Adaptations of the vestibular system to short and long-term exposures to altered gravity

NASA Astrophysics Data System (ADS)

Bruce, L.

Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival. We are studying two aspects of this vestibular adaptation: (1) How does long-term exposure to microgravity and hypergravity affect the development of vestibular afferents? (2) How does short- term exposure to extremely rapid changes in gravity, such as those that occur during launch and landing, affect the vestibular system. During space flight the gravistatic receptors in the otolith organs are effectively unloaded. In hypergravity conditions they are overloaded. However, the angular acceleration receptors of the semicircular canals receive relatively normal stimulation in both micro- and hypergravity.Rat embryos exposed to microgravity from gestation day 10 (prior to vestibular function) until gestation day 20 (vestibular system is somewhat functional) showed that afferents from the posterior vertical canal projecting to the medial vestibular nucleus developed similarly in microgravity, hypergravity, and in controls . However, afferents from the saccule showed delayed development in microgravity as compared to development in hypergravity and in controls. Cerebellar plasticity is crucial for modification of sensory-motor control and learning. Thus we explored the possibility that strong vestibular stimuli would modify cerebellar motor control (i.e., eye movement, postural control, gut motility) by altering the morphology of cerebellar Purkinje cells. To study the effects of short-term exposures to strong vestibular stimuli we focused on structural changes in the vestibulo-cerebellum that are caused by strong vestibular stimuli. Adult mice were exposed to various combinations of constant and/or rapidly changing angular and linear accelerations for 8.5 min (the time length of shuttle launch). Our data shows that these stimuli cause intense excitation of cerebellar Purkinje cells, inducing up-regulation of clathrin-mediated endocytosis

The Mediating Role of Insight for Long-Term Improvements in Psychodynamic Therapy

ERIC Educational Resources Information Center

Johansson, Paul; Hoglend, Per; Ulberg, Randi; Amlo, Svein; Marble, Alice; Bogwald, Kjell-Petter; Sorbye, Oystein; Sjaastad, Mary Cosgrove; Heyerdahl, Oscar

2010-01-01

Objective: According to psychoanalytic theory, interpretation of transference leads to increased insight that again leads to improved interpersonal functioning over time. In this study, we performed a full mediational analysis to test whether insight gained during treatment mediates the long-term effects of transference interpretation in dynamic…

Adaptations of the vestibular system to short and long-term exposures to altered gravity

NASA Astrophysics Data System (ADS)

Bruce, L. L.

2003-10-01

Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival of a given organism. The development and maintenance of vestibular connections are controlled by environmental gravitational stimulation as well as genetically controlled molecular interactions. This paper describes the effects of hypergravity on axonal growth and dendritic morphology, respectively. Two aspects of this vestibular adaptation are examined: (1) How does long-term exposure to hypergravity affect the development of vestibular axons? (2) How does short-term exposure to extremely rapid changes in gravity, such as those that occur during shuttle launch and landing, affect dendrites of the vestibulocerebellar system? To study the effects of longterm exposures to altered gravity, embryonic rats that developed in hypergravity were compared to microgravity-exposed and control rats. Examination of the vestibular projections from epithelia devoted to linear and angular acceleration revealed that the terminal fields segregate differently in rat embryos that gestated in each of the gravitational environments.To study the effects of short-term exposures to altered gravity, mice were exposed briefly to strong vestibular stimuli and the vestibulocerebellum was examined for any resulting morphological changes. My data show that these stimuli cause intense vestibular excitation of cerebellar Purkinje cells, which induce up-regulation of clathrin-mediated endocytosis and other morphological changes that are comparable to those seen in long-term depression. This system provides a basis for studying how the vestibular environment can modify cerebellar function, allowing animals to adapt to new environments.

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. © The Author(s) 2015.

Muscarinic acetylcholine receptor in cerebellar cortex participates in acetylcholine-mediated blood depressor response in rats.

PubMed

Zhou, Peiling; Zhu, Qingfeng; Liu, Ming; Li, Jing; Wang, Yong; Zhang, Changzheng; Hua, Tianmiao

2015-04-23

Our previous investigations have revealed that cerebellar cholinergic innervation is involved in cardiovascular regulation. This study was performed to examine the effects of the muscarinic cholinergic receptor (mAChR) in the cerebellar cortex on blood pressure (BP) modulation in rats. Acetylcholine (ACh, 100mM), nonselective mAChR agonist (oxotremorine M; Oxo-M, 10, 30 and 100mM) and 100mM ACh mixed with nonselective mAChR antagonist atropine (1, 3 and 10mM) were microinjected into the cerebellar cortex of anesthetized rats. Mean arterial pressure (MAP), maximal decreased MAP (MDMAP), and reaction time (duration required for BP to return to basal values) were measured and analyzed. The results showed that Oxo-M dose-dependently decreased MAP, increased MDMAP, and prolonged reaction time, which displayed a homodromous effect of ACh-mediated blood depressor response; meanwhile, atropine concentration-dependently blocked the effect of ACh on the BP regulation. In conclusion, the present study showed for the first time that mAChRs in cerebellar cortex could modulate somatic BP by participation in ACh-mediated depressor response. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Preterm birth disrupts cerebellar development by affecting granule cell proliferation program and Bergmann glia.

PubMed

Iskusnykh, Igor Y; Buddington, Randal K; Chizhikov, Victor V

2018-08-01

Preterm birth is a leading cause of long-term motor and cognitive deficits. Clinical studies suggest that some of these deficits result from disruption of cerebellar development, but the mechanisms that mediate cerebellar abnormalities in preterm infants are largely unknown. Furthermore, it remains unclear whether preterm birth and precocious exposure to the ex-utero environment directly disrupt cerebellar development or indirectly by increasing the probability of cerebellar injury, including that resulting from clinical interventions and protocols associated with the care of preterm infants. In this study, we analyzed the cerebellum of preterm pigs delivered via c-section at 91% term and raised for 10 days, until term-equivalent age. The pigs did not receive any treatments known or suspected to affect cerebellar development and had no evidence of brain damage. Term pigs sacrificed at birth were used as controls. Immunohistochemical analysis revealed that preterm birth did not affect either size or numbers of Purkinje cells or molecular layer interneurons at term-equivalent age. The number of granule cell precursors and Bergmann glial fibers, however, were reduced in preterm pigs. Preterm pigs had reduced proliferation but not differentiation of granule cells. qRT-PCR analysis of laser capture microdissected external granule cell layer showed that preterm pigs had a reduced expression of Ccnd1 (Cyclin D1), Ccnb1 (Cyclin B1), granule cell master regulatory transcription factor Atoh1, and signaling molecule Jag1. In vitro rescue experiments identified Jag1 as a central granule cell gene affected by preterm birth. Thus, preterm birth and precocious exposure to the ex-utero environment disrupt cerebellum by modulating expression of key cerebellar developmental genes, predominantly affecting development of granule precursors and Bergmann glia. Copyright © 2018 Elsevier Inc. All rights reserved.

Resilience and rejection sensitivity mediate long-term outcomes of parental divorce.

PubMed

Schaan, Violetta K; Vögele, Claus

2016-11-01

Increasing divorce rates leave more and more children to deal with the separation of their parents. Recent research suggests that children of divorced parents more often experience psychological and physical symptoms than children of non-divorced parents. The processes that mediate the relationship between parental divorce and ill-health, however, are still elusive. This study investigated the mediating role of psychological factors such as resilience and rejection sensitivity on the long-term consequences of parental divorce in young adults. One hundred and ninety-nine participants (mean age 22.3 years) completed an online survey, including measures of mental health, childhood trauma, resilience, and rejection sensitivity. Participants with divorced parents (33 %) reported increased levels of psychological symptoms, childhood trauma, rejection sensitivity, and lower levels of resilience. The association between parental divorce and mental health was fully mediated by resilience, rejection sensitivity, and childhood trauma. The mediation model explained up to 44 % of the total variance in mental health symptoms. Resilience and rejection sensitivity are crucial factors for successful coping with the experience of parental separation. Prevention programs that help to boost children's resilience might help to reduce the long-term effects of parental divorce on their attachment style (e.g., rejection sensitivity), thereby improving their mental health on the long run. Furthermore, the results call for parental awareness and counseling to target and reduce the observed increased level of childhood trauma. Limitations concern the cross-sectional and retrospective design of the study.

The mediating role of insight for long-term improvements in psychodynamic therapy.

PubMed

Johansson, Paul; Høglend, Per; Ulberg, Randi; Amlo, Svein; Marble, Alice; Bøgwald, Kjell-Petter; Sørbye, Oystein; Sjaastad, Mary Cosgrove; Heyerdahl, Oscar

2010-06-01

According to psychoanalytic theory, interpretation of transference leads to increased insight that again leads to improved interpersonal functioning over time. In this study, we performed a full mediational analysis to test whether insight gained during treatment mediates the long-term effects of transference interpretation in dynamic psychotherapy. This study is a randomized clinical trial with a dismantling design. One hundred outpatients seeking psychotherapy for depression, anxiety, personality disorders, and interpersonal problems were randomly assigned to 1 year of weekly sessions of dynamic psychotherapy with transference interpretation or to the same type and duration of treatment with the same therapists but without the use of transference interpretation. Interpersonal functioning and insight were measured pretreatment, posttreatment, and 1 year and 3 years after treatment termination. Contrary to common expectation, patients with a life-long pattern of low quality of object relations and personality disorder pathology profited more from therapy with transference interpretation than from therapy with no transference interpretation. This long-term effect was mediated by an increase in the level of insight during treatment. Insight seems to be a key mechanism of change in dynamic psychotherapy. Our results bridge the gap between clinical theory and empirical research.

Gating of Long-Term Potentiation by Nicotinic Acetylcholine Receptors at the Cerebellum Input Stage

PubMed Central

Prestori, Francesca; Bonardi, Claudia; Mapelli, Lisa; Lombardo, Paola; Goselink, Rianne; De Stefano, Maria Egle; Gandolfi, Daniela; Mapelli, Jonathan; Bertrand, Daniel; Schonewille, Martijn; De Zeeuw, Chris; D’Angelo, Egidio

2013-01-01

The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the α7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective α7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of α7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, α7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptation. PMID:23741401

A left cerebellar pathway mediates language in prematurely-born young adults

PubMed Central

Constable, R. Todd; Vohr, Betty R.; Scheinost, Dustin; Benjamin, Jennifer R.; Fulbright, Robert K.; Lacadie, Cheryl; Schneider, Karen C.; Katz, Karol H.; Zhang, Heping; Papademetris, Xenophon; Ment, Laura R.

2012-01-01

Preterm (PT) subjects are at risk for developmental delay, and task-based studies suggest that developmental disorders may be due to alterations in neural connectivity. Since emerging data imply the importance of right cerebellar function for language acquisition in typical development, we hypothesized that PT subjects would have alternate areas of cerebellar connectivity, and that these areas would be responsible for differences in cognitive outcomes between PT subjects and term controls at age 20 years. Nineteen PT and 19 term control young adults were prospectively studied using resting-state functional MRI (fMRI) to create voxel-based contrast maps reflecting the functional connectivity of each tissue element in the grey matter through analysis of the intrinsic connectivity contrast degree (ICC-d). Left cerebellar ICC-d differences between subjects identified a region of interest that was used for subsequent seed-based connectivity analyses. Subjects underwent standardized language testing, and correlations with cognitive outcomes were assessed. There were no differences in gender, hand preference, maternal education, age at study, or Peabody Picture Vocabulary Test (PPVT) scores. Functional connectivity (FcMRI) demonstrated increased tissue connectivity in the biventer, simple and quadrangular lobules of the L cerebellum (p<0.05) in PTs compared to term controls; seed-based analyses from these regions demonstrated alterations in connectivity from L cerebellum to both R and L inferior frontal gyri (IFG) in PTs compared to term controls. For PTs but not term controls, there were significant positive correlations between these connections and PPVT scores (R IFG: r=0.555, p=0.01; L IFG: r=0.454, p=0.05), as well as Verbal Comprehension Index (VCI) scores (R IFG: r=0.472, p=0.04). These data suggest the presence of a left cerebellar language circuit in PT subjects at young adulthood. These findings may represent either a delay in maturation or the engagement of

The organization of plasticity in the cerebellar cortex: from synapses to control.

PubMed

D'Angelo, Egidio

2014-01-01

The cerebellum is thought to play a critical role in procedural learning, but the relationship between this function and the underlying cellular and synaptic mechanisms remains largely speculative. At present, at least nine forms of long-term synaptic and nonsynaptic plasticity (some of which are bidirectional) have been reported in the cerebellar cortex and deep cerebellar nuclei. These include long-term potentiation (LTP) and long-term depression at the mossy fiber-granule cell synapse, at the synapses formed by parallel fibers, climbing fibers, and molecular layer interneurons on Purkinje cells, and at the synapses formed by mossy fibers and Purkinje cells on deep cerebellar nuclear cells, as well as LTP of intrinsic excitability in granule cells, Purkinje cells, and deep cerebellar nuclear cells. It is suggested that the complex properties of cerebellar learning would emerge from the distribution of plasticity in the network and from its dynamic remodeling during the different phases of learning. Intrinsic and extrinsic factors may hold the key to explain how the different forms of plasticity cooperate to select specific transmission channels and to regulate the signal-to-noise ratio through the cerebellar cortex. These factors include regulation of neuronal excitation by local inhibitory networks, engagement of specific molecular mechanisms by spike bursts and theta-frequency oscillations, and gating by external neuromodulators. Therefore, a new and more complex view of cerebellar plasticity is emerging with respect to that predicted by the original "Motor Learning Theory," opening issues that will require experimental and computational testing. © 2014 Elsevier B.V. All rights reserved.

Mechanisms of potentiation of mossy fiber EPSCs in the cerebellar nuclei by coincident synaptic excitation and inhibition

PubMed Central

Pugh, Jason R.; Raman, Indira M.

2008-01-01

Neurons of the cerebellar nuclei receive synaptic excitation from cerebellar mossy fibers. Unlike in many principal neurons, coincident presynaptic activity and postsynaptic depolarization do not generate long-term potentiation at these synapses. Instead, EPSCs are potentiated by high-frequency trains of presynaptic activity applied with postsynaptic hyperpolarization, in patterns resembling the mossy fiber-mediated excitation and Purkinje cell-mediated inhibition predicted to occur during delay eyelid conditioning. Here, we have used electrophysiology and Ca imaging to test how synaptic excitation and inhibition interact to generate long-lasting synaptic plasticity in nuclear cells in cerebellar slices. We find that the extent of plasticity varies with the relative timing of synaptic excitation and hyperpolarization. Potentiation is most effective when synaptic stimuli precede the post-inhibitory rebound by ~400 ms, whereas with longer intervals, or with a reverse sequence, EPSCs tend to depress. When basal intracellular Ca is raised by spontaneous firing or reduced by voltage-clamping at subthreshold potentials, potentiation is induced as long as the synaptic-rebound temporal sequence is maintained, suggesting that plasticity does not require Ca levels to exceed a threshold or attain a specific concentration. Although rebound and spike-dependent Ca influx are global, potentiation is synapse-specific, and is disrupted by inhibitors of calcineurin or CaMKII, but not PKC. When IPSPs replace the hyperpolarizing step in the induction protocol, potentiation proceeds normally. These results lead us to propose that synaptic and inhibitory/rebound stimuli initiate separate processes, with local NMDA-receptor-mediated Ca influx “priming” synapses, and Ca changes from the inhibition and rebound “triggering” potentiation at recently activated synapses. PMID:18923031

The mediating effects of job satisfaction on turnover intention for long-term care nurses in Taiwan.

PubMed

Kuo, Huai-Ting; Lin, Kuan-Chia; Li, I-Chuan

2014-03-01

This study explores the mediating effects of job satisfaction on work stress and turnover intention among long-term care nurses in Taiwan. Healthcare institutions face a nursing shortage, and it is important to examine the factors that influence turnover intention among nurses. Excessive levels of work stress may lead to employee dissatisfaction and a significant inverse relationship between work stress and job satisfaction, including subsequent effects on turnover among nurses. However, little is known about the mediating role of job satisfaction on work stress and turnover intention among long-term care nurses. A cross-sectional survey and a correlation design were used. Multistage linear regression was used to test the mediation model. This study showed that job satisfaction significantly mediated the relationship between work stress and turnover intention. Thirty-eight percent of the variance in turnover intention explained by work stress was accounted for by the mediation pathway. The results of this study showed that higher job satisfaction significantly decreased work stress and turnover intention among long-term care nurses. This study provides nursing administrators with a resource to build a supportive environment to increase nurses' job satisfaction and to decrease their stress and turnover. © 2013 John Wiley & Sons Ltd.

Modeling the Cerebellar Microcircuit: New Strategies for a Long-Standing Issue.

PubMed

D'Angelo, Egidio; Antonietti, Alberto; Casali, Stefano; Casellato, Claudia; Garrido, Jesus A; Luque, Niceto Rafael; Mapelli, Lisa; Masoli, Stefano; Pedrocchi, Alessandra; Prestori, Francesca; Rizza, Martina Francesca; Ros, Eduardo

2016-01-01

The cerebellar microcircuit has been the work bench for theoretical and computational modeling since the beginning of neuroscientific research. The regular neural architecture of the cerebellum inspired different solutions to the long-standing issue of how its circuitry could control motor learning and coordination. Originally, the cerebellar network was modeled using a statistical-topological approach that was later extended by considering the geometrical organization of local microcircuits. However, with the advancement in anatomical and physiological investigations, new discoveries have revealed an unexpected richness of connections, neuronal dynamics and plasticity, calling for a change in modeling strategies, so as to include the multitude of elementary aspects of the network into an integrated and easily updatable computational framework. Recently, biophysically accurate "realistic" models using a bottom-up strategy accounted for both detailed connectivity and neuronal non-linear membrane dynamics. In this perspective review, we will consider the state of the art and discuss how these initial efforts could be further improved. Moreover, we will consider how embodied neurorobotic models including spiking cerebellar networks could help explaining the role and interplay of distributed forms of plasticity. We envisage that realistic modeling, combined with closed-loop simulations, will help to capture the essence of cerebellar computations and could eventually be applied to neurological diseases and neurorobotic control systems.

Potential mechanisms of cerebellar hypoplasia in prematurity.

PubMed

Tam, Emily W Y

2013-09-01

The cerebellum undergoes dramatic growth and maturation over the neonatal period after preterm birth and is thus particularly sensitive to impaired development due to various clinical factors. Impairments in growth can occur independent of cerebellar parenchymal damage, such as from local hemorrhage, resulting from reduced expression of sonic hedgehog signaling to trigger the appropriate expansion of the granule precursor cells. The primary risk factors for impaired cerebellar development include postnatal glucocorticoid exposure, which has direct effects on the sonic hedgehog pathway, and supratentorial brain injury, including intraventricular hemorrhage and white matter injury, which may result in crossed cerebellar diaschisis and local toxic effects of blood products on the external granular layer. Other cardiorespiratory and nutritional factors may also exist. Impaired cerebellar development is associated with adverse outcomes in motor and cognitive development. New approaches to care to counteract these risk factors may help improve long-term outcome after preterm birth.

Modeling the Cerebellar Microcircuit: New Strategies for a Long-Standing Issue

PubMed Central

D’Angelo, Egidio; Antonietti, Alberto; Casali, Stefano; Casellato, Claudia; Garrido, Jesus A.; Luque, Niceto Rafael; Mapelli, Lisa; Masoli, Stefano; Pedrocchi, Alessandra; Prestori, Francesca; Rizza, Martina Francesca; Ros, Eduardo

2016-01-01

The cerebellar microcircuit has been the work bench for theoretical and computational modeling since the beginning of neuroscientific research. The regular neural architecture of the cerebellum inspired different solutions to the long-standing issue of how its circuitry could control motor learning and coordination. Originally, the cerebellar network was modeled using a statistical-topological approach that was later extended by considering the geometrical organization of local microcircuits. However, with the advancement in anatomical and physiological investigations, new discoveries have revealed an unexpected richness of connections, neuronal dynamics and plasticity, calling for a change in modeling strategies, so as to include the multitude of elementary aspects of the network into an integrated and easily updatable computational framework. Recently, biophysically accurate “realistic” models using a bottom-up strategy accounted for both detailed connectivity and neuronal non-linear membrane dynamics. In this perspective review, we will consider the state of the art and discuss how these initial efforts could be further improved. Moreover, we will consider how embodied neurorobotic models including spiking cerebellar networks could help explaining the role and interplay of distributed forms of plasticity. We envisage that realistic modeling, combined with closed-loop simulations, will help to capture the essence of cerebellar computations and could eventually be applied to neurological diseases and neurorobotic control systems. PMID:27458345

Long-term social recognition memory is mediated by oxytocin-dependent synaptic plasticity in the medial amygdala.

PubMed

Gur, Rotem; Tendler, Alex; Wagner, Shlomo

2014-09-01

Recognition of specific individuals is fundamental to mammalian social behavior and is mediated in most mammals by the main and accessory olfactory systems. Both these systems innervate the medial amygdala (MeA), where activity of the neuropeptide oxytocin is thought to mediate social recognition memory (SRM). The specific contribution of the MeA to SRM formation and the specific actions of oxytocin in the MeA are unknown. We used the social discrimination test to evaluate short-term and long-term SRM in adult Sprague-Dawley male rats (n = 38). The role of protein synthesis in the MeA was investigated by local application of the protein synthesis blocker anisomycin (n = 11). Synaptic plasticity was assessed in vivo by recording the MeA evoked field potential responses to stimulation of the main (n = 21) and accessory (n = 56) olfactory bulbs before and after theta burst stimulation. Intracerebroventricular administration of saline, oxytocin, or oxytocin receptor antagonist was used to measure the effect of oxytocin on synaptic plasticity. Anisomycin application to the MeA prevented the formation of long-term SRM. In addition, the responses of MeA neurons underwent long-term depression (LTD) after theta burst stimulation of the accessory olfactory bulb, but not the main accessory bulb, in an oxytocin-dependent manner. No LTD was found in socially isolated rats, which are known to lack long-term SRM. Finally, accessory olfactory bulb stimulation before SRM acquisition blocked long-term SRM, supporting the involvement of LTD in the MeA in formation of long-term SRM. Our results indicate that long-term SRM in rats involves protein synthesis and oxytocin-dependent LTD in the MeA. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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

Effect of long-term fertilization on humic redox mediators in multiple microbial redox reactions.

PubMed

Guo, Peng; Zhang, Chunfang; Wang, Yi; Yu, Xinwei; Zhang, Zhichao; Zhang, Dongdong

2018-03-01

This study investigated the effects of different long-term fertilizations on humic substances (HSs), humic acids (HAs) and humins, functioning as redox mediators for various microbial redox biotransformations, including 2,2',4,4',5,5'- hexachlorobiphenyl (PCB 153 ) dechlorination, dissimilatory iron reduction, and nitrate reduction, and their electron-mediating natures. The redox activity of HSs for various microbial redox metabolisms was substantially enhanced by long-term application of organic fertilizer (pig manure). As a redox mediator, only humin extracted from soils with organic fertilizer amendment (OF-HM) maintained microbial PCB 153 dechlorination activity (1.03 μM PCB 153 removal), and corresponding HA (OF-HA) most effectively enhanced iron reduction and nitrate reduction by Shewanella putrefaciens. Electrochemical analysis confirmed the enhancement of their electron transfer capacity and redox properties. Fourier transform infrared analysis showed that C=C and C=O bonds, and carboxylic or phenolic groups in HSs might be the redox functional groups affected by fertilization. This research enhances our understanding of the influence of anthropogenic fertility on the biogeochemical cycling of elements and in situ remediation ability in agroecosystems through microorganisms' metabolisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ca currents activated by spontaneous firing and synaptic disinhibition in neurons of the cerebellar nuclei

PubMed Central

Zheng, Nan; Raman, Indira M.

2009-01-01

In neurons of the cerebellar nuclei, long-term potentiation of EPSCs is induced by high-frequency synaptic excitation by mossy fibers followed by synaptic inhibition by Purkinje cells. Induction requires activation of synaptic receptors as well as voltage-gated Ca channels. To examine how Purkinje-mediated inhibition of nuclear neurons affects Ca levels during plasticity-inducing stimuli, we have combined electrophysiology, Ca imaging, and pharmacology of cerebellar nuclear neurons in mouse cerebellar slices. We find that spontaneous firing generates tonic Ca signals in both somata and dendrites, which drop during 500-ms, 100-Hz trains of Purkinje IPSPs or hyperpolarizing steps. Although the presence of low-voltage-activated (T-type) Ca channels in nuclear neurons has fostered the inference that disinhibition activates these channels, synaptic inhibition with a physiological ECl (−75 mV) fails to hyperpolarize neurons sufficiently for T-type channels to recover substantially. Consequently, after IPSPs, Ca signals return to baseline, although firing is accelerated by ∼20 Hz for ∼300 ms. Only after hyperpolarizations beyond ECl does Ca rise gradually beyond baseline, as firing further exceeds spontaneous rates. Cd2+ (100 μM), which nearly eliminates L-type, N-type, P/Q-type, and R-type Ca currents while sparing about half the T-type current, prevents Ca changes during and after hyperpolarizations to ECl. Thus, high-frequency IPSPs in cerebellar nuclear neurons evoke little post-inhibitory current through T-type channels. Instead, inhibition regulates Ca levels simply by preventing action potentials, which usually permit Ca influx through high-voltage-activated channels. The decreases and restoration of Ca levels associated with Purkinje-mediated inhibition are likely to contribute to synaptic plasticity. PMID:19657035

Consensus Paper: Revisiting the Symptoms and Signs of Cerebellar Syndrome

PubMed Central

Bodranghien, Florian; Bastian, Amy; Casali, Carlo; Hallett, Mark; Louis, Elan D.; Mariën, Peter; Nowak, Dennis A.; Schmahmann, Jeremy D.; Serrao, Mariano; Steiner, Katharina Marie; Strupp, Michael; Tilikete, Caroline; Timmann, Dagmar; van Dun, Kim

2017-01-01

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

Magnetic resonance imaging findings in patients presenting with (sub)acute cerebellar ataxia.

PubMed

Schneider, Tanja; Thomalla, Götz; Goebell, Einar; Piotrowski, Anna; Yousem, David Mark

2015-06-01

Acute or subacute cerebellar inflammation is mainly caused by postinfectious, toxic, neoplastic, vascular, or idiopathic processes and can result in cerebellar ataxia. Previous magnetic resonance (MR) studies in single patients who developed acute or subacute ataxia showed varying imaging features. Eighteen patients presenting with acute and subacute onset of ataxia were included in this study. Cases of chronic-progressive/hereditary and noncerebellar causes (ischemia, multiple sclerosis lesions, metastasis, bleedings) were excluded. MR imaging findings were then matched with the clinical history of the patient. An underlying etiology for ataxic symptoms were found in 14/18 patients (postinfectious/infectious, paraneoplastic, autoimmune, drug-induced). In two of five patients without MR imaging findings and three of eight patients with minimal imaging features (cerebellar atrophy, slight signal alterations, and small areas of restricted diffusion), adverse clinical outcomes were documented. Of the five patients with prominent MR findings (cerebellar swelling, contrast enhancement, or broad signal abnormalities), two were lost to follow-up and two showed long-term sequelae. No correlation was found between the presence of initial MRI findings in subacute or acute ataxia patients and their long-term clinical outcome. MR imaging was more flagrantly positive in cases due to encephalitis.

Long-term course of orthostatic tremor in serial posturographic measurement.

PubMed

Feil, K; Böttcher, N; Guri, F; Krafczyk, S; Schöberl, F; Zwergal, A; Strupp, M

2015-08-01

Primary orthostatic tremor (OT) is a rare neurological disease of unknown pathophysiology characterized by a high-frequency tremor mainly of the legs when standing. The aim of this study was to examine its long-term course by subjective estimation and objective recording by serial posturography and to obtain further standardized epidemiological and clinical data on patients with OT. A clinical cohort of 37 patients with the diagnosis of primary OT was screened for this longitudinal follow-up study. Eighteen patients consented to participate. During study visit all patients underwent a standardized neurological examination and completed subjective scales and scores. Posturographic recordings at follow-up were compared to prior clinical posturographic measurements in 15 cases. In our cohort the mean duration of symptoms was 14.1 ± 6.8 years. Subjectively, 78% of patients reported progression of the disease. Posturographic data (5.4 ± 4.0 years) revealed a significant increase of the total sway path (standing on firm ground with eyes open) from 2.4 ± 1.3 to 3.4 ± 1.4 m/min (p = 0.022) and of the total root mean square values from 9.8 ± 4.3 to 12.4 ± 4.8 mm (p = 0.028). None of these observations are explained by aging of the patients. Mean frequency of the tremor did not change over time (14.7 ± 1.9 Hz vs. 14.9 ± 2.0 Hz at follow-up). Clinically, most patients had signs of cerebellar dysfunction and a substantial portion also showed proprioceptive deficits in the long-term course. This long-term follow-up study indicates, that primary OT is a progressive disorder. Furthermore, the clinical observation of cerebellar dysfunction in most OT patients in the long-term course might indicate an important role of the cerebellum in its pathophysiology. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cerebellar Modulation of Cortically Evoked Complex Movements in Rats.

PubMed

Viaro, Riccardo; Bonazzi, Laura; Maggiolini, Emma; Franchi, Gianfranco

2017-07-01

Intracortical microstimulation (ICMS) delivered to the motor cortex (M1) via long- or short-train duration (long- or short-duration ICMS) can evoke coordinated complex movements or muscle twitches, respectively. The role of subcortical cerebellar input in M1 output, in terms of long- and short-duration ICMS-evoked movement and motor skill performance, was evaluated in rats with bilateral lesion of the deep cerebellar nuclei. After the lesion, distal forelimb movements were seldom observed, and almost 30% of proximal forelimb movements failed to match criteria defining the movement class observed under control conditions. The classifiable movements could be evoked in different cortical regions with respect to control and many kinematic variables were strongly affected. Furthermore, movement endpoints within the rat's workspace shrunk closer to the body, while performance in the reaching/grasping task worsened. Surprisingly, neither the threshold current values for evoking movements nor the overall size of forelimb movement representation changed with respect to controls in either long- or short-duration ICMS. We therefore conclude that cerebellar input via the motor thalamus is crucial for expressing the basic functional features of the motor cortex. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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

PubMed

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

2015-11-09

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 (LKB1(Atoh1) CKO) to investigate the function of LKB1 in cerebellar development. The LKB1(Atoh1) CKO mice displayed motor dysfunction. In the LKB1(Atoh1) CKO cerebellum, the overall structure had a larger volume and more lobules. LKB1 inactivation led 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 LKB1(Atoh1) 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.

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

Interparental violence and children's long-term psychosocial adjustment: the mediating role of parenting practices.

PubMed

Gámez-Guadix, Manuel; Almendros, Carmen; Carrobles, José Antonio; Muñoz-Rivas, Marina

2012-03-01

The objectives of this study were: (a) to examine the direct and indirect relationships among witnessing interparental violence, parenting practices, and children's long-term psychosocial adjustment; (b) to analyze the possible gender differences in the relationships specified. The sample consisted of 1295 Spanish university students (M age = 21.21, SD = 4.04). We performed statistical analyses using structural equation modeling. The results showed that witnessing parental violence as a child is related to poor long-term psychosocial adjustment during the child's adult years. Furthermore, we found that parenting practices fully mediated the relation between witnessing interparental violence and the child's long-term adjustment. The multigroup analyses showed that most of the relations among the variables did not differ significantly by gender. However, the relation between harsh discipline and antisocial behavior was stronger for males, whereas the relation between harsh discipline and depressive symptoms was stronger for females. Finally, we discuss the implications of these findings for the clinicians and specialists who plan and develop intervention programs for populations at risk.

Cerebellar Development and Disease

PubMed Central

Gleeson, Joseph G.

2008-01-01

Recent Advances The molecular control of cell type specification within the developing cerebellum as well as the genetic causes of the most common human developmental cerebellar disorders have long remained mysterious. Recent genetic lineage and loss-of-function data from mice have revealed unique and non-overlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitter-specific cell types in the cerebral cortex. Mouse studies elucidating the role of Ptf1a as a cerebellar ventricular zone GABerigic fate switch were actually preceded by the recognition that PTF1A mutations in humans cause cerebellar agenesis, a birth defect of the human cerebellum. Indeed, several genes for congenital human cerebellar malformations have recently been identified, including genes causing Joubert syndrome, Dandy-Walker malformation and Ponto-cerebellar hypoplasia. These studies have pointed to surprisingly complex roles for transcriptional regulation, mitochondrial function and neuronal cilia in patterning, homeostasis and cell proliferation during cerebellar development. Together mouse and human studies are synergistically advancing our understanding of the developmental mechanisms that generate the uniquely complex mature cerebellum. PMID:18513948

Delayed reverberation through time windows as a key to cerebellar function.

PubMed

Kistler, W M; Leo van Hemmen, J

1999-11-01

We present a functional model of the cerebellum comprising cerebellar cortex, inferior olive, deep cerebellar nuclei, and brain stem nuclei. The discerning feature of the model being time coding, we consistently describe the system in terms of postsynaptic potentials, synchronous action potentials, and propagation delays. We show by means of detailed single-neuron modeling that (i) Golgi cells can fulfill a gating task in that they form short and well-defined time windows within which granule cells can reach firing threshold, thus organizing neuronal activity in discrete 'time slices', and that (ii) rebound firing in cerebellar nuclei cells is a robust mechanism leading to a delayed reverberation of Purkinje cell activity through cerebellar-reticular projections back to the cerebellar cortex. Computer simulations of the whole cerebellar network consisting of several thousand neurons reveal that reverberation in conjunction with long-term plasticity at the parallel fiber-Purkinje cell synapses enables the system to learn, store, and recall spatio-temporal patterns of neuronal activity. Climbing fiber spikes act both as a synchronization and as a teacher signal, not as an error signal. They are due to intrinsic oscillatory properties of inferior olivary neurons and to delayed reverberation within the network. In addition to clear experimental predictions the present theory sheds new light on a number of experimental observation such as the synchronicity of climbing fiber spikes and provides a novel explanation of how the cerebellum solves timing tasks on a time scale of several hundreds of milliseconds.

Recent Advances in Cerebellar Ischemic Stroke Syndromes Causing Vertigo and Hearing Loss.

PubMed

Kim, Hyun-Ah; Yi, Hyon-Ah; Lee, Hyung

2016-12-01

Cerebellar ischemic stroke is one of the common causes of vascular vertigo. It usually accompanies other neurological symptoms or signs, but a small infarct in the cerebellum can present with vertigo without other localizing symptoms. Approximately 11 % of the patients with isolated cerebellar infarction simulated acute peripheral vestibulopathy, and most patients had an infarct in the territory of the medial branch of the posterior inferior cerebellar artery (PICA). A head impulse test can differentiate acute isolated vertigo associated with PICA territory cerebellar infarction from more benign disorders involving the inner ear. Acute hearing loss (AHL) of a vascular cause is mostly associated with cerebellar infarction in the territory of the anterior inferior cerebellar artery (AICA), but PICA territory cerebellar infarction rarely causes AHL. To date, at least eight subgroups of AICA territory infarction have been identified according to the pattern of neurotological presentations, among which the most common pattern of audiovestibular dysfunction is the combined loss of auditory and vestibular functions. Sometimes acute isolated audiovestibular loss can be the initial symptom of impending posterior circulation ischemic stroke (particularly within the territory of the AICA). Audiovestibular loss from cerebellar infarction has a good long-term outcome than previously thought. Approximately half of patients with superior cerebellar artery territory (SCA) cerebellar infarction experienced true vertigo, suggesting that the vertigo and nystagmus in the SCA territory cerebellar infarctions are more common than previously thought. In this article, recent findings on clinical features of vertigo and hearing loss from cerebellar ischemic stroke syndrome are summarized.

Astrocytic β2-adrenergic receptors mediate hippocampal long-term memory consolidation.

PubMed

Gao, Virginia; Suzuki, Akinobu; Magistretti, Pierre J; Lengacher, Sylvain; Pollonini, Gabriella; Steinman, Michael Q; Alberini, Cristina M

2016-07-26

Emotionally relevant experiences form strong and long-lasting memories by critically engaging the stress hormone/neurotransmitter noradrenaline, which mediates and modulates the consolidation of these memories. Noradrenaline acts through adrenergic receptors (ARs), of which β2-adrenergic receptors (βARs) are of particular importance. The differential anatomical and cellular distribution of βAR subtypes in the brain suggests that they play distinct roles in memory processing, although much about their specific contributions and mechanisms of action remains to be understood. Here we show that astrocytic rather than neuronal β2ARs in the hippocampus play a key role in the consolidation of a fear-based contextual memory. These hippocampal β2ARs, but not β1ARs, are coupled to the training-dependent release of lactate from astrocytes, which is necessary for long-term memory formation and for underlying molecular changes. This key metabolic role of astrocytic β2ARs may represent a novel target mechanism for stress-related psychopathologies and neurodegeneration.

Long Pauses in Cerebellar Interneurons in Anesthetized Animals.

PubMed

Givon-Mayo, Ronit; Haar, Shlomi; Aminov, Yoav; Simons, Esther; Donchin, Opher

2017-04-01

Are long pauses in the firing of cerebellar interneurons (CINs) related to Purkinje cell (PC) pauses? If PC pauses affect the larger network, then we should find a close relationship between CIN pauses and those in PCs. We recorded activity of 241 cerebellar cortical neurons (206 CINs and 35 PCs) in three anesthetized cats. One fifth of the CINs and more than half of the PCs were identified as pausing. Pauses in CINs and PCs showed some differences: CIN mean pause length was shorter, and, after pauses, only CINs had sustained reduction in their firing rate (FR). Almost all pausing CINs fell into same cluster when we used different methods of clustering CINs by their spontaneous activity. The mean spontaneous firing rate of that cluster was approximately 53 Hz. We also examined cross-correlations in simultaneously recorded neurons. Of 39 cell pairs examined, 14 (35 %) had cross-correlations significantly different from those expected by chance. Almost half of the pairs with two CINs showed statistically significant negative correlations. In contrast, PC/CIN pairs did not often show significant effects in the cross-correlation (12/15 pairs). However, for both CIN/CIN and PC/CIN pairs, pauses in one unit tended to correspond to a reduction in the firing rate of the adjacent unit. In our view, our results support the possibility that previously reported PC bistability is part of a larger network response and not merely a biophysical property of PCs. Any functional role for PC bistability should probably be sought in the context of the broader network.

Neural correlates of cerebellar-mediated timing during finger tapping in children with fetal alcohol spectrum disorders.

PubMed

du Plessis, Lindie; Jacobson, Sandra W; Molteno, Christopher D; Robertson, Frances C; Peterson, Bradley S; Jacobson, Joseph L; Meintjes, Ernesta M

2015-01-01

Classical eyeblink conditioning (EBC), an elemental form of learning, is among the most sensitive indicators of fetal alcohol spectrum disorders. The cerebellum plays a key role in maintaining timed movements with millisecond accuracy required for EBC. Functional MRI (fMRI) was used to identify cerebellar regions that mediate timing in healthy controls and the degree to which these areas are also recruited in children with prenatal alcohol exposure. fMRI data were acquired during an auditory rhythmic/non-rhythmic finger tapping task. We present results for 17 children with fetal alcohol syndrome (FAS) or partial FAS, 17 heavily exposed (HE) nonsyndromal children and 16 non- or minimally exposed controls. Controls showed greater cerebellar blood oxygen level dependent (BOLD) activation in right crus I, vermis IV-VI, and right lobule VI during rhythmic than non-rhythmic finger tapping. The alcohol-exposed children showed smaller activation increases during rhythmic tapping in right crus I than the control children and the most severely affected children with either FAS or PFAS showed smaller increases in vermis IV-V. Higher levels of maternal alcohol intake per occasion during pregnancy were associated with reduced activation increases during rhythmic tapping in all four regions associated with rhythmic tapping in controls. The four cerebellar areas activated by the controls more during rhythmic than non-rhythmic tapping have been implicated in the production of timed responses in several previous studies. These data provide evidence linking binge-like drinking during pregnancy to poorer function in cerebellar regions involved in timing and somatosensory processing needed for complex tasks requiring precise timing.

Online and offline effects of cerebellar transcranial direct current stimulation on motor learning in healthy older adults: a randomized double-blind sham-controlled study.

