar function at multiple levels of analysis. This paper highlights the diversity of current opinion, providing a framework for debate and discussion on the role of this quintessential vertebrate structure. PMID:22161499

  1. Robust algorithmic detection of the developed cardiac pathologies and emerging or transient abnormalities from short periods of RR data

    NASA Astrophysics Data System (ADS)

    Gavrishchaka, Valeriy V.; Senyukova, Olga

    2011-06-01

    Numerous research efforts and clinical testing have confirmed validity of heart rate variability (HRV) analysis as one of the cardiac diagnostics modalities. The majority of HRV analysis tools currently used in practice are based on linear indicators. Methods from nonlinear dynamics (NLD) provide more natural modeling framework for adaptive biological systems with multiple feedback loops. Compared to linear indicators, many NLD-based measures are much less sensitive to data artifacts and non-stationarity. However, majority of NLD measures require long time series for stable calculation. Similar restrictions also apply for linear indicators. Such requirements could drastically limit practical usability of HRV analysis in many applications, including express diagnostics, early indication of subtle directional changes during personalization of medical treatment, and robust detection of emerging or transient abnormalities. Recently we have illustrated that these challenges could be overcome by using classification framework based on boosting-like ensemble learning techniques that are capable of discovering robust meta-indicators from existing HRV measures and other incomplete empirical knowledge. In this paper we demonstrate universality of such meta-indicators and discuss operational details of their practical usage. Using such pathology examples as congestive heart failure (CHF) and arrhythmias, we show that classifiers trained on short RR segments (down to several minutes) could achieve reasonable classification accuracy (˜80-85% and higher). These indicators calculated from longer RR segments could be applicable for accurate diagnostics with classification accuracy approaching 100%. In addition, it is feasible to discover single "normal-abnormal" meta-classifier capable of detecting multiple abnormalities.

  2. Delineation of candidate genes responsible for structural brain abnormalities in patients with terminal deletions of chromosome 6q27

    PubMed Central

    Peddibhotla, Sirisha; Nagamani, Sandesh CS; Erez, Ayelet; Hunter, Jill V; Holder Jr, J Lloyd; Carlin, Mary E; Bader, Patricia I; Perras, Helene MF; Allanson, Judith E; Newman, Leslie; Simpson, Gayle; Immken, LaDonna; Powell, Erin; Mohanty, Aaron; Kang, Sung-Hae L; Stankiewicz, Pawel; Bacino, Carlos A; Bi, Weimin; Patel, Ankita; Cheung, Sau W

    2015-01-01

    Patients with terminal deletions of chromosome 6q present with structural brain abnormalities including agenesis of corpus callosum, hydrocephalus, periventricular nodular heterotopia, and cerebellar malformations. The 6q27 region harbors genes that are important for the normal development of brain and delineation of a critical deletion region for structural brain abnormalities may lead to a better genotype–phenotype correlation. We conducted a detailed clinical and molecular characterization of seven unrelated patients with deletions involving chromosome 6q27. All patients had structural brain abnormalities. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. The smallest region of overlap spans 1.7 Mb and contains DLL1, THBS2, PHF10, and C6orf70 (ERMARD) that are plausible candidates for the causation of structural brain abnormalities. Our study reiterates the importance of 6q27 region in normal development of brain and helps identify putative genes in causation of structural brain anomalies. PMID:24736736

  3. Delineation of candidate genes responsible for structural brain abnormalities in patients with terminal deletions of chromosome 6q27.

    PubMed

    Peddibhotla, Sirisha; Nagamani, Sandesh C S; Erez, Ayelet; Hunter, Jill V; Holder, J Lloyd; Carlin, Mary E; Bader, Patricia I; Perras, Helene M F; Allanson, Judith E; Newman, Leslie; Simpson, Gayle; Immken, LaDonna; Powell, Erin; Mohanty, Aaron; Kang, Sung-Hae L; Stankiewicz, Pawel; Bacino, Carlos A; Bi, Weimin; Patel, Ankita; Cheung, Sau W

    2015-01-01

    Patients with terminal deletions of chromosome 6q present with structural brain abnormalities including agenesis of corpus callosum, hydrocephalus, periventricular nodular heterotopia, and cerebellar malformations. The 6q27 region harbors genes that are important for the normal development of brain and delineation of a critical deletion region for structural brain abnormalities may lead to a better genotype-phenotype correlation. We conducted a detailed clinical and molecular characterization of seven unrelated patients with deletions involving chromosome 6q27. All patients had structural brain abnormalities. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. The smallest region of overlap spans 1.7 Mb and contains DLL1, THBS2, PHF10, and C6orf70 (ERMARD) that are plausible candidates for the causation of structural brain abnormalities. Our study reiterates the importance of 6q27 region in normal development of brain and helps identify putative genes in causation of structural brain anomalies.

  4. Cerebellar ataxia as presenting feature of hypothyroidism.

    PubMed

    Kotwal, Suman Kumar; Kotwal, Shalija; Gupta, Rohan; Singh, Jang Bhadur; Mahajan, Annil

    2016-04-01

    Symptoms and signs of the hypothyroidism vary in relation to the magnitude and acuteness of the thyroid hormone deficiency. The usual clinical features are constipation, fatigue, cold intolerance and weight gain. Rarely it can present with neurologic problems like reversible cerebellar ataxia, dementia, peripheral neuropathy, psychosis and coma. Hypothyroidism should be suspected in all cases of ataxia, as it is easily treatable. A 40 year-old male presented with the history facial puffiness, hoarseness of voice and gait-ataxia. Investigations revealed frank primary hypothyroidism. Anti-TPO antibody was positive. Thyroxine was started and patient improved completely within eight weeks. Hypothyroidism can present with ataxia as presenting feature. Hypothyroidism should be considered in all cases of cerebellar ataxia as it is a reversible cause of ataxia. PMID:26886095

  5. Developing Software to “Track and Catch” Missed Follow-up of Abnormal Test Results in a Complex Sociotechnical Environment

    PubMed Central

    Smith, M.; Murphy, D.; Laxmisan, A.; Sittig, D.; Reis, B.; Esquivel, A.; Singh, H.

    2013-01-01

    Summary Background Abnormal test results do not always receive timely follow-up, even when providers are notified through electronic health record (EHR)-based alerts. High workload, alert fatigue, and other demands on attention disrupt a provider’s prospective memory for tasks required to initiate follow-up. Thus, EHR-based tracking and reminding functionalities are needed to improve follow-up. Objectives The purpose of this study was to develop a decision-support software prototype enabling individual and system-wide tracking of abnormal test result alerts lacking follow-up, and to conduct formative evaluations, including usability testing. Methods We developed a working prototype software system, the Alert Watch And Response Engine (AWARE), to detect abnormal test result alerts lacking documented follow-up, and to present context-specific reminders to providers. Development and testing took place within the VA’s EHR and focused on four cancer-related abnormal test results. Design concepts emphasized mitigating the effects of high workload and alert fatigue while being minimally intrusive. We conducted a multifaceted formative evaluation of the software, addressing fit within the larger socio-technical system. Evaluations included usability testing with the prototype and interview questions about organizational and workflow factors. Participants included 23 physicians, 9 clinical information technology specialists, and 8 quality/safety managers. Results Evaluation results indicated that our software prototype fit within the technical environment and clinical workflow, and physicians were able to use it successfully. Quality/safety managers reported that the tool would be useful in future quality assurance activities to detect patients who lack documented follow-up. Additionally, we successfully installed the software on the local facility’s “test” EHR system, thus demonstrating technical compatibility. Conclusion To address the factors involved in missed

  6. Cerebellar secretin modulates eyeblink classical conditioning.

    PubMed

    Fuchs, Jason R; Robinson, Gain M; Dean, Aaron M; Schoenberg, Heidi E; Williams, Michael R; Morielli, Anthony D; Green, John T

    2014-12-01

    We have previously shown that intracerebellar infusion of the neuropeptide secretin enhances the acquisition phase of eyeblink conditioning (EBC). Here, we sought to test whether endogenous secretin also regulates EBC and to test whether the effect of exogenous and endogenous secretin is specific to acquisition. In Experiment 1, rats received intracerebellar infusions of the secretin receptor antagonist 5-27 secretin or vehicle into the lobulus simplex of cerebellar cortex immediately prior to sessions 1-3 of acquisition. Antagonist-infused rats showed a reduction in the percentage of eyeblink CRs compared with vehicle-infused rats. In Experiment 2, rats received intracerebellar infusions of secretin or vehicle immediately prior to sessions 1-2 of extinction. Secretin did not significantly affect extinction performance. In Experiment 3, rats received intracerebellar infusions of 5-27 secretin or vehicle immediately prior to sessions 1-2 of extinction. The secretin antagonist did not significantly affect extinction performance. Together, our current and previous results indicate that both exogenous and endogenous cerebellar secretin modulate acquisition, but not extinction, of EBC. We have previously shown that (1) secretin reduces surface expression of the voltage-gated potassium channel α-subunit Kv1.2 in cerebellar cortex and (2) intracerebellar infusions of a Kv1.2 blocker enhance EBC acquisition, much like secretin. Kv1.2 is almost exclusively expressed in cerebellar cortex at basket cell-Purkinje cell pinceaus and Purkinje cell dendrites; we propose that EBC-induced secretin release from PCs modulates EBC acquisition by reducing surface expression of Kv1.2 at one or both of these sites.

  7. Cerebellar secretin modulates eyeblink classical conditioning

    PubMed Central

    Fuchs, Jason R.; Robinson, Gain M.; Dean, Aaron M.; Schoenberg, Heidi E.; Williams, Michael R.; Morielli, Anthony D.

    2014-01-01

    We have previously shown that intracerebellar infusion of the neuropeptide secretin enhances the acquisition phase of eyeblink conditioning (EBC). Here, we sought to test whether endogenous secretin also regulates EBC and to test whether the effect of exogenous and endogenous secretin is specific to acquisition. In Experiment 1, rats received intracerebellar infusions of the secretin receptor antagonist 5-27 secretin or vehicle into the lobulus simplex of cerebellar cortex immediately prior to sessions 1–3 of acquisition. Antagonist-infused rats showed a reduction in the percentage of eyeblink CRs compared with vehicle-infused rats. In Experiment 2, rats received intracerebellar infusions of secretin or vehicle immediately prior to sessions 1–2 of extinction. Secretin did not significantly affect extinction performance. In Experiment 3, rats received intracerebellar infusions of 5-27 secretin or vehicle immediately prior to sessions 1–2 of extinction. The secretin antagonist did not significantly affect extinction performance. Together, our current and previous results indicate that both exogenous and endogenous cerebellar secretin modulate acquisition, but not extinction, of EBC. We have previously shown that (1) secretin reduces surface expression of the voltage-gated potassium channel α-subunit Kv1.2 in cerebellar cortex and (2) intracerebellar infusions of a Kv1.2 blocker enhance EBC acquisition, much like secretin. Kv1.2 is almost exclusively expressed in cerebellar cortex at basket cell–Purkinje cell pinceaus and Purkinje cell dendrites; we propose that EBC-induced secretin release from PCs modulates EBC acquisition by reducing surface expression of Kv1.2 at one or both of these sites. PMID:25403455

  8. Homozygous Mutations in NEUROD1 Are Responsible for a Novel Syndrome of Permanent Neonatal Diabetes and Neurological Abnormalities

    PubMed Central

    Rubio-Cabezas, Oscar; Minton, Jayne A.L.; Kantor, Iren; Williams, Denise; Ellard, Sian; Hattersley, Andrew T.

    2010-01-01

    OBJECTIVE NEUROD1 is expressed in both developing and mature β-cells. Studies in mice suggest that this basic helix-loop-helix transcription factor is critical in the development of endocrine cell lineage. Heterozygous mutations have previously been identified as a rare cause of maturity-onset diabetes of the young (MODY). We aimed to explore the potential contribution of NEUROD1 mutations in patients with permanent neonatal diabetes. RESEARCH DESIGN AND METHODS We sequenced the NEUROD1 gene in 44 unrelated patients with permanent neonatal diabetes of unknown genetic etiology. RESULTS Two homozygous mutations in NEUROD1 (c.427_ 428del and c.364dupG) were identified in two patients. Both mutations introduced a frameshift that would be predicted to generate a truncated protein completely lacking the activating domain. Both patients had permanent diabetes diagnosed in the first 2 months of life with no evidence of exocrine pancreatic dysfunction and a morphologically normal pancreas on abdominal imaging. In addition to diabetes, they had learning difficulties, severe cerebellar hypoplasia, profound sensorineural deafness, and visual impairment due to severe myopia and retinal dystrophy. CONCLUSIONS We describe a novel clinical syndrome that results from homozygous loss of function mutations in NEUROD1. It is characterized by permanent neonatal diabetes and a consistent pattern of neurological abnormalities including cerebellar hypoplasia, learning difficulties, sensorineural deafness, and visual impairment. This syndrome highlights the critical role of NEUROD1 in both the development of the endocrine pancreas and the central nervous system in humans. PMID:20573748

  9. Deep Learning for Cerebellar Ataxia Classification and Functional Score Regression

    PubMed Central

    Yang, Zhen; Zhong, Shenghua; Carass, Aaron; Ying, Sarah H.; Prince, Jerry L.

    2014-01-01

    Cerebellar ataxia is a progressive neuro-degenerative disease that has multiple genetic versions, each with a characteristic pattern of anatomical degeneration that yields distinctive motor and cognitive problems. Studying this pattern of degeneration can help with the diagnosis of disease subtypes, evaluation of disease stage, and treatment planning. In this work, we propose a learning framework using MR image data for discriminating a set of cerebellar ataxia types and predicting a disease related functional score. We address the difficulty in analyzing high-dimensional image data with limited training subjects by: 1) training weak classifiers/regressors on a set of image subdomains separately, and combining the weak classifier/regressor outputs to make the decision; 2) perturbing the image subdomain to increase the training samples; 3) using a deep learning technique called the stacked auto-encoder to develop highly representative feature vectors of the input data. Experiments show that our approach can reliably classify between one of four categories (healthy control and three types of ataxia), and predict the functional staging score for ataxia. PMID:25553339

  10. From cerebellar texture to movement optimization.

    PubMed

    Sultan, Fahad

    2014-10-01

    The cerebellum is a major site for supervised procedural learning and appears to be crucial for optimizing sensorimotor performance. However, the site and origin of the supervising signal are still elusive. Furthermore, its relationship with the prominent neuronal circuitry remains puzzling. In this paper, I will review the relevant information and seek to synthesize a working hypothesis that explains the unique cerebellar structure. The aim of this review was to link the distinctive functions of the cerebellum, as derived from cerebellar lesion studies, with potential elementary computations, as observed by a bottom-up approach from the cerebellar microcircuitry. The parallel fiber geometry is ideal for performing millisecond computations that extract instructive signals. In this scenario, the higher time derivatives of kinematics such as acceleration and/or jerk that occur during motor performance are detected via a tidal wave mechanism and are used (with appropriate gating) as the instructive signal to guide motor smoothing. The advantage of such a mechanism is that movements are optimized by reducing "jerkiness" which, in turn, lowers their energy requirements. PMID:25037239

  11. Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

    PubMed Central

    Sepulveda-Falla, Diego; Barrera-Ocampo, Alvaro; Hagel, Christian; Korwitz, Anne; Vinueza-Veloz, Maria Fernanda; Zhou, Kuikui; Schonewille, Martijn; Zhou, Haibo; Velazquez-Perez, Luis; Rodriguez-Labrada, Roberto; Villegas, Andres; Ferrer, Isidro; Lopera, Francisco; Langer, Thomas; De Zeeuw, Chris I.; Glatzel, Markus

    2014-01-01

    Familial Alzheimer’s disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A–associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca2+ channels IP3Rs and CACNA1A were downregulated, and Ca2+-dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration. PMID:24569455

  12. Isolated lateropulsion of the trunk in cerebellar infarct.

    PubMed

    Shan, D E; Wang, V; Chen, J T

    1995-05-01

    MRI in a 63-year-old male with isolated lateropulsion of the trunk disclosed an infarct in the inferior portion of the right cerebellar hemisphere, suggesting an end-zone type infarct in the lateral branch of the right posterior inferior cerebellar artery (1PICA) or a borderzone infarct between 1PICA and superior cerebellar artery. A close clinico-topographical relationship between isolated lateropulsion of the trunk and lesion in the territory of 1PICA was demonstrated.

  13. Acute bilateral cerebellar infarction in the territory of the medial branches of posterior inferior cerebellar arteries.

    PubMed

    Gurer, G; Sahin, G; Cekirge, S; Tan, E; Saribas, O

    2001-10-01

    The most frequent type of cerebellar infarcts involved the posterior inferior cerebellar artery (PICA) and superior cerebellar artery territories but bilateral involvement of lateral or medial branches of PICA is extremely rare. In this report, we present a 55-year-old male who admitted to hospital with vomiting, nausea and dizziness. On examination left-sided hemiparesia and ataxic gait were detected. Infarct on bilateral medial branch of PICA artery territories was found out with cranial magnetic resonance imaging (MRI) technique and 99% stenosis of the left vertebral artery was found out with digital subtraction arteriography. The patient was put on heparin treatment. After 3 weeks, his complaints and symptoms had disappeared except for mild gait ataxia. PMID:11532563

  14. Altered mRNA Splicing, Chondrocyte Gene Expression and Abnormal Skeletal Development due to SF3B4 Mutations in Rodriguez Acrofacial Dysostosis

    PubMed Central

    Nevarez, Lisette; Pogue, Robert; Krakow, Deborah; Cohn, Daniel H.

    2016-01-01

    The acrofacial dysostoses (AFD) are a genetically heterogeneous group of inherited disorders with craniofacial and limb abnormalities. Rodriguez syndrome is a severe, usually perinatal lethal AFD, characterized by severe retrognathia, oligodactyly and lower limb abnormalities. Rodriguez syndrome has been proposed to be a severe form of Nager syndrome, a non-lethal AFD that results from mutations in SF3B4, a component of the U2 small nuclear ribonucleoprotein particle (U2 snRNP). Furthermore, a case with a phenotype intermediate between Rodriguez and Nager syndromes has been shown to have an SF3B4 mutation. We identified heterozygosity for SF3B4 mutations in Rodriguez syndrome, confirming that the phenotype is a dominant disorder that is allelic with Nager syndrome. The mutations led to reduced SF3B4 synthesis and defects in mRNA splicing, primarily exon skipping. The mutations also led to reduced expression in growth plate chondrocytes of target genes, including the DLX5, DLX6, SOX9, and SOX6 transcription factor genes, which are known to be important for skeletal development. These data provide mechanistic insight toward understanding how SF3B4 mutations lead to the skeletal abnormalities observed in the acrofacial dysostoses. PMID:27622494

  15. A case of human immunodeficiency virus infection with cerebellar ataxia that suggested by an association with autoimmunity.

    PubMed

    Nagao, Shigeto; Kondo, Takayuki; Nakamura, Takashi; Nakagawa, Tomokazu; Matsumoto, Sadayuki

    2016-04-28

    We report a case of human immunodeficiency virus (HIV) infection that showed subacute progressive cerebellar ataxia without HIV encephalopathy or other encephalopathies, including progressive multifocal leukoencephalopathy or encephalitis of other human herpes virus (HHV) infections. A 43-year-old man exhibited unsteady gait. Neurological examination disclosed ataxia of the trunk and lower extremities. Personality change and dementia were absent. Magnetic resonance imaging did not reveal any abnormal finding, including of the cerebellum. The serum HIV-1-RNA was 1.2 × 10(5) copies/ml, and the absolute CD4 lymphocyte count was 141 cells/ml. Remarkably, the serum anti-Yo antibody, as an anti-cerebellar antibody of paraneoplastic syndrome, and anti-gliadin antibody, associated with celiac disease or gluten ataxia, were positive. The cerebrospinal fluid (CSF) immunoglobulin G index was 1.2 (< 0.8), and oligoclonal bands were present. PCR of the CSF was negative for HIV, JC virus, other HHVs, and mycosis. Previous reports presented HIV-infected patients with concurrent autoimmune diseases such as systemic lupus erythematosus, anti-phospholipid syndrome, autoimmune thrombocytopenia, vasculitis, polymyositis and dermatomyositis, sarcoidosis, Graves' disease, and hepatic diseases. These might have been present in patients with a CD4 T lymphocyte count of more than 200 cells/ml. On the other hand, paraneoplastic syndrome, gluten ataxia, cerebellar ataxia associated with anti-glutamic acid decarboxylase antibody, and Hashimoto's encephalopathy might manifest as autoimmune cerebellar ataxia. As regards the association of HIV infection and autoimmune cerebellar ataxia, a previous report suggested that anti-gliadin antibody was detected in about 30% of HIV-infected children, though there is no reference to an association with cerebellar ataxia. Moreover, to our knowledge, detection of anti-Yo antibody in an HIV-infected patient with cerebellar ataxia has not been reported

  16. [Buspirone in the treatment of cerebellar ataxia].

    PubMed

    Svetel, M; Vojvodić, N; Filipović, S R; Dragasević, N; Sternić, N; Kostić, V S

    1999-01-01

    Ataxia is defined as a disturbance which, quite independent of any motor weakness, alters direction and extent of voluntary movement and impairs the sustained voluntary of reflex muscle contraction necessary for maintaining postiue and equilibrium [1]. Since pathophysiological basis of cerebeller ataxia is still not completely clear, the current therapeutic attempts are mainly symptom-oriented [3]. One possible approach could be a modification of potentially involved neurotransmitter systems of the cerebellum, where particularly interesting is the serotonergic system. However, attempts with levorotatory form of tryptophan (5-HT precursors) proved to be ineffective [4, 5]. Since receptors in the cerebellum are mainly of 5-HTIA subtype, the use of specific agonists might be a more reasonable therapy [6]. The study initially involved 11 patients, but only 9 completed the protocol due to unfavorable side effects. Our open label prospective study lasted for 15 weeks. The patients were tested before the beginning of the treatment (initial visit), at 7th (first visit) and 11th week (second visit) of continuous therapy, and eventually at 15th week (final visit). The daily dose was 40 mg at the first and 60 mg at the second visit. We used the evaluation scale gurposed for cerebellar functions testing (speech, gait, coordination and ocular movements). Significant improvement of cerebellar ataxia in patients under buspiron therapy has been noted. We analyzed the results obtained from our 9 patients (4 females and 5 males), of which 6 patients suffered from cerebellar degeneration, one from multiple sclerosis, one from Ramsey-Hunt syndrome, and one from pontine myelinolysis. At the initial visit the patient score was 18.9 (SD = 7.3), subsequently, at the iirst visit the score was 15.4 (SD = 8), while the second visit yielded the score of 12.9 (SD = 8.2), and finally, after a two-weeks lasting wash-out period, it was 17.7 (SD = 7.1) (Table 1). It was found that patients

  17. The role of calcium and cyclic nucleotide signaling in cerebellar granule cell migration under normal and pathological conditions.