PubMed

Samaei, Afshin; Ehsani, Fatemeh; Zoghi, Maryam; Hafez Yosephi, Mohaddese; Jaberzadeh, Shapour

2017-05-01

The aim of this randomized double blinded sham-controlled study was to determine the effect of cerebellar anodal transcranial direct current stimulation (a-tDCS) on online and offline motor learning in healthy older individuals. Thirty participants were randomly assigned in experimental (n = 15) or sham tDCS (n = 15) groups. Participants in experimental group received 2 mA cerebellar a-tDCS for 20 min. However, the tDCS was turned off after 30 seconds in sham group. Response time (RT) and error rate (ER) in serial RT test were assessed before, during 35 minutes and 48 h after the intervention. Reduction of RT and ER following the intervention session was considered as short-term (35 min post intervention) and long-term offline learning (48 h post intervention), respectively. Online RT and ER reduction were similar in both groups (P > 0.05). RT was significantly reduced 48 hours post intervention in cerebellar a-tDCS group (P = 0.03). Moreover, RT was significantly increased after 35 minutes and 48 hours in sham tDCS group (P = 0.03, P = 0.007), which indicates a lack of short-term and long-term offline learning in older adults. A-tDCS on cerebellar region produced more short-term and long-term offline improvement in RT (P = 0.014, P = 0.01) compared to sham tDCS. In addition, online, short-term and long-term (48 h) offline error reduced in cerebellar a-tDCS as compared to sham-control group, although this reduction was not significant (P > 0.05). A deficit suggests that a direct comparison to a younger group was made. The findings suggested that cerebellar a-tDCS might be useful for improvement of offline motor learning in older individuals. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Long-term depression of neuron to glial signalling in rat cerebellar cortex.

PubMed

Bellamy, Tomas C; Ogden, David

2006-01-01

Bergmann glial cells enclose synapses throughout the molecular layer of the cerebellum and express extrasynaptic AMPA receptors and glutamate transporters. Accordingly, stimulation of parallel fibres leads to the generation of inward currents in the glia due to AMPA receptor activation and electrogenic uptake of glutamate. Elimination of AMPA receptor Ca(2+) permeability leads to the withdrawal of glial processes and synaptic dysfunction, suggesting that AMPA receptor-mediated Ca(2+) signalling is essential for glial support of the neuronal network. Here we show that glial extrasynaptic currents (ESCs) exhibit activity-dependent plasticity, specifically, long-term depression during repetitive stimulation of parallel fibres at low frequencies (0.033-1 Hz) -- conditions in which Purkinje neuron excitatory postsynaptic currents (EPSCs) remain stable. Both the rate of onset and the magnitude of ESC depression increased with stimulation frequency. Depression was reversible following brief periods of stimulation, but became increasingly persistent as the duration of repetitive stimulation increased. All glial currents -- AMPA receptors, glutamate transporter and a recently discovered slow 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulphonamide (NBQX)-sensitive current -- were depressed. Increasing presynaptic release probability by doubling external Ca(2+) concentration did not affect the time course of depression, suggesting that neither decreased release probability nor fatigue of release sites contribute to depression. Inhibition of glutamate uptake caused a dramatic enhancement of the rate of depression, implicating glutamate in the underlying mechanism. The strength of neuron to glial signalling in the cerebellum is therefore dynamically regulated, independently of adjacent synapses, by the frequency of parallel fibre activity.

Hippocampal Focal Knockout of CBP Affects Specific Histone Modifications, Long-Term Potentiation, and Long-Term Memory

PubMed Central

Barrett, Ruth M; Malvaez, Melissa; Kramar, Eniko; Matheos, Dina P; Arrizon, Abraham; Cabrera, Sara M; Lynch, Gary; Greene, Robert W; Wood, Marcelo A

2011-01-01

To identify the role of the histone acetyltransferase (HAT) CREB-binding protein (CBP) in neurons of the CA1 region of the hippocampus during memory formation, we examine the effects of a focal homozygous knockout of CBP on histone modifications, gene expression, synaptic plasticity, and long-term memory. We show that CBP is critical for the in vivo acetylation of lysines on histones H2B, H3, and H4. CBP's homolog p300 was unable to compensate for the loss of CBP. Neurons lacking CBP maintained phosphorylation of the transcription factor CREB, yet failed to activate CREB:CBP-mediated gene expression. Loss of CBP in dorsal CA1 of the hippocampus resulted in selective impairments to long-term potentiation and long-term memory for contextual fear and object recognition. Together, these results suggest a necessary role for specific chromatin modifications, selectively mediated by CBP in the consolidation of memories. PMID:21508930

Cerebellar Growth Impairment Characterizes School-Aged Children Born Preterm without Perinatal Brain Lesions.

PubMed

Pieterman, K; White, T J; van den Bosch, G E; Niessen, W J; Reiss, I K M; Tibboel, D; Hoebeek, F E; Dudink, J

2018-05-01

Infants born preterm are commonly diagnosed with structural brain lesions known to affect long-term neurodevelopment negatively. Yet, the effects of preterm birth on brain development in the absence of intracranial lesions remain to be studied in detail. In this study, we aim to quantify long term consequences of preterm birth on brain development in this specific group. Neonatal cranial sonography and follow-up T1-weighted MR imaging and DTI were performed to evaluate whether the anatomic characteristics of the cerebrum and cerebellum in a cohort of school-aged children (6-12 years of age) were related to gestational age at birth in children free of brain lesions in the perinatal period. In the cohort consisting of 36 preterm (28-37 weeks' gestational age) and 66 term-born infants, T1-weighted MR imaging and DTI at 6-12 years revealed a reduction of cerebellar white matter volume (β = 0.387, P < .001), altered fractional anisotropy of cerebellar white matter (β = -0.236, P = .02), and a reduction of cerebellar gray and white matter surface area (β = 0.337, P < .001; β = 0.375, P < .001, respectively) in relation to birth age. Such relations were not observed for the cerebral cortex or white matter volume, surface area, or diffusion quantities. The results of our study show that perinatal influences that are not primarily neurologic are still able to disturb long-term neurodevelopment, particularly of the developing cerebellum. Including the cerebellum in future neuroprotective strategies seems therefore essential. © 2018 by American Journal of Neuroradiology.

Nothing can be coincidence: synaptic inhibition and plasticity in the cerebellar nuclei

PubMed Central

Pugh, Jason R.; Raman, Indira M.

2009-01-01

Many cerebellar neurons fire spontaneously, generating 10–100 action potentials per second even without synaptic input. This high basal activity correlates with information-coding mechanisms that differ from those of cells that are quiescent until excited synaptically. For example, in the deep cerebellar nuclei, Hebbian patterns of coincident synaptic excitation and postsynaptic firing fail to induce long-term increases in the strength of excitatory inputs. Instead, excitatory synaptic currents are potentiated by combinations of inhibition and excitation that resemble the activity of Purkinje and mossy fiber afferents that is predicted to occur during cerebellar associative learning tasks. Such results indicate that circuits with intrinsically active neurons have rules for information transfer and storage that distinguish them from other brain regions. PMID:19178955

Enhanced AMPA Receptor Function Promotes Cerebellar Long-Term Depression Rather than Potentiation

ERIC Educational Resources Information Center

van Beugen, Boeke J.; Qiao, Xin; Simmons, Dana H.; De Zeeuw, Chris I.; Hansel, Christian

2014-01-01

Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar…

[Type I Chiari malformation associated with cerebellar atrophy. Case report].

PubMed

Moscote-Salazar, Luis Rafael; Calderón-Miranda, Willem Guillermo; Alvis-Miranda, Hernando Raphael; Lee-Aguirre, Ángel; Alcalá-Cerra, Gabriel

2017-01-01

Chiari malformation is characterized by caudal displacement of the cerebellar tonsils that penetrate into the spinal canal through the foramen magnum, achieving reach the atlas or axis. trunk and any drop of the fourth ventricle is observed. Typically is seen in young adults. In some cases scoliosis and Syringomyelic cavities may occur. The authors present (as far as they know) the first case in the literature with long term follow-up, of a caucasian woman with an unusual form of cerebellar atrophy and Chiari Type I malformation, suffering from weakness in his upper and lower extremities with rapidly progression. The patient was successfully treated with suboccipital decompression and C1 laminectomy.

Phonological short-term store impairment after cerebellar lesion: a single case study.

PubMed

Chiricozzi, Francesca R; Clausi, Silvia; Molinari, Marco; Leggio, Maria G

2008-01-01

The cerebellum is a recent addition to the growing list of cerebral areas involved in the multifaceted structural system that sustains verbal working memory (vWM), but its contribution is still a matter of debate. Here, we present a patient with a selective deficit of vWM resulting from a bilateral cerebellar ischemic lesion. After this acute event, the patient had impaired immediate and delayed word-serial recall and auditory-verbal delayed recognition. The digit span, however, was completely preserved. To investigate the cerebellar contribution to vWM, four experiments addressing the function of different vWM phonological loop components were performed 18 months after the lesion, and results were compared with normative data or, when needed, with a small group of matched controls. In Experiment 1, digit span was assessed with different presentation and response modalities using lists of digits of varying lengths. In Experiment 2, the articulatory rehearsal system was analyzed by measurement of word length and articulatory suppression effects. Experiment 3 was devoted to analyzing the phonological short-term store (ph-STS) by the recency effect, the phonological similarity effect, short-term forgetting, and unattended speech. Data suggested a possible key role of the semantic component of the processed material, which was tested in Experiment 4, in which word and nonword-serial recall with or without interpolating activity were analyzed. The patient showed noticeably reduced scores in the tasks that primarily or exclusively engaged activity of the ph-STS, namely those of Experiment 3, and good performance in the tests that investigated the recirculation of verbal information. This pattern of results implicates the ph-STS as the cognitive locus of the patient's deficit. This report demonstrates a cerebellar role in encoding and/or strengthening the phonological traces in vWM.

Review article: Environmental heatstroke and long-term clinical neurological outcomes: A literature review of case reports and case series 2000-2016.

PubMed

Lawton, Emily M; Pearce, Helen; Gabb, Genevieve M

2018-05-31

Global temperatures are rising; extreme environmental heat can result in adverse health effects including heatstroke. Acute effects of heat are well recognised, but there is less understanding of potential long-term adverse outcomes. Our aim was to review recent medical literature for clinical cases of environmental heatstroke with a focus on neurological outcome. Structured search strategies were designed to retrieve publications of heatstroke case reports using Ovid Medline and Embase (2000-2016). One thousand and forty-nine abstracts were identified, and after application of exclusion criteria 71 articles deemed relevant. Ninety cases were identified from 71 articles. 100% presented with acute neurological symptoms; 87.8% presented with non-neurological symptoms. 44.4% patients recovered fully, 23.3% died, 23.3% suffered convalescent or long-term neurological sequelae, and in 8.9% no long-term follow up was available. 57.1% of the patients who died or had a neurological deficit had no documented co-morbidity. Patterns of neurological deficits included 66.7% patients with motor dysfunction, 9.5% cognitive impairment, 19% both motor and cognitive impairment and 4.7% other. In total 71.4% of the impaired patients had long-term cerebellar dysfunction. Adverse long-term neurological outcomes were common in surviving patients presenting with environmental heatstroke. Permanent neurological deficits were present in 34.4% of survivors where outcome was known; many were young, healthy individuals. Cerebellar injury was common suggesting cerebellar structures are vulnerable to heat. These findings highlight that people of all ages and pre-morbid states are at risk of severe heat-related illness. In the face of climate change, effective interventions for heat-related illness, including both treatment and prevention are necessary. © 2018 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.

Cerebellar peduncle injury predicts motor impairments in preterm infants: A quantitative tractography study at term-equivalent age.

PubMed

Hasegawa, Tatsuji; Yamada, Kei; Tozawa, Takenori; Chiyonobu, Tomohiro; Tokuda, Sachiko; Nishimura, Akira; Hosoi, Hajime; Morimoto, Masafumi

2018-05-15

Cerebellar injury is well established as an important finding in preterm infants with cerebral palsy (CP). In this study, we investigated associations between injury to the cerebellar peduncles and motor impairments in preterm infants using quantitative tractography at term-equivalent age, which represents an early phase before the onset of motor impairments. We studied 64 preterm infants who were born at <33 weeks gestational age. These infants were divided into three groups: CP, Non-CP (defined as infants with periventricular leukomalacia but having normal motor function), and a Normal group. Diffusion tensor imaging was performed at term-equivalent age and motor function was assessed no earlier than a corrected age of 2 years. Using tractography, we measured fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of the superior cerebellar peduncles (SCP) and middle cerebellar peduncles (MCP), as well as the motor/sensory tracts. The infants in the CP group had significantly lower FA of the SCP and sensory tract than those in the other groups. There was no significant difference in FA and ADC of the motor tract among the three groups. Severity of CP had a significant correlation with FA of the MCP, but not with the FA of other white matter tracts. Our results suggested that the infants with CP had injuries of the ascending tracts (e.g. the SCP and sensory tract), and that additional MCP injury might increase the severity of CP. Quantitative tractography assessment at term-equivalent age may be useful for screening preterm infants for prediction of future motor impairments. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

The Role of Lactate-Mediated Metabolic Coupling between Astrocytes and Neurons in Long-Term Memory Formation

PubMed Central

Steinman, Michael Q.; Gao, Virginia; Alberini, Cristina M.

2016-01-01

Long-term memory formation, the ability to retain information over time about an experience, is a complex function that affects multiple behaviors, and is an integral part of an individual’s identity. In the last 50 years many scientists have focused their work on understanding the biological mechanisms underlying memory formation and processing. Molecular studies over the last three decades have mostly investigated, or given attention to, neuronal mechanisms. However, the brain is composed of different cell types that, by concerted actions, cooperate to mediate brain functions. Here, we consider some new insights that emerged from recent studies implicating astrocytic glycogen and glucose metabolisms, and particularly their coupling to neuronal functions via lactate, as an essential mechanism for long-term memory formation. PMID:26973477

Long-Term Effects of Child Corporal Punishment on Depressive Symptoms in Young Adults: Potential Moderators and Mediators

ERIC Educational Resources Information Center

Turner, Heather A.; Muller, Paul A.

2004-01-01

Based on a sample of 649 students from 3 New England colleges, this study examined the long-term effects of childhood corporal punishment on symptoms of depression and considered factors that may moderate or mediate the association. Similar to national studies, approximately 40% of the sample reported experiencing some level of corporal punishment…

Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit.

PubMed

Mapelli, Lisa; Pagani, Martina; Garrido, Jesus A; D'Angelo, Egidio

2015-01-01

The way long-term potentiation (LTP) and depression (LTD) are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network, in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei) and correspondingly regulate the function of their three main neurons: granule cells (GrCs), Purkinje cells (PCs) and deep cerebellar nuclear (DCN) cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

Divergent short- and long-term effects of acute stress in object recognition memory are mediated by endogenous opioid system activation.

PubMed

Nava-Mesa, Mauricio O; Lamprea, Marisol R; Múnera, Alejandro

2013-11-01

Acute stress induces short-term object recognition memory impairment and elicits endogenous opioid system activation. The aim of this study was thus to evaluate whether opiate system activation mediates the acute stress-induced object recognition memory changes. Adult male Wistar rats were trained in an object recognition task designed to test both short- and long-term memory. Subjects were randomly assigned to receive an intraperitoneal injection of saline, 1 mg/kg naltrexone or 3 mg/kg naltrexone, four and a half hours before the sample trial. Five minutes after the injection, half the subjects were submitted to movement restraint during four hours while the other half remained in their home cages. Non-stressed subjects receiving saline (control) performed adequately during the short-term memory test, while stressed subjects receiving saline displayed impaired performance. Naltrexone prevented such deleterious effect, in spite of the fact that it had no intrinsic effect on short-term object recognition memory. Stressed subjects receiving saline and non-stressed subjects receiving naltrexone performed adequately during the long-term memory test; however, control subjects as well as stressed subjects receiving a high dose of naltrexone performed poorly. Control subjects' dissociated performance during both memory tests suggests that the short-term memory test induced a retroactive interference effect mediated through light opioid system activation; such effect was prevented either by low dose naltrexone administration or by strongly activating the opioid system through acute stress. Both short-term memory retrieval impairment and long-term memory improvement observed in stressed subjects may have been mediated through strong opioid system activation, since they were prevented by high dose naltrexone administration. Therefore, the activation of the opioid system plays a dual modulating role in object recognition memory. Copyright © 2013 Elsevier Inc. All rights

DTI fiber tractography of cerebro-cerebellar pathways and clinical evaluation of ataxia in childhood posterior fossa tumor survivors.

PubMed

Oh, Myung Eun; Driever, Pablo Hernáiz; Khajuria, Rajiv K; Rueckriegel, Stefan Mark; Koustenis, Elisabeth; Bruhn, Harald; Thomale, Ulrich-Wilhelm

2017-01-01

Pediatric posterior fossa (PF) tumor survivors experience long-term motor deficits. Specific cerebrocerebellar connections may be involved in incidence and severity of motor dysfunction. We examined the relationship between long-term ataxia as well as fine motor function and alteration of differential cerebellar efferent and afferent pathways using diffusion tensor imaging (DTI) and tractography. DTI-based tractography was performed in 19 patients (10 pilocytic astrocytoma (PA) and 9 medulloblastoma patients (MB)) and 20 healthy peers. Efferent Cerebello-Thalamo-Cerebral (CTC) and afferent Cerebro-Ponto-Cerebellar (CPC) tracts were reconstructed and analyzed concerning fractional anisotropy (FA) and volumetric measurements. Clinical outcome was assessed with the International Cooperative Ataxia Rating Scale (ICARS). Kinematic parameters of fine motor function (speed, automation, variability, and pressure) were obtained by employing a digitizing graphic tablet. ICARS scores were significantly higher in MB patients than in PA patients. Poorer ICARS scores and impaired fine motor function correlated significantly with volume loss of CTC pathway in MB patients, but not in PA patients. Patients with pediatric post-operative cerebellar mutism syndrome showed higher loss of CTC pathway volume and were more atactic. CPC pathway volume was significantly reduced in PA patients, but not in MB patients. Neither relationship was observed between the CPC pathway and ICARS or fine motor function. There was no group difference of FA values between the patients and healthy peers. Reduced CTC pathway volumes in our cohorts were associated with severity of long-term ataxia and impaired fine motor function in survivors of MBs. We suggest that the CTC pathway seems to play a role in extent of ataxia and fine motor dysfunction after childhood cerebellar tumor treatment. DTI may be a useful tool to identify relevant structures of the CTC pathway and possibly avoid surgically induced long-term

Neurodevelopmental Malformations of the Cerebellar Vermis in Genetically Engineered Rats.

PubMed

Ramos, Raddy L; Van Dine, Sarah E; Gilbert, Mary E; Leheste, Joerg R; Torres, German

2015-12-01

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. Malformations are almost exclusively found along the primary fissure and are indicative of deficits of neuronal migration during cerebellar development. In the present report, we test the prediction that genetically engineered rats on Sprague-Dawley or Long-Evans backgrounds will also exhibit the same cerebellar malformations. Consistent with our hypothesis, we found that three different transgenic lines on two different backgrounds had cerebellar malformations. Heterotopia in transgenic rats had identical cytoarchitecture as that observed in wild-type rats including altered morphology of Bergmann glia. In light of the possibility that heterotopia could affect results from behavioral studies, these data suggest that histological analyses be performed in studies of cerebellar function or development when using genetically engineered rats on these backgrounds in order to have more careful interpretation of experimental findings.

Long-term health and germline transmission in transgenic cattle following transposon-mediated gene transfer.

PubMed

Yum, Soo-Young; Lee, Song-Jeon; Park, Sin-Gi; Shin, In-Gang; Hahn, Sang-Eun; Choi, Woo-Jae; Kim, Hee-Soo; Kim, Hyeong-Jong; Bae, Seong-Hun; Lee, Je-Hyeong; Moon, Joo-Yeong; Lee, Woo-Sung; Lee, Ji-Hyun; Lee, Choong-Il; Kim, Seong-Jin; Jang, Goo

2018-05-23

Transposon-mediated, non-viral gene delivery is a powerful tool for generating stable cell lines and transgenic animals. However, as multi-copy insertion is the preferred integration pattern, there is the potential for uncontrolled changes in endogenous gene expression and detrimental effects in cells or animals. Our group has previously reported on the generation of several transgenic cattle by using microinjection of the Sleeping Beauty (SB) and PiggyBac (PB) transposons and seeks to explore the long-term effects of this technology on cattle. Transgenic cattle, one female (SNU-SB-1) and one male (SNU-PB-1), reached over 36 months of age with no significant health issues and normal blood parameters. The detection of transgene integration and fluorescent signal in oocytes and sperm suggested the capacity for germline transmission in both of the founder animals. After natural breeding, the founder transgenic cow delivered a male calf and secreted milk containing fluorescent transgenic proteins. The calf expressed green fluorescent protein in primary cells from ear skin, with no significant change in overall genomic stability and blood parameters. Three sites of transgene integration were identified by next-generation sequencing of the calf's genome. Overall, these data demonstrate that transposon-mediated transgenesis can be applied to cattle without being detrimental to their long-term genomic stability or general health. We further suggest that this technology may be usefully applied in other fields, such as the generation of transgenic animal models.

Short-Term and Long-Term Effects of Orthopedic Biodegradable Implants

PubMed Central

Amini, Ami R.; Wallace, James S.; Nukavarapu, Syam P.

2012-01-01

Presently, orthopedic and oral/maxillofacial implants represent a combined $2.8 billion market, a figure expected to experience significant and continued growth. Although traditional permanent implants have been proved clinically efficacious, they are also associated with several drawbacks, including secondary revision and removal surgeries. Non-permanent, biodegradable implants offer a promising alternative for patients, as they provide temporary support and degrade at a rate matching tissue formation, and thus, eliminate the need for secondary surgeries. These implants have been in clinical use for nearly 25 years, competing directly with, or maybe even exceeding, the performance of permanent implants. The initial implantation of biodegradable materials, as with permanent materials, mounts an acute host inflammatory response. Over time, the implant degradation profile and possible degradation product toxicity mediate long-term biodegradable implant-induced inflammation. However, unlike permanent implants, this inflammation is likely to cease once the material disappears. Implant-mediated inflammation is a critical determinant for implant success. Thus, for the development of a proactive biodegradable implant that has the ability to promote optimal bone regeneration and minimal detrimental inflammation, a thorough understanding of short- and long-term inflammatory events is required. Here, we discuss an array of biodegradable orthopedic implants, their associated short- and long- term inflammatory effects, and methods to mediate these inflammatory events. PMID:22043969

Origin, lineage and function of cerebellar glia.

PubMed

Buffo, Annalisa; Rossi, Ferdinando

2013-10-01

The glial cells of the cerebellum, and particularly astrocytes and oligodendrocytes, are characterized by a remarkable phenotypic variety, in which highly peculiar morphological features are associated with specific functional features, unique among the glial cells of the entire CNS. Here, we provide a critical report about the present knowledge of the development of cerebellar glia, including lineage relationships between cerebellar neurons, astrocytes and oligodendrocytes, the origins and the genesis of the repertoire of glial types, and the processes underlying their acquisition of mature morphological and functional traits. In parallel, we describe and discuss some fundamental roles played by specific categories of glial cells during cerebellar development. In particular, we propose that Bergmann glia exerts a crucial scaffolding activity that, together with the organizing function of Purkinje cells, is necessary to achieve the normal pattern of foliation and layering of the cerebellar cortex. Moreover, we discuss some of the functional tasks of cerebellar astrocytes and oligodendrocytes that are distinctive of cerebellar glia throughout the CNS. Notably, we report about the regulation of synaptic signalling in the molecular and granular layer mediated by Bergmann glia and parenchymal astrocytes, and the functional interaction between oligodendrocyte precursor cells and neurons. On the whole, this review provides an extensive overview of the available literature and some novel insights about the origin and differentiation of the variety of cerebellar glial cells and their function in the developing and mature cerebellum. Copyright © 2013 Elsevier Ltd. All rights reserved.

The indirect association of job strain with long-term sickness absence through bullying: a mediation analysis using structural equation modeling.

PubMed

Janssens, Heidi; Braeckman, Lutgart; De Clercq, Bart; Casini, Annalisa; De Bacquer, Dirk; Kittel, France; Clays, Els

2016-08-22

In this longitudinal study the complex interplay between both job strain and bullying in relation to sickness absence was investigated. Following the "work environment hypothesis", which establishes several work characteristics as antecedents of bullying, we assumed that job strain, conceptualized by the Job-Demand-Control model, has an indirect relation with long-term sickness absence through bullying. The sample consisted of 2983 Belgian workers, aged 30 to 55 years, who participated in the Belstress III study. They completed a survey, including the Job Content Questionnaire and a bullying inventory, at baseline. Their sickness absence figures were registered during 1 year follow-up. Long-term sickness absence was defined as at least 15 consecutive days. A mediation analysis, using structural equation modeling, was performed to examine the indirect association of job strain through bullying with long-term sickness absence. The full structural model was adjusted for several possible confounders: age, gender, occupational group, educational level, company, smoking habits, alcohol use, body mass index, self-rated health, baseline long-term sickness absence and neuroticism. The results support the hypothesis: a significant indirect association of job strain with long-term sickness absence through bullying was observed, suggesting that bullying is an intermediate variable between job strain and long-term sickness absence. No evidence for the reversed pathway of an indirect association of bullying through job strain was found. Bullying was observed as a mediating variable in the relation between job strain and sickness absence. The results suggest that exposure to job strain may create circumstances in which a worker risks to become a target of bullying. Our findings are generally in line with the work environment hypothesis, which emphasizes the importance of organizational work factors in the origin of bullying. This study highlights that remodeling jobs to reduce

Structure–function relationships in the developing cerebellum: evidence from early-life cerebellar injury and neurodevelopmental disorders

PubMed Central

Stoodley, Catherine J.; Limperopoulos, Catherine

2016-01-01

SUMMARY The increasing appreciation of the role of the cerebellum in motor and non-motor functions is crucial to understanding the outcomes of acquired cerebellar injury and developmental lesions in high-risk fetal and neonatal populations, children with cerebellar damage (e.g. posterior fossa tumors), and neurodevelopmental disorders (e.g. autism). We review available data regarding the relationship between the topography of cerebellar injury or abnormality and functional outcomes. We report emerging structure–function relationships with specific symptoms: cerebellar regions that interconnect with sensorimotor cortices are associated with motor impairments when damaged; disruption to posterolateral cerebellar regions that form circuits with association cortices impact long-term cognitive outcomes; and midline posterior vermal damage is associated with behavioral dysregulation and an autism-like phenotype. We also explore the impact of age and the potential role for critical periods on cerebellar structure and child function. These findings suggest that the cerebellum plays a critical role in motor, cognitive, and social–behavioral development, possibly via modulatory effects on the developing cerebral cortex. PMID:27184461

Effects of long term ethanol consumption mediated oxidative stress on neovessel generation in liver.

PubMed

Das, Subir Kumar; Mukherjee, Sukhes; Vasudevan, D M

2012-06-01

Angiogenesis, the growth of new blood vessels, is essential during tissue repair. Though most molecular mechanisms of angiogenesis are common to the liver and other organs, there was no report available whether alcoholic liver disease also causes angiogenesis. In this study, we examined the effects of long term ethanol (1.6 g/kg body weight/day) consumption on angiogenic responses in the liver of male Wistar strain albino rats (16-18 weeks old, weighing 200-220 g) up to 36 weeks. Chronic ethanol consumption was associated with not only elevated oxidative stress, and altered cytokines expression, but also developed large von Willebrand factor, fibrosis and activation of matrix metalloproteinases. Moreover, vascular endothelial growth factor-receptor 2 (VEGF-R2, fetal liver kinase 1: Flk-1/KDR) expression and neovessel generation in the rat liver were noted after 36 weeks of ethanol consumption. Thus our study provides novel evidence that long-term ethanol consumption is associated with angiogenesis through delicate and coordinated action of a variety of mediators.

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

Different Molecular Mechanisms Mediate Direct or Glia-Dependent Prion Protein Fragment 90-231 Neurotoxic Effects in Cerebellar Granule Neurons.

PubMed

Thellung, Stefano; Gatta, Elena; Pellistri, Francesca; Villa, Valentina; Corsaro, Alessandro; Nizzari, Mario; Robello, Mauro; Florio, Tullio

2017-10-01

Glia over-stimulation associates with amyloid deposition contributing to the progression of central nervous system neurodegenerative disorders. Here we analyze the molecular mechanisms mediating microglia-dependent neurotoxicity induced by prion protein (PrP)90-231, an amyloidogenic polypeptide corresponding to the protease-resistant portion of the pathological prion protein scrapie (PrP Sc ). PrP90-231 neurotoxicity is enhanced by the presence of microglia within neuronal culture, and associated to a rapid neuronal [Ca ++ ] i increase. Indeed, while in "pure" cerebellar granule neuron cultures, PrP90-231 causes a delayed intracellular Ca ++ entry mediated by the activation of NMDA receptors; when neuron and glia are co-cultured, a transient increase of [Ca ++ ] i occurs within seconds after treatment in both granule neurons and glial cells, then followed by a delayed and sustained [Ca ++ ] i raise, associated with the induction of the expression of inducible nitric oxide synthase and phagocytic NADPH oxidase. [Ca ++ ] i fast increase in neurons is dependent on the activation of multiple pathways since it is not only inhibited by the blockade of voltage-gated channel activity and NMDA receptors but also prevented by the inhibition of nitric oxide and PGE 2 release from glial cells. Thus, Ca ++ homeostasis alteration, directly induced by PrP90-231 in cerebellar granule cells, requires the activation of NMDA receptors, but is greatly enhanced by soluble molecules released by activated glia. In glia-enriched cerebellar granule cultures, the activation of inducible nitric oxide (iNOS) and NADPH oxidase represents the main mechanism of toxicity since their pharmacological inhibition prevented PrP90-231 neurotoxicity, whereas NMDA blockade by D(-)-2-amino-5-phosphonopentanoic acid is ineffective; conversely, in pure cerebellar granule cultures, NMDA blockade but not iNOS inhibition strongly reduced PrP90-231 neurotoxicity. These data indicate that amyloidogenic peptides

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...

Differential effects of primary motor cortex and cerebellar transcranial direct current stimulation on motor learning in healthy individuals: A randomized double-blind sham-controlled study.

PubMed

Ehsani, F; Bakhtiary, A H; Jaberzadeh, S; Talimkhani, A; Hajihasani, A

2016-11-01

The purpose of study was to compare the effect of primary motor cortex (M1) and cerebellar anodal transcranial direct current stimulation (a-tDCS) on online and offline motor learning in healthy individuals. Fifty-nine healthy volunteers were randomly divided into three groups (n=20 in two experimental groups and n=19 in sham-control group). One experimental group received M1a-tDCSand another received cerebellar a-tDCS. The main outcome measure were response time (RT) and number of errors during serial response time test (SRTT) which were assessed prior, 35min and 48h after the interventions. Reduction of response time (RT) and error numbers at last block of the test compared to the first block was considered online learning. Comparison of assessments during retention tests was considered as short-term and long-term offline learning. Online RT reduction was not different among groups (P>0.05), while online error reduction was significantly greater in cerebellar a-tDCS than sham-control group (P<0.017). Moreover, a-tDCS on both M1 and cerebellar regions produced more long-term offline learning as compared to sham tDCS (P<0.01), while short-term offline RT reduction was significantly greater in M1a-tDCS than sham-control group (P<0.05). The findings indicated that although cerebellar a-tDCS enhances online learning and M1a-tDCS has more effect on short-term offline learning, both M 1 and cerebellar a-tDCS can be used as a boosting technique for improvement of offline motor learning in healthy individuals. Crown Copyright © 2016. Published by Elsevier Ireland Ltd. All rights reserved.

Relation of Long-term Exposure to Air Pollution to Brachial Artery Flow-Mediated Dilation and Reactive Hyperemia

PubMed Central

Wilker, Elissa H.; Ljungman, Petter L.; Rice, Mary B.; Kloog, Itai; Schwartz, Joel; Gold, Diane R.; Koutrakis, Petros; Vita, Joseph A.; Mitchell, Gary F.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Hamburg, Naomi M.; Mittleman, Murray A.

2014-01-01

Long-term exposure to ambient air pollution has been associated with cardiovascular morbidity and mortality. Impaired vascular responses may in part explain these findings, but the association of such long-term exposure with measures of both conduit artery and microvascular function have not been widely reported. We evaluated the association between residential proximity to a major roadway (primary or secondary highway) and spatially resolved average fine particulate matter (PM2.5) and baseline brachial artery diameter and mean flow velocity, flow mediated dilation % and hyperemic flow velocity, in the Framingham Offspring and Third Generation Cohorts. We examined 5,112 participants (2,731 (53%) women, mean age 49±14 years). Spatially resolved average PM2.5 was associated with lower flow mediated dilation% and hyperemic flow velocity. An interquartile range difference in PM2.5 (1.99 μg/m3) was associated with −0.16% (95%CI: −0.27%, −0.05%) lower FMD% and −0.72 (95%CI: −1.38, −0.06) cm/s lower hyperemic flow velocity %. Residential proximity to a major roadway was negatively associated with flow mediated dilation %. Compared to living ≥400 m away, living <50 m from a major roadway was associated with 0.32% lower flow mediated dilation (95% confidence interval (CI): −0.58%, −0.06%), but results for hyperemic flow velocity had wide confidence intervals −0.68 cm/s (95%CI: −2.29, 0.93). In conclusion, residential proximity to a major roadway and higher levels of spatially resolved estimates of PM2.5 at participant residences are associated with impaired conduit artery and microvascular function in this large community-based cohort of middle-aged and elderly adults. PMID:24793676

Cerebellar dentate nuclei lesions reduce motivation in appetitive operant conditioning and open field exploration.

PubMed

Bauer, David J; Kerr, Abigail L; Swain, Rodney A

2011-02-01

Recently identified pathways from the dentate nuclei of the cerebellum to the rostral cerebral cortex via the thalamus suggest a cerebellar role in frontal and prefrontal non-motor functioning. Disturbance of cerebellar morphology and connectivity, particularly involving these cerebellothalamocortical (CTC) projections, has been implicated in motivational and cognitive deficits. The current study explored the effects of CTC disruption on motivation in male Long Evans rats. The results of two experiments demonstrate that electrolytic lesions of the cerebellar dentate nuclei lower breaking points on an operant conditioning progressive ratio schedule and decrease open field exploration compared to sham controls. Changes occurred in the absence of motor impairment, assessed via lever pressing frequency and rotarod performance. Similar elevated plus maze performances between lesioned and sham animals indicated that anxiety did not influence task performance. Our results demonstrate hedonic and purposive motivational reduction and suggest a CTC role in global motivational processes. These implications are discussed in terms of psychiatric disorders such as schizophrenia and autism, in which cerebellar damage and motivational deficits often present concomitantly. Copyright © 2010 Elsevier Inc. All rights reserved.

The Cerebellar-Cerebral Microstructure Is Disrupted at Multiple Sites in Very Preterm Infants with Cerebellar Haemorrhage.

PubMed

Neubauer, Vera; Djurdjevic, Tanja; Griesmaier, Elke; Biermayr, Marlene; Gizewski, Elke Ruth; Kiechl-Kohlendorfer, Ursula

2018-01-01

Recent advances in magnetic resonance imaging (MRI) techniques have prompted reconsideration of the anatomical correlates of adverse outcomes in preterm infants. The importance of the contribution made by the cerebellum is now increasingly appreciated. The effect of cerebellar haemorrhage (CBH) on the microstructure of the cerebellar-cerebral circuit is largely unexplored. To investigate the effect of CBH on the microstructure of cerebellar-cerebral connections in preterm infants aged <32 gestational weeks. Infants underwent diffusion tensor MRI at term-equivalent age. MRI was evaluated for CBH and additional supratentorial brain injury using a validated scoring system. Region of interest-based measures of brain microstructure (fractional anisotropy [FA] and apparent diffusion coefficient) were quantified in 5 vulnerable regions (the centrum semiovale, posterior limb of the internal capsule, corpus callosum, and superior and middle cerebellar peduncles). Group differences between infants with CBH and infants without CBH were assessed. There were 267 infants included in the study. Infants with CBH (isolated and combined) had significantly lower FA values in all regions investigated. Infants with isolated CBH showed lower FA in the middle and superior cerebellar peduncles and in the posterior limb of the internal capsule. This study provides evidence that CBH causes alterations in localised and remote WM pathways in the developing brain. The disruption of the cerebellar-cerebral microstructure at multiple sites adds further support for the concept of developmental diaschisis, which is propagated as an explanation for the consequences of early cerebellar injury on cognitive and affective domains. © 2017 S. Karger AG, Basel.

Long-Term Predictive and Feedback Encoding of Motor Signals in the Simple Spike Discharge of Purkinje Cells

PubMed Central

Popa, Laurentiu S.; Streng, Martha L.

2017-01-01

Abstract Most hypotheses of cerebellar function emphasize a role in real-time control of movements. However, the cerebellum’s use of current information to adjust future movements and its involvement in sequencing, working memory, and attention argues for predicting and maintaining information over extended time windows. The present study examines the time course of Purkinje cell discharge modulation in the monkey (Macaca mulatta) during manual, pseudo-random tracking. Analysis of the simple spike firing from 183 Purkinje cells during tracking reveals modulation up to 2 s before and after kinematics and position error. Modulation significance was assessed against trial shuffled firing, which decoupled simple spike activity from behavior and abolished long-range encoding while preserving data statistics. Position, velocity, and position errors have the most frequent and strongest long-range feedforward and feedback modulations, with less common, weaker long-term correlations for speed and radial error. Position, velocity, and position errors can be decoded from the population simple spike firing with considerable accuracy for even the longest predictive (-2000 to -1500 ms) and feedback (1500 to 2000 ms) epochs. Separate analysis of the simple spike firing in the initial hold period preceding tracking shows similar long-range feedforward encoding of the upcoming movement and in the final hold period feedback encoding of the just completed movement, respectively. Complex spike analysis reveals little long-term modulation with behavior. We conclude that Purkinje cell simple spike discharge includes short- and long-range representations of both upcoming and preceding behavior that could underlie cerebellar involvement in error correction, working memory, and sequencing. PMID:28413823

Distributed Circuit Plasticity: New Clues for the Cerebellar Mechanisms of Learning.

PubMed

D'Angelo, Egidio; Mapelli, Lisa; Casellato, Claudia; Garrido, Jesus A; Luque, Niceto; Monaco, Jessica; Prestori, Francesca; Pedrocchi, Alessandra; Ros, Eduardo

2016-04-01

The cerebellum is involved in learning and memory of sensory motor skills. However, the way this process takes place in local microcircuits is still unclear. The initial proposal, casted into the Motor Learning Theory, suggested that learning had to occur at the parallel fiber-Purkinje cell synapse under supervision of climbing fibers. However, the uniqueness of this mechanism has been questioned, and multiple forms of long-term plasticity have been revealed at various locations in the cerebellar circuit, including synapses and neurons in the granular layer, molecular layer and deep-cerebellar nuclei. At present, more than 15 forms of plasticity have been reported. There has been a long debate on which plasticity is more relevant to specific aspects of learning, but this question turned out to be hard to answer using physiological analysis alone. Recent experiments and models making use of closed-loop robotic simulations are revealing a radically new view: one single form of plasticity is insufficient, while altogether, the different forms of plasticity can explain the multiplicity of properties characterizing cerebellar learning. These include multi-rate acquisition and extinction, reversibility, self-scalability, and generalization. Moreover, when the circuit embeds multiple forms of plasticity, it can easily cope with multiple behaviors endowing therefore the cerebellum with the properties needed to operate as an effective generalized forward controller.

Gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene.