    PubMed

    Komuro, Yutaro; Galas, Ludovic; Lebon, Alexis; Raoult, Emilie; Fahrion, Jennifer K; Tilot, Amanda; Kumada, Tasturo; Ohno, Nobuhiko; Vaudry, David; Komuro, Hitoshi

    2015-04-01

    In the developing brain, immature neurons migrate from their sites of origin to their final destination, where they reside for the rest of their lives. This active movement of immature neurons is essential for the formation of normal neuronal cytoarchitecture and proper differentiation. Deficits in migration result in the abnormal development of the brain, leading to a variety of neurological disorders. A myriad of extracellular guidance molecules and intracellular effector molecules is involved in controlling the migration of immature neurons in a cell type, cortical layer and birth-date-specific manner. To date, little is known about how extracellular guidance molecules transfer their information to the intracellular effector molecules, which regulate the migration of immature neurons. In this article, to fill the gap between extracellular guidance molecules and intracellular effector molecules, using the migration of cerebellar granule cells as a model system of neuronal cell migration, we explore the role of second messenger signaling (specifically Ca(2+) and cyclic nucleotide signaling) in the regulation of neuronal cell migration. We will, first, describe the cortical layer-specific changes in granule cell migration. Second, we will discuss the roles of Ca(2+) and cyclic nucleotide signaling in controlling granule cell migration. Third, we will present recent studies showing the roles of Ca(2+) and cyclic nucleotide signaling in the deficits in granule cell migration in mouse models of fetal alcohol spectrum disorders and fetal Minamata disease.

  18. Cerebellar-Dependent Expression of Motor Learning during Eyeblink Conditioning in Head-Fixed Mice

    PubMed Central

    Heiney, Shane A.; Wohl, Margot P.; Chettih, Selmaan N.; Ruffolo, Luis I.

    2014-01-01

    Eyeblink conditioning in restrained rabbits has served as an excellent model of cerebellar-dependent motor learning for many decades. In mice, the role of the cerebellum in eyeblink conditioning is less clear and remains controversial, partly because learning appears to engage fear-related circuits and lesions of the cerebellum do not abolish the learned behavior completely. Furthermore, experiments in mice are performed using freely moving systems, which lack the stability necessary for mapping out the essential neural circuitry with electrophysiological approaches. We have developed a novel apparatus for eyeblink conditioning in head-fixed mice. Here, we show that the performance of mice in our apparatus is excellent and that the learned behavior displays two hallmark features of cerebellar-dependent eyeblink conditioning in rabbits: (1) gradual acquisition; and (2) adaptive timing of conditioned movements. Furthermore, we use a combination of pharmacological inactivation, electrical stimulation, single-unit recordings, and targeted microlesions to demonstrate that the learned behavior is completely dependent on the cerebellum and to pinpoint the exact location in the deep cerebellar nuclei that is necessary. Our results pave the way for using eyeblink conditioning in head-fixed mice as a platform for applying next-generation genetic tools to address molecular and circuit-level questions about cerebellar function in health and disease. PMID:25378152

  19. Cerebellar contributions to motor control and language comprehension: searching for common computational principles.

    PubMed

    Moberget, Torgeir; Ivry, Richard B

    2016-04-01

    The past 25 years have seen the functional domain of the cerebellum extend beyond the realm of motor control, with considerable discussion of how this subcortical structure contributes to cognitive domains including attention, memory, and language. Drawing on evidence from neuroanatomy, physiology, neuropsychology, and computational work, sophisticated models have been developed to describe cerebellar function in sensorimotor control and learning. In contrast, mechanistic accounts of how the cerebellum contributes to cognition have remained elusive. Inspired by the homogeneous cerebellar microanatomy and a desire for parsimony, many researchers have sought to extend mechanistic ideas from motor control to cognition. One influential hypothesis centers on the idea that the cerebellum implements internal models, representations of the context-specific dynamics of an agent's interactions with the environment, enabling predictive control. We briefly review cerebellar anatomy and physiology, to review the internal model hypothesis as applied in the motor domain, before turning to extensions of these ideas in the linguistic domain, focusing on speech perception and semantic processing. While recent findings are consistent with this computational generalization, they also raise challenging questions regarding the nature of cerebellar learning, and may thus inspire revisions of our views on the role of the cerebellum in sensorimotor control. PMID:27206249

  20. Long-term supratentorial brain structure and cognitive function following cerebellar tumour resections in childhood.

    PubMed

    Moberget, T; Andersson, S; Lundar, T; Due-Tønnessen, B J; Heldal, A; Endestad, T; Westlye, L T

    2015-03-01

    The cerebellum is connected to extensive regions of the cerebrum, and cognitive deficits following cerebellar lesions may thus be related to disrupted cerebello-cerebral connectivity. Moreover, early cerebellar lesions could affect distal brain development, effectively inducing long-term changes in brain structure and cognitive function. Here, we characterize supratentorial brain structure and cognitive function in 20 adult patients treated for cerebellar tumours in childhood (mean age at surgery: 7.1 years) and 26 matched controls. Relative to controls, patients showed reduced cognitive function and increased grey matter density in bilateral cingulum, left orbitofrontal cortex and the left hippocampus. Within the patient group, increased grey matter density in these regions was associated with decreased performance on tests of processing speed and executive function. Further, diffusion tensor imaging revealed widespread alterations in white matter microstructure in patients. While current ventricle volume (an index of previous hydrocephalus severity it patients) was associated with grey matter density and white matter microstructure in patients, this could only partially account for the observed group differences in brain structure and cognitive function. In conclusion, our results show distal effects of cerebellar lesions on cerebral integrity and wiring, likely caused by a combination of neurodegenerative processes and perturbed neurodevelopment.

  1. New supervised learning theory applied to cerebellar modeling for suppression of variability of saccade end points.

    PubMed

    Fujita, Masahiko

    2013-06-01

    A new supervised learning theory is proposed for a hierarchical neural network with a single hidden layer of threshold units, which can approximate any continuous transformation, and applied to a cerebellar function to suppress the end-point variability of saccades. In motor systems, feedback control can reduce noise effects if the noise is added in a pathway from a motor center to a peripheral effector; however, it cannot reduce noise effects if the noise is generated in the motor center itself: a new control scheme is necessary for such noise. The cerebellar cortex is well known as a supervised learning system, and a novel theory of cerebellar cortical function developed in this study can explain the capability of the cerebellum to feedforwardly reduce noise effects, such as end-point variability of saccades. This theory assumes that a Golgi-granule cell system can encode the strength of a mossy fiber input as the state of neuronal activity of parallel fibers. By combining these parallel fiber signals with appropriate connection weights to produce a Purkinje cell output, an arbitrary continuous input-output relationship can be obtained. By incorporating such flexible computation and learning ability in a process of saccadic gain adaptation, a new control scheme in which the cerebellar cortex feedforwardly suppresses the end-point variability when it detects a variation in saccadic commands can be devised. Computer simulation confirmed the efficiency of such learning and showed a reduction in the variability of saccadic end points, similar to results obtained from experimental data.

  2. Cerebellar-dependent expression of motor learning during eyeblink conditioning in head-fixed mice.

    PubMed

    Heiney, Shane A; Wohl, Margot P; Chettih, Selmaan N; Ruffolo, Luis I; Medina, Javier F

    2014-11-01

    Eyeblink conditioning in restrained rabbits has served as an excellent model of cerebellar-dependent motor learning for many decades. In mice, the role of the cerebellum in eyeblink conditioning is less clear and remains controversial, partly because learning appears to engage fear-related circuits and lesions of the cerebellum do not abolish the learned behavior completely. Furthermore, experiments in mice are performed using freely moving systems, which lack the stability necessary for mapping out the essential neural circuitry with electrophysiological approaches. We have developed a novel apparatus for eyeblink conditioning in head-fixed mice. Here, we show that the performance of mice in our apparatus is excellent and that the learned behavior displays two hallmark features of cerebellar-dependent eyeblink conditioning in rabbits: (1) gradual acquisition; and (2) adaptive timing of conditioned movements. Furthermore, we use a combination of pharmacological inactivation, electrical stimulation, single-unit recordings, and targeted microlesions to demonstrate that the learned behavior is completely dependent on the cerebellum and to pinpoint the exact location in the deep cerebellar nuclei that is necessary. Our results pave the way for using eyeblink conditioning in head-fixed mice as a platform for applying next-generation genetic tools to address molecular and circuit-level questions about cerebellar function in health and disease.

  3. Cerebellar Nicotinic Cholinergic Receptors are Intrinsic to the Cerebellum: Implications for Diverse Functional Roles

    PubMed Central

    Turner, Jill R.; Ortinski, Pavel I.; Sherrard, Rachel M.

    2016-01-01

    Although recent studies have delineated the specific nicotinic subtypes present in the mammalian cerebellum, very little is known about their location or function within the cerebellum. This is of increased interest since nicotinic receptors (nAChRs) in the cerebellum have recently been implicated in the pathology of autism spectrum disorders. To begin to better understand the roles of these heteromeric nAChRs in the cerebellar circuitry and their therapeutic potential as targets for drug development, we used various chemical and stereotaxic lesion models in conjunction with slice electrophysiology to examine how specific heteromeric nAChR subtypes may influence the surrounding cerebellar circuitry. Using subunit-specific immunoprecipitation of radiolabeled nAChRs in the cerebella following N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, p-chloroamphetamine, and pendunculotomy lesions, we show that most, if not all, cerebellar nicotinic receptors are present in cells within the cerebellum itself and not in extracerebellar afferents. Furthermore, we demonstrate that the β4-containing, but not the β2-containing, nAChRs intrinsic to the cerebellum can regulate inhibitory synaptic efficacy at two major classes of cerebellar neurons. These tandem findings suggest that nAChRs may present a potential drug target for disorders involving the cerebellum. PMID:21562921

  4. Expression of classical cadherins in the cerebellar anlage: quantitative and functional aspects.

    PubMed

    Gliem, Michael; Weisheit, Gunnar; Mertz, Kirsten D; Endl, Elmar; Oberdick, John; Schilling, Karl

    2006-12-01

    During central nervous system (CNS) development, cell migration precedes and is key to the integration of diverse sets of cells. Mechanistically, CNS histogenesis is realized through a balanced interplay of cell-cell and cell-matrix adhesion molecules. Here, we summarize experiments that probe the developmental expression and potential significance of a set of cadherins, including M-, N- and R-cadherin, for patterning of the cerebellar cortex. We established a transgenic marker that allows cerebellar granule cells to be followed from the neuroblast stage to their final, postmitotic settlement. In conjunction with flow cytometry, this allowed us to derive a quantitative view of cadherin expression in differentiating granule cells and relate it to the expression of the same cadherins in cerebellar inhibitory interneuronal precursors. In vitro reaggregation analysis supports a role for cadherins in cell sorting and migration within the nascent cerebellar cortex that may be rationalized within the context of the differential adhesion hypothesis (Foty, R.A. and Steinberg, M.S., 2005. The differential adhesion hypothesis: a direct evaluation. Dev. Biol. 278, 255-263.).

  5. Sex Chromosome Meiotic Drive Systems in DROSOPHILA MELANOGASTER I. Abnormal Spermatid Development in Males with a Heterochromatin-Deficient X Chromosome (sc4sc8)

    PubMed Central

    Peacock, W. J.; Miklos, George L. Gabor; Goodchild, D. J.

    1975-01-01

    The meiotic drive characteristics of the In(1)sc4Lsc8R/Y system have been examined by genetic analysis and by light and electron microscopy. sc4sc8/Y males show a direct correlation between nondisjunction frequency and meiotic drive. Temperature-shift experiments reveal that the temperature-sensitive period for nondisjunction is at meiosis, whereas that for meiotic drive has both meiotic and post-meiotic components. Cytological analyses in the light and electron microscopes reveal failures in spermiogenesis in the testes of sc4sc8 males. The extent of abnormal spermatid development increases as nondisjunction becomes more extreme. PMID:805751

  6. The p53 inhibitor MDM2 facilitates Sonic Hedgehog-mediated tumorigenesis and influences cerebellar foliation.

    PubMed

    Malek, Reem; Matta, Jennifer; Taylor, Natalie; Perry, Mary Ellen; Mendrysa, Susan M

    2011-01-01

    Disruption of cerebellar granular neuronal precursor (GNP) maturation can result in defects in motor coordination and learning, or in medulloblastoma, the most common childhood brain tumor. The Sonic Hedgehog (Shh) pathway is important for GNP proliferation; however, the factors regulating the extent and timing of GNP proliferation, as well as GNP differentiation and migration are poorly understood. The p53 tumor suppressor has been shown to negatively regulate the activity of the Shh effector, Gli1, in neural stem cells; however, the contribution of p53 to the regulation of Shh signaling in GNPs during cerebellar development has not been determined. Here, we exploited a hypomorphic allele of Mdm2 (Mdm2(puro)), which encodes a critical negative regulator of p53, to alter the level of wild-type MDM2 and p53 in vivo. We report that mice with reduced levels of MDM2 and increased levels of p53 have small cerebella with shortened folia, reminiscent of deficient Shh signaling. Indeed, Shh signaling in Mdm2-deficient GNPs is attenuated, concomitant with decreased expression of the Shh transducers, Gli1 and Gli2. We also find that Shh stimulation of GNPs promotes MDM2 accumulation and enhances phosphorylation at serine 166, a modification known to increase MDM2-p53 binding. Significantly, loss of MDM2 in Ptch1(+/-) mice, a model for Shh-mediated human medulloblastoma, impedes cerebellar tumorigenesis. Together, these results place MDM2 at a major nexus between the p53 and Shh signaling pathways in GNPs, with key roles in cerebellar development, GNP survival, cerebellar foliation, and MB tumorigenesis. PMID:21437245

  7. [Cerebellar Control of Ocular Movements: Application to the Topographical Diagnosis of Cerebellar Lesions].

    PubMed

    Hirose, Genjiro

    2016-03-01

    Over the last decade, substantial information on cerebellar oculomotor control has been provided by the use of sophisticated neuroanatomical, neurophysiological, and imaging techniques. We now know that an intact cerebellum is a prerequisite for normal oculomotor performance. This review clarifies the current knowledge on structure-function correlations of the cerebellum in relation to ocular movements and allows them to be applied to topographical diagnosis of cerebellar lesions. The cerebellar regions most closely related to oculomotor function are: (1) the flocculus/paraflocculus for VOR suppression, cancellation, smooth pursuit eye movement and gaze-holding, (2) the nodulus/ventral uvula for velocity storage and low frequency prolonged vestibular response, and (3) the dorsal oculomotor vermis (declive VI, folium VII) and the posterior portion of the fastigial nucleus (fastigial oculomotor region) for saccades and smooth pursuit initiation. Symptomatically, defects in the flocculus/parflocculus cause saccadic pursuit, downbeat nystagmus, and impairments to visual suppression of the VOR. Lesions of the nodulus/uvula reveal as periodic alternating nystagmus. Lesions of the oculomotor vermis and the fastigial nucleus can induce saccadic dysmetria, while fastigial nucleus lesions may also cause ocular flutter/opsoclonus. A detailed knowledge of cerebellar anatomy and the physiology of eye movements enables localization of lesions to specific areas of the cerebellum. PMID:27001776

  8. Cerebellar grey-matter deficits, cannabis use and first-episode schizophrenia in adolescents and young adults.

    PubMed

    Cohen, Martin; Rasser, Paul E; Peck, Greg; Carr, Vaughan J; Ward, Philip B; Thompson, Paul M; Johnston, Patrick; Baker, Amanda; Schall, Ulrich

    2012-04-01

    Epidemiological data link adolescent cannabis use to psychosis and schizophrenia, but its contribution to schizophrenia neuropathology remains controversial. First-episode schizophrenia (FES) patients show regional cerebral grey- and white-matter changes as well as a distinct pattern of regional grey-matter loss in the vermis of the cerebellum. The cerebellum possesses a high density of cannabinoid type 1 receptors involved in the neuronal diversification of the developing brain. Cannabis abuse may interfere with this process during adolescent brain maturation leading to 'schizophrenia-like' cerebellar pathology. Magnetic resonance imaging and cortical pattern matching techniques were used to investigate cerebellar grey and white matter in FES patients with and without a history of cannabis use and non-psychiatric cannabis users. In the latter group we found lifetime dose-dependent regional reduction of grey matter in the right cerebellar lobules and a tendency for more profound grey-matter reduction in lobule III with younger age at onset of cannabis use. The overall regional grey-matter differences in cannabis users were within the normal variability of grey-matter distribution. By contrast, FES subjects had lower total cerebellar grey-matter:total cerebellar volume ratio and marked grey-matter loss in the vermis, pedunculi, flocculi and lobules compared to pair-wise matched healthy control subjects. This pattern and degree of grey-matter loss did not differ from age-matched FES subjects with comorbid cannabis use. Our findings indicate small dose-dependent effects of juvenile cannabis use on cerebellar neuropathology but no evidence of an additional effect of cannabis use on FES cerebellar grey-matter pathology.

  9. Role of Synchronous Activation of Cerebellar Purkinje Cell Ensembles in Multi-joint Movement Control

    PubMed Central

    Hoogland, Tycho M.; De Gruijl, Jornt R.; Witter, Laurens; Canto, Cathrin B.; De Zeeuw, Chris I.

    2015-01-01

    Summary It is a longstanding question in neuroscience how elaborate multi-joint movements are coordinated coherently. Microzones of cerebellar Purkinje cells (PCs) are thought to mediate this coordination by controlling the timing of particular motor domains. However, it remains to be elucidated to what extent motor coordination deficits can be correlated with abnormalities in coherent activity within these microzones and to what extent artificially evoked synchronous activity within PC ensembles can elicit multi-joint motor behavior. To study PC ensemble correlates of limb, trunk, and tail movements, we developed a transparent disk treadmill that allows quantitative readout of locomotion and posture parameters in head-fixed mice and simultaneous cellular-resolution imaging and/or optogenetic manipulation. We show that PC ensembles in the ataxic and dystonic mouse mutant tottering have a reduced level of complex spike co-activation, which is delayed relative to movement onset and co-occurs with prolonged swing duration and reduced phase coupling of limb movements as well as with enlarged deflections of body-axis and tail movements. Using optogenetics to increase simple spike rate in PC ensembles, we find that preferred locomotion and posture patterns can be elicited or perturbed depending on the behavioral state. At rest, preferred sequences of limb movements can be elicited, whereas during locomotion, preferred gait-inhibition patterns are evoked. Our findings indicate that synchronous activation of PC ensembles can facilitate initiation and coordination of limb and trunk movements, presumably by tuning downstream systems involved in the execution of behavioral patterns. PMID:25843032

  10. Dystonia and Cerebellar Degeneration in the Leaner Mouse Mutant

    PubMed Central

    Raike, Robert S.; Hess, Ellen J.; Jinnah, H.A.

    2015-01-01

    Cerebellar degeneration is traditionally associated with ataxia. Yet, there are examples of both ataxia and dystonia occurring in individuals with cerebellar degeneration. There is also substantial evidence suggesting that cerebellar dysfunction alone may cause dystonia. The types of cerebellar defects that may cause ataxia, dystonia, or both have not been delineated. In the current study, we explored the relationship between cerebellar degeneration and dystonia using the leaner mouse mutant. Leaner mice have severe dystonia that is associated with dysfunctional and degenerating cerebellar Purkinje cells. Whereas the density of Purkinje cells was not significantly reduced in 4 week-old leaner mice, approximately 50% of the neurons were lost by 34 weeks of age. On the other hand, the dystonia and associated functional disability became significantly less severe during this same interval. In other words, dystonia improved as Purkinje cells were lost, suggesting that dysfunctional Purkinje cells, rather than Purkinje cell loss, contribute to the dystonia. These results provide evidence that distorted cerebellar function may cause dystonia and support the concept that different types of cerebellar defects can have different functional consequences. PMID:25791619

  11. Cerebellar disorders: clinical/radiologic findings and modern imaging tools.

    PubMed

    Manto, Mario; Habas, Christophe

    2016-01-01

    Cerebellar disorders, also called cerebellar ataxias, comprise a large group of sporadic and genetic diseases. Their core clinical features include impaired control of coordination and gait, as well as cognitive/behavioral deficits usually not detectable by a standard neurologic examination and therefore often overlooked. Two forms of cognitive/behavioral syndromes are now well identified: (1) the cerebellar cognitive affective syndrome, which combines an impairment of executive functions, including planning and working memory, deficits in visuospatial skills, linguistic deficiencies such as agrammatism, and inappropriate behavior; and (2) the posterior fossa syndrome, a very acute form of cerebellar cognitive affective syndrome occurring essentially in children. Sporadic ataxias include stroke, toxic causes, immune ataxias, infectious/parainfectious ataxias, traumatic causes, neoplasias and paraneoplastic syndromes, endocrine disorders affecting the cerebellum, and the so-called "degenerative ataxias" (multiple system atrophy, and sporadic adult-onset ataxias). Genetic ataxias include mainly four groups of disorders: autosomal-recessive cerebellar ataxias, autosomal-dominant ataxias (spinocerebellar ataxias and episodic ataxias), mitochondrial disorders, and X-linked ataxias. In addition to biochemical studies and genetic tests, brain imaging techniques are a cornerstone for the diagnosis, clinicoanatomic correlations, and follow-up of cerebellar ataxias. Modern radiologic tools to assess cerebellar ataxias include: functional imaging studies, magnetic resonance spectroscopy, volumetric studies, and tractography. These complementary methods provide a multimodal appreciation of the whole long-range cerebellar network functioning, and allow the extraction of potential biomarkers for prognosis and rating level of recovery after treatment. PMID:27432679

  12. Humor and laughter in patients with cerebellar degeneration.

    PubMed

    Frank, B; Propson, B; Göricke, S; Jacobi, H; Wild, B; Timmann, D

    2012-06-01

    Humor is a complex behavior which includes cognitive, affective and motor responses. Based on observations of affective changes in patients with cerebellar lesions, the cerebellum may support cerebral and brainstem areas involved in understanding and appreciation of humorous stimuli and expression of laughter. The aim of the present study was to examine if humor appreciation, perception of humorous stimuli, and the succeeding facial reaction differ between patients with cerebellar degeneration and healthy controls. Twenty-three adults with pure cerebellar degeneration were compared with 23 age-, gender-, and education-matched healthy control subjects. No significant difference in humor appreciation and perception of humorous stimuli could be found between groups using the 3 Witz-Dimensionen Test, a validated test asking for funniness and aversiveness of jokes and cartoons. Furthermore, while observing jokes, humorous cartoons, and video sketches, facial expressions of subjects were videotaped and afterwards analysed using the Facial Action Coding System. Using depression as a covariate, the number, and to a lesser degree, the duration of facial expressions during laughter were reduced in cerebellar patients compared to healthy controls. In sum, appreciation of humor appears to be largely preserved in patients with chronic cerebellar degeneration. Cerebellar circuits may contribute to the expression of laughter. Findings add to the literature that non-motor disorders in patients with chronic cerebellar disease are generally mild, but do not exclude that more marked disorders may show up in acute cerebellar disease and/or in more specific tests of humor appreciation.

  13. Distinct Critical Cerebellar Subregions for Components of Verbal Working Memory

    ERIC Educational Resources Information Center

    Cooper, Freya E.; Grube, Manon; Von Kriegstein, Katharina; Kumar, Sukhbinder; English, Philip; Kelly, Thomas P.; Chinnery, Patrick F.; Griffiths, Timothy D.

    2012-01-01

    A role for the cerebellum in cognition has been proposed based on studies suggesting a profile of cognitive deficits due to cerebellar stroke. Such studies are limited in the determination of the detailed organisation of cerebellar subregions that are critical for different aspects of cognition. In this study we examined the correlation between…

  14. Postirradiation cerebellar glioma. Case report

    SciTech Connect

    Raffel, C.; Edwards, M.S.; Davis, R.L.; Ablin, A.R.