PubMed

Melo, Luis G; Agrawal, Reitu; Zhang, Lunan; Rezvani, Mojgan; Mangi, Abeel A; Ehsan, Afshin; Griese, Daniel P; Dell'Acqua, Giorgio; Mann, Michael J; Oyama, Junichi; Yet, Shaw-Fang; Layne, Matthew D; Perrella, Mark A; Dzau, Victor J

2002-02-05

Ischemia and oxidative stress are the leading mechanisms for tissue injury. An ideal strategy for preventive/protective therapy would be to develop an approach that could confer long-term transgene expression and, consequently, tissue protection from repeated ischemia/reperfusion injury with a single administration of a therapeutic gene. In the present study, we used recombinant adeno-associated virus (rAAV) as a vector for direct delivery of the cytoprotective gene heme oxygenase-1 (HO-1) into the rat myocardium, with the purpose of evaluating this strategy as a therapeutic approach for long-term protection from ischemia-induced myocardial injury. Human HO-1 gene (hHO-1) was delivered to normal rat hearts by intramyocardial injection. AAV-mediated transfer of the hHO-1 gene 8 weeks before acute coronary artery ligation and release led to a dramatic reduction (>75%) in left ventricular myocardial infarction. The reduction in infarct size was accompanied by decreases in myocardial lipid peroxidation and in proapoptotic Bax and proinflammatory interleukin-1beta protein abundance, concomitant with an increase in antiapoptotic Bcl-2 protein level. This suggested that the transgene exerts its cardioprotective effects in part by reducing oxidative stress and associated inflammation and apoptotic cell death. This study documents the beneficial therapeutic effect of rAAV-mediated transfer, before myocardial injury, of a cytoprotective gene that confers long-term myocardial protection from ischemia/reperfusion injury. Our data suggest that this novel "pre-event" gene transfer approach may provide sustained tissue protection from future repeated episodes of injury and may be beneficial as preventive therapy for patients with or at risk of developing coronary ischemic events.

Recovery of biological motion perception and network plasticity after cerebellar tumor removal.

PubMed

Sokolov, Arseny A; Erb, Michael; Grodd, Wolfgang; Tatagiba, Marcos S; Frackowiak, Richard S J; Pavlova, Marina A

2014-10-01

Visual perception of body motion is vital for everyday activities such as social interaction, motor learning or car driving. Tumors to the left lateral cerebellum impair visual perception of body motion. However, compensatory potential after cerebellar damage and underlying neural mechanisms remain unknown. In the present study, visual sensitivity to point-light body motion was psychophysically assessed in patient SL with dysplastic gangliocytoma (Lhermitte-Duclos disease) to the left cerebellum before and after neurosurgery, and in a group of healthy matched controls. Brain activity during processing of body motion was assessed by functional magnetic resonance imaging (MRI). Alterations in underlying cerebro-cerebellar circuitry were studied by psychophysiological interaction (PPI) analysis. Visual sensitivity to body motion in patient SL before neurosurgery was substantially lower than in controls, with significant improvement after neurosurgery. Functional MRI in patient SL revealed a similar pattern of cerebellar activation during biological motion processing as in healthy participants, but located more medially, in the left cerebellar lobules III and IX. As in normalcy, PPI analysis showed cerebellar communication with a region in the superior temporal sulcus, but located more anteriorly. The findings demonstrate a potential for recovery of visual body motion processing after cerebellar damage, likely mediated by topographic shifts within the corresponding cerebro-cerebellar circuitry induced by cerebellar reorganization. The outcome is of importance for further understanding of cerebellar plasticity and neural circuits underpinning visual social cognition.

A Multiple-Plasticity Spiking Neural Network Embedded in a Closed-Loop Control System to Model Cerebellar Pathologies.

PubMed

Geminiani, Alice; Casellato, Claudia; Antonietti, Alberto; D'Angelo, Egidio; Pedrocchi, Alessandra

2018-06-01

The cerebellum plays a crucial role in sensorimotor control and cerebellar disorders compromise adaptation and learning of motor responses. However, the link between alterations at network level and cerebellar dysfunction is still unclear. In principle, this understanding would benefit of the development of an artificial system embedding the salient neuronal and plastic properties of the cerebellum and operating in closed-loop. To this aim, we have exploited a realistic spiking computational model of the cerebellum to analyze the network correlates of cerebellar impairment. The model was modified to reproduce three different damages of the cerebellar cortex: (i) a loss of the main output neurons (Purkinje Cells), (ii) a lesion to the main cerebellar afferents (Mossy Fibers), and (iii) a damage to a major mechanism of synaptic plasticity (Long Term Depression). The modified network models were challenged with an Eye-Blink Classical Conditioning test, a standard learning paradigm used to evaluate cerebellar impairment, in which the outcome was compared to reference results obtained in human or animal experiments. In all cases, the model reproduced the partial and delayed conditioning typical of the pathologies, indicating that an intact cerebellar cortex functionality is required to accelerate learning by transferring acquired information to the cerebellar nuclei. Interestingly, depending on the type of lesion, the redistribution of synaptic plasticity and response timing varied greatly generating specific adaptation patterns. Thus, not only the present work extends the generalization capabilities of the cerebellar spiking model to pathological cases, but also predicts how changes at the neuronal level are distributed across the network, making it usable to infer cerebellar circuit alterations occurring in cerebellar pathologies.

Cerebellar Volume and Proton Magnetic Resonance Spectroscopy at Term, and Neurodevelopment at 2 Years of Age in Preterm Infants

ERIC Educational Resources Information Center

van Kooij, Britt J. M.; Benders, Manon J. N. L.; Anbeek, Petronella; van Haastert, Ingrid C.; de Vries, Linda S.; Groenendaal, Floris

2012-01-01

Aim: To assess the relation between cerebellar volume and spectroscopy at term equivalent age, and neurodevelopment at 24 months corrected age in preterm infants. Methods: Magnetic resonance imaging of the brain was performed around term equivalent age in 112 preterm infants (mean gestational age 28wks 3d [SD 1wk 5d]; birthweight 1129g [SD 324g]).…

Phytochrome-mediated long-term memory of seeds.

PubMed

Hartmann, K M; Grundy, A C; Market, R

2005-12-01

The question is how long phytochrome, stored within the cytoplasm of plant diaspores, may stimulate their germination. This question arose from the observation that soil cultivations in darkness for weed control gave inconsistent results. Namely, after a single nighttime or daytime cultivation during spring and summer, differences in weed emergence became hardly detectable after a period of six weeks. However, after nighttime and daytime cultivations in late autumn, emergence differences persisted for up to nine months. To examine whether this differing memory effect is phytochrome-mediated, seeds of Chenopodium album and Stellaria media were sown in pots with wet peat, either in daylight or after sunset. In the latter, seeds were irradiated with far-red light for one day prior to being covered and buried. For more than two years the far-red irradiated seeds produced significantly reduced emergence, indicating that germination and emergence of weeds in the field may be supported by maternal far-red absorbing seed phytochrome B(fr) over several months or even years. This conclusion allows refining of the strategy of lightless tillage.

Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model.

PubMed

Kucerova, L; Skolekova, S; Demkova, L; Bohovic, R; Matuskova, M

2014-10-01

Mesenchymal stromal cells (MSC) can be exploited as cellular delivery vehicles for the enzymes converting non-toxic prodrugs to toxic substances. Because of their inherent chemoresistance, they exert potent bystander and antitumor effect. Here we show that the human adipose tissue-derived MSC expressing fusion yeast cytosine deaminase::uracil phosphoribosyltransferase (CD-MSC) in combination with 5-fluorocytosine (5FC) mediated a long-term tumor-free survival in the 83.3% of tumor-bearing animals. CD-MSC/5FC treatment induced cytotoxicity against model human melanoma cells EGFP-A375. Only 4% of the therapeutic CD-MSC cells eliminated >98.5% of the tumor cells in vitro. Long-term tumor-free survival was confirmed in 15 out of the 18 animals. However, repeatedly used CD-MSC/5FC therapeutic regimen generated more aggressive and metastatic variant of the melanoma cells EGFP-A375/Rel3. These cells derived from the refractory xenotransplants exhibited increased resistance to the CD-MSC/5FC treatment, altered cell adhesion, migration, tumorigenic and metastatic properties. However, long-term curative effect was achieved by the augmentation of the CD-MSC/5FC regimen along with the inhibition of c-Met/hepatocyte growth factor signaling axis in this aggressive melanoma derivative. In summary, the CD-MSC/5FC regimen can be regarded as a very effective antitumor approach to achieve long-term tumor-free survival as demonstrated on a mouse model of aggressive human melanoma xenografts.

[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. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Long-term T-cell-mediated immunologic memory to hepatitis B vaccine in young adults following neonatal vaccination.

PubMed

Saffar, Hiva; Saffar, Mohammed Jafar; Ajami, Abolghasem; Khalilian, Ali Reza; Shams-Esfandabad, Kian; Mirabi, Araz Mohammad

2014-09-01

The long-term duration of cell-mediated immunity induced by neonatal hepatitis B virus (HBV) vaccination is unknown. Study was designed to determine the cellular immunity memory status among young adults twenty years after infantile HB immunization. Study subjects were party selected from a recent seroepidemiologic study in young adults, who had been vaccinated against HBV twenty years earlier. Just before and ten to 14 days after one dose of HBV vaccine booster injection, blood samples were obtained and sera concentration of cytokines (interleukin 2 and interferon) was measured. More than twofold increase after boosting was considered positive immune response. With regard to the serum level of antibody against HBV surface antigen (HBsAb) before boosting, the subjects were divided into four groups as follow: GI, HBsAb titer < 2; GII, titer 2 to 9.9; GIII, titer 10 to 99; and GIV, titers ≥ 100 IU/L. Mean concentration level (MCL) of each cytokines for each group at preboosting and postboosting and the proportion of responders in each groups were determined. Paired descriptive statistical analysis method (t test) was used to compare the MCL of each cytokines in each and between groups and the frequency of responders in each group. Before boosting, among 176 boosted individuals, 75 (42.6%) had HBsAb 10 IU/L and were considered seroprotected. Among 101 serosusceptible persons, more than 80% of boosted individuals showed more than twofold increase in cytokines concentration, which meant positive HBsAg-specific cell-mediated immunity. MCL of both cytokines after boosting in GIV were decreased more than twofold, possibly because of recent natural boosting. Findings showed that neonatal HBV immunization was efficacious in inducing long-term immunity and cell-mediated immune memory for up to two decades, and booster vaccination are not required. Further monitoring of vaccinated subjects for HBV infections are recommended.

LXR agonist rescued the deficit in the proliferation of the cerebellar granule cells induced by dexamethasone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bian, Xuting; Zhong, Hongyu; Li, Fen

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 externalmore » 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.« less

Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling.

PubMed

Puighermanal, Emma; Marsicano, Giovanni; Busquets-Garcia, Arnau; Lutz, Beat; Maldonado, Rafael; Ozaita, Andrés

2009-09-01

Cognitive impairment is one of the most important negative consequences associated with cannabis consumption. We found that CB1 cannabinoid receptor (CB1R) activation transiently modulated the mammalian target of rapamycin (mTOR)/p70S6K pathway and the protein synthesis machinery in the mouse hippocampus, which correlated with the amnesic properties of delta9-tetrahydrocannabinol (THC). In addition, non-amnesic doses of either the mTOR blocker rapamycin or the protein synthesis inhibitor anisomycin abrogated the amnesic-like effects of THC, pointing to a mechanism involving new protein synthesis. Moreover, using pharmacological and genetic tools, we found that THC long-term memory deficits were mediated by CB1Rs expressed on GABAergic interneurons through a glutamatergic mechanism, as both the amnesic-like effects and p70S6K phosphorylation were reduced in GABA-CB1R knockout mice and by NMDA blockade.

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.

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.

The Prevention of Child Maltreatment Through the Nurse Family Partnership Program: Mediating Effects in a Long-Term Follow-Up Study.

PubMed

Eckenrode, John; Campa, Mary I; Morris, Pamela A; Henderson, Charles R; Bolger, Kerry E; Kitzman, Harriet; Olds, David L

2017-05-01

We examine maternal life-course mediators of the impact of a nurse home visitation program on reducing child maltreatment among participants in the Elmira trial of the Nurse Family Partnership program from the first child's birth through age 15. For women having experienced low to moderate levels of domestic violence, program effects on the number of confirmed maltreatment reports were mediated by reductions in numbers of subsequent children born to mothers and their reported use of public assistance. Together, the two mediators explained nearly one half of the total effect of nurse home visiting on child maltreatment. The long-term success of this program on reducing child maltreatment can be explained, at least in part, by its positive effect on pregnancy planning and economic self-sufficiency.

Tubulin-related cerebellar dysplasia: definition of a distinct pattern of cerebellar malformation.

PubMed

Romaniello, Romina; Arrigoni, Filippo; Panzeri, Elena; Poretti, Andrea; Micalizzi, Alessia; Citterio, Andrea; Bedeschi, Maria Francesca; Berardinelli, Angela; Cusmai, Raffaella; D'Arrigo, Stefano; Ferraris, Alessandro; Hackenberg, Annette; Kuechler, Alma; Mancardi, Margherita; Nuovo, Sara; Oehl-Jaschkowitz, Barbara; Rossi, Andrea; Signorini, Sabrina; Tüttelmann, Frank; Wahl, Dagmar; Hehr, Ute; Boltshauser, Eugen; Bassi, Maria Teresa; Valente, Enza Maria; Borgatti, Renato

2017-12-01

To determine the neuroimaging pattern of cerebellar dysplasia (CD) and other posterior fossa morphological anomalies associated with mutations in tubulin genes and to perform clinical and genetic correlations. Twenty-eight patients harbouring 23 heterozygous pathogenic variants (ten novel) in tubulin genes TUBA1A (n = 10), TUBB2B (n = 8) or TUBB3 (n = 5) were studied by a brain MRI scan performed either on a 1.5 T (n = 10) or 3 T (n = 18) MR scanner with focus on the posterior fossa. Cerebellar anomalies were detected in 24/28 patients (86%). CD was recognised in 19/28 (68%) including cortical cerebellar dysplasia (CCD) in 18/28, either involving only the cerebellar hemispheres (12/28) or associated with vermis dysplasia (6/28). CCD was located only in the right hemisphere in 13/18 (72%), including four TUBB2B-, four TUBB3- and five TUBA1A-mutated patients, while in the other five TUBA1A cases it was located only in the left hemisphere or in both hemispheres. The postero-superior region of the cerebellar hemispheres was most frequently affected. The cerebellar involvement in tubulinopathies shows specific features that may be labelled as 'tubulin-related CD'. This pattern is unique and differs from other genetic causes of cerebellar dysplasia. • Cortical cerebellar dysplasia without cysts is suggestive of tubulin-related disorder. • Cerebellar dysplasia in tubulinopathies shows specific features labelled as 'tubulin-related CD'. • Focal and unilateral involvement of cerebellar hemispheres has important implications for counselling.

Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis.

PubMed

Dong, Zhifang; Han, Huili; Li, Hongjie; Bai, Yanrui; Wang, Wei; Tu, Man; Peng, Yan; Zhou, Limin; He, Wenting; Wu, Xiaobin; Tan, Tao; Liu, Mingjing; Wu, Xiaoyan; Zhou, Weihui; Jin, Wuyang; Zhang, Shu; Sacktor, Todd Charlton; Li, Tingyu; Song, Weihong; Wang, Yu Tian

2015-01-01

Long-term potentiation (LTP) of synaptic strength between hippocampal neurons is associated with learning and memory, and LTP dysfunction is thought to underlie memory loss. LTP can be temporally and mechanistically classified into decaying (early-phase) LTP and nondecaying (late-phase) LTP. While the nondecaying nature of LTP is thought to depend on protein synthesis and contribute to memory maintenance, little is known about the mechanisms and roles of decaying LTP. Here, we demonstrated that inhibiting endocytosis of postsynaptic α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptors (AMPARs) prevents LTP decay, thereby converting it into nondecaying LTP. Conversely, restoration of AMPAR endocytosis by inhibiting protein kinase Mζ (PKMζ) converted nondecaying LTP into decaying LTP. Similarly, inhibition of AMPAR endocytosis prolonged memory retention in normal animals and reduced memory loss in a murine model of Alzheimer's disease. These results strongly suggest that an active process that involves AMPAR endocytosis mediates the decay of LTP and that inhibition of this process can prolong the longevity of LTP as well as memory under both physiological and pathological conditions.

White matter integrity of the cerebellar peduncles as a mediator of effects of prenatal alcohol exposure on eyeblink conditioning

PubMed Central

Fan, Jia; Meintjes, Ernesta M.; Molteno, Christopher D.; Spottiswoode, Bruce S.; Dodge, Neil C.; Alhamud, Alkathafi A.; Stanton, Mark E.; Peterson, Bradley S.; Jacobson, Joseph L.; Jacobson, Sandra W.

2015-01-01

Fetal alcohol spectrum disorders (FASD) are characterized by a range of neurodevelopmental deficits that result from prenatal exposure to alcohol. These can include cognitive, behavioural, and neurological impairment, as well as structural and functional brain damage. Eyeblink conditioning (EBC) is among the most sensitive endpoints affected in FASD. The cerebellar peduncles, large bundles of myelinated nerve fibers that connect the cerebellum to the brainstem, constitute the principal white matter element of the EBC circuit. Diffusion tensor imaging (DTI) is used to assess white matter integrity in fibre pathways linking brain regions. DTI scans of 54 children with FASD and 23 healthy controls, mean age 10.1±1.0 yrs, from the Cape Town Longitudinal Cohort were processed using voxelwise group comparisons. Prenatal alcohol exposure was related to lower fractional anisotropy (FA) bilaterally in the superior cerebellar peduncles and higher mean diffusivity (MD) in the left middle peduncle, effects that remained significant after controlling for potential confounding variables. Lower FA and higher MD in these regions were associated with poorer EBC performance. Moreover, effects of alcohol exposure on EBC decreased significantly after inclusion of these DTI measures in regression models, suggesting that these white matter deficits partially mediate the relation of prenatal alcohol exposure to EBC. The associations of greater alcohol consumption with these DTI measures are largely attributable to greater radial diffusivity, possibly indicating poorer myelination. Thus, these data suggest that fetal alcohol-related deficits in EBC are attributable, in part, to poorer myelination in key regions of the cerebellar peduncles. PMID:25783559

Anti-Yo Mediated Paraneoplastic Cerebellar Degeneration Associated with Pseudobulbar Affect in a Patient with Breast Cancer.

PubMed

Martin, Allison N; Dillon, Patrick M; Jones, David E; Brenin, David R; Lapides, David A

2017-01-01

Paraneoplastic cerebellar degeneration (PCD) is a rare anti-Yo mediated paraneoplastic syndromes rarely that is infrequently associated with breast cancer. We present a case of a 52-year-old female presenting with diplopia, gait instability, dysarthria, dysphagia, nystagmus, and, most notably, new onset paroxysmal episodes of uncontrollable crying concerning for pseudobulbar affect (PBA). Serologic testing showed anti-Yo antibodies. The patient was found to have stage IIIA breast cancer as the inciting cause of the paraneoplastic syndrome. The patient was treated with neoadjuvant chemotherapy, modified radical mastectomy, adjuvant Herceptin, and pertuzumab. She was given IVIG for paraneoplastic syndrome, antidepressants, and dextromethorphan-quinidine (Nuedexta), the first FDA-approved therapy for PBA. With multimodality therapy, she demonstrated significant improvement in neurologic and mood symptoms associated with PCD and PBA.

Attention Problems, Phonological Short-Term Memory, and Visuospatial Short-Term Memory: Differential Effects on Near- and Long-Term Scholastic Achievement

ERIC Educational Resources Information Center

Sarver, Dustin E.; Rapport, Mark D.; Kofler, Michael J.; Scanlan, Sean W.; Raiker, Joseph S.; Altro, Thomas A.; Bolden, Jennifer

2012-01-01

The current study examined individual differences in children's phonological and visuospatial short-term memory as potential mediators of the relationship among attention problems and near- and long-term scholastic achievement. Nested structural equation models revealed that teacher-reported attention problems were associated negatively with…

Why Does Placement of Persons with Alzheimer's Disease into Long-term Care Improve Caregivers’ Well-Being? Examination of Psychological Mediators

PubMed Central

Mausbach, Brent T.; Chattillion, Elizabeth A.; Ho, Jennifer; Flynn, Laura M.; Tiznado, Denisse; von Känel, Roland; Patterson, Thomas L.; Grant, Igor

2014-01-01

Caregiving for individuals with Alzheimer's Disease (AD) is associated with chronic stress and elevated symptoms of depression. Placement of the care receiver (CR) into a long-term care setting may be associated with improved caregiver well-being; however, the psychological mechanisms underlying this relationship are unclear. This study evaluated whether decreases in activity restriction and increases in personal mastery mediated placement-related reductions in caregiver depressive symptoms. In a five-year longitudinal study of 126 spousal AD caregivers, we used multilevels models to evaluate placement-related changes in depressive symptoms (CESD-10), activity restriction (Activity Restriction Scale), and personal mastery (Pearlin Mastery Scale) in 44 caregivers who placed their spouses into long-term care relative to caregivers who never placed their CRs. The Monte Carlo Method for Assessing Mediation (MCMAM) was used to evaluate the significance of the indirect effect of activity restriction and personal mastery on post-placement changes in depressive symptoms. Placement of the CR was associated with significant reductions in depressive symptoms and activity restriction, while also being associated with increased personal mastery. Lower activity restriction and higher personal mastery were associated with reduced depressive symptoms. Furthermore, both variables significantly mediated the effect of placement on depressive symptoms. Placement-related reductions in activity restriction and increases in personal mastery are important psychological factors that help explain post-placement reductions in depressive symptoms. The implications for clinical care provided to caregivers are discussed. PMID:25133414

Cerebellar infarction in the territory of the medial branch of the superior cerebellar artery.

PubMed

Sohn, Sung-Il; Lee, Hyung; Lee, Seong-Ryong; Baloh, Robert W

2006-01-10

The authors studied 14 patients with an isolated cerebellar infarct in the territory of the medial branch of the superior cerebellar artery (MSCA). The most common clinical finding was severe gait ataxia with sudden falling (n = 9) or severe veering (n = 2). Cerebellar dysarthria was found in 8 patients. Eight patients had a mild unilateral limb ataxia. These findings emphasize that MSCA territory cerebellar infarction presented with the prominent gait ataxia and cerebellar dysarthria.

The interaction of short-term and long-term memory in phonetic category formation

NASA Astrophysics Data System (ADS)

Harnsberger, James D.

2002-05-01

This study examined the role that short-term memory capacity plays in the relationship between novel stimuli (e.g., non-native speech sounds, native nonsense words) and phonetic categories in long-term memory. Thirty native speakers of American English were administered five tests: categorial AXB discrimination using nasal consonants from Malayalam; categorial identification, also using Malayalam nasals, which measured the influence of phonetic categories in long-term memory; digit span; nonword span, a short-term memory measure mediated by phonetic categories in long-term memory; and paired-associate word learning (word-word and word-nonword pairs). The results showed that almost all measures were significantly correlated with one another. The strongest predictor for the discrimination and word-nonword learning results was nonword (r=+0.62) and digit span (r=+0.51), respectively. When the identification test results were partialed out, only nonword span significantly correlated with discrimination. The results show a strong influence of short-term memory capacity on the encoding of phonetic detail within phonetic categories and suggest that long-term memory representations regulate the capacity of short-term memory to preserve information for subsequent encoding. The results of this study will also be discussed with regards to resolving the tension between episodic and abstract models of phonetic category structure.

Long-term effects of a universal family intervention: mediation through parent-adolescent conflict.

PubMed

Jensen, Michaeline R; Wong, Jessie J; Gonzales, Nancy A; Dumka, Larry E; Millsap, Roger; Coxe, Stefany

2014-01-01

This randomized trial of a family-focused preventive intervention for Mexican American middle schoolers examined internalizing, externalizing, and substance use outcomes in late adolescence, 5 years after completing the intervention. Parent-adolescent conflict was tested as a mediator of these effects. The role of parent and adolescent acculturation in these pathways was also examined. There were 494 seventh-grade adolescents and their primary female caregivers randomized to receive either a 9-week multicomponent intervention or a brief workshop control group. Assessments were conducted at pretest, 2-year follow-up (9th grade), and 5-year follow-up (when most participants were in the 12th grade). The Bridges program significantly reduced mother-adolescent conflict measured in the 9th grade, with conflict mediating program effects on internalizing and externalizing symptoms, adolescent substance use, and diagnosed internalizing disorder in late adolescence. Mother and child acculturation were both significantly predictive of late adolescence outcomes. Contrary to hypotheses, neither mother nor child acculturation emerged as a significant predictor of mother-adolescent conflict, and the interaction of mother and adolescent acculturation was similarly not related to mother-adolescent conflict. Intervention effects were largely consistent across different levels of acculturation. These findings provide support for the efficacy of family-focused intervention during early adolescence, both in reducing mental health problems and substance use in the long term and in impacting parent-adolescent conflict processes that appear to play an important role in the development of later adjustment problems.

Anti-Yo Mediated Paraneoplastic Cerebellar Degeneration Associated with Pseudobulbar Affect in a Patient with Breast Cancer

PubMed Central

Martin, Allison N.; Jones, David E.; Brenin, David R.; Lapides, David A.

2017-01-01

Paraneoplastic cerebellar degeneration (PCD) is a rare anti-Yo mediated paraneoplastic syndromes rarely that is infrequently associated with breast cancer. We present a case of a 52-year-old female presenting with diplopia, gait instability, dysarthria, dysphagia, nystagmus, and, most notably, new onset paroxysmal episodes of uncontrollable crying concerning for pseudobulbar affect (PBA). Serologic testing showed anti-Yo antibodies. The patient was found to have stage IIIA breast cancer as the inciting cause of the paraneoplastic syndrome. The patient was treated with neoadjuvant chemotherapy, modified radical mastectomy, adjuvant Herceptin, and pertuzumab. She was given IVIG for paraneoplastic syndrome, antidepressants, and dextromethorphan-quinidine (Nuedexta), the first FDA-approved therapy for PBA. With multimodality therapy, she demonstrated significant improvement in neurologic and mood symptoms associated with PCD and PBA. PMID:28377827

Effects of Long-Term Treatment on Brain Volume in Patients with Obstructive Sleep Apnea Syndrome

PubMed Central

Kim, Hosung; Joo, Eun Yeon; Suh, Sooyeon; Kim, Jae-Hun; Kim, Sung Tae; Hong, Seung Bong

2015-01-01

We assessed structural brain damage in obstructive sleep apnea syndrome (OSA) patients (21 males) and the effects of long-term continuous positive airway pressure (CPAP) treatment (18.2 ± 12.4 months; 8-44 months) on brain structures and investigated the relationship between severity of OSA and effects of treatment. Using deformation-based morphometry to measure local volume changes, we identified widespread neocortical and cerebellar atrophy in untreated patients compared to controls (59 males; Cohen's D = 0.6; FDR < 0.05). Analysis of longitudinally scanned magnetic resonance imaging (MRI) scans both before and after treatment showed increased brain volume following treatment (FDR < 0.05). Volume increase was correlated with longer treatment in the cortical areas that largely overlapped with the initial atrophy. The areas overlying the hippocampal dentate gyrus and the cerebellar dentate nucleus displayed a volume increase after treatment. Patients with very severe OSA (AHI > 64) presented with prefrontal atrophy and displayed an additional volume increase in this area following treatment. Higher impairment of working memory in patients prior to treatment correlated with prefrontal volume increase after treatment. The large overlap between the initial brain damage and the extent of recovery after treatment suggests partial recovery of non-permanent structural damage. Volume increases in the dentate gyrus and the dentate nucleus possibly likely indicate compensatory neurogenesis in response to diminishing oxidative stress. Such changes in other brain structures may explain gliosis, dendritic volume increase, or inflammation. This study provides neuroimaging evidence that revealed the positive effects of long-term CPAP treatment in patients with OSA. PMID:26503297

Evolution of the cerebellar cortex: the selective expansion of prefrontal-projecting cerebellar lobules.

PubMed

Balsters, J H; Cussans, E; Diedrichsen, J; Phillips, K A; Preuss, T M; Rilling, J K; Ramnani, N

2010-02-01

It has been suggested that interconnected brain areas evolve in tandem because evolutionary pressures act on complete functional systems rather than on individual brain areas. The cerebellar cortex has reciprocal connections with both the prefrontal cortex and motor cortex, forming independent loops with each. Specifically, in capuchin monkeys cerebellar cortical lobules Crus I and Crus II connect with prefrontal cortex, whereas the primary motor cortex connects with cerebellar lobules V, VI, VIIb, and VIIIa. Comparisons of extant primate species suggest that the prefrontal cortex has expanded more than cortical motor areas in human evolution. Given the enlargement of the prefrontal cortex relative to motor cortex in humans, our hypothesis would predict corresponding volumetric increases in the parts of the cerebellum connected to the prefrontal cortex, relative to cerebellar lobules connected to the motor cortex. We tested the hypothesis by comparing the volumes of cerebellar lobules in structural MRI scans in capuchins, chimpanzees and humans. The fractions of cerebellar volume occupied by Crus I and Crus II were significantly larger in humans compared to chimpanzees and capuchins. Our results therefore support the hypothesis that in the cortico-cerebellar system, functionally related structures evolve in concert with each other. The evolutionary expansion of these prefrontal-projecting cerebellar territories might contribute to the evolution of the higher cognitive functions of humans. Copyright (c) 2009 Elsevier Inc. All rights reserved.

Changes in the cerebellar and cerebro-cerebellar circuit in type 2 diabetes.

PubMed

Fang, Peng; An, Jie; Tan, Xin; Zeng, Ling-Li; Shen, Hui; Qiu, Shijun; Hu, Dewen

2017-04-01

Currently, 422 million adults suffer from diabetes worldwide, leading to tremendous disabilities and a great burden to families and society. Functional and structural MRIs have demonstrated that patients with type 2 diabetes mellitus (T2DM) exhibit abnormalities in brain regions in the cerebral cortex. However, the changes of cerebellar anatomical connections in diabetic patients remains unclear. In the current study, diffusion tensor imaging deterministic tractography and statistical analysis were employed to investigate abnormal cerebellar anatomical connections in diabetic patients. This is the first study to investigate the altered cerebellar anatomical connectivity in T2DM patients. Decreased anatomical connections were found in the cerebellar and cerebro-cerebellar circuits of T2DM patients, providing valuable new insights into the potential neuro-pathophysiology of diabetes-related motor and cognitive deficits. Copyright © 2017. Published by Elsevier Inc.

Reorganization of circuits underlying cerebellar modulation of prefrontal cortical dopamine in mouse models of autism spectrum disorder

PubMed Central

Rogers, Tiffany D.; Dickson, Price E.; McKimm, Eric; Heck, Detlef H.; Goldowitz, Dan; Blaha, Charles D.; Mittleman, Guy

2013-01-01

Imaging, clinical and pre-clinical studies have provided ample evidence for a cerebellar involvement in cognitive brain function including cognitive brain disorders, such as autism and schizophrenia. We previously reported that cerebellar activity modulates dopamine release in the mouse medial prefrontal cortex (mPFC) via two distinct pathways: (1) cerebellum to mPFC via dopaminergic projections from the ventral tegmental area [VTA] and (2) cerebellum to mPFC via glutamatergic projections from the mediodorsal and ventrolateral thalamus (ThN md and vl). The present study compared functional adaptations of cerebello-cortical circuitry following developmental cerebellar pathology in a mouse model of developmental loss of Purkinje cells (Lurcher) and a mouse model of fragile X syndrome (Fmr1 KO mice). Fixed potential amperometry was used to measure mPFC dopamine release in response to cerebellar electrical stimulation. Mutant mice of both strains showed an attenuation in cerebellar-evoked mPFC dopamine release compared to respective wildtype mice. This was accompanied by a functional reorganization of the VTA and thalamic pathways mediating cerebellar modulation of mPFC dopamine release. Inactivation of the VTA pathway by intra-VTA lidocaine or kynurenate infusions decreased dopamine release by 50% in wildtype and 20-30% in mutant mice of both strains. Intra-ThN vl infusions of either drug decreased dopamine release by 15% in wildtype and 40% in mutant mice of both strains, while dopamine release remained relatively unchanged following intra-ThN md drug infusions. These results indicate a shift in strength towards the thalamic vl projection, away from the VTA. Thus, cerebellar neuropathologies associated with autism spectrum disorders may cause a reduction in cerebellar modulation of mPFC dopamine release that is related to a reorganization of the mediating neuronal pathways. PMID:23436049

Reorganization of circuits underlying cerebellar modulation of prefrontal cortical dopamine in mouse models of autism spectrum disorder.

PubMed

Rogers, Tiffany D; Dickson, Price E; McKimm, Eric; Heck, Detlef H; Goldowitz, Dan; Blaha, Charles D; Mittleman, Guy

2013-08-01

Imaging, clinical, and pre-clinical studies have provided ample evidence for a cerebellar involvement in cognitive brain function including cognitive brain disorders, such as autism and schizophrenia. We previously reported that cerebellar activity modulates dopamine release in the mouse medial prefrontal cortex (mPFC) via two distinct pathways: (1) cerebellum to mPFC via dopaminergic projections from the ventral tegmental area (VTA) and (2) cerebellum to mPFC via glutamatergic projections from the mediodorsal and ventrolateral thalamus (ThN md and vl). The present study compared functional adaptations of cerebello-cortical circuitry following developmental cerebellar pathology in a mouse model of developmental loss of Purkinje cells (Lurcher) and a mouse model of fragile X syndrome (Fmr1 KO mice). Fixed potential amperometry was used to measure mPFC dopamine release in response to cerebellar electrical stimulation. Mutant mice of both strains showed an attenuation in cerebellar-evoked mPFC dopamine release compared to respective wildtype mice. This was accompanied by a functional reorganization of the VTA and thalamic pathways mediating cerebellar modulation of mPFC dopamine release. Inactivation of the VTA pathway by intra-VTA lidocaine or kynurenate infusions decreased dopamine release by 50 % in wildtype and 20-30 % in mutant mice of both strains. Intra-ThN vl infusions of either drug decreased dopamine release by 15 % in wildtype and 40 % in mutant mice of both strains, while dopamine release remained relatively unchanged following intra-ThN md drug infusions. These results indicate a shift in strength towards the thalamic vl projection, away from the VTA. Thus, cerebellar neuropathologies associated with autism spectrum disorders may cause a reduction in cerebellar modulation of mPFC dopamine release that is related to a reorganization of the mediating neuronal pathways.

Late effects of radiotherapy on patients with cerebellar medulloblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Silverman, C.L.; Palkes, H.; Talent, B.

1984-09-01

Nine long-term survivors of cerebellar medulloblastoma treated with surgery and irradiation were retrospectively examined with a complete battery of neuropsychological tests and the results compared with their nonirradiated siblings. Significant decreased scores were found in the full-scale intelligence quotients (IQ), performance IQ, and verbal IQ with all nine irradiated patients scoring below their siblings. Also, educational quotients (EQ) of the irradiated patients were 12 to 17 points below the nonirradiated siblings with arithmetic EQ significantly decreased. Most severely affected were those children younger than 8 years at time of irradiation. No correlation was found with whole-brain dose, or objective physicalmore » or neurologic findings.« less

Cerebellar learning properties are modulated by the CRF receptor in granular cells.

PubMed

Ezra-Nevo, Gili; Prestori, Francesca; Locatelli, Francesca; Soda, Teresa; Ten Brinke, Michiel M; Engel, Mareen; Boele, Henk-Jan; Botta, Laura; Leshkowitz, Dena; Ramot, Assaf; Tsoory, Michael; Biton, Inbal E; Deussing, Jan; D'Angelo, Egidio; De Zeeuw, Chris I; Chen, Alon

2018-06-22

Corticotropin-releasing factor (CRF) and its type 1 receptor (CRFR 1 ) play an important role in the responses to stressful challenges. Despite the well-established expression of CRFR 1 in granular cells (GrCs), its role in procedural motor performance and memory formation remains elusive. To investigate the role of CRFR 1 expression in cerebellar GrCs, we used a mouse model depleted of CRFR 1 in these cells. We detected changes in the cellular learning mechanisms in GrCs depleted of CRFR 1 in that they showed changes in intrinsic excitability and long-term synaptic plasticity. Moreover, male mice depleted of CRFR 1 specifically in GrCs showed accelerated Pavlovian associative eye-blink conditioning, but no differences in baseline motor performance, locomotion or fear and anxiety-related behaviors. Last, we analyzed cerebella transcriptome of KO and control mice and detected prominent alterations in the expression of calcium signaling pathways components. Our findings shed light on the interplay between stress-related central mechanisms and cerebellar motor conditioning, highlighting the role of the CRF system in regulating particular forms of cerebellar learning. SIGNIFICANCE STATEMENT Although it is known that CRFR 1 is highly expressed in the cerebellum, little attention has been given to its role in cerebellar functions in the behaving animal. Moreover, most of the attention was directed to the effect of CRF on Purkinje cells at the cellular level, and to this date, almost no data exist on the role of this stress-related receptor in other cerebellar structures. Here, we explored the behavioral and cellular effect of GrCs specific ablation of CRFR 1 We found a profound effect on learning, both at the cellular and behavioral levels, without affecting baseline motor skills. Copyright © 2018 the authors.

Global dysrhythmia of cerebro-basal ganglia-cerebellar networks underlies motor tics following striatal disinhibition.

PubMed

McCairn, Kevin W; Iriki, Atsushi; Isoda, Masaki

2013-01-09

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.

The effect, moderators, and mediators of resistance and aerobic exercise on health-related quality of life in older long-term survivors of prostate cancer.

PubMed

Buffart, Laurien M; Newton, Robert U; Chinapaw, Mai J; Taaffe, Dennis R; Spry, Nigel A; Denham, James W; Joseph, David J; Lamb, David S; Brug, Johannes; Galvão, Daniel A

2015-08-15

The current study examined effects, moderators (for whom), and mediators (working mechanisms) of 12 months of exercise on health-related quality of life (HRQoL) in older long-term survivors of prostate cancer. In total, 100 men aged 71.7 years (standard deviation, 6.4 years) were randomly assigned to 6 months of supervised aerobic and resistance exercise followed by 6 months of a home-based exercise maintenance program (EX group) or printed education material regarding physical activity for 12 months (PA group). Assessments took place at baseline and after 6 and 12 months. Generalized estimating equations were used to study the effects of EX versus PA on HRQoL at 6 and 12 months, adjusting for baseline HRQoL. The authors examined potential sociodemographic and clinical moderators by adding interaction terms, and potential physical and psychological mediators using the product-of-coefficients test. At 6 months, significant beneficial effects were found for global QoL, physical function, and social function in the EX group compared with the PA group. For physical function, beneficial effects were sustained at 12 months. Moderation analyses demonstrated larger effects of EX versus PA for patients who were married, started exercising sooner after their diagnosis, and previously used bisphosphonates. Changes in lower body functional performance significantly mediated the effect of EX on global QoL, physical function, and social function. No mediating effects on HRQoL were found for aerobic fitness, physical activity, fatigue, distress, or falls self-efficacy. Aerobic and resistance exercise appears to have beneficial effects on HRQoL among older, long-term survivors of prostate cancer. Effects were moderated by marital status, time since diagnosis, and use of bisphosphonates, and were mediated by lower body functional performance. © 2015 American Cancer Society.

Insulin induces long-term depression of VTA dopamine neurons via an endocannabinoid-mediated mechanism

PubMed Central

Labouèbe, Gwenaël; Liu, Shuai; Dias, Carine; Zou, Haiyan; Wong, Jovi C.Y.; Karunakaran, Subashini; Clee, Susanne M.; Phillips, Anthony; Boutrel, Benjamin; Borgland, Stephanie L.

2014-01-01

The prevalence of obesity has drastically increased over the last few decades. Exploration into how hunger and satiety signals influence the reward system can help us to understand non-homeostatic mechanisms of feeding. Evidence suggests that insulin may act in the ventral tegmental area (VTA), a critical site for reward-seeking behavior, to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA remain unknown. We demonstrate that insulin, a circulating catabolic peptide that inhibits feeding, can induce a long-term depression (LTD) of excitatory synapses onto VTA dopamine neurons. This effect requires endocannabinoid-mediated presynaptic inhibition of glutamate release. Furthermore, after a sweetened high fat meal, which elevates endogenous insulin levels, insulin-induced LTD is occluded. Finally, insulin in the VTA reduces food anticipatory behavior and conditioned place preference for food. Taken together, these results suggest that insulin in the VTA suppresses excitatory synaptic transmission and reduces salience of food-related cues. PMID:23354329

Long-Term Effects of a Universal Family Intervention: Mediation Through Parent-Adolescent Conflict

PubMed Central

Jensen, M.; Wong, J.J.; Gonzales, N.A.; Dumka, L.E.; Millsap, R.; Coxe, S.