    1985-02-01

    A 13-year-old girl developed an anaplastic astrocytoma of the cerebellum 7 years after irradiation of the central nervous system and prophylactic chemotherapy for acute lymphocytic leukemia. The fact that the astrocytoma was anaplastic and infiltrative was unusual for astroglial tumors at this site. It is proposed that this is a radiation-induced glioma.

  15. An integrator circuit in cerebellar cortex.

    PubMed

    Maex, Reinoud; Steuber, Volker

    2013-09-01

    The brain builds dynamic models of the body and the outside world to predict the consequences of actions and stimuli. A well-known example is the oculomotor integrator, which anticipates the position-dependent elasticity forces acting on the eye ball by mathematically integrating over time oculomotor velocity commands. Many models of neural integration have been proposed, based on feedback excitation, lateral inhibition or intrinsic neuronal nonlinearities. We report here that a computational model of the cerebellar cortex, a structure thought to implement dynamic models, reveals a hitherto unrecognized integrator circuit. In this model, comprising Purkinje cells, molecular layer interneurons and parallel fibres, Purkinje cells were able to generate responses lasting more than 10 s, to which both neuronal and network mechanisms contributed. Activation of the somatic fast sodium current by subthreshold voltage fluctuations was able to maintain pulse-evoked graded persistent activity, whereas lateral inhibition among Purkinje cells via recurrent axon collaterals further prolonged the responses to step and sine wave stimulation. The responses of Purkinje cells decayed with a time-constant whose value depended on their baseline spike rate, with integration vanishing at low (< 1 per s) and high rates (> 30 per s). The model predicts that the apparently fast circuit of the cerebellar cortex may control the timing of slow processes without having to rely on sensory feedback. Thus, the cerebellar cortex may contain an adaptive temporal integrator, with the sensitivity of integration to the baseline spike rate offering a potential mechanism of plasticity of the response time-constant.

  16. Cerebellar vermis plays a causal role in visual motion discrimination.

    PubMed

    Cattaneo, Zaira; Renzi, Chiara; Casali, Stefano; Silvanto, Juha; Vecchi, Tomaso; Papagno, Costanza; D'Angelo, Egidio

    2014-09-01

    Cerebellar patients have been found to show deficits in visual motion discrimination, suggesting that the cerebellum may play a role in visual sensory processing beyond mediating motor control. Here we show that triple-pulse online transcranial magnetic stimulation (TMS) over cerebellar vermis but not over the cerebellar hemispheres significantly impaired motion discrimination. Critically, the interference caused by vermis TMS on motion discrimination did not depend on an indirect effect of TMS over nearby visual areas, as demonstrated by a control experiment in which TMS over V1 but not over cerebellar vermis significantly impaired orientation discrimination. These findings demonstrate the causal role of the cerebellar vermis in visual motion processing in neurologically normal participants.

  17. New evidence for the cerebellar involvement in personality traits

    PubMed Central

    Picerni, Eleonora; Petrosini, Laura; Piras, Fabrizio; Laricchiuta, Daniela; Cutuli, Debora; Chiapponi, Chiara; Fagioli, Sabrina; Girardi, Paolo; Caltagirone, Carlo; Spalletta, Gianfranco

    2013-01-01

    Following the recognition of its role in sensory-motor coordination and learning, the cerebellum has been involved in cognitive, emotional, and even personality domains. This study investigated the relationships between cerebellar macro- and micro-structural variations and temperamental traits measured by Temperament and Character Inventory (TCI). High resolution T1-weighted, and Diffusion Tensor Images of 100 healthy subjects aged 18–59 years were acquired by 3 Tesla Magnetic Resonance scanner. In multiple regression analyses, cerebellar Gray Matter (GM) or White Matter (WM) volumes, GM Mean Diffusivity (MD), and WM Fractional Anisotropy (FA) were used as dependent variables, TCI scores as regressors, gender, age, and education years as covariates. Novelty Seeking scores were associated positively with the cerebellar GM volumes and FA, and negatively with MD. No significant association between Harm Avoidance, Reward Dependence or Persistence scores and cerebellar structural measures was found. The present data put toward a cerebellar involvement in the management of novelty. PMID:24106465

  18. Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics.

    PubMed

    Fujioka, Shinsuke; Sundal, Christina; Wszolek, Zbigniew K

    2013-01-01

    Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments. PMID:23331413

  19. Nerve growth factor enhances DNA synthesis in cultured cerebellar neuroblasts.

    PubMed

    Confort, C; Charrasse, S; Clos, J

    1991-10-01

    The cerebellar neuroblasts in primary cultures from five-day-old rats bore NGF receptor immunoreactivity, suggesting a potential responsive to NGF. At low plating density, NGF was found to enhance DNA synthesis in these cells in a dose-dependent manner. As these cells synthesize NGF, one possibility to account for the lack of response of neuroblasts plated at high density is that the amount of endogenous trophic agent produced in this culture condition is sufficient to ensure an optimal effect. The results demonstrate that premitotic neuroblasts in the CNS, as well postmitotic neurons, are responsive to NGF. At the early stage of its development, the cerebellum therefore appears to be a very good autocrine model of NGF action.

  20. Nerve growth factor enhances DNA synthesis in cultured cerebellar neuroblasts.

    PubMed

    Confort, C; Charrasse, S; Clos, J

    1991-10-01

    The cerebellar neuroblasts in primary cultures from five-day-old rats bore NGF receptor immunoreactivity, suggesting a potential responsive to NGF. At low plating density, NGF was found to enhance DNA synthesis in these cells in a dose-dependent manner. As these cells synthesize NGF, one possibility to account for the lack of response of neuroblasts plated at high density is that the amount of endogenous trophic agent produced in this culture condition is sufficient to ensure an optimal effect. The results demonstrate that premitotic neuroblasts in the CNS, as well postmitotic neurons, are responsive to NGF. At the early stage of its development, the cerebellum therefore appears to be a very good autocrine model of NGF action. PMID:1661619

  1. Craniotomy for cerebellar hemangioblastoma excision in a patient with von Hippel–Lindau disease complicated by uncontrolled hypertension due to pheochromocytoma

    PubMed Central

    Mizobuchi, Yoshifumi; Kageji, Teruyoshi; Tadashi, Yamaguchi; Nagahiro, Shinji

    2015-01-01

    Introduction This report describes a patient with Von Hippel–Lindau (VHL) syndrome and uncontrolled hypertension due to pheochromocytoma who underwent craniotomy for the excision of a cerebellar hemangioblastoma combined with a laparoscopic adrenalectomy. Case report A 31-year-old man presented with severe headache. MRI showed areas of abnormal enhancement in the left cerebellum that were determined to be hemangioblastoma with mass effect and obstructive hydrocephalus. His blood pressure rose abruptly and could not be controlled. CT of the abdomen revealed bilateral suprarenal tumors, and the patient was diagnosed as having VHL syndrome.On the third day, he presented with increasing headache, a decreased level of consciousness, and hemiparesis. We were not able to perform an craniotomy because abdominal compression in the prone or sitting position resulted in severe hypertension. We performed ventricular drainage to control his ICP. On the fifth day, we first performed a bilateral laparoscopic adrenalectomy to control ICP and then moved the patient to the prone position before performing a craniotomy to remove the left cerebellar hemangioblastoma. Discu ssion & conclusion In patients with pheochromocytoma, the effects of catecholamine oversecretion can cause significant perioperative morbidity and mortality, but these can be prevented by appropriate preoperative medical management. When carrying out an excision of cerebellar hemangioblastomas in patients with intracranial hypertension complicated by abnormal hypertension due to pheochromocytoma whose blood pressure is not sufficiently controlled, tumor resection of the pheochromocytoma prior to cerebellar hemangioblastoma excision in the same surgery may prevent increased ICP and reduce perioperative risk. PMID:26595895

  2. Greater disruption to control of voluntary saccades in autistic disorder than Asperger's disorder: evidence for greater cerebellar involvement in autism?

    PubMed

    Stanley-Cary, Chloe; Rinehart, Nicole; Tonge, Bruce; White, Owen; Fielding, Joanne

    2011-03-01

    It remains unclear whether autism and Asperger's disorder (AD) exist on a symptom continuum or are separate disorders with discrete neurobiological underpinnings. In addition to impairments in communication and social cognition, motor deficits constitute a significant clinical feature in both disorders. It has been suggested that motor deficits and in particular the integrity of cerebellar modulation of movement may differentiate these disorders. We used a simple volitional saccade task to comprehensively profile the integrity of voluntary ocular motor behaviour in individuals with high functioning autism (HFA) or AD, and included measures sensitive to cerebellar dysfunction. We tested three groups of age-matched young males with normal intelligence (full scale, verbal, and performance IQ estimates >70) aged between 11 and 19 years; nine with AD, eight with HFA, and ten normally developing males as the comparison group. Overall, the metrics and dynamics of the voluntary saccades produced in this task were preserved in the AD group. In contrast, the HFA group demonstrated relatively preserved mean measures of ocular motricity with cerebellar-like deficits demonstrated in increased variability on measures of response time, final eye position, and movement dynamics. These deficits were considered to be consistent with reduced cerebellar online adaptation of movement. The results support the notion that the integrity of cerebellar modulation of movement may be different in AD and HFA, suggesting potentially differential neurobiological substrates may underpin these complex disorders.

  3. [Surgical decompression for massive cerebellar infarction].

    PubMed

    Ogasawara, K; Koshu, K; Nagamine, Y; Fujiwara, S; Mizoi, K; Yoshimoto, T

    1995-01-01

    The authors report 10 patients with progressive neurological deterioration due to massive cerebellar infarctions. Computerized tomography scans confirmed obstructive hydrocephalus and brain stem compression. All 10 patients (seven men, three women; mean age, 59 years) were treated by external ventricular drainage and decompressive suboccipital craniectomy. After discharge from the hospital, they were followed up (23-101 months) and their functional independence was evaluated by the Barthel Index. The condition of three patients with brain-stem infarction had deteriorated despite decompressive surgery. Two of these died during the acute stage and one because severely disabled. The remaining seven patients showed neurological improvement during the postoperative period. Four patients with preoperative Japan Coma Scale of 100 returned to their previous jobs within the follow-up period and three patients with preoperative Japan Coma Scale of 200 required some assistance in daily activities. It is suggested that decompressive surgery may be beneficial for massive cerebellar infarction. The postoperative prognosis depends mainly on the presence or absence of coexisting brain-stem infarction. It is possible that, without brain-stem infarction, patients who remained in a "dependent" state may have recovered better if they had been operated on earlier.

  4. Human COL2A1-directed SV40 T antigen expression in transgenic and chimeric mice results in abnormal skeletal development

    PubMed Central

    1995-01-01

    The ability of SV40 T antigen to cause abnormalities in cartilage development in transgenic mice and chimeras has been tested. The cis- regulatory elements of the COL2A1 gene were used to target expression of SV40 T antigen to differentiating chondrocytes in transgenic mice and chimeras derived from embryonal stem (ES) cells bearing the same transgene. The major phenotypic consequences of transgenic (pAL21) expression are malformed skeleton, disproportionate dwarfism, and perinatal/neonatal death. Expression of T antigen was tissue specific and in the main characteristic of the mouse alpha 1(II) collagen gene. Chondrocyte densities and levels of alpha 1(II) collagen mRNAs were reduced in the transgenic mice. Islands of cells which express cartilage characteristic genes such as type IIB procollagen, long form alpha 1(IX) collagen, alpha 2(XI) collagen, and aggrecan were found in the articular and growth cartilages of pAL21 chimeric fetuses and neonates. But these cells, which were expressing T antigen, were not properly organized into columns of proliferating chondrocytes. Levels of alpha 1(II) collagen mRNA were reduced in these chondrocytes. In addition, these cells did not express type X collagen, a marker for hypertrophic chondrocytes. The skeletal abnormality in pAL21 mice may therefore be due to a retardation of chondrocyte maturation or an impaired ability of chondrocytes to complete terminal differentiation and an associated paucity of some cartilage matrix components. PMID:7822417

  5. Prenatal Cerebellar Disruptions: Neuroimaging Spectrum of Findings in Correlation with Likely Mechanisms and Etiologies of Injury.

    PubMed

    Poretti, Andrea; Boltshauser, Eugen; Huisman, Thierry A G M

    2016-08-01

    There is increasing evidence that the cerebellum is susceptible to prenatal infections and hemorrhages and that congenital morphologic anomalies of the cerebellum may be caused by disruptive (acquired) causes. Starting from the neuroimaging pattern, this report describes a spectrum of prenatal cerebellar disruptions including cerebellar agenesis, unilateral cerebellar hypoplasia, cerebellar cleft, global cerebellar hypoplasia, and vanishing cerebellum in Chiari type II malformation. The neuroimaging findings, possible causative disruptive events, and clinical features of each disruption are discussed. Recognition of cerebellar disruptions and their differentiation from cerebellar malformations is important in terms of diagnosis, prognosis, and genetic counselling. PMID:27423799

  6. Recognizable cerebellar dysplasia associated with mutations in multiple tubulin genes

    PubMed Central

    Oegema, Renske; Cushion, Thomas D.; Phelps, Ian G.; Chung, Seo-Kyung; Dempsey, Jennifer C.; Collins, Sarah; Mullins, Jonathan G.L.; Dudding, Tracy; Gill, Harinder; Green, Andrew J.; Dobyns, William B.; Ishak, Gisele E.; Rees, Mark I.; Doherty, Dan

    2015-01-01

    Mutations in alpha- and beta-tubulins are increasingly recognized as a major cause of malformations of cortical development (MCD), typically lissencephaly, pachygyria and polymicrogyria; however, sequencing tubulin genes in large cohorts of MCD patients has detected tubulin mutations in only 1–13%. We identified patients with a highly characteristic cerebellar dysplasia but without lissencephaly, pachygyria and polymicrogyria typically associated with tubulin mutations. Remarkably, in seven of nine patients (78%), targeted sequencing revealed mutations in three different tubulin genes (TUBA1A, TUBB2B and TUBB3), occurring de novo or inherited from a mosaic parent. Careful re-review of the cortical phenotype on brain imaging revealed only an irregular pattern of gyri and sulci, for which we propose the term tubulinopathy-related dysgyria. Basal ganglia (100%) and brainstem dysplasia (80%) were common features. On the basis of in silico structural predictions, the mutations affect amino acids in diverse regions of the alpha-/beta-tubulin heterodimer, including the nucleotide binding pocket. Cell-based assays of tubulin dynamics reveal various effects of the mutations on incorporation into microtubules: TUBB3 p.Glu288Lys and p.Pro357Leu do not incorporate into microtubules at all, whereas TUBB2B p.Gly13Ala shows reduced incorporation and TUBA1A p.Arg214His incorporates fully, but at a slower rate than wild-type. The broad range of effects on microtubule incorporation is at odds with the highly stereotypical clinical phenotype, supporting differential roles for the three tubulin genes involved. Identifying this highly characteristic phenotype is important due to the low recurrence risk compared with the other (recessive) cerebellar dysplasias and the apparent lack of non-neurological medical issues. PMID:26130693

  7. Recognizable cerebellar dysplasia associated with mutations in multiple tubulin genes.

    PubMed

    Oegema, Renske; Cushion, Thomas D; Phelps, Ian G; Chung, Seo-Kyung; Dempsey, Jennifer C; Collins, Sarah; Mullins, Jonathan G L; Dudding, Tracy; Gill, Harinder; Green, Andrew J; Dobyns, William B; Ishak, Gisele E; Rees, Mark I; Doherty, Dan

    2015-09-15

    Mutations in alpha- and beta-tubulins are increasingly recognized as a major cause of malformations of cortical development (MCD), typically lissencephaly, pachygyria and polymicrogyria; however, sequencing tubulin genes in large cohorts of MCD patients has detected tubulin mutations in only 1-13%. We identified patients with a highly characteristic cerebellar dysplasia but without lissencephaly, pachygyria and polymicrogyria typically associated with tubulin mutations. Remarkably, in seven of nine patients (78%), targeted sequencing revealed mutations in three different tubulin genes (TUBA1A, TUBB2B and TUBB3), occurring de novo or inherited from a mosaic parent. Careful re-review of the cortical phenotype on brain imaging revealed only an irregular pattern of gyri and sulci, for which we propose the term tubulinopathy-related dysgyria. Basal ganglia (100%) and brainstem dysplasia (80%) were common features. On the basis of in silico structural predictions, the mutations affect amino acids in diverse regions of the alpha-/beta-tubulin heterodimer, including the nucleotide binding pocket. Cell-based assays of tubulin dynamics reveal various effects of the mutations on incorporation into microtubules: TUBB3 p.Glu288Lys and p.Pro357Leu do not incorporate into microtubules at all, whereas TUBB2B p.Gly13Ala shows reduced incorporation and TUBA1A p.Arg214His incorporates fully, but at a slower rate than wild-type. The broad range of effects on microtubule incorporation is at odds with the highly stereotypical clinical phenotype, supporting differential roles for the three tubulin genes involved. Identifying this highly characteristic phenotype is important due to the low recurrence risk compared with the other (recessive) cerebellar dysplasias and the apparent lack of non-neurological medical issues.

  8. Inactivation of ca10a and ca10b Genes Leads to Abnormal Embryonic Development and Alters Movement Pattern in Zebrafish

    PubMed Central

    Aspatwar, Ashok; Barker, Harlan R.; Saralahti, Anni K.; Bäuerlein, Carina A.; Ortutay, Csaba; Pan, Peiwen; Kuuslahti, Marianne; Parikka, Mataleena; Rämet, Mika; Parkkila, Seppo

    2015-01-01

    Carbonic anhydrase related proteins (CARPs) X and XI are highly conserved across species and are predominantly expressed in neural tissues. The biological role of these proteins is still an enigma. Ray-finned fish have lost the CA11 gene, but instead possess two co-orthologs of CA10. We analyzed the expression pattern of zebrafish ca10a and ca10b genes during embryonic development and in different adult tissues, and studied 61 CARP X/XI-like sequences to evaluate their phylogenetic relationship. Sequence analysis of zebrafish ca10a and ca10b reveals strongly predicted signal peptides, N-glycosylation sites, and a potential disulfide, all of which are conserved, suggesting that all of CARP X and XI are secretory proteins and potentially dimeric. RT-qPCR showed that zebrafish ca10a and ca10b genes are expressed in the brain and several other tissues throughout the development of zebrafish. Antisense morpholino mediated knockdown of ca10a and ca10b showed developmental delay with a high rate of mortality in larvae. Zebrafish morphants showed curved body, pericardial edema, and abnormalities in the head and eye, and there was increased apoptotic cell death in the brain region. Swim pattern showed abnormal movement in morphant zebrafish larvae compared to the wild type larvae. The developmental phenotypes of the ca10a and ca10b morphants were confirmed by inactivating these genes with the CRISPR/Cas9 system. In conclusion, we introduce a novel zebrafish model to investigate the mechanisms of CARP Xa and CARP Xb functions. Our data indicate that CARP Xa and CARP Xb have important roles in zebrafish development and suppression of ca10a and ca10b expression in zebrafish larvae leads to a movement disorder. PMID:26218428

  9. Neural correlates of impaired emotional face recognition in cerebellar lesions.

    PubMed

    Adamaszek, Michael; Kirkby, Kenneth C; D'Agata, Fedrico; Olbrich, Sebastian; Langner, Sönke; Steele, Christopher; Sehm, Bernhard; Busse, Stefan; Kessler, Christof; Hamm, Alfons

    2015-07-10

    Clinical and neuroimaging data indicate a cerebellar contribution to emotional processing, which may account for affective-behavioral disturbances in patients with cerebellar lesions. We studied the neurophysiology of cerebellar involvement in recognition of emotional facial expression. Participants comprised eight patients with discrete ischemic cerebellar lesions and eight control patients without any cerebrovascular stroke. Event-related potentials (ERP) were used to measure responses to faces from the Karolinska Directed Emotional Faces Database (KDEF), interspersed in a stream of images with salient contents. Images of faces augmented N170 in both groups, but increased late positive potential (LPP) only in control patients without brain lesions. Dipole analysis revealed altered activation patterns for negative emotions in patients with cerebellar lesions, including activation of the left inferior prefrontal area to images of faces showing fear, contralateral to controls. Correlation analysis indicated that lesions of cerebellar area Crus I contribute to ERP deviations. Overall, our results implicate the cerebellum in integrating emotional information at different higher order stages, suggesting distinct cerebellar contributions to the proposed large-scale cerebral network of emotional face recognition. PMID:25912431

  10. Developmental dyslexia and widespread activation across the cerebellar hemispheres.

    PubMed

    Baillieux, Hanne; Vandervliet, Everhard J M; Manto, Mario; Parizel, Paul M; De Deyn, Peter P; Mariën, Peter

    2009-02-01

    Developmental dyslexia is the most common learning disability in school-aged children with an estimated incidence of five to ten percent. The cause and pathophysiological substrate of this developmental disorder is unclear. Recently, a possible involvement of the cerebellum in the pathogenesis of dyslexia has been postulated. In this study, 15 dyslexic children and 7 age-matched control subjects were investigated by means of functional neuroimaging (fMRI) using a noun-verb association paradigm. Comparison of activation patterns between dyslexic and control subjects revealed distinct and significant differences in cerebral and cerebellar activation. Control subjects showed bilaterally well-defined and focal activation patterns in the frontal and parietal lobes and the posterior regions of the cerebellar hemispheres. The dyslexic children, however, presented widespread and diffuse activations on the cerebral and cerebellar level. Cerebral activations were found in frontal, parietal, temporal and occipital regions. Activations in the cerebellum were found predominantly in the cerebellar cortex, including Crus I, Crus II, hemispheric lobule VI, VII and vermal lobules I, II, III, IV and VII. This preliminary study is the first to reveal a significant difference in cerebellar functioning between dyslexic children and controls during a semantic association task. As a result, we propose a new hypothesis regarding the pathophysiological mechanisms of developmental dyslexia. Given the sites of activation in the cerebellum in the dyslexic group, a defect of the intra-cerebellar distribution of activity is suspected, suggesting a disorder of the processing or transfer of information within the cerebellar cortex. PMID:18986695

  11. Contribution of Cerebellar Sensorimotor Adaptation to Hippocampal Spatial Memory

    PubMed Central

    Passot, Jean-Baptiste; Sheynikhovich, Denis; Duvelle, Éléonore; Arleo, Angelo

    2012-01-01

    Complementing its primary role in motor control, cerebellar learning has also a bottom-up influence on cognitive functions, where high-level representations build up from elementary sensorimotor memories. In this paper we examine the cerebellar contribution to both procedural and declarative components of spatial cognition. To do so, we model a functional interplay between the cerebellum and the hippocampal formation during goal-oriented navigation. We reinterpret and complete existing genetic behavioural observations by means of quantitative accounts that cross-link synaptic plasticity mechanisms, single cell and population coding properties, and behavioural responses. In contrast to earlier hypotheses positing only a purely procedural impact of cerebellar adaptation deficits, our results suggest a cerebellar involvement in high-level aspects of behaviour. In particular, we propose that cerebellar learning mechanisms may influence hippocampal place fields, by contributing to the path integration process. Our simulations predict differences in place-cell discharge properties between normal mice and L7-PKCI mutant mice lacking long-term depression at cerebellar parallel fibre-Purkinje cell synapses. On the behavioural level, these results suggest that, by influencing the accuracy of hippocampal spatial codes, cerebellar deficits may impact the exploration-exploitation balance during spatial navigation. PMID:22485133

  12. Cerebellar Processing of Sensory Inputs Primes Motor Cortex Plasticity

    PubMed Central

    Velayudhan, B.; Hubsch, C.; Pradeep, S.; Roze, E.; Vidailhet, M.; Meunier, S.; Kishore, A.