2014-01-01

Objective This randomized trial of a family-focused preventive intervention for Mexican American middle schoolers examined internalizing, externalizing, and substance use outcomes in late adolescence, five years after completing the intervention. Parent-adolescent conflict was tested as a mediator of these effects. The role of parent and adolescent acculturation in these pathways was also examined. Method 498 7th grade adolescents and their primary female caregivers were randomized to receive either a 9-week, multi-component intervention or a brief workshop control group. Assessments were conducted at pre-test, two year follow-up (9th grade), and five year follow-up (when most participants were in the 12th grade). Results The Bridges program significantly reduced mother-adolescent conflict measured in the 9th grade, with conflict mediating program effects on internalizing and externalizing symptoms, adolescent substance use, and diagnosed internalizing disorder in late adolescence. Mother and child acculturation were both significantly predictive of late adolescence outcomes. Contrary to hypotheses, neither mother nor child acculturation emerged as a significant predictor of mother-adolescent conflict, and the interaction of mother and adolescent acculturation was similarly not related to mother-adolescent conflict. Intervention effects were largely consistent across different levels of acculturation. Conclusions These findings provide support for the efficacy of family-focused intervention during early adolescence, both in reducing mental health problems and substance use in the long term, as well as in impacting parent-adolescent conflict processes that appear to play an important role in the development of later adjustment problems. PMID:24730357

Promoting Motor Cortical Plasticity with Acute Aerobic Exercise: A Role for Cerebellar Circuits

PubMed Central

Mang, Cameron S.; Brown, Katlyn E.; Neva, Jason L.; Snow, Nicholas J.; Campbell, Kristin L.; Boyd, Lara A.

2016-01-01

Acute aerobic exercise facilitated long-term potentiation-like plasticity in the human primary motor cortex (M1). Here, we investigated the effect of acute aerobic exercise on cerebellar circuits, and their potential contribution to altered M1 plasticity in healthy individuals (age: 24.8 ± 4.1 years). In Experiment   1, acute aerobic exercise reduced cerebellar inhibition (CBI) (n = 10, p = 0.01), elicited by dual-coil paired-pulse transcranial magnetic stimulation. In Experiment   2, we evaluated the facilitatory effects of aerobic exercise on responses to paired associative stimulation, delivered with a 25 ms (PAS25) or 21 ms (PAS21) interstimulus interval (n = 16 per group). Increased M1 excitability evoked by PAS25, but not PAS21, relies on trans-cerebellar sensory pathways. The magnitude of the aerobic exercise effect on PAS response was not significantly different between PAS protocols (interaction effect: p = 0.30); however, planned comparisons indicated that, relative to a period of rest, acute aerobic exercise enhanced the excitatory response to PAS25 (p = 0.02), but not PAS21 (p = 0.30). Thus, the results of these planned comparisons indirectly provide modest evidence that modulation of cerebellar circuits may contribute to exercise-induced increases in M1 plasticity. The findings have implications for developing aerobic exercise strategies to “prime” M1 plasticity for enhanced motor skill learning in applied settings. PMID:27127659

NPY-Induced Phase Shifts of PER2::LUC Rhythms are Mediated by Long-Term Suppression of Neuronal Excitability in a Phase-Specific Manner

PubMed Central

Besing, Rachel C.; Hablitz, Lauren M.; Paul, Jodi R.; Johnson, Russell L.; Prosser, Rebecca A.; Gamble, Karen L.

2013-01-01

Endogenous circadian rhythms are entrained to the 24-h light/dark cycle by both light and nonphotic stimuli. During the day, nonphotic stimuli, such as novel-wheel induced exercise, produce large phase advances. Neuropeptide Y (NPY) release from the thalamus onto suprachiasmatic nucleus (SCN) neurons at least partially mediates this nonphotic signal. We examined the hypothesis that NPY-induced phase advances are accompanied by suppression of PER2 and are mediated by long-term depression of neuronal excitability in a phase-specific manner. First, we found that NPY-induced phase advances in PER2::LUC SCN cultures are largest when NPY (2.35 µM) is given in the early part of the day (circadian time [CT] 0–6). In addition, PER2::LUC levels in NPY-treated (compared to vehicle-treated) samples were suppressed beginning 6–7 h after treatment. Similar NPY application to organotypic Per1::GFP SCN cultures resulted in long-term suppression of spike rate of GFP+ cells when slices were treated with NPY during the early or middle of the day (zeitgeber time [ZT] 2 or 6), but not during the late day (ZT 10). Furthermore, 1-h bath application of NPY to acute SCN brain slices decreased general neuronal activity measured through extracellular recordings. Finally, NPY-induced phase advances of PER2::LUC rhythms were blocked by latent depolarization with 34.5 mM [K+] 3 h after NPY application. These results suggest that NPY-induced phase advances may be mediated by long-term depression of neuronal excitability. This model is consistent with findings in other brain regions that NPY-induced persistent hyperpolarization underlies mechanisms of energy homeostasis, anxiety-related behavior, and thalamocortical synchronous firing. PMID:22324550

Optogenetic fMRI and electrophysiological identification of region-specific connectivity between the cerebellar cortex and forebrain.

PubMed

Choe, Katrina Y; Sanchez, Carlos F; Harris, Neil G; Otis, Thomas S; Mathews, Paul J

2018-06-01

Complex animal behavior is produced by dynamic interactions between discrete regions of the brain. As such, defining functional connections between brain regions is critical in gaining a full understanding of how the brain generates behavior. Evidence suggests that discrete regions of the cerebellar cortex functionally project to the forebrain, mediating long-range communication potentially important in motor and non-motor behaviors. However, the connectivity map remains largely incomplete owing to the challenge of driving both reliable and selective output from the cerebellar cortex, as well as the need for methods to detect region specific activation across the entire forebrain. Here we utilize a paired optogenetic and fMRI (ofMRI) approach to elucidate the downstream forebrain regions modulated by activating a region of the cerebellum that induces stereotypical, ipsilateral forelimb movements. We demonstrate with ofMRI, that activating this forelimb motor region of the cerebellar cortex results in functional activation of a variety of forebrain and midbrain areas of the brain, including the hippocampus and primary motor, retrosplenial and anterior cingulate cortices. We further validate these findings using optogenetic stimulation paired with multi-electrode array recordings and post-hoc staining for molecular markers of activated neurons (i.e. c-Fos). Together, these findings demonstrate that a single discrete region of the cerebellar cortex is capable of influencing motor output and the activity of a number of downstream forebrain as well as midbrain regions thought to be involved in different aspects of behavior. Copyright © 2018 Elsevier Inc. All rights reserved.

Questioning the cerebellar doctrine.

PubMed

Galliano, Elisa; De Zeeuw, Chris I

2014-01-01

The basic principles of cerebellar function were originally described by Flourens, Cajal, and Marr/Albus/Ito, and they constitute the pillars of what can be considered to be the classic cerebellar doctrine. In their concepts, the main cerebellar function is to control motor behavior, Purkinje cells are the only cortical neuron receiving and integrating inputs from climbing fiber and mossy-parallel fiber pathways, and plastic modification at the parallel fiber synapses onto Purkinje cells constitutes the substrate of motor learning. Yet, because of recent technical advances and new angles of investigation, all pillars of the cerebellar doctrine now face regular re-examination. In this review, after summarizing the classic concepts and recent disputes, we attempt to synthesize an integrated view and propose a revisited version of the cerebellar doctrine. © 2014 Elsevier B.V. All rights reserved.

Neurogranin restores amyloid β-mediated synaptic transmission and long-term potentiation deficits.

PubMed

Kaleka, Kanwardeep Singh; Gerges, Nashaat Z

2016-03-01

Amyloid β (Aβ) is widely considered one of the early causes of cognitive deficits observed in Alzheimer's disease. Many of the deficits caused by Aβ are attributed to its disruption of synaptic function represented by its blockade of long-term potentiation (LTP) and its induction of synaptic depression. Identifying pathways that reverse these synaptic deficits may open the door to new therapeutic targets. In this study, we explored the possibility that Neurogranin (Ng)-a postsynaptic calmodulin (CaM) targeting protein that enhances synaptic function-may rescue Aβ-mediated deficits in synaptic function. Our results show that Ng is able to reverse synaptic depression and LTP deficits induced by Aβ. Furthermore, Ng's restoration of synaptic transmission is through the insertion of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs). These restorative effects of Ng are dependent on the interaction of Ng and CaM and CaM-dependent activation of CaMKII. Overall, this study identifies a novel mechanism to rescue synaptic deficits induced by Aβ oligomers. It also suggests Ng and CaM signaling as potential therapeutic targets for Alzheimer's disease as well as important tools to further explore the pathophysiology underlying the disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Regular Patterns in Cerebellar Purkinje Cell Simple Spike Trains

PubMed Central

Shin, Soon-Lim; Hoebeek, Freek E.; Schonewille, Martijn; De Zeeuw, Chris I.; Aertsen, Ad; De Schutter, Erik

2007-01-01

Background Cerebellar Purkinje cells (PC) in vivo are commonly reported to generate irregular spike trains, documented by high coefficients of variation of interspike-intervals (ISI). In strong contrast, they fire very regularly in the in vitro slice preparation. We studied the nature of this difference in firing properties by focusing on short-term variability and its dependence on behavioral state. Methodology/Principal Findings Using an analysis based on CV2 values, we could isolate precise regular spiking patterns, lasting up to hundreds of milliseconds, in PC simple spike trains recorded in both anesthetized and awake rodents. Regular spike patterns, defined by low variability of successive ISIs, comprised over half of the spikes, showed a wide range of mean ISIs, and were affected by behavioral state and tactile stimulation. Interestingly, regular patterns often coincided in nearby Purkinje cells without precise synchronization of individual spikes. Regular patterns exclusively appeared during the up state of the PC membrane potential, while single ISIs occurred both during up and down states. Possible functional consequences of regular spike patterns were investigated by modeling the synaptic conductance in neurons of the deep cerebellar nuclei (DCN). Simulations showed that these regular patterns caused epochs of relatively constant synaptic conductance in DCN neurons. Conclusions/Significance Our findings indicate that the apparent irregularity in cerebellar PC simple spike trains in vivo is most likely caused by mixing of different regular spike patterns, separated by single long intervals, over time. We propose that PCs may signal information, at least in part, in regular spike patterns to downstream DCN neurons. PMID:17534435

Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants exposed to morphine

PubMed Central

Zwicker, Jill G; Miller, Steven P; Grunau, Ruth E; Chau, Vann; Brant, Rollin; Studholme, Colin; Liu, Mengyuan; Synnes, Anne; Poskitt, Kenneth J; Stiver, Mikaela L; Tam, Emily WY

2017-01-01

Objective To examine the relationship between morphine exposure and growth of the cerebellum and cerebrum in very preterm neonates from early in life to term-equivalent age, as well as to examine morphine exposure and brain volumes in relation to neurodevelopmental outcomes at 18 months corrected age (CA). Study design A prospective cohort of 136 very preterm neonates (24–32 weeks gestational age) was serially scanned with MRI near birth and at term-equivalent age for volumetric measurements of the cerebellum and cerebrum. Motor outcomes were assessed with the Peabody Scales of Motor Development-2 and cognitive outcomes with the Bayley-III at 18 months CA. Generalized least squares models and linear regression models were used to assess relationships between morphine exposure, brain volumes, and neurodevelopmental outcomes. Results A 10-fold increase in morphine exposure was associated with a 5.5% decrease in cerebellar volume, after adjustment for multiple clinical confounders and total brain volume (P=0.04). When infants exposed to glucocorticoids were excluded, the association of morphine was more pronounced, with an 8.2% decrease in cerebellar volume. Morphine exposure was not associated with cerebral volume (P=0.30). Greater morphine exposure also predicted poorer motor (P<0.001) and cognitive outcomes (P=0.006) at 18 months CA, an association mediated, in part, by slower brain growth. Conclusions Morphine exposure in very preterm neonates is independently associated with impaired cerebellar growth in the neonatal period and poorer neurodevelopmental outcomes in early childhood. Alternatives to better manage pain in preterm neonates that optimize brain development and functional outcomes are urgently needed. PMID:26763312

Differential Effects of Intraventricular Hemorrhage and White Matter Injury on Preterm Cerebellar Growth

PubMed Central

Tam, Emily W.Y.; Miller, Steven P.; Studholme, Colin; Chau, Vann; Glidden, David; Poskitt, Kenneth J.; Ferriero, Donna M.; Barkovich, A. James

2010-01-01

Objective To hypothesize that detailed examination of early cerebellar volumes over time would distinguish differences in cerebellar growth associated with intraventricular hemorrhage (IVH) and white matter injury (WMI) in preterm infants. Study design Preterm newborns at the University of California San Francisco (n=57) and the University of British Columbia (n=115) were studied using serial MRI scans near birth and again at near term-equivalent age. Interactive semi-automated tools were used to determine volumes of the cerebellar hemispheres. Results Adjusting for supratentorial brain injury, cerebellar hemorrhage, and study site, cerebellar volume increased 1.7cm3/week postmenstrual age (95% CI 1.6–1.7, P<0.001). More severe supratentorial IVH was associated with slower growth of cerebellar volumes (P<0.001). Volumes by 40 weeks were 1.4 cm3 lower in premature infants with grade 1–2 IVH and 5.4 cm3 lower with grade 3–4 IVH. The same magnitude of decrease was found between ipsilateral and contralateral IVH. No association was found with severity of WMI (P=0.3). Conclusions Early effects of decreased cerebellar volume associated with supratentorial IVH in either hemisphere may be a result of concurrent cerebellar injury or direct effects of subarachnoid blood on cerebellar development. PMID:20961562

Transplantation of cerebellar neural stem cells improves motor coordination and neuropathology in Machado-Joseph disease mice.

PubMed

Mendonça, Liliana S; Nóbrega, Clévio; Hirai, Hirokazu; Kaspar, Brian K; Pereira de Almeida, Luís

2015-02-01

Machado-Joseph disease is a neurodegenerative disease without effective treatment. Patients with Machado-Joseph disease exhibit significant motor impairments such as gait ataxia, associated with multiple neuropathological changes including mutant ATXN3 inclusions, marked neuronal loss and atrophy of the cerebellum. Thus, an effective treatment of symptomatic patients with Machado-Joseph disease may require cell replacement, which we investigated in this study. For this purpose, we injected cerebellar neural stem cells into the cerebellum of adult Machado-Joseph disease transgenic mice and assessed the effect on the neuropathology, neuroinflammation mediators and neurotrophic factor levels and motor coordination. We found that upon transplantation into the cerebellum of adult Machado-Joseph disease mice, cerebellar neural stem cells differentiate into neurons, astrocytes and oligodendrocytes. Importantly, cerebellar neural stem cell transplantation mediated a significant and robust alleviation of the motor behaviour impairments, which correlated with preservation from Machado-Joseph disease-associated neuropathology, namely reduction of Purkinje cell loss, reduction of cellular layer shrinkage and mutant ATXN3 aggregates. Additionally, a significant reduction of neuroinflammation and an increase of neurotrophic factors levels was observed, indicating that transplantation of cerebellar neural stem cells also triggers important neuroprotective effects. Thus, cerebellar neural stem cells have the potential to be used as a cell replacement and neuroprotective approach for Machado-Joseph disease therapy. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Representational Specificity of Within-Category Phonetic Variation in the Long-Term Mental Lexicon

ERIC Educational Resources Information Center

Ju, Min; Luce, Paul A.

2006-01-01

This study examines the potential encoding in long-term memory of subphonemic, within-category variation in voice onset time (VOT) and the degree to which this encoding of subtle variation is mediated by lexical competition. In 4 long-term repetition-priming experiments, magnitude of priming was examined as a function of variation in VOT in words…

High-Frequency Network Oscillations in Cerebellar Cortex

PubMed Central

Middleton, Steven J.; Racca, Claudia; Cunningham, Mark O.; Traub, Roger D.; Monyer, Hannah; Knöpfel, Thomas; Schofield, Ian S.; Jenkins, Alistair; Whittington, Miles A.

2016-01-01

SUMMARY Both cerebellum and neocortex receive input from the somatosensory system. Interaction between these regions has been proposed to underpin the correct selection and execution of motor commands, but it is not clear how such interactions occur. In neocortex, inputs give rise to population rhythms, providing a spatiotemporal coding strategy for inputs and consequent outputs. Here, we show that similar patterns of rhythm generation occur in cerebellum during nicotinic receptor subtype activation. Both gamma oscillations (30–80 Hz) and very fast oscillations (VFOs, 80–160 Hz) were generated by intrinsic cerebellar cortical circuitry in the absence of functional glutamatergic connections. As in neocortex, gamma rhythms were dependent on GABAA receptor-mediated inhibition, whereas VFOs required only nonsynaptically connected intercellular networks. The ability of cerebellar cortex to generate population rhythms within the same frequency bands as neocortex suggests that they act as a common spatiotemporal code within which corticocerebellar dialog may occur. PMID:18549787

Cerebro-Cerebellar Functional Connectivity is Associated with Cerebellar Excitation-Inhibition Balance in Autism Spectrum Disorder.

PubMed

Hegarty, John P; Weber, Dylan J; Cirstea, Carmen M; Beversdorf, David Q

2018-05-23

Atypical functional connectivity (FC) and an imbalance of excitation-to-inhibition (E/I) have been previously reported in cerebro-cerebellar circuits in autism spectrum disorder (ASD). The current investigation used resting state fMRI and proton magnetic resonance spectroscopy ( 1 H-MRS) to examine the relationships between E/I (glutamate + glutamine/GABA) and FC of the dorsolateral prefrontal cortex and posterolateral cerebellar hemisphere from 14 adolescents/adults with ASD and 12 age/sex/IQ-matched controls. In this pilot sample, cerebro-cerebellar FC was positively associated with cerebellar E/I and listening comprehension abilities in individuals with ASD but not controls. Additionally, a subgroup of individuals with ASD and low FC (n = 5) exhibited reduced E/I and impaired listening comprehension. Thus, altered functional coherence of cerebro-cerebellar circuits in ASD may be related with a cerebellar E/I imbalance.

'Distributed health literacy': longitudinal qualitative analysis of the roles of health literacy mediators and social networks of people living with a long-term health condition.

PubMed

Edwards, Michelle; Wood, Fiona; Davies, Myfanwy; Edwards, Adrian

2015-10-01

The role of one's social network in the process of becoming health literate is not well understood. We aim to explain the 'distributed' nature of health literacy and how people living with a long-term condition draw on their social network for support with health literacy-related tasks such as managing their condition, interacting with health professionals and making decisions about their health. This paper reports a longitudinal qualitative interview and observation study of the development and practice of health literacy in people with long-term health conditions, living in South Wales, UK. Participants were recruited from health education groups (n = 14) and community education venues (n = 4). The 44 interview transcripts were analysed using the 'Framework' approach. Health literacy was distributed through family and social networks, and participants often drew on the health literacy skills of others to seek, understand and use health information. Those who passed on their health literacy skills acted as health literacy mediators and supported participants in becoming more health literate about their condition. The distribution of health literacy supported participants to manage their health, become more active in health-care decision-making processes, communicate with health professionals and come to terms with living with a long-term condition. Participants accessed health literacy mediators through personal and community networks. Distributed health literacy is a potential resource for managing one's health, communicating with health professionals and making health decisions. © 2013 John Wiley & Sons Ltd.

Concept Formation Skills in Long-Term Cochlear Implant Users

ERIC Educational Resources Information Center

Castellanos, Irina; Kronenberger, William G.; Beer, Jessica; Colson, Bethany G.; Henning, Shirley C.; Ditmars, Allison; Pisoni, David B.

2015-01-01

This study investigated if a period of auditory sensory deprivation followed by degraded auditory input and related language delays affects visual concept formation skills in long-term prelingually deaf cochlear implant (CI) users. We also examined if concept formation skills are mediated or moderated by other neurocognitive domains (i.e.,…

Conversion of short-term to long-term memory in the novel object recognition paradigm.

PubMed

Moore, Shannon J; Deshpande, Kaivalya; Stinnett, Gwen S; Seasholtz, Audrey F; Murphy, Geoffrey G

2013-10-01

It is well-known that stress can significantly impact learning; however, whether this effect facilitates or impairs the resultant memory depends on the characteristics of the stressor. Investigation of these dynamics can be confounded by the role of the stressor in motivating performance in a task. Positing a cohesive model of the effect of stress on learning and memory necessitates elucidating the consequences of stressful stimuli independently from task-specific functions. Therefore, the goal of this study was to examine the effect of manipulating a task-independent stressor (elevated light level) on short-term and long-term memory in the novel object recognition paradigm. Short-term memory was elicited in both low light and high light conditions, but long-term memory specifically required high light conditions during the acquisition phase (familiarization trial) and was independent of the light level during retrieval (test trial). Additionally, long-term memory appeared to be independent of stress-mediated glucocorticoid release, as both low and high light produced similar levels of plasma corticosterone, which further did not correlate with subsequent memory performance. Finally, both short-term and long-term memory showed no savings between repeated experiments suggesting that this novel object recognition paradigm may be useful for longitudinal studies, particularly when investigating treatments to stabilize or enhance weak memories in neurodegenerative diseases or during age-related cognitive decline. Copyright © 2013 Elsevier Inc. All rights reserved.

Conversion of short-term to long-term memory in the novel object recognition paradigm

PubMed Central

Moore, Shannon J.; Deshpande, Kaivalya; Stinnett, Gwen S.; Seasholtz, Audrey F.; Murphy, Geoffrey G.

2013-01-01

It is well-known that stress can significantly impact learning; however, whether this effect facilitates or impairs the resultant memory depends on the characteristics of the stressor. Investigation of these dynamics can be confounded by the role of the stressor in motivating performance in a task. Positing a cohesive model of the effect of stress on learning and memory necessitates elucidating the consequences of stressful stimuli independently from task-specific functions. Therefore, the goal of this study was to examine the effect of manipulating a task-independent stressor (elevated light level) on short-term and long-term memory in the novel object recognition paradigm. Short-term memory was elicited in both low light and high light conditions, but long-term memory specifically required high light conditions during the acquisition phase (familiarization trial) and was independent of the light level during retrieval (test trial). Additionally, long-term memory appeared to be independent of stress-mediated glucocorticoid release, as both low and high light produced similar levels of plasma corticosterone, which further did not correlate with subsequent memory performance. Finally, both short-term and long-term memory showed no savings between repeated experiments suggesting that this novel object recognition paradigm may be useful for longitudinal studies, particularly when investigating treatments to stabilize or enhance weak memories in neurodegenerative diseases or during age-related cognitive decline. PMID:23835143

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.

Out of Place: Mediating Health and Social Care in Ontario's Long-Term Care Sector

ERIC Educational Resources Information Center

Daly, Tamara

2007-01-01

The paper discusses two reforms in Ontario's long-term care. The first is the commercialization of home care as a result of the implementation of a "managed competition" delivery model. The second is the Ministry of Health and Long-Term Care's privileging of "health care" over "social care" through changes to which…

Long-term consequences of adolescent cannabis use: Examining intermediary processes.

PubMed

Green, Kerry M; Doherty, Elaine E; Ensminger, Margaret E

2017-09-01

In the United States, perceptions of marijuana's acceptability are at an all-time high, risk perceptions among youth are low, and rates are rising among Black youth. Thus, it is imperative to increase the understanding of long-term effects of adolescent marijuana use and ways to mitigate adverse consequences. To identify the midlife consequences of heavy adolescent marijuana use and the mechanisms driving effects among a Black, urban population. This study analyzed the propensity score-matched prospective data from the Woodlawn Study, a community cohort study of urban Black youth followed from ages 6-42. After matching the 165 adolescents who used marijuana heavily to 165 non-heavy/nonusers on background confounders to reduce selection effects (64.5% male), we tested the association of heavy marijuana use by age 16 with social, economic, and physical and psychological health outcomes in midlife and the ability of adult drug trajectories (marijuana, cocaine, and heroin use from ages 17-42) and school dropout to mediate effects. Heavy adolescent marijuana use was associated with an increased risk of being poor and of being unmarried in midlife. Marijuana use also predicted lower income and greater anxious mood in midlife. Both adult drug use trajectories and school dropout significantly mediated socioeconomic effects but not marital or anxious mood outcomes. Heavy adolescent marijuana use seems to set Black, urban youth on a long-term trajectory of disadvantage that persists into midlife. It is critical to interrupt this long-term disadvantage through the prevention of heavy adolescent marijuana use, long-term marijuana and other drug use, and school dropout.

Dandy-Walker Variant with Schizophrenia: Comorbidity or Cerebellar Cognitive Affective Syndrome?

PubMed

Sinha, Pallavi; Tarwani, Jatin; Kumar, Pankaj; Garg, Amit

2017-01-01

Dandy-Walker complex (DWC) is a series of neurodevelopmental anomalies involving the posterior cranial fossa. The cerebellum has long been considered to be involved in motor coordination and balance. However, it has now been noted to play an important role in higher order cognitive, emotional, and behavioral functions. The concept of cerebellar cognitive affective syndrome, describing a coherent spectrum of cognitive and behavioral disturbances in adults following cerebellar damage has long been proposed. There have been reported cases of co-occurring psychiatric symptoms and DWC in literature, but the conclusive evidence for an association between the same remains lacking. Herein, we report a case of schizophrenia presenting along with Dandy-Walker Variant.

Dandy–Walker Variant with Schizophrenia: Comorbidity or Cerebellar Cognitive Affective Syndrome?

PubMed Central

Sinha, Pallavi; Tarwani, Jatin; Kumar, Pankaj; Garg, Amit

2017-01-01

Dandy–Walker complex (DWC) is a series of neurodevelopmental anomalies involving the posterior cranial fossa. The cerebellum has long been considered to be involved in motor coordination and balance. However, it has now been noted to play an important role in higher order cognitive, emotional, and behavioral functions. The concept of cerebellar cognitive affective syndrome, describing a coherent spectrum of cognitive and behavioral disturbances in adults following cerebellar damage has long been proposed. There have been reported cases of co-occurring psychiatric symptoms and DWC in literature, but the conclusive evidence for an association between the same remains lacking. Herein, we report a case of schizophrenia presenting along with Dandy–Walker Variant. PMID:28515557

A novel model for studies of blood-mediated long-term responses to cellular transplants

PubMed Central

Lindblom, Susanne; Hong, Jaan; Nilsson, Bo; Korsgren, Olle; Ronquist, Gunnar

2015-01-01

Aims Interaction between blood and bio-surfaces is important in many medical fields. With the aim of studying blood-mediated reactions to cellular transplants, we developed a whole-blood model for incubation of small volumes for up to 48 h. Methods Heparinized polyvinyl chloride tubing was cut in suitable lengths and sealed to create small bags. Multiple bags, with fresh venous blood, were incubated attached to a rotating wheel at 37°C. Physiological variables in blood were monitored: glucose, blood gases, mono- and divalent cations and chloride ions, osmolality, coagulation (platelet consumption, thrombin-antithrombin complexes (TAT)), and complement activation (C3a and SC5b-9), haemolysis, and leukocyte viability. Results Basic glucose consumption was high. Glucose depletion resulted in successive elevation of extracellular potassium, while sodium and calcium ions decreased due to inhibition of energy-requiring ion pumps. Addition of glucose improved ion balance but led to metabolic acidosis. To maintain a balanced physiological environment beyond 6 h, glucose and sodium hydrogen carbonate were added regularly based on analyses of glucose, pH, ions, and osmotic pressure. With these additives haemolysis was prevented for up to 72 h and leukocyte viability better preserved. Despite using non-heparinized blood, coagulation and complement activation were lower during long-term incubations compared with addition of thromboplastin and collagen. Conclusion A novel whole-blood model for studies of blood-mediated responses to a cellular transplant is presented allowing extended observations for up to 48 h and highlights the importance of stringent evaluations and adjustment of physiological conditions. PMID:25322825

Protein kinase M ζ and the maintenance of long-term memory.

PubMed

Zhang, Yang; Zong, Wei; Zhang, Lei; Ma, Yuanye; Wang, Jianhong

2016-10-01

Although various molecules have been found to mediate the processes of memory acquisition and consolidation, the molecular mechanism to maintain memory still remains elusive. In recent years, a molecular pathway focusing on protein kinase Mζ (PKMζ) has become of interest to researchers because of its potential role in long-term memory maintenance. PKMζ is an isoform of protein kinase C (PKC) and has a related structure that influences its function in maintaining memory. Considerable evidence has been gathered on PKMζ activity, including loss of function studies using PKMζ inhibitors, such as PKMζ inhibitory peptide (ZIP), suggesting PKMζ plays an important role in long-term memory maintenance. This review provides an overview of the role of PKMζ in long-term memory and outlines the molecular structure of PKMζ, the molecular mechanism of PKMζ in long-term memory maintenance and future directions of PKMζ research. Copyright © 2016 Elsevier Ltd. All rights reserved.

Resting State Synchrony in Long-Term Abstinent Alcoholics

PubMed Central

Camchong, Jazmin; Stenger, Andy; Fein, George

2012-01-01

BACKGROUND Alcohol dependence (ALC) is a disorder with an impulsive and compulsive “drive” towards alcohol consumption and an inability to inhibit alcohol consumption. Neuroimaging studies suggest that these behavioral components correspond to an increased involvement of regions that mediate appetitive drive and reduced involvement of regions that mediate executive control within top-down networks. Little is known, however, about whether these characteristics are present after long periods of abstinence. METHODS Resting state functional magnetic resonance imaging data were collected to examine resting state synchrony (RSS) differences between 23 long-term abstinent alcoholics (LTAA; 8 females, age: M=48.46, SD=7.10), and 23 non-substance abusing controls (NSAC; 8 females, age: M=47.99, SD=6.70). Using seed-based measures, we examined resting-state synchrony with the nucleus accumbens (NAcc) and the subgenual anterior cingulate cortex (ACC). All participants were assessed with the intra/extradimensional set shift task outside of the scanner to explore the relationship between RSS and cognitive flexibility. RESULTS Compared to NSAC, LTAA showed (a) decreased synchrony of limbic reward regions (e.g., caudate and thalamus) with both the ACC seed and the NAcc seed and (b) increased synchrony of executive control regions (e.g., DLPFC) with both the NAcc seed and the subgenual ACC seed. RSS differences were significantly correlated with task performance. CONCLUSIONS The results are consistent with an interpretation of an ongoing compensatory mechanism in long-term abstinent alcoholics evident during rest, in which decision making networks show reduced synchrony with appetitive drive regions and increased synchrony with inhibitory control regions. In addition, RSS differences were associated with cognitive flexibility. These resting state findings indicate an adaptive mechanism present in long-term abstinence that may facilitate the behavioral control required for to

Cerebellar abiotrophy in a miniature schnauzer.

PubMed

Berry, Michelle L; Blas-Machado, Uriel

2003-08-01

A 3.5-month-old miniature schnauzer was presented for signs of progressive cerebellar ataxia. Necropsy revealed cerebellar abiotrophy. This is the first reported case of cerebellar abiotrophy in a purebred miniature schnauzer.

Neurological signs in 23 dogs with suspected rostral cerebellar ischaemic stroke.

PubMed

Thomsen, Barbara; Garosi, Laurent; Skerritt, Geoff; Rusbridge, Clare; Sparrow, Tim; Berendt, Mette; Gredal, Hanne

2016-06-07

In dogs with ischaemic stroke, a very common site of infarction is the cerebellum. The aim of this study was to characterise neurological signs in relation to infarct topography in dogs with suspected cerebellar ischaemic stroke and to report short-term outcome confined to the hospitalisation period. A retrospective multicentre study of dogs with suspected cerebellar ischaemic stroke examined from 2010-2015 at five veterinary referral hospitals was performed. Findings from clinical, neurological, and paraclinical investigations including magnetic resonance imaging were assessed. Twenty-three dogs, 13 females and 10 males with a median age of 8 years and 8 months, were included in the study. The Cavalier King Charles Spaniel (n = 9) was a commonly represented breed. All ischaemic strokes were located to the vascular territory of the rostral cerebellar artery including four extensive and 19 limited occlusions. The most prominent neurological deficits were gait abnormalities (ataxia with hypermetria n = 11, ataxia without hypermetria n = 4, non-ambulatory n = 6), head tilt (n = 13), nystagmus (n = 8), decreased menace response (n = 7), postural reaction deficits (n = 7), and proprioceptive deficits (n = 5). Neurological signs appeared irrespective of the infarct being classified as extensive or limited. All dogs survived and were discharged within 1-10 days of hospitalisation. Dogs affected by rostral cerebellar ischaemic stroke typically present with a collection of neurological deficits characterised by ataxia, head tilt, and nystagmus irrespective of the specific cerebellar infarct topography. In dogs with peracute to acute onset of these neurological deficits, cerebellar ischaemic stroke should be considered an important differential diagnosis, and neuroimaging investigations are indicated. Although dogs are often severely compromised at presentation, short-term prognosis is excellent and rapid clinical improvement may be observed within the

The Histone Deacetylase HDAC4 Regulates Long-Term Memory in Drosophila

PubMed Central

Fitzsimons, Helen L.; Schwartz, Silvia; Given, Fiona M.; Scott, Maxwell J.

2013-01-01

A growing body of research indicates that pharmacological inhibition of histone deacetylases (HDACs) correlates with enhancement of long-term memory and current research is concentrated on determining the roles that individual HDACs play in cognitive function. Here, we investigate the role of HDAC4 in long-term memory formation in Drosophila. We show that overexpression of HDAC4 in the adult mushroom body, an important structure for memory formation, resulted in a specific impairment in long-term courtship memory, but had no affect on short-term memory. Overexpression of an HDAC4 catalytic mutant also abolished LTM, suggesting a mode of action independent of catalytic activity. We found that overexpression of HDAC4 resulted in a redistribution of the transcription factor MEF2 from a relatively uniform distribution through the nucleus into punctate nuclear bodies, where it colocalized with HDAC4. As MEF2 has also been implicated in regulation of long-term memory, these data suggest that the repressive effects of HDAC4 on long-term memory may be through interaction with MEF2. In the same genetic background, we also found that RNAi-mediated knockdown of HDAC4 impairs long-term memory, therefore we demonstrate that HDAC4 is not only a repressor of long-term memory, but also modulates normal memory formation. PMID:24349558

The associations between workplace bullying, salivary cortisol, and long-term sickness absence: a longitudinal study.

PubMed

Grynderup, Matias Brødsgaard; Nabe-Nielsen, Kirsten; Lange, Theis; Conway, Paul Maurice; Bonde, Jens Peter; Garde, Anne Helene; Gullander, Maria; Kaerlev, Linda; Persson, Roger; Rugulies, Reiner; Vammen, Marianne Agergaard; Høgh, Annie; Hansen, Åse Marie

2017-09-16

Workplace stressors, such as bullying, are strongly related to subsequent long-term sickness absence, but little is known of the possible physiological mechanisms linking workplace stressors and sickness absence. The primary aim of this study was to investigate to what extent cortisol levels were associated with subsequent sickness absence and if cortisol mediated the association between workplace bullying and sickness absence. We additionally investigated possible bidirectional associations between bullying, cortisol, and long-term sickness absence. Participants came from two Danish cohort studies, the "Psychosocial RIsk factors for Stress and MEntal disease" (PRISME) cohort and the "Workplace Bullying and Harassment" (WBH) cohort (n = 5418). Information about exposure to workplace bullying and morning and evening salivary cortisol was collected at three time points with approximately two years in between. After each data collection, all participants were followed for two years in registers, and cases with long-term sickness absence lasting 30 or more consecutive days were identified. The association between cortisol levels and subsequent sickness absence was assessed by logistic regression, while the extent to which the association between bullying and sickness absence was mediated by cortisol was quantified through natural direct and indirect effects. High evening cortisol was associated with a decreased risk of sickness absence (OR = 0.82, 95% CI = 0.68-0.99), but we did not find that high morning cortisol levels (OR = 0.98, 95% CI = 0.81-1.18) or high morning-to-evening slope (OR = 0.99, 95% CI = 0.82-1.18) were associated with subsequent sickness absence. We also tested for reverse causation and found that long-term sickness absence, but not salivary cortisol, was a strong risk factor for subsequent workplace bullying. There was no indication that cortisol mediated the association between workplace bullying and sickness absence. We found no

Cerebellar abiotrophy in a miniature schnauzer

PubMed Central

Berry, Michelle L.; Blas-Machado, Uriel

2003-01-01

A 3.5-month-old miniature schnauzer was presented for signs of progressive cerebellar ataxia. Necropsy revealed cerebellar abiotrophy. This is the first reported case of cerebellar abiotrophy in a purebred miniature schnauzer. PMID:13677598

Avoidant coping and self-efficacy mediate relationships between perceived social constraints and symptoms among long-term breast cancer survivors.

PubMed

Adams, Rebecca N; Mosher, Catherine E; Cohee, Andrea A; Stump, Timothy E; Monahan, Patrick O; Sledge, George W; Cella, David; Champion, Victoria L

2017-07-01

Many breast cancer survivors feel constrained in discussing their cancer experience with others. Limited evidence suggests that social constraints (e.g., avoidance and criticism) from loved ones may negatively impact breast cancer survivors' global health, but research has yet to examine relationships between social constraints and common physical symptoms. Informed by social cognitive processing theory, this study examined whether perceived social constraints from partners and healthcare providers (HCPs) were associated with fatigue, sleep disturbance, and attentional functioning among long-term breast cancer survivors (N = 1052). In addition, avoidant coping and self-efficacy for symptom management were examined as potential mediators of these relationships. Long-term breast cancer survivors (mean years since diagnosis = 6) completed questionnaires assessing social constraints from partners and HCPs, avoidant coping, self-efficacy for symptom management, and symptoms (i.e., fatigue, sleep disturbance, and attentional functioning). Structural equation modeling was used to evaluate the hypothesized relationships among variables in two models: one focused on social constraints from partners and one focused on social constraints from HCPs. Both models demonstrated good fit. Consistent with theory and prior research, greater social constraints from both partners and HCPs were associated with greater symptom burden (i.e., greater fatigue and sleep disturbance, poorer attentional functioning). In addition, all relationships were mediated by avoidant coping and self-efficacy for symptom management. Findings are consistent with social cognitive processing theory and suggest that symptom management interventions may be enhanced by addressing the impact of social constraints from survivors' partners and HCPs on their coping and self-efficacy. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Distributed cerebellar plasticity implements generalized multiple-scale memory components in real-robot sensorimotor tasks.

PubMed

Casellato, Claudia; Antonietti, Alberto; Garrido, Jesus A; Ferrigno, Giancarlo; D'Angelo, Egidio; Pedrocchi, Alessandra

2015-01-01

The cerebellum plays a crucial role in motor learning and it acts as a predictive controller. Modeling it and embedding it into sensorimotor tasks allows us to create functional links between plasticity mechanisms, neural circuits and behavioral learning. Moreover, if applied to real-time control of a neurorobot, the cerebellar model has to deal with a real noisy and changing environment, thus showing its robustness and effectiveness in learning. A biologically inspired cerebellar model with distributed plasticity, both at cortical and nuclear sites, has been used. Two cerebellum-mediated paradigms have been designed: an associative Pavlovian task and a vestibulo-ocular reflex, with multiple sessions of acquisition and extinction and with different stimuli and perturbation patterns. The cerebellar controller succeeded to generate conditioned responses and finely tuned eye movement compensation, thus reproducing human-like behaviors. Through a productive plasticity transfer from cortical to nuclear sites, the distributed cerebellar controller showed in both tasks the capability to optimize learning on multiple time-scales, to store motor memory and to effectively adapt to dynamic ranges of stimuli.

Neurosurgical treatment of low-grade cerebellar astrocytoma in children and adolescents: a single consecutive institutional series of 100 patients.

PubMed

Due-Tønnessen, Bernt Johan; Lundar, Tryggve; Egge, Arild; Scheie, David

2013-03-01

The objective of this study was to delineate the long-term results of surgical treatment of pediatric low-grade cerebellar astrocytoma. One hundred consecutive children and adolescents (0-19 years old) who underwent primary tumor resection for a low-grade cerebellar astrocytoma during the years 1980-2011 were included in this retrospective study on surgical morbidity, mortality rate, academic achievement, and/or work participation. Gross motor function and activities of daily living were scored according to the Barthel Index. Of the 100 patients, 61 children were in the 1st decade, and 39 were 10-19 years old. The male/female ratio was 1.13:1 (53 males, 47 females). No patients were lost to follow-up. There were no deaths in this series and all 100 patients are currently alive. In 29 patients, the follow-up duration was less than 10 years, in 37 it was between 10 and 19 years, and in 34 it was between 20 and 31 years. The Barthel Index was 100 (normal) in 97 patients, 90 in 2 patients, and 40 in the last patient. A total of 113 tumor resections were performed. Two patients underwent further tumor resection due to MRI-confirmed residual tumor demonstrated on the immediate postoperative MR image (obtained the day after the initial procedure). Furthermore, 9 children underwent repeat tumor resection after MRI-confirmed progressive tumor recurrence up to 10 years after the initial operation. Two of these patients also underwent a third resection, without subsequent radiation therapy, and have experienced 8 and 12 years of tumor-free follow-up thereafter, respectively. A total of 15% of the patients required treatment for persistent hydrocephalus. Low-grade cerebellar astrocytoma is a surgical disease, in need of long-term follow-up, but with excellent long-term results. Nine percent of the children in this study underwent repeated surgery due to progressive tumor recurrence, and 15% were treated for persistent hydrocephalus.

Asialofetuin liposome-mediated human alpha1-antitrypsin gene transfer in vivo results in stationary long-term gene expression.

PubMed

Dasí, F; Benet, M; Crespo, J; Crespo, A; Aliño, S F

2001-05-01

The development of nonviral vectors for in vivo gene delivery to hepatocytes is an interesting topic in view of their safety and tremendous gene therapy potential. Since cationic liposomes and liposome uptake by receptor-mediated mechanisms could offer advantages in the efficacy of liposome-mediated gene transfer, we studied the effect of liposome charge (anionic vs. cationic) and the covalently coupled asialofetuin ligand on the liposome surface in mediating human alpha1-antitrypsin (hAAT) gene transfer to mice in vivo. The changes in liposome charge were made by adding the following lipids to the backbone liposomes: anionic phosphatidylserine, cationic N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethyl-ammonium methylsulfate or a lipopeptide synthesized from dipalmitoylphosphatidylethanolamine and covalently coupled to the cationic nuclear localization signal peptide. Two plasmids containing the hAAT gene were used: pTG7101, containing the complete genomic sequence of the human gene driven by the natural promoter, and p216, containing the human hAAT cDNA under the control of the CMV promoter. The results indicate that both untargeted anionic and cationic liposomes mediate plasma levels of hAAT that decline over time. However, asialofetuin liposomes increase the plasma levels of hAAT and can mediate long-term gene expression (>12 months) with stationary plasma levels of protein. Results from quantitative and qualitative reverse transcriptase polymerase chain reaction match those from protein plasma levels and confirm both the human origin of the message and the liver as source of the protein. The use of asialofetuin liposomes in hepatic gene therapy may both increase and prolong in vivo gene expression of hAAT and other clinically important genes.

Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal Morphine.

PubMed

Zwicker, Jill G; Miller, Steven P; Grunau, Ruth E; Chau, Vann; Brant, Rollin; Studholme, Colin; Liu, Mengyuan; Synnes, Anne; Poskitt, Kenneth J; Stiver, Mikaela L; Tam, Emily W Y

2016-05-01

To examine the relationship between morphine exposure and growth of the cerebellum and cerebrum in very preterm neonates from early in life to term-equivalent age, as well as to examine morphine exposure and brain volumes in relation to neurodevelopmental outcomes at 18 months corrected age (CA). A prospective cohort of 136 very preterm neonates (24-32 weeks gestational age) was serially scanned with magnetic resonance imaging near birth and at term-equivalent age for volumetric measurements of the cerebellum and cerebrum. Motor outcomes were assessed with the Peabody Developmental Motor Scales, Second Edition and cognitive outcomes with the Bayley Scales of Infant and Toddler Development, Third Edition at 18 months CA. Generalized least squares models and linear regression models were used to assess relationships between morphine exposure, brain volumes, and neurodevelopmental outcomes. A 10-fold increase in morphine exposure was associated with a 5.5% decrease in cerebellar volume, after adjustment for multiple clinical confounders and total brain volume (P = .04). When infants exposed to glucocorticoids were excluded, the association of morphine was more pronounced, with an 8.1% decrease in cerebellar volume. Morphine exposure was not associated with cerebral volume (P = .30). Greater morphine exposure also predicted poorer motor (P < .001) and cognitive outcomes (P = .006) at 18 months CA, an association mediated, in part, by slower brain growth. Morphine exposure in very preterm neonates is independently associated with impaired cerebellar growth in the neonatal period and poorer neurodevelopmental outcomes in early childhood. Alternatives to better manage pain in preterm neonates that optimize brain development and functional outcomes are urgently needed. Copyright © 2016 Elsevier Inc. All rights reserved.

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

Upregulation of CREB-mediated transcription enhances both short- and long-term memory.

PubMed

Suzuki, Akinobu; Fukushima, Hotaka; Mukawa, Takuya; Toyoda, Hiroki; Wu, Long-Jun; Zhao, Ming-Gao; Xu, Hui; Shang, Yuze; Endoh, Kengo; Iwamoto, Taku; Mamiya, Nori; Okano, Emiko; Hasegawa, Shunsuke; Mercaldo, Valentina; Zhang, Yue; Maeda, Ryouta; Ohta, Miho; Josselyn, Sheena A; Zhuo, Min; Kida, Satoshi

2011-06-15

Unraveling the mechanisms by which the molecular manipulation of genes of interest enhances cognitive function is important to establish genetic therapies for cognitive disorders. Although CREB is thought to positively regulate formation of long-term memory (LTM), gain-of-function effects of CREB remain poorly understood, especially at the behavioral level. To address this, we generated four lines of transgenic mice expressing dominant active CREB mutants (CREB-Y134F or CREB-DIEDML) in the forebrain that exhibited moderate upregulation of CREB activity. These transgenic lines improved not only LTM but also long-lasting long-term potentiation in the CA1 area in the hippocampus. However, we also observed enhanced short-term memory (STM) in contextual fear-conditioning and social recognition tasks. Enhanced LTM and STM could be dissociated behaviorally in these four lines of transgenic mice, suggesting that the underlying mechanism for enhanced STM and LTM are distinct. LTM enhancement seems to be attributable to the improvement of memory consolidation by the upregulation of CREB transcriptional activity, whereas higher basal levels of BDNF, a CREB target gene, predicted enhanced shorter-term memory. The importance of BDNF in STM was verified by microinfusing BDNF or BDNF inhibitors into the hippocampus of wild-type or transgenic mice. Additionally, increasing BDNF further enhanced LTM in one of the lines of transgenic mice that displayed a normal BDNF level but enhanced LTM, suggesting that upregulation of BDNF and CREB activity cooperatively enhances LTM formation. Our findings suggest that CREB positively regulates memory consolidation and affects memory performance by regulating BDNF expression.

Structural Basis of Cerebellar Microcircuits in the Rat

PubMed Central

Cerminara, Nadia L.; Aoki, Hanako; Loft, Michaela; Apps, Richard

2013-01-01

The topography of the cerebellar cortex is described by at least three different maps, with the basic units of each map termed “microzones,” “patches,” and “bands.” These are defined, respectively, by different patterns of climbing fiber input, mossy fiber input, and Purkinje cell (PC) phenotype. Based on embryological development, the “one-map” hypothesis proposes that the basic units of each map align in the adult animal and the aim of the present study was to test this possibility. In barbiturate anesthetized adult rats, nanoinjections of bidirectional tracer (Retrobeads and biotinylated dextran amine) were made into somatotopically identified regions within the hindlimb C1 zone in copula pyramidis. Injection sites were mapped relative to PC bands defined by the molecular marker zebrin II and were correlated with the pattern of retrograde cell labeling within the inferior olive and in the basilar pontine nuclei to determine connectivity of microzones and patches, respectively, and also with the distributions of biotinylated dextran amine-labeled PC terminals in the cerebellar nuclei. Zebrin bands were found to be related to both climbing fiber and mossy fiber inputs and also to cortical representation of different parts of the ipsilateral hindpaw, indicating a precise spatial organization within cerebellar microcircuitry. This precise connectivity extends to PC terminal fields in the cerebellar nuclei and olivonuclear projections. These findings strongly support the one-map hypothesis and suggest that, at the microcircuit level of resolution, the cerebellar cortex has a common plan of spatial organization for major inputs, outputs, and PC phenotype. PMID:24133249

HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses.

PubMed

Pigna, Eva; Renzini, Alessandra; Greco, Emanuela; Simonazzi, Elena; Fulle, Stefania; Mancinelli, Rosa; Moresi, Viviana; Adamo, Sergio

2018-02-24

Denervation triggers numerous molecular responses in skeletal muscle, including the activation of catabolic pathways and oxidative stress, leading to progressive muscle atrophy. Histone deacetylase 4 (HDAC4) mediates skeletal muscle response to denervation, suggesting the use of HDAC inhibitors as a therapeutic approach to neurogenic muscle atrophy. However, the effects of HDAC4 inhibition in skeletal muscle in response to long-term denervation have not been described yet. To further study HDAC4 functions in response to denervation, we analyzed mutant mice in which HDAC4 is specifically deleted in skeletal muscle. After an initial phase of resistance to neurogenic muscle atrophy, skeletal muscle with a deletion of HDAC4 lost structural integrity after 4 weeks of denervation. Deletion of HDAC4 impaired the activation of the ubiquitin-proteasome system, delayed the autophagic response, and dampened the OS response in skeletal muscle. Inhibition of the ubiquitin-proteasome system or the autophagic response, if on the one hand, conferred resistance to neurogenic muscle atrophy; on the other hand, induced loss of muscle integrity and inflammation in mice lacking HDAC4 in skeletal muscle. Moreover, treatment with the antioxidant drug Trolox prevented loss of muscle integrity and inflammation in in mice lacking HDAC4 in skeletal muscle, despite the resistance to neurogenic muscle atrophy. These results reveal new functions of HDAC4 in mediating skeletal muscle response to denervation and lead us to propose the combined use of HDAC inhibitors and antioxidant drugs to treat neurogenic muscle atrophy.

Short-Term and Long-Term Educational Mobility of Families: A Two-Sex Approach.

PubMed

Song, Xi; Mare, Robert D

2017-02-01

We use a multigenerational perspective to investigate how families reproduce and pass their educational advantages to succeeding generations. Unlike traditional mobility studies that have typically focused on one-sex influences from fathers to sons, we rely on a two-sex approach that accounts for interactions between males and females-the process in which males and females mate and have children with those of similar educational statuses and jointly determine the educational status attainment of their offspring. Using data from the Panel Study of Income Dynamics, we approach this issue from both a short-term and a long-term perspective. For the short term, grandparents' educational attainments have a direct association with grandchildren's education as well as an indirect association that is mediated by parents' education and demographic behaviors. For the long term, initial educational advantages of families may benefit as many as three subsequent generations, but such advantages are later offset by the lower fertility of highly educated persons. Yet, all families eventually achieve the same educational distribution of descendants because of intermarriages between families of high- and low-education origin.

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.

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

Long-term consequences of adolescent cannabis use: Examining intermediary processes

PubMed Central

Green, Kerry M.; Doherty, Elaine E.; Ensminger, Margaret E.

2018-01-01

Background In the United States, perceptions of marijuana’s acceptability are at an all-time high, risk perceptions among youth are low, and rates are rising among Black youth. Thus, it is imperative to increase the understanding of long-term effects of adolescent marijuana use and ways to mitigate adverse consequences. Objectives To identify the midlife consequences of heavy adolescent marijuana use and the mechanisms driving effects among a Black, urban population. Methods This study analyzed the propensity score-matched prospective data from the Woodlawn Study, a community cohort study of urban Black youth followed from ages 6–42. After matching the 165 adolescents who used marijuana heavily to 165 non-heavy/nonusers on background confounders to reduce selection effects (64.5% male), we tested the association of heavy marijuana use by age 16 with social, economic, and physical and psychological health outcomes in midlife and the ability of adult drug trajectories (marijuana, cocaine, and heroin use from ages 17–42) and school dropout to mediate effects. Results Heavy adolescent marijuana use was associated with an increased risk of being poor and of being unmarried in midlife. Marijuana use also predicted lower income and greater anxious mood in midlife. Both adult drug use trajectories and school dropout significantly mediated socioeconomic effects but not marital or anxious mood outcomes. Conclusion Heavy adolescent marijuana use seems to set Black, urban youth on a long-term trajectory of disadvantage that persists into midlife. It is critical to interrupt this long-term disadvantage through the prevention of heavy adolescent marijuana use, long-term marijuana and other drug use, and school dropout. PMID:27929672

Modulation of error-sensitivity during a prism adaptation task in people with cerebellar degeneration

PubMed Central

Shadmehr, Reza; Ohminami, Shinya; Tsutsumi, Ryosuke; Shirota, Yuichiro; Shimizu, Takahiro; Tanaka, Nobuyuki; Terao, Yasuo; Tsuji, Shoji; Ugawa, Yoshikazu; Uchimura, Motoaki; Inoue, Masato; Kitazawa, Shigeru

2015-01-01

Cerebellar damage can profoundly impair human motor adaptation. For example, if reaching movements are perturbed abruptly, cerebellar damage impairs the ability to learn from the perturbation-induced errors. Interestingly, if the perturbation is imposed gradually over many trials, people with cerebellar damage may exhibit improved adaptation. However, this result is controversial, since the differential effects of gradual vs. abrupt protocols have not been observed in all studies. To examine this question, we recruited patients with pure cerebellar ataxia due to cerebellar cortical atrophy (n = 13) and asked them to reach to a target while viewing the scene through wedge prisms. The prisms were computer controlled, making it possible to impose the full perturbation abruptly in one trial, or build up the perturbation gradually over many trials. To control visual feedback, we employed shutter glasses that removed visual feedback during the reach, allowing us to measure trial-by-trial learning from error (termed error-sensitivity), and trial-by-trial decay of motor memory (termed forgetting). We found that the patients benefited significantly from the gradual protocol, improving their performance with respect to the abrupt protocol by exhibiting smaller errors during the exposure block, and producing larger aftereffects during the postexposure block. Trial-by-trial analysis suggested that this improvement was due to increased error-sensitivity in the gradual protocol. Therefore, cerebellar patients exhibited an improved ability to learn from error if they experienced those errors gradually. This improvement coincided with increased error-sensitivity and was present in both groups of subjects, suggesting that control of error-sensitivity may be spared despite cerebellar damage. PMID:26311179

Increased cerebellar gray matter volume in head chefs.

PubMed

Cerasa, Antonio; Sarica, Alessia; Martino, Iolanda; Fabbricatore, Carmelo; Tomaiuolo, Francesco; Rocca, Federico; Caracciolo, Manuela; Quattrone, Aldo

2017-01-01

Chefs exert expert motor and cognitive performances on a daily basis. Neuroimaging has clearly shown that that long-term skill learning (i.e., athletes, musicians, chess player or sommeliers) induces plastic changes in the brain thus enabling tasks to be performed faster and more accurately. How a chef's expertise is embodied in a specific neural network has never been investigated. Eleven Italian head chefs with long-term brigade management expertise and 11 demographically-/ psychologically- matched non-experts underwent morphological evaluations. Voxel-based analysis performed with SUIT, as well as, automated volumetric measurement assessed with Freesurfer, revealed increased gray matter volume in the cerebellum in chefs compared to non-experts. The most significant changes were detected in the anterior vermis and the posterior cerebellar lobule. The magnitude of the brigade staff and the higher performance in the Tower of London test correlated with these specific gray matter increases, respectively. We found that chefs are characterized by an anatomical variability involving the cerebellum. This confirms the role of this region in the development of similar expert brains characterized by learning dexterous skills, such as pianists, rock climbers and basketball players. However, the nature of the cellular events underlying the detected morphological differences remains an open question.

Increased cerebellar gray matter volume in head chefs

PubMed Central

Sarica, Alessia; Martino, Iolanda; Fabbricatore, Carmelo; Tomaiuolo, Francesco; Rocca, Federico; Caracciolo, Manuela; Quattrone, Aldo

2017-01-01

Objective Chefs exert expert motor and cognitive performances on a daily basis. Neuroimaging has clearly shown that that long-term skill learning (i.e., athletes, musicians, chess player or sommeliers) induces plastic changes in the brain thus enabling tasks to be performed faster and more accurately. How a chef's expertise is embodied in a specific neural network has never been investigated. Methods Eleven Italian head chefs with long-term brigade management expertise and 11 demographically-/ psychologically- matched non-experts underwent morphological evaluations. Results Voxel-based analysis performed with SUIT, as well as, automated volumetric measurement assessed with Freesurfer, revealed increased gray matter volume in the cerebellum in chefs compared to non-experts. The most significant changes were detected in the anterior vermis and the posterior cerebellar lobule. The magnitude of the brigade staff and the higher performance in the Tower of London test correlated with these specific gray matter increases, respectively. Conclusions We found that chefs are characterized by an anatomical variability involving the cerebellum. This confirms the role of this region in the development of similar expert brains characterized by learning dexterous skills, such as pianists, rock climbers and basketball players. However, the nature of the cellular events underlying the detected morphological differences remains an open question. PMID:28182712

Cerebellar Hypoplasia and Dysmorphia in Neurofibromatosis Type 1.

PubMed

Toelle, Sandra P; Poretti, Andrea; Weber, Peter; Seute, Tatjana; Bromberg, Jacoline E C; Scheer, Ianina; Boltshauser, Eugen

2015-12-01

Unidentified bright objects (UBO) and tumors are well-known cerebellar abnormalities in neurofibromatosis type 1 (NF1). Literature reports on malformative cerebellar anomalies in neurofibromatosis type 1 (NF1), however, are scant. We retrospectively studied the clinical and neuroimaging findings of 5 patients with NF1 (4 females, age 6 to 29 years at last follow-up) and cerebellar anomalies. Cerebellar symptoms on neurological examination were mild or even not evident whereas learning disabilities were more or less pronounced in four patients. Two patients had cerebellar hypoplasia (diffusely enlarged cerebellar interfoliar spaces) and three cerebellar dysmorphias involving mainly one cerebellar hemisphere. In NF1, malformative cerebellar anomalies are rare (estimated prevalence of about 1%), but most likely underestimated and easily overlooked, because physicians tend to focus on more prevalent, obvious, and well-known findings such as optic pathway gliomas, other tumors, and UBO. This kind of cerebellar anomaly in NF1 has most likely a malformative origin, but the exact pathogenesis is unknown. The individual clinical significance is difficult to determine. We suggest that cerebellar anomalies should be systematically evaluated in neuroimaging studies of NF1 patients.

Long-Term Habituation of the C-Start Escape Response in Zebrafish Larvae

PubMed Central

Roberts, Adam C.; Pearce, Kaycey C.; Choe, Ronny C.; Alzagatiti, Joseph B.; Yeung, Anthony K.; Bill, Brent R.; Glanzman, David L.

2016-01-01

The cellular and molecular basis of long-term memory in vertebrates remains poorly understood. Knowledge regarding long-term memory has been impeded by the enormous complexity of the vertebrate brain, particularly the mammalian brain, as well as by the relative complexity of the behavioral alterations examined in most studies of long-term memory in vertebrates. Here, we demonstrate a long-term form of nonassociative learning—specifically, long-term habituation (LTH)—of a simple reflexive escape response, the C-start, in zebrafish larvae. The C-start is triggered by the activation of one of a pair of giant neurons in the zebrafish’s hindbrain, the Mauthner cells. We show that LTH of the C-start requires the activity of NMDA receptors and involves macromolecular synthesis. We further show that the long-term habituated reflex can by rapidly dishabituated by a brief tactile stimulus. Our results set the stage for rigorous, mechanistic investigations of the long-term memory for habituation of a reflexive behavioral response, one that is mediated by a relatively simple, neurobiologically tractable, neural circuit. Moreover, the demonstration of NMDAR and transcriptionally dependent LTH in a translucent vertebrate organism should facilitate the use of optical recording, and optogenetic manipulation, of neuronal activity to elucidate the cellular basis of a long-term vertebrate memory. PMID:27555232

Narp regulates long-term aversive effects of morphine withdrawal

PubMed Central

Reti, Irving M.; Crombag, Hans S.; Takamiya, Kogo; Sutton, Jeffrey M.; Guo, Ning; Dinenna, Megan L.; Huganir, Richard L.; Holland, Peter C.; Baraban, Jay M.

2008-01-01

Although long-lasting effects of drug withdrawal are thought to play a key role in motivating continued drug use, the mechanisms mediating this type of drug-induced plasticity are unclear. As Narp is an immediate early gene product that is secreted at synaptic sites and binds to AMPA receptors, it has been implicated in mediating enduring forms of synaptic plasticity. In previous studies, we found that Narp is selectively induced by morphine withdrawal in the extended amygdala, a group of limbic nuclei that mediate aversive behavioral responses. Accordingly, in this study, we evaluated whether long-term aversive effects of morphine withdrawal are altered in Narp KO mice. We found that acute physical signs of morphine withdrawal are unaffected by Narp deletion. However, Narp KO mice acquire and sustain more aversive responses to the environment conditioned with morphine withdrawal than WT controls. Paradoxically, Narp KO mice undergo accelerated extinction of this heightened aversive response. Taken together, these studies suggest that Narp modulates both acquisition and extinction of aversive responses to morphine withdrawal and, therefore, may regulate plasticity processes underlying drug addiction. PMID:18729628

Bisphenol A influences oestrogen- and thyroid hormone-regulated thyroid hormone receptor expression in rat cerebellar cell culture.

PubMed

Somogyi, Virág; Horváth, Tamás L; Tóth, István; Bartha, Tibor; Frenyó, László Vilmos; Kiss, Dávid Sándor; Jócsák, Gergely; Kerti, Annamária; Naftolin, Frederick; Zsarnovszky, Attila

2016-12-01

Thyroid hormones (THs) and oestrogens are crucial in the regulation of cerebellar development. TH receptors (TRs) mediate these hormone effects and are regulated by both hormone families. We reported earlier that THs and oestradiol (E 2 ) determine TR levels in cerebellar cell culture. Here we demonstrate the effects of low concentrations (10 -10 M) of the endocrine disruptor (ED) bisphenol A (BPA) on the hormonal (THs, E 2 ) regulation of TRα,β in rat cerebellar cell culture. Primary cerebellar cell cultures, glia-containing and glia-destroyed, were treated with BPA or a combination of BPA and E 2 and/or THs. Oestrogen receptor and TH receptor mRNA and protein levels were determined by real-time qPCR and Western blot techniques. The results show that BPA alone decreases, while BPA in combination with THs and/or E 2 increases TR mRNA expression. In contrast, BPA alone increased receptor protein expressions, but did not further increase them in combination with THs and/or E 2 . The modulatory effects of BPA were mediated by the glia; however, the degree of changes also depended on the specific hormone ligand used. The results signify the importance of the regulatory mechanisms interposed between transcription and translation and raise the possibility that BPA could act to influence nuclear hormone receptor levels independently of ligand-receptor interaction.

Cerebellar mutism--report of four cases.

PubMed

Ozimek, A; Richter, S; Hein-Kropp, C; Schoch, B; Gorissen, B; Kaiser, O; Gizewski, E; Ziegler, W; Timmann, D

2004-08-01

The aim of the present study was to investigate the manifestations of mutism after surgery in children with cerebellar tumors. Speech impairment following cerebellar mutism in children was investigated based on standardized acoustic speech parameters and perceptual criteria. Mutistic and non-mutistic children after cerebellar surgery as well as orthopedic controls were tested pre-and postoperatively. Speech impairment was compared with the localization of cerebellar lesions (i. e. affected lobules and nuclei). Whereas both control groups showed no abnormalities in speech and behavior, the mutistic group could be divided into children with dysarthria in post mutistic phase and children with mainly behavioral disturbances. In the mutistic children involvement of dentate and fastigial nuclei tended to be more frequent and extended than in the nonmutistic cerebellar children. Cerebellar mutism is a complex phenomenon of at least two types. Dysarthric symptoms during resolution of mutism support the anarthria hypothesis, while mainly behavioral changes suggest an explanation independent from speech motor control.

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

Cerebellar liponeurocytoma with extracranial extension: case report.

PubMed

Ben Nsir, A; Ben Said, I; Hammami, N; Sebai, R; Jemel, H

2014-01-01

Cerebellar liponeurocytoma is a newly recognized, rare clinicopathological entity commonly described in the cerebellar hemispheres or the vermis. We present a rare case of cerebellar liponeurocytoma arising from the left cerebellar amygdala with extracranial extension. Such a condition has never been previously reported. Copyright © 2014 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

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. Copyright © 2016 Elsevier Inc. All rights reserved.

The cerebellar Golgi cell and spatiotemporal organization of granular layer activity

PubMed Central

D'Angelo, Egidio; Solinas, Sergio; Mapelli, Jonathan; Gandolfi, Daniela; Mapelli, Lisa; Prestori, Francesca

2013-01-01

The cerebellar granular layer has been suggested to perform a complex spatiotemporal reconfiguration of incoming mossy fiber signals. Central to this role is the inhibitory action exerted by Golgi cells over granule cells: Golgi cells inhibit granule cells through both feedforward and feedback inhibitory loops and generate a broad lateral inhibition that extends beyond the afferent synaptic field. This characteristic connectivity has recently been investigated in great detail and been correlated with specific functional properties of these neurons. These include theta-frequency pacemaking, network entrainment into coherent oscillations and phase resetting. Important advances have also been made in terms of determining the membrane and synaptic properties of the neuron, and clarifying the mechanisms of activation by input bursts. Moreover, voltage sensitive dye imaging and multi-electrode array (MEA) recordings, combined with mathematical simulations based on realistic computational models, have improved our understanding of the impact of Golgi cell activity on granular layer circuit computations. These investigations have highlighted the critical role of Golgi cells in: generating dense clusters of granule cell activity organized in center-surround structures, implementing combinatorial operations on multiple mossy fiber inputs, regulating transmission gain, and cut-off frequency, controlling spike timing and burst transmission, and determining the sign, intensity and duration of long-term synaptic plasticity at the mossy fiber-granule cell relay. This review considers recent advances in the field, highlighting the functional implications of Golgi cells for granular layer network computation and indicating new challenges for cerebellar research. PMID:23730271

GluA2-dependent AMPA receptor endocytosis and the decay of early and late long-term potentiation: possible mechanisms for forgetting of short- and long-term memories.

PubMed

Hardt, Oliver; Nader, Karim; Wang, Yu-Tian

2014-01-05

The molecular processes involved in establishing long-term potentiation (LTP) have been characterized well, but the decay of early and late LTP (E-LTP and L-LTP) is poorly understood. We review recent advances in describing the mechanisms involved in maintaining LTP and homeostatic plasticity. We discuss how these phenomena could relate to processes that might underpin the loss of synaptic potentiation over time, and how they might contribute to the forgetting of short-term and long-term memories. We propose that homeostatic downscaling mediates the loss of E-LTP, and that metaplastic parameters determine the decay rate of L-LTP, while both processes require the activity-dependent removal of postsynaptic GluA2-containing AMPA receptors.

Cerebellar syndrome with hydrocephalus due to Mycoplasma pneumoniae infection.

PubMed Central

Coleman, R. J.; Brown, J. S.; Butler, P.; Swash, M.

1990-01-01

A 27 year old woman developed a cerebellar syndrome with serological evidence of recent Mycoplasma pneumoniae infection. The cranial computed tomographic scan showed effacement of the fourth ventricle, enhancement of the basal meninges and hydrocephalus affecting the lateral and third ventricles. Clinical and radiological recovery occurred over 5 weeks. We propose that this was a manifestation of immune-mediated encephalomyelitis induced by the infection rather than direct invasion of the central nervous system. Images Figure 1 PMID:2217014

Histological long-term outcomes from acute antibody-mediated rejection following ABO-compatible liver transplantation.

PubMed

Del Bello, Arnaud; Danjoux, Marie; Congy-Jolivet, Nicolas; Lavayssière, Laurence; Esposito, Laure; Muscari, Fabrice; Kamar, Nassim

2017-04-01

Acute antibody-mediated rejection (aAMR) is an unusual complication after orthotopic ABO-compatible liver transplantation. To date, the clinical and histological long-term outcomes after aAMR are not well known. Herein, we describe nine cases of aAMR that occurred in our liver-transplant center between 2008 and 2016, with an initial and reevaluation liver biopsy available for reexamination. Two patients presented with aAMR at 10.5 (10, 11) days post-transplantation, caused by preformed donor-specific antibodies. Seven other recipients developed de novo donor-specific antibodies and aAMR at 11.2 (3-24) months post-transplantation. Eight of the nine patients received a B-cell targeting agent (rituximab, with or without plasma exchange), associated with polyclonal antibodies (three patients) or intravenous immunoglobulins (three patients). At the last follow up (i.e. 21 [4-90] months post-aAMR), seven patients were alive, including two patients with normal liver tests. Grafts' survival was 66%. A liver biopsy performed at 11.5 (5-48.5) months after the first biopsy showed no significant improvement in aAMR score (from 2 ± 1.3 to 1.6 ± 1.5, P = 0.6), a significant improvement in chronic AMR score (from 37 ± 9 to 25 ± 8, P = 0.003) and an increase in the Metavir score (1.2 ± 0.6 to 2.1 ± 0.9, P = 0.03). In this study, a B-cell-depleting agent seemed to improve the prognosis of aAMR in selected cases, but several patients kept active lesions antibody-mediated rejection. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Short-Term and Long-Term Educational Mobility of Families: A Two-Sex Approach

PubMed Central

Mare, Robert D.

2017-01-01

We use a multigenerational perspective to investigate how families reproduce and pass their educational advantages to succeeding generations. Unlike traditional mobility studies that have typically focused on one-sex influences from fathers to sons, we rely on a two-sex approach that accounts for interactions between males and females—the process in which males and females mate and have children with those of similar educational statuses and jointly determine the educational status attainment of their offspring. Using data from the Panel Study of Income Dynamics, we approach this issue from both a short-term and a long-term perspective. For the short term, grandparents’ educational attainments have a direct association with grandchildren’s education as well as an indirect association that is mediated by parents’ education and demographic behaviors. For the long term, initial educational advantages of families may benefit as many as three subsequent generations, but such advantages are later offset by the lower fertility of highly educated persons. Yet, all families eventually achieve the same educational distribution of descendants because of intermarriages between families of high- and low-education origin. PMID:28058636

Long-term continuous corticosterone treatment decreases VEGF receptor-2 expression in frontal cortex.

PubMed

Howell, Kristy R; Kutiyanawalla, Ammar; Pillai, Anilkumar

2011-01-01

Stress and increased glucocorticoid levels are associated with many neuropsychiatric disorders including schizophrenia and depression. Recently, the role of vascular endothelial factor receptor-2 (VEGFR2/Flk1) signaling has been implicated in stress-mediated neuroplasticity. However, the mechanism of regulation of VEGF/Flk1 signaling under long-term continuous glucocorticoid exposure has not been elucidated. We examined the possible effects of long-term continuous glucocorticoid exposure on VEGF/Flk1 signaling in cultured cortical neurons in vitro, mouse frontal cortex in vivo, and in post mortem human prefrontal cortex of both control and schizophrenia subjects. We found that long-term continuous exposure to corticosterone (CORT, a natural glucocorticoid) reduced Flk1 protein levels both in vitro and in vivo. CORT treatment resulted in alterations in signaling molecules downstream to Flk1 such as PTEN, Akt and mTOR. We demonstrated that CORT-induced changes in Flk1 levels are mediated through glucocorticoid receptor (GR) and calcium. A significant reduction in Flk1-GR interaction was observed following CORT exposure. Interestingly, VEGF levels were increased in cortex, but decreased in serum following CORT treatment. Moreover, significant reductions in Flk1 and GR protein levels were found in postmortem prefrontal cortex samples from schizophrenia subjects. The alterations in VEGF/Flk1 signaling following long-term continuous CORT exposure represents a molecular mechanism of the neurobiological effects of chronic stress.

Dendritic sodium spikes are required for long-term potentiation at distal synapses on hippocampal pyramidal neurons

PubMed Central

Kim, Yujin; Hsu, Ching-Lung; Cembrowski, Mark S; Mensh, Brett D; Spruston, Nelson

2015-01-01

Dendritic integration of synaptic inputs mediates rapid neural computation as well as longer-lasting plasticity. Several channel types can mediate dendritically initiated spikes (dSpikes), which may impact information processing and storage across multiple timescales; however, the roles of different channels in the rapid vs long-term effects of dSpikes are unknown. We show here that dSpikes mediated by Nav channels (blocked by a low concentration of TTX) are required for long-term potentiation (LTP) in the distal apical dendrites of hippocampal pyramidal neurons. Furthermore, imaging, simulations, and buffering experiments all support a model whereby fast Nav channel-mediated dSpikes (Na-dSpikes) contribute to LTP induction by promoting large, transient, localized increases in intracellular calcium concentration near the calcium-conducting pores of NMDAR and L-type Cav channels. Thus, in addition to contributing to rapid neural processing, Na-dSpikes are likely to contribute to memory formation via their role in long-lasting synaptic plasticity. DOI: http://dx.doi.org/10.7554/eLife.06414.001 PMID:26247712

Mitotic events in cerebellar granule progenitor cells that expand cerebellar surface area are critical for normal cerebellar cortical lamination in mice.

PubMed

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

2015-03-01

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 stereologic principles. We demonstrate that, during the proliferative phase of the external granular 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 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 intermitotic times for β events on a per-cell basis in postnatal 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 stereologic studies.

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.

Cerebellar Hematoma Location: Implications for the Underlying Microangiopathy.

PubMed

Pasi, Marco; Marini, Sandro; Morotti, Andrea; Boulouis, Gregoire; Xiong, Li; Charidimou, Andreas; Ayres, Alison M; Lee, Myung Joo; Biffi, Alessandro; Goldstein, Joshua N; Rosand, Jonathan; Gurol, M Edip; Greenberg, Steven M; Viswanathan, Anand

2018-01-01

Spontaneous cerebellar intracerebral hemorrhage (ICH) has been reported to be mainly associated with vascular changes secondary to hypertension. However, a subgroup of cerebellar ICH seems related to vascular amyloid deposition (cerebral amyloid angiopathy). We sought to determine whether location of hematoma in the cerebellum (deep and superficial regions) was suggestive of a particular hemorrhage-prone small-vessel disease pathology (cerebral amyloid angiopathy or hypertensive vasculopathy). Consecutive patients with cerebellar ICH from a single tertiary care medical center were recruited. Based on data from pathological reports, patients were divided according to the location of the primary cerebellar hematoma (deep versus superficial). Location of cerebral microbleeds (CMBs; strictly lobar, strictly deep, and mixed CMB) was evaluated on magnetic resonance imaging. One-hundred and eight patients (84%) had a deep cerebellar hematoma, and 20 (16%) a superficial cerebellar hematoma. Hypertension was more prevalent in deep than in patients with superficial cerebellar ICH (89% versus 65%, respectively; P <0.05). Among patients who underwent magnetic resonance imaging, those with superficial cerebellar ICH had higher prevalence of strictly lobar CMB (43%) and lower prevalence of strictly deep or mixed CMB (0%) compared with those with deep superficial cerebellar ICH (6%, 17%, and 38%, respectively). In a multivariable model, presence of strictly lobar CMB was associated with superficial cerebellar ICH (odds ratio, 3.8; 95% confidence interval, 1.5-8.5; P =0.004). Our study showed that superficial cerebellar ICH is related to the presence of strictly lobar CMB-a pathologically proven marker of cerebral amyloid angiopathy. Cerebellar hematoma location may thus help to identify those patients likely to have cerebral amyloid angiopathy pathology. © 2017 American Heart Association, Inc.

Narp regulates long-term aversive effects of morphine withdrawal.

PubMed

Reti, Irving M; Crombag, Hans S; Takamiya, Kogo; Sutton, Jeffrey M; Guo, Ning; Dinenna, Megan L; Huganir, Richard L; Holland, Peter C; Baraban, Jay M

2008-08-01

Although long-lasting effects of drug withdrawal are thought to play a key role in motivating continued drug use, the mechanisms mediating this type of drug-induced plasticity are unclear. Because Narp is an immediate early gene product that is secreted at synaptic sites and binds to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, it has been implicated in mediating enduring forms of synaptic plasticity. In previous studies, the authors found that Narp is selectively induced by morphine withdrawal in the extended amygdala, a group of limbic nuclei that mediate aversive behavioral responses. Accordingly, in this study, the authors evaluate whether long-term aversive effects of morphine withdrawal are altered in Narp knockout (KO) mice. The authors found that acute physical signs of morphine withdrawal are unaffected by Narp deletion. However, Narp KO mice acquire and sustain more aversive responses to the environment conditioned with morphine withdrawal than do wild type (WT) controls. Paradoxically, Narp KO mice undergo accelerated extinction of this heightened aversive response. Taken together, these studies suggest that Narp modulates both acquisition and extinction of aversive responses to morphine withdrawal and, therefore, may regulate plasticity processes underlying drug addiction.

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.

Successful neuropsychological rehabilitation in a patient with Cerebellar Cognitive Affective Syndrome.

PubMed

Ruffieux, N; Colombo, F; Gentaz, E; Annoni, J-M; Chouiter, L; Roulin Hefti, S; Ruffieux, A; Bihl, T

2017-01-01

The objective of this case study was to describe the neuropsychological rehabilitation of a 16-year-old patient who presented a Cerebellar Cognitive Affective Syndrome (CCAS) following a bilateral cerebellar hemorrhage. The patient presented severe and diffuse cognitive deficits, massive behavioral disorders, and emotion regulation difficulties. The cognitive rehabilitation was performed in the chronic phase (one year after the onset of the hemorrhage) using a transdisciplinary neurobehavioral approach based on the patient's favorite interest (soccer). A significant behavioral and cognitive improvement was observed. The patient became progressively independent in all activities of daily living and was discharged home. The Functional Independence Measure at discharge was 124/126 (vs. 37/126 at entry). The patient was able to complete his schooling despite the mild cognitive and behavioral sequelae. This first description of the use of neurobehavioral therapy in a case of chronic CCAS suggests that (a) major clinical improvement can occur more than one year after the onset of the CCAS, showing the importance of long-term and intensive neurorehabilitation; and (b) when the cerebellum cannot properly play its regulator role in cognition, neuropsychological intervention through a behavioral and cognitive approach can be of great help by acting as an external modulator to help the patient regain control over himself.

[Long-term psychiatric hospitalizations].

PubMed

Plancke, L; Amariei, A

2017-02-01

Long-term hospitalizations in psychiatry raise the question of desocialisation of the patients and the inherent costs. Individual indicators were extracted from a medical administrative database containing full-time psychiatric hospitalizations for the period 2011-2013 of people over 16 years old living in the French region of Nord-Pas-de-Calais. We calculated the proportion of people who had experienced a hospitalization with a duration of 292 days or more during the study period. A bivariate analysis was conducted, then ecological data (level of health-care offer, the deprivation index and the size of the municipalities of residence) were included into a multilevel regression model in order to identify the factors significantly related to variability of long-term hospitalization rates. Among hospitalized individuals in psychiatry, 2.6% had had at least one hospitalization of 292 days or more during the observation period; the number of days in long-term hospitalization represented 22.5% of the total of days of full-time hospitalization in psychiatry. The bivariate analysis revealed that seniority in the psychiatric system was strongly correlated with long hospitalization rates. In the multivariate analysis, the individual indicators the most related to an increased risk of long-term hospitalization were: total lack of autonomy (OR=9.0; 95% CI: 6.7-12.2; P<001); diagnoses of psychological development disorders (OR=9.7; CI95%: 4.5-20.6; P<.001); mental retardation (OR=4.5; CI95%: 2.5-8.2; P<.001): schizophrenia (OR=3.0; CI95%: 1.7-5.2; P<.001); compulsory hospitalization (OR=1.7; CI95%: 1.4-2.1; P<.001); having experienced therapeutic isolation (OR=1.8; CI95%: 1.5-2.1; P<.001). Variations of long-term hospitalization rates depending on the type of establishment were very high, but the density of hospital beds or intensity of ambulatory activity services were not significantly linked to long-term hospitalization. The inhabitants of small urban units had

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

PubMed

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

2016-02-27

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.

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.

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. Copyright © 2015 Elsevier Inc. All rights reserved.