    2013-01-01

    Plasticity of the human primary motor cortex (M1) has a critical role in motor control and learning. The cerebellum facilitates these functions using sensory feedback. We investigated whether cerebellar processing of sensory afferent information influences the plasticity of the primary motor cortex (M1). Theta-burst stimulation protocols (TBS), both excitatory and inhibitory, were used to modulate the excitability of the posterior cerebellar cortex and to condition an ongoing M1 plasticity. M1 plasticity was subsequently induced in 2 different ways: by paired associative stimulation (PAS) involving sensory processing and TBS that exclusively involves intracortical circuits of M1. Cerebellar excitation attenuated the PAS-induced M1 plasticity, whereas cerebellar inhibition enhanced and prolonged it. Furthermore, cerebellar inhibition abolished the topography-specific response of PAS-induced M1 plasticity, with the effects spreading to adjacent motor maps. Conversely, cerebellar excitation had no effect on the TBS-induced M1 plasticity. This demonstrates the key role of the cerebellum in priming M1 plasticity, and we propose that it is likely to occur at the thalamic or olivo-dentate nuclear level by influencing the sensory processing. We suggest that such a cerebellar priming of M1 plasticity could shape the impending motor command by favoring or inhibiting the recruitment of several muscle representations. PMID:22351647

  13. Neural correlates of impaired emotional face recognition in cerebellar lesions.

    PubMed

    Adamaszek, Michael; Kirkby, Kenneth C; D'Agata, Fedrico; Olbrich, Sebastian; Langner, Sönke; Steele, Christopher; Sehm, Bernhard; Busse, Stefan; Kessler, Christof; Hamm, Alfons

    2015-07-10

    Clinical and neuroimaging data indicate a cerebellar contribution to emotional processing, which may account for affective-behavioral disturbances in patients with cerebellar lesions. We studied the neurophysiology of cerebellar involvement in recognition of emotional facial expression. Participants comprised eight patients with discrete ischemic cerebellar lesions and eight control patients without any cerebrovascular stroke. Event-related potentials (ERP) were used to measure responses to faces from the Karolinska Directed Emotional Faces Database (KDEF), interspersed in a stream of images with salient contents. Images of faces augmented N170 in both groups, but increased late positive potential (LPP) only in control patients without brain lesions. Dipole analysis revealed altered activation patterns for negative emotions in patients with cerebellar lesions, including activation of the left inferior prefrontal area to images of faces showing fear, contralateral to controls. Correlation analysis indicated that lesions of cerebellar area Crus I contribute to ERP deviations. Overall, our results implicate the cerebellum in integrating emotional information at different higher order stages, suggesting distinct cerebellar contributions to the proposed large-scale cerebral network of emotional face recognition.

  14. The Role of Chronic Hypoxia in the Development of Neurocognitive Abnormalities in Preterm Infants with Bronchopulmonary Dysplasia

    ERIC Educational Resources Information Center

    Raman, Lakshmi; Georgieff, Michael K.; Rao, Raghavendra

    2006-01-01

    Bronchopulmonary dysplasia is the most common pulmonary morbidity in preterm infants and is associated with chronic hypoxia. Animal studies have demonstrated structural, neurochemical and functional alterations due to chronic hypoxia in the developing brain. Long-term impairments in visual-motor, gross and fine motor, articulation, reading,…

  15. Selective loss of Purkinje cells in a patient with anti‐glutamic acid decarboxylase antibody‐associated cerebellar ataxia

    PubMed Central

    Ishida, Kazuyuki; Mitoma, Hiroshi; Wada, Yoshiaki; Oka, Teruaki; Shibahara, Junji; Saito, Yuko; Murayama, Shigeo; Mizusawa, Hidehiro

    2007-01-01

    Anti‐glutamic acid decarboxylase antibody is associated with the development of progressive cerebellar ataxia and slowly progressive insulin‐dependent diabetes mellitus. Previously, the neurophysiological characteristics of IgG in the cerebrospinal fluid of a patient with anti‐glutamic acid decarboxylase antibody‐associated progressive cerebellar ataxia and slowly progressive insulin‐dependent diabetes mellitus were reported. Using a voltage‐gated whole‐cell recording technique, it was observed that the IgG in the cerebrospinal fluid of the patient selectively suppressed the inhibitory postsynaptic currents in the Purkinje cells. The patient died from aspiration pneumonia. Postmortem examination showed almost complete depletion of the Purkinje cells with Bergmann gliosis. Therefore, the main cause of cerebellar ataxia observed in this case may be attributed to the near‐complete depletion of the Purkinje cells. In this paper, the pathomechanisms underlying Purkinje cell damage are discussed. PMID:17119008

  16. Development of a diet-induced murine model of diabetes featuring cardinal metabolic and pathophysiological abnormalities of type 2 diabetes

    PubMed Central

    Morris, Jodie L.; Bridson, Tahnee L.; Alim, Md Abdul; Rush, Catherine M.; Rudd, Donna M.; Govan, Brenda L.; Ketheesan, Natkunam

    2016-01-01

    ABSTRACT The persistent rise in global incidence of type 2 diabetes (T2D) continues to have significant public health and economic implications. The availability of relevant animal models of T2D is critical to elucidating the complexity of the pathogenic mechanisms underlying this disease and the implications this has on susceptibility to T2D complications. Whilst many high-fat diet-induced rodent models of obesity and diabetes exist, growing appreciation of the contribution of high glycaemic index diets on the development of hyperglycaemia and insulin resistance highlight the requirement for animal models that more closely represent global dietary patterns reflective of modern society. To that end, we sought to develop and validate a murine model of T2D based on consumption of an energy-dense diet containing moderate levels of fat and a high glycaemic index to better reflect the aetiopathogenesis of T2D. Male C57BL/6 mice were fed an energy-dense (ED) diet and the development of pathological features used in the clinical diagnosis of T2D was assessed over a 30-week period. Compared with control mice, 87% of mice fed an ED diet developed pathognomonic signs of T2D including glucose intolerance, hyperglycaemia, glycosylated haemoglobin (HbA1c) and glycosuria within 30 weeks. Furthermore, dyslipidaemia, chronic inflammation, alterations in circulating leucocytes and renal impairment were also evident in ED diet-fed mice compared with mice receiving standard rodent chow. Longitudinal profiling of metabolic and biochemical parameters provide support of an aetiologically and clinically relevant model of T2D that will serve as a valuable tool for mechanistic and therapeutic studies investigating the pathogenic complications of T2D. PMID:27402965

  17. Distal myopathy with rimmed vacuoles and cerebellar atrophy.

    PubMed

    Merkli, Hajnalka; Pál, Endre; Gáti, István; Czopf, József

    2006-01-01

    Distal myopathies constitute a clinically and pathologically heterogeneous group of genetically determined neuromuscular disorders, where the distal muscles of the upper or lower limbs are affected. The disease of a 41-year-old male patient started with gait disturbances, when he was 25. The progression was slow, but after 16 years he became seriously disabled. Neurological examination showed moderate to severe weakness in distal muscles of all extremities, marked cerebellar sign and steppage gait. Muscle biopsy resulted in myopathic changes with rimmed vacuoles. Brain MRI scan showed cerebellar atrophy. This case demonstrates a rare association of distal myopathy and cerebellar atrophy.

  18. Cerebellar morphological alterations in rats induced by prenatal ozone exposure.

    PubMed

    Rivas-Manzano, P; Paz, C

    1999-11-26

    The present study analyzes the morphological aspects of the cerebellum of rats with prenatal exposure to ozone. A double blind histological and planimetric analysis was performed studying sagittal sections of the anterior cerebellar lobe at postnatal days 0, 12 and 60. Ozone exposed rats showed cerebellar necrotic signs at age 0, diminished area of the molecular layer with Purkinje cells with pale nucleoli and perinucleolar bodies at age 12, and Purkinje cells showing nuclei with unusual clumps of chromatin in the periphery at age 60. We conclude that exposure to high concentrations of ozone during gestation induces permanent cerebellar damage in rats.

  19. Consensus Paper: Revisiting the Symptoms and Signs of Cerebellar Syndrome.

    PubMed

    Bodranghien, Florian; Bastian, Amy; Casali, Carlo; Hallett, Mark; Louis, Elan D; Manto, Mario; Mariën, Peter; Nowak, Dennis A; Schmahmann, Jeremy D; Serrao, Mariano; Steiner, Katharina Marie; Strupp, Michael; Tilikete, Caroline; Timmann, Dagmar; van Dun, Kim

    2016-06-01

    The cerebellum is involved in sensorimotor operations, cognitive tasks and affective processes. Here, we revisit the concept of the cerebellar syndrome in the light of recent advances in our understanding of cerebellar operations. The key symptoms and signs of cerebellar dysfunction, often grouped under the generic term of ataxia, are discussed. Vertigo, dizziness, and imbalance are associated with lesions of the vestibulo-cerebellar, vestibulo-spinal, or cerebellar ocular motor systems. The cerebellum plays a major role in the online to long-term control of eye movements (control of calibration, reduction of eye instability, maintenance of ocular alignment). Ocular instability, nystagmus, saccadic intrusions, impaired smooth pursuit, impaired vestibulo-ocular reflex (VOR), and ocular misalignment are at the core of oculomotor cerebellar deficits. As a motor speech disorder, ataxic dysarthria is highly suggestive of cerebellar pathology. Regarding motor control of limbs, hypotonia, a- or dysdiadochokinesia, dysmetria, grasping deficits and various tremor phenomenologies are observed in cerebellar disorders to varying degrees. There is clear evidence that the cerebellum participates in force perception and proprioceptive sense during active movements. Gait is staggering with a wide base, and tandem gait is very often impaired in cerebellar disorders. In terms of cognitive and affective operations, impairments are found in executive functions, visual-spatial processing, linguistic function, and affective regulation (Schmahmann's syndrome). Nonmotor linguistic deficits including disruption of articulatory and graphomotor planning, language dynamics, verbal fluency, phonological, and semantic word retrieval, expressive and receptive syntax, and various aspects of reading and writing may be impaired after cerebellar damage. The cerebellum is organized into (a) a primary sensorimotor region in the anterior lobe and adjacent part of lobule VI, (b) a second sensorimotor

  20. Development of Abnormal Hemispheric Vascular Networks Mimicking Cerebral Proliferative Angiopathy in a Child Originally Diagnosed with Deep-Seated Arteriovenous Fistula.

    PubMed

    Sakata, Hiroyuki; Fujimura, Miki; Sato, Kenichi; Niizuma, Kuniyasu; Endo, Hidenori; Tominaga, Teiji

    2016-10-01

    Cerebral proliferative angiopathy (CPA), which is characterized by diffuse vascular abnormalities with intermingled normal brain parenchyma, is a rare clinical entity distinct from classical cerebral arteriovenous malformations. Its pathology at initial state and subsequent course of progression has totally been undetermined. We herein presented a case of a child who was initially diagnosed with deep-seated arteriovenous fistula (AVF), and ultimately developed symptomatic CPA-like vascular lesion over a long period of clinical follow-up. A 7-month-old boy was incidentally found to have an AVF in the right basal ganglia and conservatively followed up. Serial magnetic resonance angiograms revealed the gradual proliferation and enlargement of pial and medullary vessels surrounding the AVF. Seven years later, he had a transient ischemic attack followed by intraventricular hemorrhage. A catheter angiogram showed a diffuse large vascular malformation composed of 2 distinct structures, including AVF in the right basal ganglia and the surrounding proliferated pial and medullary arteries in the right hemisphere. Single-photon emission computed tomography with N-isopropyl[123I]-p-iodoamphetamine revealed apparent hemodynamic compromise on the right hemisphere. Targeted embolization of the pseudoaneurysm originating from the right A1 perforator was performed to prevent rebleeding without complications. The patient had no further cerebrovascular events. Perinidal hypoperfusion induced by a deep-seated AVF could be one of the underlying pathologies of progressive angiogenic activity. This is the first case showing the development of abnormal hemispheric vascular networks mimicking CPA, which offers insight into the pathogenesis of this new entity.