Long-term potentiation and long-term depression: a clinical perspective

PubMed Central

Bliss, Timothy V.P.; Cooke, Sam F

2011-01-01

Long-term potentiation and long-term depression are enduring changes in synaptic strength, induced by specific patterns of synaptic activity, that have received much attention as cellular models of information storage in the central nervous system. Work in a number of brain regions, from the spinal cord to the cerebral cortex, and in many animal species, ranging from invertebrates to humans, has demonstrated a reliable capacity for chemical synapses to undergo lasting changes in efficacy in response to a variety of induction protocols. In addition to their physiological relevance, long-term potentiation and depression may have important clinical applications. A growing insight into the molecular mechanisms underlying these processes, and technological advances in non-invasive manipulation of brain activity, now puts us at the threshold of harnessing long-term potentiation and depression and other forms of synaptic, cellular and circuit plasticity to manipulate synaptic strength in the human nervous system. Drugs may be used to erase or treat pathological synaptic states and non-invasive stimulation devices may be used to artificially induce synaptic plasticity to ameliorate conditions arising from disrupted synaptic drive. These approaches hold promise for the treatment of a variety of neurological conditions, including neuropathic pain, epilepsy, depression, amblyopia, tinnitus and stroke. PMID:21779718

Gaba mediated long-term depression (LTD) in the rat medial vestibular nuclei.

PubMed

Grassi, S; Della Torre, G; Zampolini, M; Pettorossi, V E

1995-01-01

As previously demonstrated, high frequency stimulation (HFS) of the primary vestibular afferents always induces a clear, long lasting depression of the polysynaptic (N2) component of the field potentials recorded in the dorsal portion of the medial vestibular nuclei (MVN). The induction of the HFS effect was mediated by the activation of glutamate NMDA receptors, since it was blocked by AP5. The mechanisms at the basis of such a depression were studied. Our results demonstrate that Gaba, acting on both GabaA and GabaB receptors, is involved in mediating this phenomenon. In fact, HFS applied during Bicuculline and Saclofen perfusion, was no longer able to induce an N2 depression, but provoked a slight potentiation. However, the N2 depression clearly emerged after drug wash-out. Furthermore, Bicuculline and Saclofen fully abolished the N2 depression and highlighted the potentiation, when administered after HFS. The possibility that the N2 depression is the result of a homosynaptic LTD can be excluded on the basis of our results. On the contrary, our findings suggest that the depression is due to an enhancement of the Gaba inhibitory effect due to an HFS dependent increase in gabaergic interneuron activity, which resets vestibular neuron excitability at a lower level.

[Cerebellar atrophy in Minamata disease: comparison with spino-cerebellar degeneration on MR images].

PubMed

Ikeda, O; Okajima, T; Korogi, Y; Kitajima, M; Uchino, M; Takahasi, M

1997-02-01

We evaluated atrophic patterns of the cerebellar vermis in seven patients with Minamata disease (MD) and nine patients with spino-cerebellar degeneration (SCD) on MR images. Twenty-five control subjects were also examined. The cerebellar vermis was divided into superior, middle, and inferior parts by the primary fissure and the prepyramidal fissure on the median sagittal T1-weighted MR image. The length and area of each part were measured. In the patients with SCD, there were no significant differences in the degree of atrophy among the three parts. However, MR images of the patients with MD showed more severe atrophy in the middle and inferior parts than in the superior part. Atrophy of the superior part was less frequently observed in MD patients.

GABA-Mediated Presynaptic Inhibition Is Required for Precision of Long-Term Memory

ERIC Educational Resources Information Center

Cullen, Patrick K.; Dulka, Brooke N.; Ortiz, Samantha; Riccio, David C.; Jasnow, Aaron M.

2014-01-01

Though much attention has been given to the neural structures that underlie the long-term consolidation of contextual memories, little is known about the mechanisms responsible for the maintenance of memory precision. Here, we demonstrate a rapid time-dependent decline in memory precision in GABA [subscript B(1a)] receptor knockout mice. First, we…

Cerebellar contributions to spatial memory.

PubMed

Tomlinson, Simon P; Davis, Nick J; Morgan, Helen M; Bracewell, R Martyn

2014-08-22

There is mounting evidence for a role for the cerebellum in working memory (WM). The majority of relevant studies has examined verbal WM and has suggested specialisation of the right cerebellar hemisphere for language processing. Our study used theta burst stimulation (TBS) to examine whether there is a converse cerebellar hemispheric specialisation for spatial WM. We conducted two experiments to examine spatial WM performance before and after TBS to mid-hemispheric and lateral locations in the posterior cerebellum. Participants were required to recall the order of presentation of targets on a screen or the targets' order of presentation and their locations. We observed impaired recollection of target order after TBS to the mid left cerebellar hemisphere and reduced response speed after TBS to the left lateral cerebellum. We suggest that these results give evidence of the contributions of the left cerebellar cortex to the encoding and retrieval of spatial information. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Distributed Cerebellar Motor Learning: A Spike-Timing-Dependent Plasticity Model

PubMed Central

Luque, Niceto R.; Garrido, Jesús A.; Naveros, Francisco; Carrillo, Richard R.; D'Angelo, Egidio; Ros, Eduardo

2016-01-01

Deep cerebellar nuclei neurons receive both inhibitory (GABAergic) synaptic currents from Purkinje cells (within the cerebellar cortex) and excitatory (glutamatergic) synaptic currents from mossy fibers. Those two deep cerebellar nucleus inputs are thought to be also adaptive, embedding interesting properties in the framework of accurate movements. We show that distributed spike-timing-dependent plasticity mechanisms (STDP) located at different cerebellar sites (parallel fibers to Purkinje cells, mossy fibers to deep cerebellar nucleus cells, and Purkinje cells to deep cerebellar nucleus cells) in close-loop simulations provide an explanation for the complex learning properties of the cerebellum in motor learning. Concretely, we propose a new mechanistic cerebellar spiking model. In this new model, deep cerebellar nuclei embed a dual functionality: deep cerebellar nuclei acting as a gain adaptation mechanism and as a facilitator for the slow memory consolidation at mossy fibers to deep cerebellar nucleus synapses. Equipping the cerebellum with excitatory (e-STDP) and inhibitory (i-STDP) mechanisms at deep cerebellar nuclei afferents allows the accommodation of synaptic memories that were formed at parallel fibers to Purkinje cells synapses and then transferred to mossy fibers to deep cerebellar nucleus synapses. These adaptive mechanisms also contribute to modulate the deep-cerebellar-nucleus-output firing rate (output gain modulation toward optimizing its working range). PMID:26973504

Decreased cerebellar-cerebral connectivity contributes to complex task performance

PubMed Central

Knops, André

2016-01-01

The cerebellum's role in nonmotor processes is now well accepted, but cerebellar interaction with cerebral targets is not well understood. Complex cognitive tasks activate cerebellar, parietal, and frontal regions, but the effective connectivity between these regions has never been tested. To this end, we used psycho-physiological interactions (PPI) analysis to test connectivity changes of cerebellar and parietal seed regions in complex (2-digit by 1-digit multiplication, e.g., 12 × 3) vs. simple (1-digit by 1-digit multiplication, e.g., 4 × 3) task conditions (“complex − simple”). For cerebellar seed regions (lobule VI, hemisphere and vermis), we found significantly decreased cerebellar-parietal, cerebellar-cingulate, and cerebellar-frontal connectivity in complex multiplication. For parietal seed regions (PFcm, PFop, PFm) we found significantly increased parietal-parietal and parietal-frontal connectivity in complex multiplication. These results suggest that decreased cerebellar-cerebral connectivity contributes to complex task performance. Interestingly, BOLD activity contrasts revealed partially overlapping parietal areas of increased BOLD activity but decreased cerebellar-parietal PPI connectivity. PMID:27334957

Surgical and clinical aspects of cerebellar pilomyxoid-spectrum astrocytomas in children.

PubMed

El Beltagy, Mohamed A; Atteya, Mostafa M E; El-Haddad, Alaa; Awad, Madiha; Taha, Hala; Kamal, Mohamed; El Naga, Sherif Abou

2014-06-01

Cerebellar pilomyxoid astrocytomas (PMAs) and intermediate pilomyxoid astrocytomas (IPAs) are collectively called "pilomyxoid-spectrum astrocytomas (PMSAs)." Cerebellar PMSAs are thought to behave more aggressively than pilocytic astrocytomas (PAs). Our objective is to compare PMSAs to PAs in terms of surgical and clinical profiles. This retrospective study included 66 cases (35 males and 31 females) with cerebellar astrocytomas treated between July 2007 and December 2012 at Children's Cancer Hospital Egypt (CCHE 57357) with a mean age of 7 (±1.5) years. Cases were divided into three subgroups as follows: 44 PAs, 10 IPAs, and 12 PMAs. Comparison between all groups was focusing on brain stem invasion, intrinsic necrotic cavitation, extent of resection, recurrence, leptomeningeal dissemination (LD), metastases, need for CSF diversion, and cerebellar mutism (CM). Cerebellar PMAs and IPAs separately and collectively had higher incidence of brain stem invasion, intrinsic necrotic cavitation, tumor recurrence, and LD when compared to PAs (P < 0.001). Gross total resection was 13.6 % in PMSAs versus 90.9 % in PAs (P < 0.001). PMAs had a higher incidence of tumor recurrence than IPAs (66.7 versus 20 %, P < 0.001). Incidence of recurrence in PAs was 9.1 % in partially resected cases. Mean interval to recurrence was 9 (±1.5) months in PMSAs and 42 (±2) months in PAs. Cerebellar PMSAs express an aggressive clinical behavior and impose more operative challenges than PAs. These tumors may represent a clinical spectrum-at its benign end lies PA, while PMA lies at the aggressive end, with IPA lying just behind. Such concepts could be used to guide management in the future.

Synaptic pathology in the cerebellar dentate nucleus in chronic multiple sclerosis.

PubMed

Albert, Monika; Barrantes-Freer, Alonso; Lohrberg, Melanie; Antel, Jack P; Prineas, John W; Palkovits, Miklós; Wolff, Joachim R; Brück, Wolfgang; Stadelmann, Christine

2017-11-01

In multiple sclerosis, cerebellar symptoms are associated with clinical impairment and an increased likelihood of progressive course. Cortical atrophy and synaptic dysfunction play a prominent role in cerebellar pathology and although the dentate nucleus is a predilection site for lesion development, structural synaptic changes in this region remain largely unexplored. Moreover, the mechanisms leading to synaptic dysfunction have not yet been investigated at an ultrastructural level in multiple sclerosis. Here, we report on synaptic changes of dentate nuclei in post-mortem cerebella of 16 multiple sclerosis patients and eight controls at the histological level as well as an electron microscopy evaluation of afferent synapses of the cerebellar dentate and pontine nuclei of one multiple sclerosis patient and one control. We found a significant reduction of afferent dentate synapses in multiple sclerosis, irrespective of the presence of demyelination, and a close relationship between glial processes and dentate synapses. Ultrastructurally, we show autophagosomes containing degradation products of synaptic vesicles within dendrites, residual bodies within intact-appearing axons and free postsynaptic densities opposed to astrocytic appendages. Our study demonstrates loss of dentate afferent synapses and provides, for the first time, ultrastructural evidence pointing towards neuron-autonomous and neuroglia-mediated mechanisms of synaptic degradation in chronic multiple sclerosis. © 2016 International Society of Neuropathology.

36 CFR 251.103 - Mediation of term grazing permit disputes.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 2 2010-07-01 2010-07-01 false Mediation of term grazing... Lands § 251.103 Mediation of term grazing permit disputes. (a) Decisions subject to mediation. In those States with Department of Agriculture certified mediation programs, any holder of a term grazing permit...

Restoring Cognitive Functions Using Non-Invasive Brain Stimulation Techniques in Patients with Cerebellar Disorders

PubMed Central

Pope, Paul A.; Miall, R. Chris

2014-01-01

Numerous studies have highlighted the possibility of modulating the excitability of cerebro–cerebellar circuits bi-directionally using transcranial electrical brain stimulation, in a manner akin to that observed using magnetic stimulation protocols. It has been proposed that cerebellar stimulation activates Purkinje cells in the cerebellar cortex, leading to inhibition of the dentate nucleus, which exerts a tonic facilitatory drive onto motor and cognitive regions of cortex through a synaptic relay in the ventral–lateral thalamus. Some cerebellar deficits present with cognitive impairments if damage to non-motor regions of the cerebellum disrupts the coupling with cerebral cortical areas for thinking and reasoning. Indeed, white matter changes in the dentato–rubral tract correlate with cognitive assessments in patients with Friedreich ataxia, suggesting that this pathway is one component of the anatomical substrate supporting a cerebellar contribution to cognition. An understanding of the physiology of the cerebro–cerebellar pathway previously helped us to constrain our interpretation of results from two recent studies in which we showed cognitive enhancements in healthy participants during tests of arithmetic after electrical stimulation of the cerebellum, but only when task demands were high. Others studies have also shown how excitation of the prefrontal cortex can enhance performance in a variety of working memory tasks. Thus, future efforts might be guided toward neuro-enhancement in certain patient populations, using what is commonly termed “non-invasive brain stimulation” as a cognitive rehabilitation tool to modulate cerebro–cerebellar circuits, or for stimulation over the cerebral cortex to compensate for decreased cerebellar drive to this region. This article will address these possibilities with a review of the relevant literature covering ataxias and cerebellar cognitive affective disorders, which are characterized by thalamo�

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.

Microinjection of acetylcholine into cerebellar fastigial nucleus induces blood depressor response in anesthetized rats.

PubMed

Zhang, Changzheng; Luo, Wen; Zhou, Peiling; Sun, Tingzhe

2016-08-26

It is well known that the cerebellar fastigial nucleus (FN) is involved in cardiovascular modulation, and has direct evidence of cholinergic activity; however, whether and how acetylcholine (ACh) in the FN modulates blood pressure has not been investigated. In this study, we analyzed mean arterial pressure, maximal change in mean arterial pressure, and the reaction time of blood pressure changes after microinjection of cholinergic reagents into the FN in anesthetized rats. The results showed that ACh evoked a concentration-dependent (10, 30 and 100mM) effect on blood pressure down-regulation. The muscarinic ACh (mACh) receptor antagonist atropine, but not the nicotinic ACh (nACh) receptor antagonist mecamylamine, blocked the ACh-mediated depressor response. The mACh receptor agonist oxotremorine M, rather than nACh receptor agonist nicotine, mimicked the ACh-mediated blood pressure decrease in a dose-dependent manner (10, 30 and 100mM). These results indicate that cholinergic input in the cerebellar FN exerts a depressor effect on systemic blood pressure regulation, and such effects are substantially contributed by mACh rather than nACh receptors, although the precise mechanism concerning the role of mACh receptor in FN-mediated blood pressure modulation remains to be elucidated. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Co-creating meaningful structures within long-term psychotherapy group culture.

PubMed

Gayle, Robin G

2009-07-01

Meaningful group structures are co-created within the long-term outpatient psychotherapy group through a hermeneutical interaction between structure and immediate experience of structure by individuals embedded in personal and collective contexts. Co-created meanings expand original group- and self-understandings and further evolve structures that are stable yet do not exist independently of the narratives and affects of the members who interact with them. Group structures do not reduce, expand, or dissolve but change in connection to the experiences and meaning attributions within the group. This intersubjective process mediates the emphasis within group theory on leader responsibility for culture building that risks overpromoting certain psychotherapeutic cultural intentions over others. Three examples of intersubjective hermeneutical interaction within long-term psychotherapy groups lend insight into global, cultural, and societal groups.

Interneuron- and GABAA receptor-specific inhibitory synaptic plasticity in cerebellar Purkinje cells

NASA Astrophysics Data System (ADS)

He, Qionger; Duguid, Ian; Clark, Beverley; Panzanelli, Patrizia; Patel, Bijal; Thomas, Philip; Fritschy, Jean-Marc; Smart, Trevor G.

2015-07-01

Inhibitory synaptic plasticity is important for shaping both neuronal excitability and network activity. Here we investigate the input and GABAA receptor subunit specificity of inhibitory synaptic plasticity by studying cerebellar interneuron-Purkinje cell (PC) synapses. Depolarizing PCs initiated a long-lasting increase in GABA-mediated synaptic currents. By stimulating individual interneurons, this plasticity was observed at somatodendritic basket cell synapses, but not at distal dendritic stellate cell synapses. Basket cell synapses predominantly express β2-subunit-containing GABAA receptors; deletion of the β2-subunit ablates this plasticity, demonstrating its reliance on GABAA receptor subunit composition. The increase in synaptic currents is dependent upon an increase in newly synthesized cell surface synaptic GABAA receptors and is abolished by preventing CaMKII phosphorylation of GABAA receptors. Our results reveal a novel GABAA receptor subunit- and input-specific form of inhibitory synaptic plasticity that regulates the temporal firing pattern of the principal output cells of the cerebellum.

Near-Term Actions to Address Long-Term Climate Risk

NASA Astrophysics Data System (ADS)

Lempert, R. J.

2014-12-01

Addressing climate change requires effective long-term policy making, which occurs when reflecting on potential events decades or more in the future causes policy makers to choose near-term actions different than those they would otherwise pursue. Contrary to some expectations, policy makers do sometimes make such long-term decisions, but not as commonly and successfully as climate change may require. In recent years however, the new capabilities of analytic decision support tools, combined with improved understanding of cognitive and organizational behaviors, has significantly improved the methods available for organizations to manage longer-term climate risks. In particular, these tools allow decision makers to understand what near-term actions consistently contribute to achieving both short- and long-term societal goals, even in the face of deep uncertainty regarding the long-term future. This talk will describe applications of these approaches for infrastructure, water, and flood risk management planning, as well as studies of how near-term choices about policy architectures can affect long-term greenhouse gas emission reduction pathways.

l-Serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons

PubMed Central

Furuya, Shigeki; Tabata, Toshihide; Mitoma, Junya; Yamada, Keiko; Yamasaki, Miwako; Makino, Asami; Yamamoto, Toshifumi; Watanabe, Masahiko; Kano, Masanobu; Hirabayashi, Yoshio

2000-01-01

Glial cells support the survival and development of central neurons through the supply of trophic factors. Here we demonstrate that l-serine (l-Ser) and glycine (Gly) also are glia-derived trophic factors. These amino acids are released by astroglial cells and promote the survival, dendritogenesis, and electrophysiological development of cultured cerebellar Purkinje neurons. Although l-Ser and Gly are generally classified as nonessential amino acids, 3-phosphoglycerate dehydrogenase (3PGDH), a key enzyme for their biosynthesis, is not expressed in Purkinje neurons. By contrast, the Bergman glia, a native astroglia in the cerebellar cortex, highly expresses 3PGDH. These data suggest that l-Ser and Gly mediate the trophic actions of glial cells on Purkinje neurons. PMID:11016963

Temperature and food mediate long-term thermotactic behavioral plasticity by association-independent mechanisms in C. elegans.

PubMed

Chi, Cynthia A; Clark, Damon A; Lee, Stella; Biron, David; Luo, Linjiao; Gabel, Christopher V; Brown, Jeffrey; Sengupta, Piali; Samuel, Aravinthan D T

2007-11-01

Thermotactic behavior in the nematode Caenorhabditis elegans exhibits long-term plasticity. On a spatial thermal gradient, C. elegans tracks isotherms near a remembered set-point (T(S)) corresponding to its previous cultivation temperature. When navigating at temperatures above its set-point (T>T(S)), C. elegans crawls down spatial thermal gradients towards the T(S) in what is called cryophilic movement. The T(S) retains plasticity in the adult stage and is reset by approximately 4 h of sustained exposure to a new temperature. Long-term plasticity in C. elegans thermotactic behavior has been proposed to represent an associative learning of specific temperatures conditioned in the presence or absence of bacterial food. Here, we use quantitative behavioral assays to define the temperature and food-dependent determinants of long-term plasticity in the different modes of thermotactic behavior. Under our experimental conditions, we find that starvation at a specific temperature neither disrupts T(S) resetting toward the starvation temperature nor induces learned avoidance of the starvation temperature. We find that prolonged starvation suppresses the cryophilic mode of thermotactic behavior. The hen-1 and tax-6 genes have been reported to affect associative learning between temperature and food-dependent cues. Under our experimental conditions, mutation in the hen-1 gene, which encodes a secreted protein with an LDL receptor motif, does not significantly affect thermotactic behavior or long-term plasticity. Mutation in the tax-6 calcineurin gene abolishes thermotactic behavior altogether. In summary, we do not find evidence that long-term plasticity requires association between temperature and the presence or absence of bacterial food.

Dyslexic Children Show Atypical Cerebellar Activation and Cerebro-Cerebellar Functional Connectivity in Orthographic and Phonological Processing.

PubMed

Feng, Xiaoxia; Li, Le; Zhang, Manli; Yang, Xiujie; Tian, Mengyu; Xie, Weiyi; Lu, Yao; Liu, Li; Bélanger, Nathalie N; Meng, Xiangzhi; Ding, Guosheng

2017-04-01

Previous neuroimaging studies have found atypical cerebellar activation in individuals with dyslexia in either motor-related tasks or language tasks. However, studies investigating atypical cerebellar activation in individuals with dyslexia have mostly used tasks tapping phonological processing. A question that is yet unanswered is whether the cerebellum in individuals with dyslexia functions properly during orthographic processing of words, as growing evidence shows that the cerebellum is also involved in visual and spatial processing. Here, we investigated cerebellar activation and cerebro-cerebellar functional connectivity during word processing in dyslexic readers and typically developing readers using tasks that tap orthographic and phonological codes. In children with dyslexia, we observed an abnormally higher engagement of the bilateral cerebellum for the orthographic task, which was negatively correlated with literacy measures. The greater the reading impairment was for young dyslexic readers, the stronger the cerebellar activation was. This suggests a compensatory role of the cerebellum in reading for children with dyslexia. In addition, a tendency for higher cerebellar activation in dyslexic readers was found in the phonological task. Moreover, the functional connectivity was stronger for dyslexic readers relative to typically developing readers between the lobule VI of the right cerebellum and the left fusiform gyrus during the orthographic task and between the lobule VI of the left cerebellum and the left supramarginal gyrus during the phonological task. This pattern of results suggests that the cerebellum compensates for reading impairment through the connections with specific brain regions responsible for the ongoing reading task. These findings enhance our understanding of the cerebellum's involvement in reading and reading impairment.

Garcinia kola aqueous suspension prevents cerebellar neurodegeneration in long-term diabetic rat - a type 1 diabetes mellitus model.

PubMed

Farahna, Mohammed; Seke Etet, Paul F; Osman, Sayed Y; Yurt, Kıymet K; Amir, Naheed; Vecchio, Lorella; Aydin, Isınsu; Aldebasi, Yousef H; Sheikh, Azimullah; Chijuka, John C; Kaplan, Süleyman; Adem, Abdu

2017-01-04

The development of compounds able to improve metabolic syndrome and mitigate complications caused by inappropriate glycemic control in type 1 diabetes mellitus is challenging. The medicinal plant with established hypoglycemic properties Garcinia kola Heckel might have the potential to mitigate diabetes mellitus metabolic syndrome and complications. We have investigated the neuroprotective properties of a suspension of G. kola seeds in long-term type 1 diabetes mellitus rat model. Wistar rats, made diabetic by single injection of streptozotocin were monitored for 8 months. Then, they were administered with distilled water or G. kola oral aqueous suspension daily for 30 days. Body weight and glycemia were determined before and after treatment. After sacrifice, cerebella were dissected out and processed for stereological quantification of Purkinje cells. Histopathological and immunohistochemical analyses of markers of neuroinflammation and neurodegeneration were performed. Purkinje cell counts were significantly increased, and histopathological signs of apoptosis and neuroinflammation decreased, in diabetic animals treated with G. kola compared to diabetic rats given distilled water. Glycemia was also markedly improved and body weight restored to non-diabetic control values, following G. kola treatment. These results suggest that G. kola treatment improved the general condition of long-term diabetic rats and protected Purkinje cells partly by improving the systemic glycemia and mitigating neuroinflammation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Prostaglandin E2 is an endogenous modulator of cerebellar development and complex behavior during a sensitive postnatal period.

PubMed

Dean, Shannon L; Knutson, Jessica F; Krebs-Kraft, Desiree L; McCarthy, Margaret M

2012-04-01

Prostaglandins are lipid-derived molecules that mediate the generation of fever in the central nervous system. In addition to their proinflammatory role, prostaglandins also impact neuronal development and synaptic plasticity, sometimes in a sex-specific manner. The cerebellum has a high expression of prostaglandin receptors during development, but the role that these molecules play during normal cerebellar maturation is unknown. We demonstrate here that disrupting prostaglandin synthesis with cyclo-oxygenase inhibitors during a time-sensitive window in early postnatal life alters cerebellar Purkinje cell development in rats, resulting in initially increased dendritic growth in both sexes. We show that this results in later cerebellar atrophy in males only, resulting in a sex-specific loss of cerebellar volume. Further, although performance in motor tasks is spared, social interaction and the sensory threshold are altered in males developmentally exposed to cyclo-oxygenase inhibitors. This work demonstrates a previously unknown role for prostaglandins in cerebellar development and emphasizes the role that the cerebellum plays outside motor tasks, in cognitive and sensory domains that may help to explain its connection to complex neurodevelopmental disorders such as autism. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

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

Cannabinoid Type 1 Receptors Transiently Silence Glutamatergic Nerve Terminals of Cultured Cerebellar Granule Cells

PubMed Central

Ramírez-Franco, Jorge; Bartolomé-Martín, David; Alonso, Beatris; Torres, Magdalena; Sánchez-Prieto, José

2014-01-01

Cannabinoid receptors are the most abundant G protein-coupled receptors in the brain and they mediate retrograde short-term inhibition of neurotransmitter release, as well as long-term depression of synaptic transmission at many excitatory synapses. The induction of presynaptically silent synapses is a means of modulating synaptic strength, which is important for synaptic plasticity. Persistent activation of cannabinoid type 1 receptors (CB1Rs) mutes GABAergic terminals, although it is unclear if CB1Rs can also induce silencing at glutamatergic synapses. Cerebellar granule cells were transfected with VGLUT1-pHluorin to visualise the exo-endocytotic cycle. We found that prolonged stimulation (10 min) of cannabinoid receptors with the agonist HU-210 induces the silencing of previously active synapses. However, the presynaptic silencing induced by HU-210 is transient as it reverses after 20 min. cAMP with forskolin prevented CB1R-induced synaptic silencing, via activation of the Exchange Protein directly Activated by cAMP (Epac). Furthermore, Epac activation accelerated awakening of already silent boutons. Electron microscopy revealed that silencing was associated with synaptic vesicle (SV) redistribution within the nerve terminal, which diminished the number of vesicles close to the active zone of the plasma membrane. Finally, by combining functional and immunocytochemical approaches, we observed a strong correlation between the release capacity of the nerve terminals and RIM1α protein content, but not that of Munc13-1 protein. These results suggest that prolonged stimulation of cannabinoid receptors can transiently silence glutamatergic nerve terminals. PMID:24533119

Impairments of long-term depression induction and motor coordination precede Aβ accumulation in the cerebellum of APPswe/PS1dE9 double transgenic mice.

PubMed

Kuwabara, Yuki; Ishizeki, Masato; Watamura, Naoto; Toba, Junya; Yoshii, Aya; Inoue, Takafumi; Ohshima, Toshio

2014-08-01

Alzheimer's disease (AD) is a neurodegenerative disorder that represents the most common type of dementia among elderly people. Amyloid beta (Aβ) peptides in extracellular Aβ plaques, produced from the amyloid precursor protein (APP) via sequential processing by β- and γ-secretases, impair hippocampal synaptic plasticity, and cause cognitive dysfunction in AD patients. Here, we report that Aβ peptides also impair another form of synaptic plasticity; cerebellar long-term depression (LTD). In the cerebellum of commonly used AD mouse model, APPswe/PS1dE9 mice, Aβ plaques were detected from 8 months and profound accumulation of Aβ plaques was observed at 18 onths of age. Biochemical analysis revealed relatively high levels of APP protein and Aβ in the cerebellum of APPswe/PS1dE9 mice. At pre-Aβ accumulation stage, LTD induction, and motor coordination are disturbed. These results indicate that soluble Aβ oligomers disturb LTD induction and cerebellar function in AD mouse model. © 2014 International Society for Neurochemistry.

Simultaneous monitoring of presynaptic transmitter release and postsynaptic receptor trafficking reveals an enhancement of presynaptic activity in metabotropic glutamate receptor-mediated long-term depression.

PubMed

Xu, Wei; Tse, Yiu Chung; Dobie, Frederick A; Baudry, Michel; Craig, Ann Marie; Wong, Tak Pan; Wang, Yu Tian

2013-03-27

Although the contribution of postsynaptic mechanisms to long-term synaptic plasticity has been studied extensively, understanding the contribution of presynaptic modifications to this process lags behind, primarily because of a lack of techniques with which to directly and quantifiably measure neurotransmitter release from synaptic terminals. Here, we developed a method to measure presynaptic activity through the biotinylation of vesicular transporters in vesicles fused with presynaptic membranes during neurotransmitter release. This method allowed us for the first time to selectively quantify the spontaneous or evoked release of glutamate or GABA at their respective synapses. Using this method to investigate presynaptic changes during the expression of group I metabotropic glutamate receptor (mGluR1/5)-mediated long-term depression (LTD) in cultured rat hippocampal neurons, we discovered that this form of LTD was associated with increased presynaptic release of glutamate, despite reduced miniature EPSCs measured with whole-cell recording. Moreover, we found that specific blockade of AMPA receptor (AMPAR) endocytosis with a membrane-permeable GluR2-derived peptide not only prevented the expression of LTD but also eliminated LTD-associated increase in presynaptic release. Thus, our work not only demonstrates that mGluR1/5-mediated LTD is associated with increased endocytosis of postsynaptic AMPARs but also reveals an unexpected homeostatic/compensatory increase in presynaptic release. In addition, this study indicates that biotinylation of vesicular transporters in live cultured neurons is a valuable tool for studying presynaptic function.

Convergence of pontine and proprioceptive streams onto multimodal cerebellar granule cells

PubMed Central

Huang, Cheng-Chiu; Sugino, Ken; Shima, Yasuyuki; Guo, Caiying; Bai, Suxia; Mensh, Brett D; Nelson, Sacha B; Hantman, Adam W

2013-01-01

Cerebellar granule cells constitute the majority of neurons in the brain and are the primary conveyors of sensory and motor-related mossy fiber information to Purkinje cells. The functional capability of the cerebellum hinges on whether individual granule cells receive mossy fiber inputs from multiple precerebellar nuclei or are instead unimodal; this distinction is unresolved. Using cell-type-specific projection mapping with synaptic resolution, we observed the convergence of separate sensory (upper body proprioceptive) and basilar pontine pathways onto individual granule cells and mapped this convergence across cerebellar cortex. These findings inform the long-standing debate about the multimodality of mammalian granule cells and substantiate their associative capacity predicted in the Marr-Albus theory of cerebellar function. We also provide evidence that the convergent basilar pontine pathways carry corollary discharges from upper body motor cortical areas. Such merging of related corollary and sensory streams is a critical component of circuit models of predictive motor control. DOI: http://dx.doi.org/10.7554/eLife.00400.001 PMID:23467508

Postoperative cerebellar mutism and autistic spectrum disorder.

PubMed

Tasdemiroğlu, Erol; Kaya, Miktat; Yildirim, Can Hakan; Firat, Levent

2011-06-01

I read the article "An Inside View of Autism" written by a 44-year-old autistic woman who had a successful international career designing livestock equipment. In this article, she wrote about her life, disease, and experiences as an autistic individual. She stated that "It is interesting that my speech resembled the stressed speech in young children who have had tumors removed from the cerebellum". In this article, we intend to review and extensively document both postoperative cerebellar mutism and autistic spectrum disorder. We reviewed the clinical and neurological findings, etio-pathogenesis, neuroanatomy, mechanisms of development, and similarities between the etio-pathogenesis of both diseases. Cerebellar lesions can produce mutism and dysarthria, symptoms sometimes seen in autistic spectrum disorder. In mammals, cerebellar lesions disturb motivated behavior and reduce social interactions, functions that are disturbed in autistic spectrum disorder and cerebellar mutism. The cerebellum and two regions within the frontal lobes are active in certain language tasks. Language is abnormal in autistic spectrum disorder and cerebellar mutism.

Synchrony and neural coding in cerebellar circuits

PubMed Central

Person, Abigail L.; Raman, Indira M.

2012-01-01

The cerebellum regulates complex movements and is also implicated in cognitive tasks, and cerebellar dysfunction is consequently associated not only with movement disorders, but also with conditions like autism and dyslexia. How information is encoded by specific cerebellar firing patterns remains debated, however. A central question is how the cerebellar cortex transmits its integrated output to the cerebellar nuclei via GABAergic synapses from Purkinje neurons. Possible answers come from accumulating evidence that subsets of Purkinje cells synchronize their firing during behaviors that require the cerebellum. Consistent with models predicting that coherent activity of inhibitory networks has the capacity to dictate firing patterns of target neurons, recent experimental work supports the idea that inhibitory synchrony may regulate the response of cerebellar nuclear cells to Purkinje inputs, owing to the interplay between unusually fast inhibitory synaptic responses and high rates of intrinsic activity. Data from multiple laboratories lead to a working hypothesis that synchronous inhibitory input from Purkinje cells can set the timing and rate of action potentials produced by cerebellar nuclear cells, thereby relaying information out of the cerebellum. If so, then changing spatiotemporal patterns of Purkinje activity would allow different subsets of inhibitory neurons to control cerebellar output at different times. Here we explore the evidence for and against the idea that a synchrony code defines, at least in part, the input–output function between the cerebellar cortex and nuclei. We consider the literature on the existence of simple spike synchrony, convergence of Purkinje neurons onto nuclear neurons, and intrinsic properties of nuclear neurons that contribute to responses to inhibition. Finally, we discuss factors that may disrupt or modulate a synchrony code and describe the potential contributions of inhibitory synchrony to other motor circuits. PMID

Cerebellar-M1 Connectivity Changes Associated with Motor Learning Are Somatotopic Specific.

PubMed

Spampinato, Danny A; Block, Hannah J; Celnik, Pablo A

2017-03-01

One of the functions of the cerebellum in motor learning is to predict and account for systematic changes to the body or environment. This form of adaptive learning is mediated by plastic changes occurring within the cerebellar cortex. The strength of cerebellar-to-cerebral pathways for a given muscle may reflect aspects of cerebellum-dependent motor adaptation. These connections with motor cortex (M1) can be estimated as cerebellar inhibition (CBI): a conditioning pulse of transcranial magnetic stimulation delivered to the cerebellum before a test pulse over motor cortex. Previously, we have demonstrated that changes in CBI for a given muscle representation correlate with learning a motor adaptation task with the involved limb. However, the specificity of these effects is unknown. Here, we investigated whether CBI changes in humans are somatotopy specific and how they relate to motor adaptation. We found that learning a visuomotor rotation task with the right hand changed CBI, not only for the involved first dorsal interosseous of the right hand, but also for an uninvolved right leg muscle, the tibialis anterior, likely related to inter-effector transfer of learning. In two follow-up experiments, we investigated whether the preparation of a simple hand or leg movement would produce a somatotopy-specific modulation of CBI. We found that CBI changes only for the effector involved in the movement. These results indicate that learning-related changes in cerebellar-M1 connectivity reflect a somatotopy-specific interaction. Modulation of this pathway is also present in the context of interlimb transfer of learning. SIGNIFICANCE STATEMENT Connectivity between the cerebellum and motor cortex is a critical pathway for the integrity of everyday movements and understanding the somatotopic specificity of this pathway in the context of motor learning is critical to advancing the efficacy of neurorehabilitation. We found that adaptive learning with the hand affects cerebellar

Cerebellar contribution to mental rotation: a cTBS study.

PubMed

Picazio, Silvia; Oliveri, Massimiliano; Koch, Giacomo; Caltagirone, Carlo; Petrosini, Laura

2013-12-01

A cerebellar role in spatial information processing has been advanced even in the absence of physical manipulation, as occurring in mental rotation. The present study was aimed at investigating the specific involvement of left and right cerebellar hemispheres in two tasks of mental rotation. We used continuous theta burst stimulation to downregulate cerebellar hemisphere excitability in healthy adult subjects performing two mental rotation tasks: an Embodied Mental Rotation (EMR) task, entailing an egocentric strategy, and an Abstract Mental Rotation (AMR) task entailing an allocentric strategy. Following downregulation of left cerebellar hemisphere, reaction times were slower in comparison to sham stimulation in both EMR and AMR tasks. Conversely, identical reaction times were obtained in both tasks following right cerebellar hemisphere and sham stimulations. No effect of cerebellar stimulation side was found on response accuracy. The present findings document a specialization of the left cerebellar hemisphere in mental rotation regardless of the kind of stimulus to be rotated.

NMDA receptor-mediated long term modulation of electrically evoked field potentials in the rat medial vestibular nuclei.

PubMed

Capocchi, G; Della Torre, G; Grassi, S; Pettorossi, V E; Zampolini, M

1992-01-01

The effect of high frequency stimulation (HFS) of the primary vestibular afferents on field potentials recorded in the ipsilateral Medial Vestibular Nuclei (MVN) was studied. Our results show that potentiation and depression can be induced in different portions of MVN, which are distinguishable by their anatomical organization. HFS induces potentiation of the monosynaptic component in the ventral portion of the MVN, whereas it provokes depression of the polysynaptic component in the dorsal portion of the same nucleus. The induction of both potentiation and depression was blocked under AP5 perfusion, thus demonstrating that NMDA receptor activation mediates both phenomena. Furthermore, the finding that the field potentials were not modified during perfusion with DL-AP5, as previously reported, supports the hypothesis that NMDA receptors are not involved in the normal synaptic transmission from the primary vestibular afferent fibres, but are only activated following hyperstimulation of this afferent system. Our results suggest that the mechanisms of long term modification of synaptic efficacy observed in MVN may underlie the plasticity phenomena occurring in vestibular nuclei.

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.

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.

PKG-Mediated MAPK Signaling Is Necessary for Long-Term Operant Memory in "Aplysia"

ERIC Educational Resources Information Center

Michel, Maximilian; Green, Charity L.; Eskin, Arnold; Lyons, Lisa C.

2011-01-01

Signaling pathways necessary for memory formation, such as the mitogen-activated protein kinase (MAPK) pathway, appear highly conserved across species and paradigms. Learning that food is inedible (LFI) represents a robust form of associative, operant learning that induces short- (STM) and long-term memory (LTM) in "Aplysia." We investigated the…

Short- and long-term black tea consumption reverses endothelial dysfunction in patients with coronary artery disease.

PubMed

Duffy, S J; Keaney , J F; Holbrook, M; Gokce, N; Swerdloff, P L; Frei, B; Vita, J A

2001-07-10

Epidemiological studies suggest that tea consumption decreases cardiovascular risk, but the mechanisms of benefit remain undefined. Endothelial dysfunction has been associated with coronary artery disease and increased oxidative stress. Some antioxidants have been shown to reverse endothelial dysfunction, and tea contains antioxidant flavonoids. Methods and Results-- To test the hypothesis that tea consumption will reverse endothelial dysfunction, we randomized 66 patients with proven coronary artery disease to consume black tea and water in a crossover design. Short-term effects were examined 2 hours after consumption of 450 mL tea or water. Long-term effects were examined after consumption of 900 mL tea or water daily for 4 weeks. Vasomotor function of the brachial artery was examined at baseline and after each intervention with vascular ultrasound. Fifty patients completed the protocol and had technically suitable ultrasound measurements. Both short- and long-term tea consumption improved endothelium- dependent flow-mediated dilation of the brachial artery, whereas consumption of water had no effect (P<0.001 by repeated-measures ANOVA). Tea consumption had no effect on endothelium-independent nitroglycerin-induced dilation. An equivalent oral dose of caffeine (200 mg) had no short-term effect on flow-mediated dilation. Plasma flavonoids increased after short- and long-term tea consumption. Short- and long-term black tea consumption reverses endothelial vasomotor dysfunction in patients with coronary artery disease. This finding may partly explain the association between tea intake and decreased cardiovascular disease events.

Early VGLUT1-specific parallel fiber synaptic deficits and dysregulated cerebellar circuit in the KIKO mouse model of Friedreich ataxia.