  1. FGF-2 signal promotes proliferation of cerebellar progenitor cells and their oligodendrocytic differentiation at early postnatal stage

    SciTech Connect

    Naruse, Masae; Shibasaki, Koji; Ishizaki, Yasuki

    2015-08-07

    The origins and developmental regulation of cerebellar oligodendrocytes are largely unknown, although some hypotheses of embryonic origins have been suggested. Neural stem cells exist in the white matter of postnatal cerebellum, but it is unclear whether these neural stem cells generate oligodendrocytes at postnatal stages. We previously showed that cerebellar progenitor cells, including neural stem cells, widely express CD44 at around postnatal day 3. In the present study, we showed that CD44-positive cells prepared from the postnatal day 3 cerebellum gave rise to neurospheres, while CD44-negative cells prepared from the same cerebellum did not. These neurospheres differentiated mainly into oligodendrocytes and astrocytes, suggesting that CD44-positive neural stem/progenitor cells might generate oligodendrocytes in postnatal cerebellum. We cultured CD44-positive cells from the postnatal day 3 cerebellum in the presence of signaling molecules known as mitogens or inductive differentiation factors for oligodendrocyte progenitor cells. Of these, only FGF-2 promoted survival and proliferation of CD44-positive cells, and these cells differentiated into O4+ oligodendrocytes. Furthermore, we examined the effect of FGF-2 on cerebellar oligodendrocyte development ex vivo. FGF-2 enhanced proliferation of oligodendrocyte progenitor cells and increased the number of O4+ and CC1+ oligodendrocytes in slice cultures. These results suggest that CD44-positive cells might be a source of cerebellar oligodendrocytes and that FGF-2 plays important roles in their development at an early postnatal stage. - Highlights: • CD44 is expressed in cerebellar neural stem/progenitor cells at postnatal day 3 (P3). • FGF-2 promoted proliferation of CD44-positive progenitor cells from P3 cerebellum. • FGF-2 promoted oligodendrocytic differentiation of CD44-positive progenitor cells. • FGF-2 increased the number of oligodendrocytes in P3 cerebellar slice culture.

  2. Germ cell specific overactivation of WNT/βcatenin signalling has no effect on folliculogenesis but causes fertility defects due to abnormal foetal development

    PubMed Central

    Kumar, Manish; Camlin, Nicole J.; Holt, Janet E.; Teixeira, Jose M.; McLaughlin, Eileen A.; Tanwar, Pradeep S.

    2016-01-01

    All the major components of the WNT signalling pathway are expressed in female germ cells and embryos. However, their functional relevance in oocyte biology is currently unclear. We examined ovaries collected from TCFGFP mice, a well-known Wnt reporter mouse model, and found dynamic changes in the Wnt/βcatenin signalling activity during different stages of oocyte development and maturation. To understand the functional importance of Wnt signalling in oocytes, we developed a mouse model with the germ cell-specific constitutive activation of βcatenin using cre recombinase driven by the DEAD (Asp-Glu-Ala-Asp) box protein 4 (Ddx4) gene promoter. Histopathological and functional analysis of ovaries from these mutant mice (Ctnnb1ex3cko) showed no defects in ovarian functions, oocytes, ovulation and early embryonic development. However, breeding of the Ctnnb1ex3cko female mice with males of known fertility never resulted in birth of mutant pups. Examination of uteri from time pregnant mutant females revealed defects in ectoderm differentiation leading to abnormal foetal development and premature death. Collectively, our work has established the role of active WNT/βcatenin signalling in oocyte biology and foetal development, and provides novel insights into the possible mechanisms of complications in human pregnancy such as repeated spontaneous abortion, sudden intrauterine unexpected foetal death syndrome and stillbirth. PMID:27265527

  3. Lack of Cul4b, an E3 Ubiquitin Ligase Component, Leads to Embryonic Lethality and Abnormal Placental Development

    PubMed Central

    Yuan, Jupeng; Qian, Yanyan; Sun, Wenjie; Zou, Yongxin; Guo, Chenhong; Chen, Bingxi; Shao, Changshun; Gong, Yaoqin

    2012-01-01

    Cullin-RING ligases (CRLs) complexes participate in the regulation of diverse cellular processes, including cell cycle progression, transcription, signal transduction and development. Serving as the scaffold protein, cullins are crucial for the assembly of ligase complexes, which recognize and target various substrates for proteosomal degradation. Mutations in human CUL4B, one of the eight members in cullin family, are one of the major causes of X-linked mental retardation. We here report the generation and characterization of Cul4b knockout mice, in which exons 3 to 5 were deleted. In contrast to the survival to adulthood of human hemizygous males with CUL4B null mutation, Cul4b null mouse embryos show severe developmental arrest and usually die before embryonic day 9.5 (E9.5). Accumulation of cyclin E, a CRL (CUL4B) substrate, was observed in Cul4b null embryos. Cul4b heterozygotes were recovered at a reduced ratio and exhibited a severe developmental delay. The placentas in Cul4b heterozygotes were disorganized and were impaired in vascularization, which may contribute to the developmental delay. As in human CUL4B heterozygotes, Cul4b null cells were selected against in Cul4b heterozygotes, leading to various degrees of skewed X-inactivation in different tissues. Together, our results showed that CUL4B is indispensable for embryonic development in the mouse. PMID:22606329

  4. Tooth - abnormal shape

    MedlinePlus

    Hutchinson incisors; Abnormal tooth shape; Peg teeth; Mulberry teeth; Conical teeth ... The appearance of normal teeth varies, especially the molars. ... conditions. Specific diseases can affect tooth shape, tooth ...

  5. Hereditary Cerebellar Ataxias: A Korean Perspective

    PubMed Central

    Kim, Ji Sun; Cho, Jin Whan

    2015-01-01

    Hereditary ataxia is a heterogeneous disorder characterized by progressive ataxia combined with/without peripheral neuropathy, extrapyramidal symptoms, pyramidal symptoms, seizure, and multiple systematic involvements. More than 35 autosomal dominant cerebellar ataxias have been designated as spinocerebellar ataxia, and there are 55 recessive ataxias that have not been named systematically. Conducting genetic sequencing to confirm a diagnosis is difficult due to the large amount of subtypes with phenotypic overlap. The prevalence of hereditary ataxia can vary among countries, and estimations of prevalence and subtype frequencies are necessary for planning a diagnostic strategy in a specific population. This review covers the various hereditary ataxias reported in the Korean population with a focus on the prevalence and subtype frequencies as the clinical characteristics of the various subtypes. PMID:26090078

  6. Abnormal differentiation of dopaminergic neurons in zebrafish trpm7 mutant larvae impairs development of the motor pattern.

    PubMed

    Decker, Amanda R; McNeill, Matthew S; Lambert, Aaron M; Overton, Jeffrey D; Chen, Yu-Chia; Lorca, Ramón A; Johnson, Nicolas A; Brockerhoff, Susan E; Mohapatra, Durga P; MacArthur, Heather; Panula, Pertti; Masino, Mark A; Runnels, Loren W; Cornell, Robert A

    2014-02-15

    Transient receptor potential, melastatin-like 7 (Trpm7) is a combined ion channel and kinase implicated in the differentiation or function of many cell types. Early lethality in mice and frogs depleted of the corresponding gene impedes investigation of the functions of this protein particularly during later stages of development. By contrast, zebrafish trpm7 mutant larvae undergo early morphogenesis normally and thus do not have this limitation. The mutant larvae are characterized by multiple defects including melanocyte cell death, transient paralysis, and an ion imbalance that leads to the development of kidney stones. Here we report a requirement for Trpm7 in differentiation or function of dopaminergic neurons in vivo. First, trpm7 mutant larvae are hypomotile and fail to make a dopamine-dependent developmental transition in swim-bout length. Both of these deficits are partially rescued by the application of levodopa or dopamine. Second, histological analysis reveals that in trpm7 mutants a significant fraction of dopaminergic neurons lack expression of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Third, trpm7 mutants are unusually sensitive to the neurotoxin 1-methyl-4-phenylpyridinium, an oxidative stressor, and their motility is partially rescued by application of the iron chelator deferoxamine, an anti-oxidant. Finally, in SH-SY5Y cells, which model aspects of human dopaminergic neurons, forced expression of a channel-dead variant of TRPM7 causes cell death. In summary, a forward genetic screen in zebrafish has revealed that both melanocytes and dopaminergic neurons depend on the ion channel Trpm7. The mechanistic underpinning of this dependence requires further investigation.

  7. Thymidine Kinase 2 Deficiency-Induced Mitochondrial DNA Depletion Causes Abnormal Development of Adipose Tissues and Adipokine Levels in Mice

    PubMed Central

    Villarroya, Joan; Dorado, Beatriz; Vilà, Maya R.; Garcia-Arumí, Elena; Domingo, Pere; Giralt, Marta; Hirano, Michio; Villarroya, Francesc

    2011-01-01

    Mammal adipose tissues require mitochondrial activity for proper development and differentiation. The components of the mitochondrial respiratory chain/oxidative phosphorylation system (OXPHOS) are encoded by both mitochondrial and nuclear genomes. The maintenance of mitochondrial DNA (mtDNA) is a key element for a functional mitochondrial oxidative activity in mammalian cells. To ascertain the role of mtDNA levels in adipose tissue, we have analyzed the alterations in white (WAT) and brown (BAT) adipose tissues in thymidine kinase 2 (Tk2) H126N knockin mice, a model of TK2 deficiency-induced mtDNA depletion. We observed respectively severe and moderate mtDNA depletion in TK2-deficient BAT and WAT, showing both tissues moderate hypotrophy and reduced fat accumulation. Electron microscopy revealed altered mitochondrial morphology in brown but not in white adipocytes from TK2-deficient mice. Although significant reduction in mtDNA-encoded transcripts was observed both in WAT and BAT, protein levels from distinct OXPHOS complexes were significantly reduced only in TK2-deficient BAT. Accordingly, the activity of cytochrome c oxidase was significantly lowered only in BAT from TK2-deficient mice. The analysis of transcripts encoding up to fourteen components of specific adipose tissue functions revealed that, in both TK2-deficient WAT and BAT, there was a consistent reduction of thermogenesis related gene expression and a severe reduction in leptin mRNA. Reduced levels of resistin mRNA were found in BAT from TK2-deficient mice. Analysis of serum indicated a dramatic reduction in circulating levels of leptin and resistin. In summary, our present study establishes that mtDNA depletion leads to a moderate impairment in mitochondrial respiratory function, especially in BAT, causes substantial alterations in WAT and BAT development, and has a profound impact in the endocrine properties of adipose tissues. PMID:22216345

  8. Abnormal pituitary development and function in three siblings of a Jamaican family: A new syndrome involving the Pit-1 gene

    SciTech Connect

    Sanchez, J.C.; Schiavi, A.; Parks, J.

    1994-09-01

    In 1967 Mckusick et al. reported three siblings in Canada who had combine pituitary hormone deficiencies (CPHD). Since that report there have been several families with multiple affected members who share the common characteristics of autosomal recessive inheritance and clinical expression of pituitary deficiencies at an early age. We report here a CPHD family of Jamaican origin with three affected and two unaffected siblings. The affected siblings have evidence of severe growth failure, growth hormone deficiency, hypothyroidism and variable prolactin deficiency. Recently, in some families with CPHD a defect has been detected in the Pit-1 gene, which encodes a transcription factor involved in the differentiation of the pituitary and the production of growth hormone, TSH and prolactin. We are studying the Pit-1 gene in this family as a candidate gene that may explain the family phenotype. The Pit-1 gene has been analyzed in DNA extracted from blood. No gross deletion were detected in exons 2, 3,