PubMed

Lin, Hong; Magrane, Jordi; Clark, Elisia M; Halawani, Sarah M; Warren, Nathan; Rattelle, Amy; Lynch, David R

2017-12-19

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with progressive ataxia that affects both the peripheral and central nervous system (CNS). While later CNS neuropathology involves loss of large principal neurons and glutamatergic and GABAergic synaptic terminals in the cerebellar dentate nucleus, early pathological changes in FRDA cerebellum remain largely uncharacterized. Here, we report early cerebellar VGLUT1 (SLC17A7)-specific parallel fiber (PF) synaptic deficits and dysregulated cerebellar circuit in the frataxin knock-in/knockout (KIKO) FRDA mouse model. At asymptomatic ages, VGLUT1 levels in cerebellar homogenates are significantly decreased, whereas VGLUT2 (SLC17A6) levels are significantly increased, in KIKO mice compared with age-matched controls. Additionally, GAD65 (GAD2) levels are significantly increased, while GAD67 (GAD1) levels remain unaltered. This suggests early VGLUT1-specific synaptic input deficits, and dysregulation of VGLUT2 and GAD65 synaptic inputs, in the cerebellum of asymptomatic KIKO mice. Immunohistochemistry and electron microscopy further show specific reductions of VGLUT1-containing PF presynaptic terminals in the cerebellar molecular layer, demonstrating PF synaptic input deficiency in asymptomatic and symptomatic KIKO mice. Moreover, the parvalbumin levels in cerebellar homogenates and Purkinje neurons are significantly reduced, but preserved in other interneurons of the cerebellar molecular layer, suggesting specific parvalbumin dysregulation in Purkinje neurons of these mice. Furthermore, a moderate loss of large principal neurons is observed in the dentate nucleus of asymptomatic KIKO mice, mimicking that of FRDA patients. Our findings thus identify early VGLUT1-specific PF synaptic input deficits and dysregulated cerebellar circuit as potential mediators of cerebellar dysfunction in KIKO mice, reflecting developmental features of FRDA in this mouse model. © 2017. Published by The Company of

Neutrophil elastase mediates acute pathogenesis and is a determinant of long-term behavioral recovery after traumatic injury to the immature brain

PubMed Central

Semple, Bridgette D; Trivedi, Alpa; Gimlin, Kayleen; Noble-Haeusslein, Linda J

2014-01-01

While neutrophil elastase (NE), released by activated neutrophils, is a key mediator of secondary pathogenesis in adult models of brain ischemia and spinal cord injury, no studies to date have examined this protease in the context of the injured immature brain, where there is notable vulnerability resulting from inadequate antioxidant reserves and prolonged exposure to infiltrating neutrophils. We thus reasoned that NE may be a key determinant of secondary pathogenesis, and as such, adversely influence long-term neurological recovery. To address this hypothesis, wild-type (WT) and NE knockout (KO) mice were subjected to a controlled cortical impact at post-natal day 21, approximating a toddler-aged child. To determine if NE is required for neutrophil infiltration into the injured brain, and whether this protease contributes to vasogenic edema, we quantified neutrophil numbers and measured water content in the brains of each of these genotypes. While leukocyte trafficking was indistinguishable between genotypes, vasogenic edema was markedly attenuated in the NE KO. To determine if early pathogenesis is dependent on NE, indices of cell death (TUNEL and activated caspase-3) were quantified across genotypes. NE KO mice showed a reduction in these markers of cell death in the injured hippocampus, which corresponded to greater preservation of neuronal integrity as well as reduced expression of heme oxygenase-1, a marker of oxidative stress. WT mice, treated with a competitive inhibitor of NE at 2, 6 and 12 h post-injury, likewise showed a reduction in cell death and oxidative stress compared to vehicle-treated controls. We next examined the long-term behavioral and structural consequences of NE deficiency. NE KO mice showed an improvement in long-term spatial memory retention and amelioration of injury-induced hyperactivity. However, volumetric and stereological analyses found comparable tissue loss in the injured cortex and hippocampus independent of genotype. Further

Neutrophil elastase mediates acute pathogenesis and is a determinant of long-term behavioral recovery after traumatic injury to the immature brain.

PubMed

Semple, Bridgette D; Trivedi, Alpa; Gimlin, Kayleen; Noble-Haeusslein, Linda J

2015-02-01

While neutrophil elastase (NE), released by activated neutrophils, is a key mediator of secondary pathogenesis in adult models of brain ischemia and spinal cord injury, no studies to date have examined this protease in the context of the injured immature brain, where there is notable vulnerability resulting from inadequate antioxidant reserves and prolonged exposure to infiltrating neutrophils. We thus reasoned that NE may be a key determinant of secondary pathogenesis, and as such, adversely influence long-term neurological recovery. To address this hypothesis, wild-type (WT) and NE knockout (KO) mice were subjected to a controlled cortical impact at post-natal day 21, approximating a toddler-aged child. To determine if NE is required for neutrophil infiltration into the injured brain, and whether this protease contributes to vasogenic edema, we quantified neutrophil numbers and measured water content in the brains of each of these genotypes. While leukocyte trafficking was indistinguishable between genotypes, vasogenic edema was markedly attenuated in the NE KO. To determine if early pathogenesis is dependent on NE, indices of cell death (TUNEL and activated caspase-3) were quantified across genotypes. NE KO mice showed a reduction in these markers of cell death in the injured hippocampus, which corresponded to greater preservation of neuronal integrity as well as reduced expression of heme oxygenase-1, a marker of oxidative stress. WT mice, treated with a competitive inhibitor of NE at 2, 6 and 12h post-injury, likewise showed a reduction in cell death and oxidative stress compared to vehicle-treated controls. We next examined the long-term behavioral and structural consequences of NE deficiency. NE KO mice showed an improvement in long-term spatial memory retention and amelioration of injury-induced hyperactivity. However, volumetric and stereological analyses found comparable tissue loss in the injured cortex and hippocampus independent of genotype. Further

Rhythmic finger tapping reveals cerebellar dysfunction in essential tremor.

PubMed

Buijink, A W G; Broersma, M; van der Stouwe, A M M; van Wingen, G A; Groot, P F C; Speelman, J D; Maurits, N M; van Rootselaar, A F

2015-04-01

Cerebellar circuits are hypothesized to play a central role in the pathogenesis of essential tremor. Rhythmic finger tapping is known to strongly engage the cerebellar motor circuitry. We characterize cerebellar and, more specifically, dentate nucleus function, and neural correlates of cerebellar output in essential tremor during rhythmic finger tapping employing functional MRI. Thirty-one propranolol-sensitive essential tremor patients with upper limb tremor and 29 healthy controls were measured. T2*-weighted EPI sequences were acquired. The task consisted of alternating rest and finger tapping blocks. A whole-brain and region-of-interest analysis was performed, the latter focusing on the cerebellar cortex, dentate nucleus and inferior olive nucleus. Activations were also related to tremor severity. In patients, dentate activation correlated positively with tremor severity as measured by the tremor rating scale part A. Patients had reduced activation in widespread cerebellar cortical regions, and additionally in the inferior olive nucleus, and parietal and frontal cortex, compared to controls. The increase in dentate activation with tremor severity supports involvement of the dentate nucleus in essential tremor. Cortical and cerebellar changes during a motor timing task in essential tremor might point to widespread changes in cerebellar output in essential tremor. Copyright © 2015 Elsevier Ltd. All rights reserved.

Long-term outcome of deep brain stimulation in fragile X-associated tremor/ataxia syndrome.

PubMed

Weiss, Daniel; Mielke, Carina; Wächter, Tobias; Bender, Benjamin; Liscic, Rajka M; Scholten, Marlieke; Naros, Georgios; Plewnia, Christian; Gharabaghi, Alireza; Krüger, Rejko

2015-03-01

Fragile X-associated tremor/ataxia syndrome (FXTAS) presents as complex movement disorder including tremor and cerebellar ataxia. The efficacy and safety of deep brain stimulation of the nucleus ventralis intermedius of the thalamus in atypical tremor syndromes like FXTAS remains to be determined. Here, we report the long-term outcome of three male genetically confirmed FXTAS patients treated with bilateral neurostimulation of the nucleus ventralis intermedius for up to four years. All patients demonstrated sustained improvement of both tremor and ataxia - the latter included improvement of intention tremor and axial tremor. Kinematic gait analyses further demonstrated a regularization of the gait cycle. Initial improvements of hand functional disability were not sustained and reached the preoperative level of impairment within one to two years from surgery. Our data on patients with a genetic cause of tremor show favorable outcome and may contribute to improved patient stratification for neurostimulation therapy in the future. Copyright © 2014 Elsevier Ltd. All rights reserved.

Long-term urethral catheterisation.

PubMed

Turner, Bruce; Dickens, Nicola

This article discusses long-term urethral catheterisation, focusing on the relevant anatomy and physiology, indications for the procedure, catheter selection and catheter care. It is important that nurses have a good working knowledge of long-term catheterisation as the need for this intervention will increase with the rise in chronic health conditions and the ageing population.

Voltage-gated calcium channel autoimmune cerebellar degeneration

PubMed Central

McKasson, Marilyn; Clawson, Susan A.; Hill, Kenneth E.; Wood, Blair; Carlson, Noel; Bromberg, Mark; Greenlee, John E.

2016-01-01

Objectives: To describe response to treatment in a patient with autoantibodies against voltage-gated calcium channels (VGCCs) who presented with autoimmune cerebellar degeneration and subsequently developed Lambert-Eaton myasthenic syndrome (LEMS), and to study the effect of the patient's autoantibodies on Purkinje cells in rat cerebellar slice cultures. Methods: Case report and study of rat cerebellar slice cultures incubated with patient VGCC autoantibodies. Results: A 53-year-old man developed progressive incoordination with ataxic speech. Laboratory evaluation revealed VGCC autoantibodies without other antineuronal autoantibodies. Whole-body PET scans 6 and 12 months after presentation detected no malignancy. The patient improved significantly with IV immunoglobulin G (IgG), prednisone, and mycophenolate mofetil, but worsened after IV IgG was halted secondary to aseptic meningitis. He subsequently developed weakness with electrodiagnostic evidence of LEMS. The patient's IgG bound to Purkinje cells in rat cerebellar slice cultures, followed by neuronal death. Reactivity of the patient's autoantibodies with VGCCs was confirmed by blocking studies with defined VGCC antibodies. Conclusions: Autoimmune cerebellar degeneration associated with VGCC autoantibodies may precede onset of LEMS and may improve with immunosuppressive treatment. Binding of anti-VGCC antibodies to Purkinje cells in cerebellar slice cultures may be followed by cell death. Patients with anti-VGCC autoantibodies may be at risk of irreversible neurologic injury over time, and treatment should be initiated early. PMID:27088118

Long-term solar-terrestrial observations

NASA Technical Reports Server (NTRS)

1988-01-01

The results of an 18-month study of the requirements for long-term monitoring and archiving of solar-terrestrial data is presented. The value of long-term solar-terrestrial observations is discussed together with parameters, associated measurements, and observational problem areas in each of the solar-terrestrial links (the sun, the interplanetary medium, the magnetosphere, and the thermosphere-ionosphere). Some recommendations are offered for coordinated planning for long-term solar-terrestrial observations.

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.

Glutamate transporter EAAT4 in Purkinje cells controls intersynaptic diffusion of climbing fiber transmitter mediating inhibition of GABA release from interneurons.

PubMed

Satake, Shin'ichiro; Song, Si-Young; Konishi, Shiro; Imoto, Keiji

2010-12-01

Neurotransmitters diffuse out of the synaptic cleft and act on adjacent synapses to exert concerted control of the synaptic strength within neural pathways that converge on single target neurons. The excitatory transmitter released from climbing fibers (CFs), presumably glutamate, is shown to inhibit γ-aminobutyric acid (GABA) release at basket cell (BC)-Purkinje cell (PC) synapses in the rat cerebellar cortex through its extrasynaptic diffusion and activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on BC axon terminals. This study aimed at examining how the CF transmitter-diffusion-mediated presynaptic inhibition is controlled by glutamate transporters. Pharmacological blockade of the PC-selective neuronal transporter EAAT4 markedly enhanced CF-induced inhibition of GABAergic transmission. Tetanic CF-stimulation elicited long-term potentiation of glutamate transporters in PCs, and thereby attenuated the CF-induced inhibition. Combined use of electrophysiology and immunohistochemistry revealed a significant inverse relationship between the level of EAAT4 expression and the inhibitory action of CF-stimulation on the GABA release at different cerebellar lobules - the CF-induced inhibition was profound in lobule III, where the EAAT4 expression level was low, whereas it was minimal in lobule X, where EAAT4 was abundant. The findings clearly demonstrate that the neuronal glutamate transporter EAAT4 in PCs plays a critical role in the extrasynaptic diffusion of CF transmitter - it appears not only to retrogradely determine the degree of CF-mediated inhibition of GABAergic inputs to the PC by controlling the glutamate concentration for intersynaptic diffusion, but also regulate synaptic information processing in the cerebellar cortex depending on its differential regional distribution as well as use-dependent plasticity of uptake efficacy. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience

Coupling internal cerebellar models enhances online adaptation and supports offline consolidation in sensorimotor tasks

PubMed Central

Passot, Jean-Baptiste; Luque, Niceto R.; Arleo, Angelo

2013-01-01

The cerebellum is thought to mediate sensorimotor adaptation through the acquisition of internal models of the body-environment interaction. These representations can be of two types, identified as forward and inverse models. The first predicts the sensory consequences of actions, while the second provides the correct commands to achieve desired state transitions. In this paper, we propose a composite architecture consisting of multiple cerebellar internal models to account for the adaptation performance of humans during sensorimotor learning. The proposed model takes inspiration from the cerebellar microcomplex circuit, and employs spiking neurons to process information. We investigate the intrinsic properties of the cerebellar circuitry subserving efficient adaptation properties, and we assess the complementary contributions of internal representations by simulating our model in a procedural adaptation task. Our simulation results suggest that the coupling of internal models enhances learning performance significantly (compared with independent forward and inverse models), and it allows for the reproduction of human adaptation capabilities. Furthermore, we provide a computational explanation for the performance improvement observed after one night of sleep in a wide range of sensorimotor tasks. We predict that internal model coupling is a necessary condition for the offline consolidation of procedural memories. PMID:23874289

Acute Cerebellar Ataxia Induced by Nivolumab

PubMed Central

Kawamura, Reina; Nagata, Eiichiro; Mukai, Masako; Ohnuki, Yoichi; Matsuzaki, Tomohiko; Ohiwa, Kana; Nakagawa, Tomoki; Kohno, Mitsutomo; Masuda, Ryota; Iwazaki, Masayuki; Takizawa, Shunya

2017-01-01

A 54-year-old woman with adenocarcinoma of the lung and lymph node metastasis experienced nystagmus and cerebellar ataxia 2 weeks after initiating nivolumab therapy. An evaluation for several autoimmune-related antibodies and paraneoplastic syndrome yielded negative results. We eventually diagnosed the patient with nivolumab-induced acute cerebellar ataxia, after excluding other potential conditions. Her ataxic gait and nystagmus resolved shortly after intravenous steroid pulse therapy followed by the administration of decreasing doses of oral steroids. Nivolumab, an immune checkpoint inhibitor, is known to induce various neurological adverse events. However, this is the first report of acute cerebellar ataxia associated with nivolumab treatment. PMID:29249765

Acute cerebellar ataxia and infectious mononucleosis.

PubMed Central

Wadhwa, N. K.; Ghose, R. R.

1983-01-01

A 28-year-old man, who presented with acute cerebellar ataxia, was found to have haematological features of infectious mononucleosis. There was serological evidence of recent infection with Epstein-Barr virus. It is speculated that cerebellar dysfunction results from virus-induced inflammatory changes within the central nervous system. PMID:6312442

[MORPHOFUNCTIONAL ADJUSTMENT VASCULAR AND CELLULAR COMPONENTS OF THE CEREBELLAR CORTEX IN EXPOSURE TO BODY SULFATES OF COPPER, ZINC AND IRON].

PubMed

Grintsova, N; Vasko, L; Kiptenko, L; Gortinsky, A; Murenets, N

2015-09-01

In order to analyze the morphological and morphometric reconstructions of the vascular bed, and Purkinje cells of the cerebellar cortex of rats in long-term action (for 90 days) on the body of sulphates of copper, zinc and iron, an experiment was conducted on 48 adult white male rats weighing 200-250 g in age 5-7 months. We used anatomical, morphometric, statistical and common methods of microanatomical research. It was found that the combined effect on the body of sulphates of copper and zinc, and iron in the cerebellum has enough expressive toxicity, which affects the condition of the vascular bed, and Purkinje cells. The degree of morphological transformations is in direct proportion to the duration of the experiment. In the pathogenesis of violations leading role played by hypoxia, develop signs of swelling of the cerebellar cortex with signs hemorrhagic infiltration, the severity of which is maximum on the 60th day of the experiment.

Long-term care: long-term care insurance--2005. End of Year Issue Brief.

PubMed

Tanner, Rachel; Bercaw, Lawren

2005-12-31

As the "Baby Boom" generation approaches retirement, state and federal lawmakers are struggling to ensure that the nation's long-term care system will provide adequate services for the growing number of senior citizens. A 2003 Administration on Aging report predicted that the elderly population will double by 2030. Accordingly, policymakers must prepare for the impending squeeze on public health and Medicaid resources. Many consumers are exploring private long-term care insurance options as a means of preparing for the cost of eldercare. Yet, a lack of market uniformity has rendered the long-term care insurance industry somewhat difficult for consumers to decipher. In addition, senior care insurance is often costly, particularly for those over age 50.

Motor Deficits and Cerebellar Atrophy in Elovl5 Knock Out Mice.

PubMed

Hoxha, Eriola; Gabriele, Rebecca M C; Balbo, Ilaria; Ravera, Francesco; Masante, Linda; Zambelli, Vanessa; Albergo, Cristian; Mitro, Nico; Caruso, Donatella; Di Gregorio, Eleonora; Brusco, Alfredo; Borroni, Barbara; Tempia, Filippo

2017-01-01

Spino-Cerebellar-Ataxia type 38 (SCA38) is caused by missense mutations in the very long chain fatty acid elongase 5 gene, ELOVL5 . The main clinical findings in this disease are ataxia, hyposmia and cerebellar atrophy. Mice in which Elovl5 has been knocked out represent a model of the loss of function hypothesis of SCA38. In agreement with this hypothesis, Elovl5 knock out mice reproduced the main symptoms of patients, motor deficits at the beam balance test and hyposmia. The cerebellar cortex of Elovl5 knock out mice showed a reduction of thickness of the molecular layer, already detectable at 6 months of age, confirmed at 12 and 18 months. The total perimeter length of the Purkinje cell (PC) layer was also reduced in Elovl5 knock out mice. Since Elovl5 transcripts are expressed by PCs, whose dendrites are a major component of the molecular layer, we hypothesized that an alteration of their dendrites might be responsible for the reduced thickness of this layer. Reconstruction of the dendritic tree of biocytin-filled PCs, followed by Sholl analysis, showed that the distribution of distal dendrites was significantly reduced in Elovl5 knock out mice. Dendritic spine density was conserved. These results suggest that Elovl5 knock out mice recapitulate SCA38 symptoms and that their cerebellar atrophy is due, at least in part, to a reduced extension of PC dendritic arborization.

Postural Ataxia in Cerebellar Downbeat Nystagmus: Its Relation to Visual, Proprioceptive and Vestibular Signals and Cerebellar Atrophy.

PubMed

Helmchen, Christoph; Kirchhoff, Jan-Birger; Göttlich, Martin; Sprenger, Andreas

2017-01-01

The cerebellum integrates proprioceptive, vestibular and visual signals for postural control. Cerebellar patients with downbeat nystagmus (DBN) complain of unsteadiness of stance and gait as well as blurred vision and oscillopsia. The aim of this study was to elucidate the differential role of visual input, gaze eccentricity, vestibular and proprioceptive input on the postural stability in a large cohort of cerebellar patients with DBN, in comparison to healthy age-matched control subjects. Oculomotor (nystagmus, smooth pursuit eye movements) and postural (postural sway speed) parameters were recorded and related to each other and volumetric changes of the cerebellum (voxel-based morphometry, SPM). Twenty-seven patients showed larger postural instability in all experimental conditions. Postural sway increased with nystagmus in the eyes closed condition but not with the eyes open. Romberg's ratio remained stable and was not different from healthy controls. Postural sway did not change with gaze position or graviceptive input. It increased with attenuated proprioceptive input and on tandem stance in both groups but Romberg's ratio also did not differ. Cerebellar atrophy (vermal lobule VI, VIII) correlated with the severity of impaired smooth pursuit eye movements of DBN patients. Postural ataxia of cerebellar patients with DBN cannot be explained by impaired visual feedback. Despite oscillopsia visual feedback control on cerebellar postural control seems to be preserved as postural sway was strongest on visual deprivation. The increase in postural ataxia is neither related to modulations of single components characterizing nystagmus nor to deprivation of single sensory (visual, proprioceptive) inputs usually stabilizing stance. Re-weighting of multisensory signals and/or inappropriate cerebellar motor commands might account for this postural ataxia.

Postural Ataxia in Cerebellar Downbeat Nystagmus: Its Relation to Visual, Proprioceptive and Vestibular Signals and Cerebellar Atrophy

PubMed Central

Helmchen, Christoph; Kirchhoff, Jan-Birger; Göttlich, Martin; Sprenger, Andreas

2017-01-01

Background The cerebellum integrates proprioceptive, vestibular and visual signals for postural control. Cerebellar patients with downbeat nystagmus (DBN) complain of unsteadiness of stance and gait as well as blurred vision and oscillopsia. Objectives The aim of this study was to elucidate the differential role of visual input, gaze eccentricity, vestibular and proprioceptive input on the postural stability in a large cohort of cerebellar patients with DBN, in comparison to healthy age-matched control subjects. Methods Oculomotor (nystagmus, smooth pursuit eye movements) and postural (postural sway speed) parameters were recorded and related to each other and volumetric changes of the cerebellum (voxel-based morphometry, SPM). Results Twenty-seven patients showed larger postural instability in all experimental conditions. Postural sway increased with nystagmus in the eyes closed condition but not with the eyes open. Romberg’s ratio remained stable and was not different from healthy controls. Postural sway did not change with gaze position or graviceptive input. It increased with attenuated proprioceptive input and on tandem stance in both groups but Romberg’s ratio also did not differ. Cerebellar atrophy (vermal lobule VI, VIII) correlated with the severity of impaired smooth pursuit eye movements of DBN patients. Conclusions Postural ataxia of cerebellar patients with DBN cannot be explained by impaired visual feedback. Despite oscillopsia visual feedback control on cerebellar postural control seems to be preserved as postural sway was strongest on visual deprivation. The increase in postural ataxia is neither related to modulations of single components characterizing nystagmus nor to deprivation of single sensory (visual, proprioceptive) inputs usually stabilizing stance. Re-weighting of multisensory signals and/or inappropriate cerebellar motor commands might account for this postural ataxia. PMID:28056109

A BTLA-mediated bait-and-switch strategy permits Listeria expansion in CD8α+ DCs to promote long term T cell responses

PubMed Central

Yang, Xuanming; Zhang, Xunmin; Sun, Yonglian; Tu, Tony; Fu, May Lynne; Miller, Mendy; Fu, Yang-Xin

2014-01-01

SUMMARY Listeria monocytogenes infected CD8α+ DCs in the spleen are essential for CD8+ T cell generation. CD8α+ DCs are also necessary for Listeria expansion and dissemination within the host. The mechanisms that regulate CD8α+ DCs to allow Listeria expansion are unclear. We find that activating the B and T lymphocyte attenuator (BTLA), a co-inhibitory receptor on CD8α+ DCs, suppresses, while blocking BTLA enhances both the primary and memory CD8 T cell responses against Listeria. Btla−/− mice have lower effector and memory CD8+ T cells while paradoxically also being more resistant to Listeria. Although bacterial entry into Btla−/− CD8α+ DCs is unaffected, Listeria fails to expand within these cells. BTLA signaling limits Fas/FasL-mediated suppression of Listeria expansion within CD8α+ DCs to more effectively alert adaptive immune cells. This study uncovers a BTLA-mediated strategy used by the host that permits Listeria proliferation to enable increasing T cell responses for long-term protection. PMID:25011109

Consolidation of episodic memories during sleep: long-term effects of retrieval practice.

PubMed

Racsmány, Mihály; Conway, Martin A; Demeter, Gyula

2010-01-01

Two experiments investigated the long-term effects of retrieval practice. In the retrieval-practice procedure, selected items from a previously studied list are repeatedly recalled. The typical retrieval-practice effects are considerably enhanced memory for practiced items accompanied by low levels of recall, relative to baseline, for previously studied items that are associated with the practiced items but were not themselves practiced. The two experiments demonstrated that the former effect persisted over 12 hr; the latter effect also persisted over 12 hr, but only if a period of nocturnal sleep occurred during the retention interval. We propose that consolidation processes occurring during sleep, and possibly featuring some form of off-line rehearsal, mediate these long-term effects of retrieval practice.

Postsynaptic Regulation of Long-Term Facilitation in Aplysia

PubMed Central

Cai, Diancai; Chen, Shanping; Glanzman, David L.

2009-01-01

Summary Repeated exposure to serotonin (5-HT), an endogenous neurotransmitter that mediates behavioral sensitization in Aplysia [1–3], induces long-term facilitation (LTF) of the Aplysia sensorimotor synapse [4]. LTF, a prominent form of invertebrate synaptic plasticity, is believed to play a major role in long-term learning in Aplysia [5]. Until now, LTF has been thought to be due predominantly to cellular processes activated by 5-HT within the presynaptic sensory neuron [6]. Recent work indicates that LTF depends on the increased expression and release of a sensory neuron-specific neuropeptide, sensorin [7]. Sensorin released during LTF appears to bind to autoreceptors on the sensory neuron, thereby activating critical presynaptic signals, including mitogen-activated protein kinase (MAPK) [8, 9]. Here, we show that LTF depends on elevated postsynaptic Ca2+ and postsynaptic protein synthesis. Furthermore, we find that the increased expression of presynaptic sensorin due to 5-HT stimulation requires elevation of postsynaptic intracellular Ca2+. Our results represent perhaps the strongest evidence to date that the increased expression of a specific presynaptic neuropeptide during LTF is regulated by retrograde signals. PMID:18571411

Long-term associative learning predicts verbal short-term memory performance.

PubMed

Jones, Gary; Macken, Bill

2018-02-01

Studies using tests such as digit span and nonword repetition have implicated short-term memory across a range of developmental domains. Such tests ostensibly assess specialized processes for the short-term manipulation and maintenance of information that are often argued to enable long-term learning. However, there is considerable evidence for an influence of long-term linguistic learning on performance in short-term memory tasks that brings into question the role of a specialized short-term memory system separate from long-term knowledge. Using natural language corpora, we show experimentally and computationally that performance on three widely used measures of short-term memory (digit span, nonword repetition, and sentence recall) can be predicted from simple associative learning operating on the linguistic environment to which a typical child may have been exposed. The findings support the broad view that short-term verbal memory performance reflects the application of long-term language knowledge to the experimental setting.

Asthma Medicines: Long-Term Control

MedlinePlus

... Size Email Print Share Asthma Medicines: Long-term Control Page Content Article Body Corticosteroids Synthetic versions of ... form, they are used exclusively for long-term control; they are not very effective for acute symptoms. ...

PKA-CREB-BDNF signaling pathway mediates propofol-induced long-term learning and memory impairment in hippocampus of rats.

PubMed

Zhong, Yu; Chen, Jing; Li, Li; Qin, Yi; Wei, Yi; Pan, Shining; Jiang, Yage; Chen, Jialin; Xie, Yubo

2018-04-20

Studies have found that propofol can induce widespread neuroapoptosis in developing brains, which leads to cause long-term learning and memory abnormalities. However, the specific cellular and molecular mechanisms underlying propofol-induced neuroapoptosis remain elusive. The aim of the present study was to explore the role of PKA-CREB-BDNF signaling pathway in propofol-induced long-term learning and memory impairment during brain development. Seven-day-old rats were randomly assigned to control, intralipid and three treatment groups (n = 5). Rats in control group received no treatment. Intralipid (10%, 10 mL/kg) for vehicle control and different dosage of propofol for three treatment groups (50, 100 and 200 mg/kg) were administered intraperitoneally. FJB staining, immunohistochemistry analysis for neuronal nuclei antigen and transmission electron microscopy were used to detect neuronal apoptosis and structure changes. MWM test examines the long-term spatial learning and memory impairment. The expression of PKA, pCREB and BDNF was quantified using western blots. Propofol induced significant increase of FJB-positive cells and decrease of PKA, pCREB and BDNF protein levels in the immature brain of P7 rats. Using the MWM test, propofol-treated rats demonstrated long-term spatial learning and memory impairment. Moreover, hippocampal NeuN-positive cell loss, long-lasting ultrastructural abnormalities of the neurons and synapses, and long-term down-regulation of PKA, pCREB and BDNF protein expression in adult hippocampus were also found. Our results indicated that neonatal propofol exposure can significantly result in long-term learning and memory impairment in adulthood. The possible mechanism involved in the propofol-induced neuroapoptosis was related to down-regulation of PKA-CREB-BDNF signaling pathway. Copyright © 2018. Published by Elsevier B.V.

Acute cerebellar ataxia

MedlinePlus

... swelling (inflammation) of the cerebellum (such as from multiple sclerosis). Cerebellar ataxia caused by a recent viral infection may not need treatment. Outlook (Prognosis) People whose condition was caused by ...

Mediating Systems of Care: Emergency Calls to Long-Term Care Facilities at Life's End.

PubMed

Waldrop, Deborah P; McGinley, Jacqueline M; Clemency, Brian

2018-04-09

Nursing home (NH) residents account for over 2.2 million emergency department visits yearly; the majority are cared for and transported by prehospital providers (emergency medical technicians and paramedics). The purpose of this study was to investigate prehospital providers' perceptions of emergency calls at life's end. This article focuses on perceptions of end-of-life calls in long-term care (LTC). This pilot study employed a descriptive cross-sectional design. Concepts from the symbolic interaction theory guided the exploration of perceptions and interpretations of emergency calls in LTC facilities. A purposeful sample of prehospital providers was developed from one agency in a small northeastern U.S. city. Semistructured interviews were conducted with 43 prehospital providers to explore their perceptions of factors that trigger emergency end-of-life calls in LTC facilities. Qualitative data analysis involved iterative coding in an inductive process that included open, systematic, focused, and axial coding. Interview themes illustrated the contributing factors as follows: care crises; dying-related turmoil; staffing ratios; and organizational protocols. Distress was crosscutting and present in all four themes. The findings illuminate how prehospital providers become mediators between NHs and emergency departments by managing tension, conflict, and challenges in patient care between these systems and suggest the importance of further exploration of interactions between LTC staff, prehospital providers, and emergency departments. Enhanced communication between LTC facilities and prehospital providers is important to address potentially inappropriate calls and transport requests and to identify means for collaboration in the care of sick frail residents.

Rotational vertebral artery occlusion: mechanisms and long-term outcome.

PubMed

Choi, Kwang-Dong; Choi, Jae-Hwan; Kim, Ji-Soo; Kim, Hyo Jung; Kim, Min-Ji; Lee, Tae-Hong; Lee, Hyung; Moon, In Soo; Oh, Hui Jong; Kim, Jae-Il

2013-07-01

To elucidate the mechanisms and prognosis of rotational vertebral artery occlusion (RVAO). We analyzed clinical and radiological characteristics, patterns of induced nystagmus, and outcome in 21 patients (13 men, aged 29-77 years) with RVAO documented by dynamic cerebral angiography during an 8-year period at 3 University Hospitals in Korea. The follow-up periods ranged from 5 to 91 months (median, 37.5 months). Most patients (n=19; 90.5%) received conservative treatments. All the patients developed vertigo accompanied by tinnitus (38%), fainting (24%), or blurred vision (19%). Only 12 (57.1%) patients showed the typical pattern of RVAO during dynamic cerebral angiography, a compression of the dominant vertebral artery at the C1-2 level during contralateral head rotation. The induced nystagmus was mostly downbeat with horizontal and torsional components beating toward the compressed vertebral artery side. None of the patients with conservative treatments developed posterior circulation stroke, and 4 of them (21.1%) showed resolution of symptoms during the follow-ups. RVAO has various patterns of vertebral artery compression, and favorable long-term outcome with conservative treatments. In most patients with RVAO, the symptoms may be ascribed to asymmetrical excitation of the bilateral labyrinth induced by transient ischemia or by disinhibition from inferior cerebellar hypoperfusion. Conservative management might be considered as the first-line treatment of RVAO.

Dysfunctions of the basal ganglia-cerebellar-thalamo-cortical system produce motor tics in Tourette syndrome

PubMed Central

Arbib, Michael A.; Baldassarre, Gianluca

2017-01-01

Motor tics are a cardinal feature of Tourette syndrome and are traditionally associated with an excess of striatal dopamine in the basal ganglia. Recent evidence increasingly supports a more articulated view where cerebellum and cortex, working closely in concert with basal ganglia, are also involved in tic production. Building on such evidence, this article proposes a computational model of the basal ganglia-cerebellar-thalamo-cortical system to study how motor tics are generated in Tourette syndrome. In particular, the model: (i) reproduces the main results of recent experiments about the involvement of the basal ganglia-cerebellar-thalamo-cortical system in tic generation; (ii) suggests an explanation of the system-level mechanisms underlying motor tic production: in this respect, the model predicts that the interplay between dopaminergic signal and cortical activity contributes to triggering the tic event and that the recently discovered basal ganglia-cerebellar anatomical pathway may support the involvement of the cerebellum in tic production; (iii) furnishes predictions on the amount of tics generated when striatal dopamine increases and when the cortex is externally stimulated. These predictions could be important in identifying new brain target areas for future therapies. Finally, the model represents the first computational attempt to study the role of the recently discovered basal ganglia-cerebellar anatomical links. Studying this non-cortex-mediated basal ganglia-cerebellar interaction could radically change our perspective about how these areas interact with each other and with the cortex. Overall, the model also shows the utility of casting Tourette syndrome within a system-level perspective rather than viewing it as related to the dysfunction of a single brain area. PMID:28358814

Dysfunctions of the basal ganglia-cerebellar-thalamo-cortical system produce motor tics in Tourette syndrome.

PubMed

Caligiore, Daniele; Mannella, Francesco; Arbib, Michael A; Baldassarre, Gianluca

2017-03-01

Motor tics are a cardinal feature of Tourette syndrome and are traditionally associated with an excess of striatal dopamine in the basal ganglia. Recent evidence increasingly supports a more articulated view where cerebellum and cortex, working closely in concert with basal ganglia, are also involved in tic production. Building on such evidence, this article proposes a computational model of the basal ganglia-cerebellar-thalamo-cortical system to study how motor tics are generated in Tourette syndrome. In particular, the model: (i) reproduces the main results of recent experiments about the involvement of the basal ganglia-cerebellar-thalamo-cortical system in tic generation; (ii) suggests an explanation of the system-level mechanisms underlying motor tic production: in this respect, the model predicts that the interplay between dopaminergic signal and cortical activity contributes to triggering the tic event and that the recently discovered basal ganglia-cerebellar anatomical pathway may support the involvement of the cerebellum in tic production; (iii) furnishes predictions on the amount of tics generated when striatal dopamine increases and when the cortex is externally stimulated. These predictions could be important in identifying new brain target areas for future therapies. Finally, the model represents the first computational attempt to study the role of the recently discovered basal ganglia-cerebellar anatomical links. Studying this non-cortex-mediated basal ganglia-cerebellar interaction could radically change our perspective about how these areas interact with each other and with the cortex. Overall, the model also shows the utility of casting Tourette syndrome within a system-level perspective rather than viewing it as related to the dysfunction of a single brain area.

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

Cognitive and Guided Mastery Therapies for Panic Disorder with Agoraphobia: 18-Year Long-Term Outcome and Predictors of Long-Term Change.

PubMed

Hoffart, Asle; Hedley, Liv M; Svanøe, Karol; Sexton, Harold

2016-01-01

In this study, we wished to compare the long-term outcome of (medication-free) panic disorder with agoraphobia patients randomized to cognitive or guided mastery therapy. Thirty-one (67.4%) of 46 patients who had completed treatment were followed up about 18 years after end of treatment. In the combined sample and using intent-to-follow-up analyses, there were large within-group effect sizes of -1.79 and -1.63 on the primary interview-based and self-report outcome measures of avoidance of situations when alone, and 56.5% no longer had a panic disorder and/or agoraphobia diagnosis. No outcome differences between the two treatments emerged. Guided mastery was associated with greater beneficial changes in catastrophic beliefs and self-efficacy. For two of five outcome measures, more reduction in panic-related beliefs about physical and mental catastrophes from pre- to post-treatment predicted lower level of anxiety from post-treatment to 18-year follow-up when the effect of treatment changes in (a) self-efficacy and (b) anxiety was controlled. However, for one of the outcome measures, this effect attenuated with time. Copyright © 2014 John Wiley & Sons, Ltd. The results suggest that the very-long-term outcome of both cognitive therapy and guided mastery therapy for agoraphobia is positive. The results support the role of catastrophic beliefs as mediator of change. The pattern of results suggests that learning processes other than catastrophic beliefs may be important for long-term outcome as well. Copyright © 2014 John Wiley & Sons, Ltd.

Short- and long-term effectiveness of a three-month individualized need-supportive physical activity counseling intervention at the workplace.

PubMed

Arrogi, Anass; Schotte, Astrid; Bogaerts, An; Boen, Filip; Seghers, Jan

2017-01-09

The objective of the present study was to evaluate the short- and long-term intervention and mediation effects of a 3-month individualized need-supportive physical activity (PA) counseling intervention on employees' PA and sedentary behavior. Insufficiently active employees (n = 300; mean age 42 ± 9 years; 78% female) were recruited from a large pharmaceutical company in Flanders, Belgium. A quasi-experimental design was used in which the intervention group (N = 246) was recruited separately from the reference group (N = 54). Intervention group participants received a 3-month behavioral support intervention, which consisted of two one-hour face-to-face counseling sessions and three follow-up counseling contacts by e-mail or telephone at weeks three, six and nine. PA counseling, delivered by qualified PA counselors, aimed to satisfy participants' basic psychological needs for autonomy, competence, and relatedness. Reference group participants did not receive individualized PA counseling. Outcome measures included objectively assessed and self-reported PA and sedentary time and psychological need satisfaction. Assessments were held at baseline, immediately after the intervention (short-term) and 6 months post-intervention (long-term). Mixed model analyses and bootstrapping analyses were used to determine intervention and mediation effects, respectively. The intervention group increased weekday daily steps both in the short- and long-term, while the reference group showed reductions in daily step count (ES = .65 and ES = .48 in the short- and long-term, respectively). In the short-term, weekday moderate-to-vigorous PA increased more pronouncedly in the intervention group compared to the reference group (ES = .34). Moreover, the intervention group demonstrated reductions in self-reported sitting time during weekends both in the short- and long-term, whereas the reference group reported increased sitting time (ES = .44 and ES = .32

Serum Response Factor (SRF) Ablation Interferes with Acute Stress-Associated Immediate and Long-Term Coping Mechanisms.

PubMed

Zimprich, Annemarie; Mroz, Gabi; Meyer Zu Reckendorf, Christopher; Anastasiadou, Sofia; Förstner, Philip; Garrett, Lillian; Hölter, Sabine M; Becker, Lore; Rozman, Jan; Prehn, Cornelia; Rathkolb, Birgit; Moreth, Kristin; Wurst, Wolfgang; Klopstock, Thomas; Klingenspor, Martin; Adamski, Jerzy; Wolf, Eckhard; Bekeredjian, Raffi; Fuchs, Helmut; Gailus-Durner, Valerie; de Angelis, Martin Hrabe; Knöll, Bernd

2017-12-01

Stress experience modulates behavior, metabolism, and energy expenditure of organisms. One molecular hallmark of an acute stress response is a rapid induction of immediate early genes (IEGs) such as c-Fos and Egr family members. IEG transcription in neurons is mediated by the neuronal activity-driven gene regulator serum response factor (SRF). We show a first role of SRF in immediate and long-lasting acute restraint stress (AS) responses. For this, we employed a standardized mouse phenotyping protocol at the German Mouse Clinic (GMC) including behavioral, metabolic, and cardiologic tests as well as gene expression profiling to analyze the consequences of forebrain-specific SRF deletion in mice exposed to AS. Adult mice with an SRF deletion in glutamatergic neurons (Srf; CaMKIIa-CreERT2 ) showed hyperactivity, decreased anxiety, and impaired working memory. In response to restraint AS, instant stress reactivity including locomotor behavior and corticosterone induction was impaired in Srf mutant mice. Interestingly, even several weeks after previous AS exposure, SRF-deficient mice showed long-lasting AS-associated changes including altered locomotion, metabolism, energy expenditure, and cardiovascular changes. This suggests a requirement of SRF for mediating long-term stress coping mechanisms in wild-type mice. SRF ablation decreased AS-mediated IEG induction and activity of the actin severing protein cofilin. In summary, our data suggest an SRF function in immediate AS reactions and long-term post-stress-associated coping mechanisms.

Zinc-mediated attenuation of hippocampal mossy fiber long-term potentiation induced by forskolin.

PubMed

Ando, Masaki; Oku, Naoto; Takeda, Atsushi

2010-11-01

The rise in presynaptic calcium induced by high-frequency stimulation activates the calcium-calmodulin-sensitive adenylyl cyclase (AC) 1 followed by the induction of long-term potentiation (LTP) at the hippocampal mossy fiber-CA3 synapse. Zinc is released with glutamate from mossy fiber terminals. However, the role of the zinc in mossy fiber LTP is controversial. In the present study, the mechanism of zinc-mediated attenuation of mossy fiber LTP was examined in that induced by forskolin, an AC activator. Mossy fiber LTP induced by tetanic stimulation (100 Hz for 1 s) was attenuated in the presence of 5 microM ZnCl(2), whereas that induced by forskolin under test stimulation (0.1 Hz) was not attenuated. Forskolin-induced mossy fiber LTP was attenuated by perfusion with 100 microM ZnCl(2) prior to the induction. However, the zinc (100 microM) pre-perfusion did not attenuate mossy fiber LTP induced by Sp-cAMPS, an activator of protein kinase A, under test stimulation. Zinc is necessary to be taken up into mossy fiber boutons for effectively inhibiting AC activity. In hippocampal slices labeled with ZnAF-2 DA, a membrane-permeable zinc indicator, intracellular ZnAF-2 signal was increased during tetanic stimulation in the presence of 5 microM ZnCl(2), but not under test stimulation. Intracellular ZnAF-2 signal was increased under test stimulation in the presence of 100 microM ZnCl(2). These results suggest that zinc taken up into mossy fibers attenuates forskolin-induced mossy fiber LTP via inhibition of AC activity. The significance of endogenous zinc uptake by mossy fibers is discussed focused on tetanus-induced mossy fiber LTP. Copyright 2010 Elsevier Ltd. All rights reserved.

Acquisition of contextual discrimination involves the appearance of a RAS-GRF1/p38 mitogen-activated protein (MAP) kinase-mediated signaling pathway that promotes long term potentiation (LTP).

PubMed

Jin, Shan-Xue; Arai, Junko; Tian, Xuejun; Kumar-Singh, Rajendra; Feig, Larry A

2013-07-26

RAS-GRF1 is a guanine nucleotide exchange factor with the ability to activate RAS and RAC GTPases in response to elevated calcium levels. We previously showed that beginning at 1 month of age, RAS-GRF1 mediates NMDA-type glutamate receptor (NMDAR)-induction of long term depression in the CA1 region of the hippocampus of mice. Here we show that beginning at 2 months of age, when mice first acquire the ability to discriminate between closely related contexts, RAS-GRF1 begins to contribute to the induction of long term potentiation (LTP) in the CA1 hippocampus by mediating the action of calcium-permeable, AMPA-type glutamate receptors (CP-AMPARs). Surprisingly, LTP induction by CP-AMPARs through RAS-GRF1 occurs via activation of p38 MAP kinase rather than ERK MAP kinase, which has more frequently been linked to LTP. Moreover, contextual discrimination is blocked by knockdown of Ras-Grf1 expression specifically in the CA1 hippocampus, infusion of a p38 MAP kinase inhibitor into the CA1 hippocampus, or the injection of an inhibitor of CP-AMPARs. These findings implicate the CA1 hippocampus in the developmentally dependent capacity to distinguish closely related contexts through the appearance of a novel LTP-supporting signaling pathway.

Acquisition of Contextual Discrimination Involves the Appearance of a RAS-GRF1/p38 Mitogen-activated Protein (MAP) Kinase-mediated Signaling Pathway That Promotes Long Term Potentiation (LTP)*

PubMed Central

Jin, Shan-Xue; Arai, Junko; Tian, Xuejun; Kumar-Singh, Rajendra; Feig, Larry A.

2013-01-01

RAS-GRF1 is a guanine nucleotide exchange factor with the ability to activate RAS and RAC GTPases in response to elevated calcium levels. We previously showed that beginning at 1 month of age, RAS-GRF1 mediates NMDA-type glutamate receptor (NMDAR)-induction of long term depression in the CA1 region of the hippocampus of mice. Here we show that beginning at 2 months of age, when mice first acquire the ability to discriminate between closely related contexts, RAS-GRF1 begins to contribute to the induction of long term potentiation (LTP) in the CA1 hippocampus by mediating the action of calcium-permeable, AMPA-type glutamate receptors (CP-AMPARs). Surprisingly, LTP induction by CP-AMPARs through RAS-GRF1 occurs via activation of p38 MAP kinase rather than ERK MAP kinase, which has more frequently been linked to LTP. Moreover, contextual discrimination is blocked by knockdown of Ras-Grf1 expression specifically in the CA1 hippocampus, infusion of a p38 MAP kinase inhibitor into the CA1 hippocampus, or the injection of an inhibitor of CP-AMPARs. These findings implicate the CA1 hippocampus in the developmentally dependent capacity to distinguish closely related contexts through the appearance of a novel LTP-supporting signaling pathway. PMID:23766509

Long-Term Teacher Orchestration of Technology-Mediated Collaborative Inquiry

ERIC Educational Resources Information Center

Viilo, Marjut; Seitamaa-Hakkarainen, Pirita; Hakkarainen, Kai

2018-01-01

This explorative case study longitudinally examines teacher orchestration of an inquiry learning process in a technology-enhanced elementary classroom. A 13-month investigative study on cultural artifacts was conducted on 32 fourth grade students who progressed to the fifth grade during the project. The activities were mediated and documented…

Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy.

PubMed

Burns, David T; Donkervoort, Sandra; Müller, Juliane S; Knierim, Ellen; Bharucha-Goebel, Diana; Faqeih, Eissa Ali; Bell, Stephanie K; AlFaifi, Abdullah Y; Monies, Dorota; Millan, Francisca; Retterer, Kyle; Dyack, Sarah; MacKay, Sara; Morales-Gonzalez, Susanne; Giunta, Michele; Munro, Benjamin; Hudson, Gavin; Scavina, Mena; Baker, Laura; Massini, Tara C; Lek, Monkol; Hu, Ying; Ezzo, Daniel; AlKuraya, Fowzan S; Kang, Peter B; Griffin, Helen; Foley, A Reghan; Schuelke, Markus; Horvath, Rita; Bönnemann, Carsten G

2018-05-03

The exosome is a conserved multi-protein complex that is essential for correct RNA processing. Recessive variants in exosome components EXOSC3, EXOSC8, and RBM7 cause various constellations of pontocerebellar hypoplasia (PCH), spinal muscular atrophy (SMA), and central nervous system demyelination. Here, we report on four unrelated affected individuals with recessive variants in EXOSC9 and the effect of the variants on the function of the RNA exosome in vitro in affected individuals' fibroblasts and skeletal muscle and in vivo in zebrafish. The clinical presentation was severe, early-onset, progressive SMA-like motor neuronopathy, cerebellar atrophy, and in one affected individual, congenital fractures of the long bones. Three affected individuals of different ethnicity carried the homozygous c.41T>C (p.Leu14Pro) variant, whereas one affected individual was compound heterozygous for c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161 ∗ ). We detected reduced EXOSC9 in fibroblasts and skeletal muscle and observed a reduction of the whole multi-subunit exosome complex on blue-native polyacrylamide gel electrophoresis. RNA sequencing of fibroblasts and skeletal muscle detected significant >2-fold changes in genes involved in neuronal development and cerebellar and motor neuron degeneration, demonstrating the widespread effect of the variants. Morpholino oligonucleotide knockdown and CRISPR/Cas9-mediated mutagenesis of exosc9 in zebrafish recapitulated aspects of the human phenotype, as they have in other zebrafish models of exosomal disease. Specifically, portions of the cerebellum and hindbrain were absent, and motor neurons failed to develop and migrate properly. In summary, we show that variants in EXOSC9 result in a neurological syndrome combining cerebellar atrophy and spinal motoneuronopathy, thus expanding the list of human exosomopathies. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Long-term functional recovery and compensation after cerebral ischemia in rats.

PubMed

Girard, Sylvie; Murray, Katie N; Rothwell, Nancy J; Metz, Gerlinde A S; Allan, Stuart M

2014-08-15

Cerebral ischemia is one of the most common causes of disabilities in adults and leads to long-term motor and cognitive impairments with limited therapeutic possibilities. Treatment options have proven efficient in preclinical models of cerebral ischemia but have failed in the clinical setting. This limited translation may be due to the suitability of models used and outcomes measured as most studies have focused on the early period after injury with gross motor scales, which have limited correlation to the clinical situation. The aim of this study was to determine long-term functional outcomes after cerebral ischemia in rats, focusing on fine motor function, social and depressive behavior as clinically relevant measures. A secondary objective was to evaluate the effects of an anti-inflammatory treatment (interleukin-1 receptor antagonist (IL-1Ra)) on functional recovery and compensation. Infarct volume was correlated with long-term (25 days) impairments in fine motor skills, but not with emotional components of behavior. Motor impairments could not be detected using conventional neurological tests and only detailed analysis allowed differentiation between recovery and compensation. Acute systemic administration of IL-1Ra (at reperfusion) led to a faster and more complete recovery, but delayed (24h) IL-1Ra treatment had no effect. In summary functional assessment after brain injury requires detailed motor tests in order to address long-term impairments and compensation processes that are mediated by intact tissues. Functional deficits in skilled movement after brain injury represent ideal predictors of long-term outcomes and should become standard measures in the assessment of preclinical animal models. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates.

PubMed

Eluvathingal, Thomas J; Behen, Michael E; Chugani, Harry T; Janisse, James; Bernardi, Bruno; Chakraborty, Pulak; Juhasz, Csaba; Muzik, Otto; Chugani, Diane C

2006-10-01

We assessed the structural and functional imaging features of cerebellar lesions and their neurobehavioral correlates in a large cohort of patients with tuberous sclerosis complex. A consecutive series of 78 patients with tuberous sclerosis complex underwent magnetic resonance imaging (MRI) and positron emission tomography (PET) studies with [(18)F]fluorodeoxyglucose (FDG) and alpha-[(11)C]methyl-l-tryptophan (AMT) as part of their evaluation for epilepsy surgery. Neurobehavioral assessment included the Gilliam Autism Rating Scales (GARS) and the Vineland Adaptive Behavior Scales (VABS). Twenty-one patients (27%) had cerebellar lesions (10 boys; mean age 9 +/- 8 years; 9 had right-sided, 10 had left-sided, and 2 had bilateral cerebellar lesions). The lesions showed decreased glucose metabolism (0.79 +/- 0.10) and increased (1.04 +/- 0.10) AMT uptake compared with the normal (nonlesional) cerebellar cortex. Comparisons between patients with (n = 20) and without (n = 57) a cerebellar lesion on neurobehavioral functioning, controlling for the number and location of cortical tubers, revealed that the cerebellar lesion group had higher overall autistic symptomatology. Within-group analyses of the cerebellar lesion group revealed that children with right-sided cerebellar lesions had higher social isolation and communicative and developmental disturbance compared with children with left-sided cerebellar lesions. The side of the cerebellar lesion was not related to adaptive behavior functioning. These findings provide additional empiric support for a role of the cerebellum in autistic symptomatology. Further investigation of the potential role of the right cerebellum in autism, particularly with regard to the dentatothalamofrontal circuit, is warranted.

Long-term results of a pilot study of low dose cranial-spinal irradiation for cerebellar medulloblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brand, W.N.; Schneider, P.A.; Tokars, R.P.

1987-11-01

Between May 1974 and March 1983, 44 children with histologically verified cerebellar medulloblastoma were seen for post-operative cranial-spinal irradiation following attempted total tumor removal. Six patients were excluded from review because they received all or part of their treatment at another institution (3 patients) or did not complete the planned course of irradiation (3 patients). All of the 38 remaining patients were treated by a previously described technique on a 4 MeV Linear Accelerator with 55 Gy delivered to the primary tumor site. Prior to December 1978, 19 consecutive children (Group A) had spinal prophylactic doses of 30-40 Gy andmore » brain prophylactic doses of 40-50 Gy. After the date, 25 Gy was given to the cranial-spinal axis of 19 consecutive children (Group B). This lower dose was arbitrarily selected with the hope of reducing morbidity in treated survivors and achieving the same tumor control. Risk factors that define good and poor prognosis were evaluated for each group, and there were no differences noted. Myelography and CSF cytology were not routinely performed. Follow-up for the 38 patients ranges from 20 months to 124 months. For the low risk patients, survival (12/15 or 80%) was independent of cranial-spinal radiation dose (Group A 6/8, Group B 6/7). For the high risk patients survival was poor (9/23 or 39%), not dependent on cranial-spinal radiation dose (Group A 5/11, Group B 4/12), and associated with failure at the primary site (10/14), often with CSF seeding (8/10). The other 4 failures include 2 who had moved outside the United States (details of failure are unknown), 1 with supratentorial, CSF seeding and distant metastases, and 1 with distant metastasis only.« less

Lesions causing freezing of gait localize to a cerebellar functional network

PubMed Central

Fasano, Alfonso; Laganiere, Simon E.; Lam, Susy; Fox, Michael D.

2016-01-01

Objective Freezing of gait is a disabling symptom in Parkinson’s disease and related disorders, but the brain regions involved in symptom generation remain unclear. Here we analyze brain lesions causing acute onset freezing of gait to identify regions causally involved in symptom generation. Methods Fourteen cases of lesion-induced freezing of gait were identified from the literature and lesions were mapped to a common brain atlas. Because lesion-induced symptoms can come from sites connected to the lesion location, not just the lesion location itself, we also identified brain regions functionally connected to each lesion location. This technique, termed lesion network mapping, has been recently shown to identify regions involved in symptom generation across a variety of lesion-induced disorders. Results Lesion location was heterogeneous and no single region could be considered necessary for symptom generation. However, over 90% (13/14) of lesions were functionally connected to a focal area in the dorsal medial cerebellum. This cerebellar area overlapped previously recognized regions that are activated by locomotor tasks, termed the cerebellar locomotor region. Connectivity to this region was specific to lesions causing freezing of gait compared to lesions causing other movement disorders (hemichorea or asterixis). Interpretation Lesions causing freezing of gait are located within a common functional network characterized by connectivity to the cerebellar locomotor region. These results based on causal brain lesions complement prior neuroimaging studies in Parkinson’s disease patients, advancing our understanding of the brain regions involved in freezing of gait. PMID:28009063

Redintegration and the benefits of long-term knowledge in verbal short-term memory: an evaluation of Schweickert's (1993) multinomial processing tree model.

PubMed

Thorn, Annabel S C; Gathercole, Susan E; Frankish, Clive R

2005-03-01

The impact of four long-term knowledge variables on serial recall accuracy was investigated. Serial recall was tested for high and low frequency words and high and low phonotactic frequency nonwords in 2 groups: monolingual English speakers and French-English bilinguals. For both groups the recall advantage for words over nonwords reflected more fully correct recalls with fewer recall attempts that consisted of fragments of the target memory items (one or two of the three target phonemes recalled correctly); completely incorrect recalls were equivalent for the 2 list types. However, word frequency (for both groups), nonword phonotactic frequency (for the monolingual group), and language familiarity all influenced the proportions of completely incorrect recalls that were made. These results are not consistent with the view that long-term knowledge influences on immediate recall accuracy can be exclusively attributed to a redintegration process of the type specified in multinomial processing tree model of immediate recall. The finding of a differential influence on completely incorrect recalls of these four long-term knowledge variables suggests instead that the beneficial effects of long-term knowledge on short-term recall accuracy are mediated by more than one mechanism.

Long-term Rebamipide and Diquafosol in Two Cases of Immune-Mediated Dry Eye

PubMed Central

Yamane, Mio; Ogawa, Yoko; Fukui, Masaki; Kamoi, Mizuka; Saijo-Ban, Yumiko; Yaguchi, Saori; Mukai, Shin; Kawakita, Tetsuya; Simmura, Shigeto; Tsubota, Kazuo

2015-01-01

ABSTRACT Purpose Two new drugs with mucin-inducing and secretion-promotive effects, rebamipide and diquafosol, were recently approved as topical dry-eye treatments. We report two cases in which the long-term use of mucin-inducing eye drops improved chronic ocular graft-versus-host disease (cGVHD)–related dry eye and ocular cicatricial pemphigoid (OCP)-like disease. Case Reports Case 1. A 61-year-old woman had cGVHD-related dry eye that resisted traditional medications. Next, we use topical diquafosol in addition to conventional treatments. The patient used diquafosol for 6 months without experiencing any side effects. The symptoms, including dry-eye sensation, ocular pain, foreign body sensation, and photophobia, as well as ocular surface findings including fluorescein and rose bengal scores and tear break-up time (TBUT), partly improved. To further improve the clinical signs and symptoms and decrease chronic inflammation, rebamipide was added to diquafosol. The symptoms, TBUT, and fluorescein and rose bengal scores markedly improved after long-term dual treatment without any side effects for 6 months. Case 2. A 77-year-old woman had OCP-like disease with dry eye. The patient did not improve using the currently available conventional treatments. Next, we use topical rebamipide in addition to conventional treatments. Symptoms including asthenopia, dry-eye sensation, ocular pain, and dull sensation, as well as fluorescein and rose bengal scores and TBUT, partly improved. Specifically, functional visual acuity was markedly improved after commencement of rebamipide. To further improve the clinical signs and symptoms and increase tear film stability and tear film volume, diquafosol was added to rebamipide. The combination of diquafosol and rebamipide worked for the patient. Improvements were seen in several symptoms, fluorescein and rose bengal scores, Schirmer test value, and TBUT without any side effects for 12 months. Conclusions Long-term treatment with topical

Long-term rebamipide and diquafosol in two cases of immune-mediated dry eye.

PubMed

Yamane, Mio; Ogawa, Yoko; Fukui, Masaki; Kamoi, Mizuka; Saijo-Ban, Yumiko; Yaguchi, Saori; Mukai, Shin; Kawakita, Tetsuya; Simmura, Shigeto; Tsubota, Kazuo

2015-04-01

Two new drugs with mucin-inducing and secretion-promotive effects, rebamipide and diquafosol, were recently approved as topical dry-eye treatments. We report two cases in which the long-term use of mucin-inducing eye drops improved chronic ocular graft-versus-host disease (cGVHD)-related dry eye and ocular cicatricial pemphigoid (OCP)-like disease. Case 1. A 61-year-old woman had cGVHD-related dry eye that resisted traditional medications. Next, we use topical diquafosol in addition to conventional treatments. The patient used diquafosol for 6 months without experiencing any side effects. The symptoms, including dry-eye sensation, ocular pain, foreign body sensation, and photophobia, as well as ocular surface findings including fluorescein and rose bengal scores and tear break-up time (TBUT), partly improved. To further improve the clinical signs and symptoms and decrease chronic inflammation, rebamipide was added to diquafosol. The symptoms, TBUT, and fluorescein and rose bengal scores markedly improved after long-term dual treatment without any side effects for 6 months. Case 2. A 77-year-old woman had OCP-like disease with dry eye. The patient did not improve using the currently available conventional treatments. Next, we use topical rebamipide in addition to conventional treatments. Symptoms including asthenopia, dry-eye sensation, ocular pain, and dull sensation, as well as fluorescein and rose bengal scores and TBUT, partly improved. Specifically, functional visual acuity was markedly improved after commencement of rebamipide. To further improve the clinical signs and symptoms and increase tear film stability and tear film volume, diquafosol was added to rebamipide. The combination of diquafosol and rebamipide worked for the patient. Improvements were seen in several symptoms, fluorescein and rose bengal scores, Schirmer test value, and TBUT without any side effects for 12 months. Long-term treatment with topical rebamipide and diquafosol can improve dry eye

Factors associated with the misdiagnosis of cerebellar infarction.

PubMed

Masuda, Yoko; Tei, Hideaki; Shimizu, Satoru; Uchiyama, Shinichiro

2013-10-01

Cerebellar infarction is easily misdiagnosed or underdiagnosed. In this study, we investigated factors leading to misdiagnosis of cerebellar infarction in patients with acute ischemic stroke. Data on neurological and radiological findings from 114 consecutive patients with acute cerebellar infarction were analyzed. We investigated factors associated with misdiagnosis from the data on clinical findings. Thirty-two (28%) patients were misdiagnosed on admission. Misdiagnosis was significantly more frequent in patients below 60 years of age and in patients with vertebral artery dissection, and significantly less frequent in patients with dysarthria. It tended to be more frequent in patients with the medial branch of posterior inferior cerebellar artery territory infarction, and infrequent in patients with the medial branch of the superior cerebellar artery territory infarction. Thirty out of 32 (94%) misdiagnosed patients were seen by physicians that were not neurologists at the first visit. Twenty-four of 32 (75%) misdiagnosed patients were screened only by brain CT. However, patients were not checked by brain MRI or follow-up CT until their conditions worsened. Patients below 60 years of age and patients with vertebral artery dissection are more likely to have a cerebellar infarction misdiagnosed by physicians other than neurologists. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Out of place: mediating health and social care in Ontario's long-term care sector.

PubMed

Daly, Tamara

2007-01-01

The paper discusses two reforms in Ontario's long-term care. The first is the commercialization of home care as a result of the implementation of a "managed competition" delivery model. The second is the Ministry of Health and Long-Term Care's privileging of "health care" over "social care" through changes to which types of home care and home support services receive public funding. It addresses the effects of these reforms on the state–non-profit relationship, and the shifting balance between public funding of health and social care. At a program level, and with few exceptions, homemaking services have been cut from home care, and home support services are more medicalized. With these changes, growing numbers of people no longer eligible to receive publicly funded home care services look for other alternatives: they draw available resources from home support, they draw on family and friend networks, they hire privately and pay out of pocket, they leave home and enter an institution, or they do without.

Caspase-mediated apoptosis induction in zebrafish cerebellar Purkinje neurons.

PubMed

Weber, Thomas; Namikawa, Kazuhiko; Winter, Barbara; Müller-Brown, Karina; Kühn, Ralf; Wurst, Wolfgang; Köster, Reinhard W

2016-11-15

The zebrafish is a well-established model organism in which to study in vivo mechanisms of cell communication, differentiation and function. Existing cell ablation methods are either invasive or they rely on the cellular expression of prokaryotic enzymes and the use of antibiotic drugs as cell death-inducing compounds. We have recently established a novel inducible genetic cell ablation system based on tamoxifen-inducible Caspase 8 activity, thereby exploiting mechanisms of cell death intrinsic to most cell types. Here, we prove its suitability in vivo by monitoring the ablation of cerebellar Purkinje cells (PCs) in transgenic zebrafish that co-express the inducible caspase and a fluorescent reporter. Incubation of larvae in tamoxifen for 8 h activated endogenous Caspase 3 and cell death, whereas incubation for 16 h led to the near-complete loss of PCs by apoptosis. We observed synchronous cell death autonomous to the PC population and phagocytosing microglia in the cerebellum, reminiscent of developmental apoptosis in the forebrain. Thus, induction of apoptosis through targeted activation of caspase by tamoxifen (ATTAC TM ) further expands the repertoire of genetic tools for conditional interrogation of cellular functions. © 2016. Published by The Company of Biologists Ltd.

Reforming long-term care financing through insurance

PubMed Central

Meiners, Mark R.

1988-01-01

Until recently, insurance for long-term care was not viewed as feasible. This perception has changed dramatically in the past few years. Several models of long-term care insurance have begun to be tested. Although the application of insurance principles to long-term care is still new, the emergence of private market interest in developing long-term care insurance has been a catalyst to renewed public-policy support for reforming the way we pay for long-term care. States, in particular, have become interested in developing public-private partnerships to support the emergence of long-term care insurance that could help relieve the mounting pressure on Medicaid budgets. PMID:10312962

GDF15 regulates Kv2.1-mediated outward K+ current through the Akt/mTOR signalling pathway in rat cerebellar granule cells.

PubMed

Wang, Chang-Ying; Huang, An-Qi; Zhou, Meng-Hua; Mei, Yan-Ai

2014-05-15

GDF15 (growth/differentiation factor 15), a novel member of the TGFβ (transforming growth factor β) superfamily, plays critical roles in the central and peripheral nervous systems, but the signal transduction pathways and receptor subtypes involved are not well understood. In the present paper, we report that GDF15 specifically increases the IK (delayed-rectifier outward K+ current) in rat CGNs (cerebellar granule neurons) in time- and concentration-dependent manners. The GDF15-induced amplification of the IK is mediated by the increased expression and reduced lysosome-dependent degradation of the Kv2.1 protein, the main α-subunit of the IK channel. Exposure of CGNs to GDF15 markedly induced the phosphorylation of ERK (extracellular-signal-regulated kinase), Akt and mTOR (mammalian target of rapamycin), but the GDF15-induced IK densities and increased expression of Kv2.1 were attenuated only by Akt and mTOR, and not ERK, inhibitors. Pharmacological inhibition of the Src-mediated phosphorylation of TGFβR2 (TGFβ receptor 2), not TGFβR1, abrogated the effect of GDF15 on IK amplification and Kv2.1 induction. Immunoprecipitation assays showed that GDF15 increased the tyrosine phosphorylation of TGFβRII in the CGN lysate. The results of the present study reveal a novel regulation of Kv2.1 by GDF15 mediated through the TGFβRII-activated Akt/mTOR pathway, which is a previously uncharacterized Smad-independent mechanism of GDF15 signalling.

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.

Normal Cerebellar Growth by Using Three-dimensional US in the Preterm Infant from Birth to Term-corrected Age.

PubMed

Benavente-Fernández, Isabel; Rodríguez-Zafra, Enrique; León-Martínez, Jesús; Jiménez-Gómez, Gema; Ruiz-González, Estefanía; Fernández-Colina, Rosalía Campuzano; Lechuga-Sancho, Alfonso M; Lubián-López, Simón P

2018-04-03

Purpose To establish cross-sectional and longitudinal reference values for cerebellar size in preterm infants with normal neuroimaging findings and normal 2-year neurodevelopmental outcome by using cranial ultrasonography (US). Materials and Methods This prospective study consecutively enrolled preterm infants admitted to a neonatal intensive care unit from June 2011 to June 2014 with a birth weight of less than or equal to 1500 g and/or gestational age (GA) of less than or equal to 32 weeks. They underwent weekly cranial US from birth to term-equivalent age and magnetic resonance (MR) imaging at term-equivalent age. The infants underwent neurodevelopmental assessments at age 2 years with Bayley Scales of Infant and Toddler Development, 3rd edition (BSID-III). Patients with adverse outcomes (death or abnormal neuroimaging findings and/or BSID-III score of <85) were excluded. The following measurements were performed: vermis height, craniocaudal diameter, superior width, inferior width, vermis area, and transcerebellar diameter. Statistical analyses were conducted by using multilevel analyses. Results A total of 137 infants with a mean GA at birth of 29.4 weeks (range, 25-32 weeks) were included. Transcerebellar diameter increased by 1.04 mm per week on average; vermis height and craniocaudal diameter increased by 0.55 mm and 0.59 mm, respectively. Superior vermian width increased by an average of 0.45 mm, whereas inferior vermian width increased by an average of 0.51 mm per week. Vermis area was found to increase by 0.22 cm 2 per week on average. The sex effect was significant (female lower than male) for vermis height (P < .05), craniocaudal diameter (P < .05), inferior vermian width (P <. 05), and vermis area (P <. 05). Conclusion Cross-sectional and longitudinal reference values were established for cerebellar growth in preterm infants, which may be included in routine cranial US. © RSNA, 2018 Online supplemental material is available for this article.

Management training in long-term care.

PubMed

Evashwick, Connie

2002-01-01

The education of health care administrators faces its most dramatic change since the inception of the field. Recent discussions at the national level call for major overhaul of curricula and teaching modalities, including moving education to position students for evidence-based practice. This paper presents recommendations for incorporating training about chronic and long-term care into health care management curricula. It asserts that all health care management students should have a basic knowledge of the fundamental policy, operating, and financing principles of long-term care. The majority of people using the health care delivery system today, and increasingly in the future, suffer from chronic conditions. Long-term care services, although less expansive in structure, far outnumber acute care services and health plans. They will grow in the future to meet the portending demand. To maximize job opportunities and to optimize performance in any job, health care administrators need to know about the long-term care delivery system. This paper delineates critical topics pertaining to long-term care, organized according to 11 fundamental management areas in which the field is developing core competencies. The contents were derived from a year-long process of asking stakeholders in the various facets of long-term care what topics they thought were essential for administrators to know. The topics delineated in this document represent the consensus about essential knowledge that all health care administrators should have about long-term care, whether specializing in long-term care or following a more general management career. The education of health care administrators faces its most dramatic change since the inception ofthe field. Recent discussions at the national level call for major overhaul of curricula and teaching modalities, including moving education to position students to perform according to evidence-based practice. It is thus timely to consider content, as

Contralateral cortico-ponto-cerebellar pathways reconstruction in humans in vivo: implications for reciprocal cerebro-cerebellar structural connectivity in motor and non-motor areas.

PubMed

Palesi, Fulvia; De Rinaldis, Andrea; Castellazzi, Gloria; Calamante, Fernando; Muhlert, Nils; Chard, Declan; Tournier, J Donald; Magenes, Giovanni; D'Angelo, Egidio; Gandini Wheeler-Kingshott, Claudia A M

2017-10-09

Cerebellar involvement in cognition, as well as in sensorimotor control, is increasingly recognized and is thought to depend on connections with the cerebral cortex. Anatomical investigations in animals and post-mortem humans have established that cerebro-cerebellar connections are contralateral to each other and include the cerebello-thalamo-cortical (CTC) and cortico-ponto-cerebellar (CPC) pathways. CTC and CPC characterization in humans in vivo is still challenging. Here advanced tractography was combined with quantitative indices to compare CPC to CTC pathways in healthy subjects. Differently to previous studies, our findings reveal that cerebellar cognitive areas are reached by the largest proportion of the reconstructed CPC, supporting the hypothesis that a CTC-CPC loop provides a substrate for cerebro-cerebellar communication during cognitive processing. Amongst the cerebral areas identified using in vivo tractography, in addition to the cerebral motor cortex, major portions of CPC streamlines leave the prefrontal and temporal cortices. These findings are useful since provide MRI-based indications of possible subtending connectivity and, if confirmed, they are going to be a milestone for instructing computational models of brain function. These results, together with further multi-modal investigations, are warranted to provide important cues on how the cerebro-cerebellar loops operate and on how pathologies involving cerebro-cerebellar connectivity are generated.

Paraneoplastic cerebellar ataxia and the paraneoplastic syndromes

PubMed Central

Afzal, Sadaf; Recio, Maria

2015-01-01

Paraneoplastic cerebellar ataxia, also known as paraneoplastic cerebellar degeneration, is one of the wide array of paraneoplastic neurological syndromes in which neurological symptoms are indirectly caused by an underlying malignancy, most commonly gynecological, breast, or lung cancer or Hodgkin's lymphoma. We describe a patient with severe cerebellar dysfunction attributed to a paraneoplastic neurological syndrome. The case highlights the need to look for paraneoplastic syndromes—both to discover malignancies early, at a treatable stage, and, as in our case, to address very distressing symptoms for the patient's relief even if the malignancy is not curable. PMID:25829659

Modality specificity in the cerebro-cerebellar neurocircuitry during working memory.

PubMed

Ng, H B Tommy; Kao, K-L Cathy; Chan, Y C; Chew, Effie; Chuang, K H; Chen, S H Annabel

2016-05-15

Previous studies have suggested cerebro-cerebellar circuitry in working memory. The present fMRI study aims to distinguish differential cerebro-cerebellar activation patterns in verbal and visual working memory, and employs a quantitative analysis to deterimine lateralization of the activation patterns observed. Consistent with Chen and Desmond (2005a,b) predictions, verbal working memory activated a cerebro-cerebellar circuitry that comprised left-lateralized language-related brain regions including the inferior frontal and posterior parietal areas, and subcortically, right-lateralized superior (lobule VI) and inferior cerebellar (lobule VIIIA/VIIB) areas. In contrast, a distributed network of bilateral inferior frontal and inferior temporal areas, and bilateral superior (lobule VI) and inferior (lobule VIIB) cerebellar areas, was recruited during visual working memory. Results of the study verified that a distinct cross cerebro-cerebellar circuitry underlies verbal working memory. However, a neural circuitry involving specialized brain areas in bilateral neocortical and bilateral cerebellar hemispheres subserving visual working memory is observed. Findings are discussed in the light of current models of working memory and data from related neuroimaging studies. Copyright © 2016 Elsevier B.V. All rights reserved.

Placenta previa and long-term morbidity of the term offspring.

PubMed

Walfisch, Asnat; Beharier, Ofer; Shoham-Vardi, Ilana; Sergienko, Ruslan; Landau, Daniella; Sheiner, Eyal

2016-08-01

The long-term impact of placenta previa on term infants is unknown. We aimed to investigate whether abnormal placentation increases the risk for long-term morbidity of the term offspring. A population-based cohort study compared the incidence of long-term hospitalizations up to the age of 18 due to cardiovascular, endocrine, neurological, hematological, respiratory and urinary morbidity of children born at term in pregnancies diagnosed with placenta previa and those without. Deliveries occurred between the years 1991-2013 in a tertiary medical center. Multiple pregnancies, and fetal congenital malformations were excluded. Kaplan-Meier survival curves were used to compare cumulative morbidity incidence over time. A multivariable generalized estimating equation (GEE) logistic regression model analysis was used to control for confounders and for maternal clusters. During the study period 233,123 term deliveries met the inclusion criteria; 0.2% (n=502) of the children were born to mothers with placenta previa. During the follow-up period, children born to mothers with placenta previa did not have an increased risk for long-term cardiovascular, endocrine, hematological, neurological, respiratory, and urinary morbidity. Term offsprings of mothers diagnosed with placenta previa do not appear to be at an increased risk for long-term morbidity up to the age of 18. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Consider long-term care as service alternative.

PubMed

Loria, L S

1987-04-01

The increasing demand for elderly care services, pressures on inpatient average length of stay and payment levels, and potential financial rewards from providing additional services, makes long-term care look attractive to hospitals. Long-term care, however, is not for every hospital. Before deciding to establish long-term care services, management should examine how the service fits within the hospital's strategic plan. The action plan below provides guidance in evaluating a decision to use hospital facilities for long-term care. Examine how long-term care services fit within the hospital's strategic plan. Study area demographics and competitors to assess the need and supply of long-term care services. Survey the medical staff, consumers and payers to determine attitudes, perceptions and interests regarding long-term care services. Develop a facility plan that identifies areas of excess capacity that can be most easily converted into long-term care with minimal effects on hospital operations. Prepare a financial feasibility analysis of the contribution margin and return on investment attributable to long-term care services. Include an impact analysis on hospital operations. Establish a management task force to develop a detailed implementation plan including assigned individual responsibilities and related timetable. Develop an effective marketing plan designed to generate increased patient market share.

Infantile onset progressive cerebellar atrophy and anterior horn cell degeneration--a late onset variant of PCH-1?

PubMed

Lev, Dorit; Michelson-Kerman, Marina; Vinkler, Chana; Blumkin, Lubov; Shalev, Stavit A; Lerman-Sagie, Tally

2008-03-01

Despite major recent advances in our understanding of developmental cerebellar disorders, classification and delineation of these disorders remains difficult. The term pontocerebellar hypoplasia is used when there is a structural defect, originating in utero of both pons and cerebellar hemispheres. The term olivopontocerebellar atrophy is used when the disorder starts later in life and the process is a primary degeneration of cerebellar neurons. Pontocerebellar hypoplasia type 1 is associated with spinal anterior horn cell degeneration, congenital contractures, microcephaly, polyhydramnion and respiratory insufficiency leading to early death. However, anterior horn cell degeneration has also been described in cases with later onset pontocerebellar atrophy and recently the spectrum has even been further extended to include the association of anterior horn cell degeneration and cerebellar atrophy without pontine involvement. We describe two siblings from a consanguineous Moslem Arabic family who presented with progressive degeneration of both the cerebellum and the anterior horn cells. The patients presented after 1 year of age with a slow neurodegenerative course that included both cognitive and motor functions. There is considerable phenotypic variability; the sister shows a much milder course. Both children are still alive at 6 and 9 years. The sister could still crawl and speak two word sentences at the age of 3 years while the brother was bedridden and only uttered guttural sounds at the same age. Our cases further extend the phenotype of the cerebellar syndromes with anterior horn cell involvement to include a childhood onset and protracted course and further prove that this neurodegenerative disorder may start in utero or later in life.

Long-term data archiving

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moore, David Steven

2009-01-01

Long term data archiving has much value for chemists, not only to retain access to research and product development records, but also to enable new developments and new discoveries. There are some recent regulatory requirements (e.g., FDA 21 CFR Part 11), but good science and good business both benefit regardless. A particular example of the benefits of and need for long term data archiving is the management of data from spectroscopic laboratory instruments. The sheer amount of spectroscopic data is increasing at a scary rate, and the pressures to archive come from the expense to create the data (or recreatemore » it if it is lost) as well as its high information content. The goal of long-term data archiving is to save and organize instrument data files as well as any needed meta data (such as sample ID, LIMS information, operator, date, time, instrument conditions, sample type, excitation details, environmental parameters, etc.). This editorial explores the issues involved in long-term data archiving using the example of Raman spectral databases. There are at present several such databases, including common data format libraries and proprietary libraries. However, such databases and libraries should ultimately satisfy stringent criteria for long term data archiving, including readability for long times into the future, robustness to changes in computer hardware and operating systems, and use of public domain data formats. The latter criterion implies the data format should be platform independent and the tools to create the data format should be easily and publicly obtainable or developable. Several examples of attempts at spectral libraries exist, such as the ASTM ANDI format, and the JCAMP-DX format. On the other hand, proprietary library spectra can be exchanged and manipulated using proprietary tools. As the above examples have deficiencies according to the three long term data archiving criteria, Extensible Markup Language (XML; a product of the World Wide

Prolonged post-inhibitory rebound firing in the cerebellar nuclei mediated by group I mGluR potentiation of L-type Ca currents

PubMed Central

Zheng, Nan; Raman, Indira M.

2011-01-01

Neurons in the cerebellar nuclei fire at accelerated rates for prolonged periods after trains of synaptic inhibition that interrupt spontaneous firing. Both in vitro and in vivo, however, this prolonged rebound firing is favored by strong stimulation of afferents, suggesting that neurotransmitters other than GABA may contribute to the increased firing rates. Here, we tested whether metabotropic glutamate receptors modulate excitability of nuclear cells in cerebellar slices from mouse. In current clamp, the prolonged rebound firing rate after high-frequency synaptic stimulation was reduced by a variety of group I mGluR antagonists, including CPCCOEt (7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester), JNJ16259685 ((3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone)+MPEP, or 3-MATIDA (α-amino-5-carboxy-3-methyl-2-thiopheneacetic acid) +MPEP, as long as both mGluR1 and mGluR5 were blocked. This mGluR-dependent acceleration of firing was reduced but still evident when IPSPs were prevented by GABAA receptor antagonists. In voltage clamp, voltage ramps revealed a non-inactivating, low-voltage-activated, nimodipine-sensitive current that was enhanced by the selective group I mGluR agonist s-DHPG ((S)-3,5-dihydroxyphenylglycine). This putative L-type current also increased when mGluRs were activated by trains of evoked synaptic currents instead of direct application of agonist. In current clamp, blocking L-type Ca channels with the specific blocker nifedipine greatly reduced prolonged post-stimulus firing and occluded the effect of adding group I mGluR antagonists. Thus, potentiation of a low-voltage-activated L-type current by synaptically released glutamate accounted nearly fully for the mGluR-dependent acceleration of firing. Together, these data suggest that prolonged rebound firing in the cerebellar nuclei in vivo is most likely to occur when GABAA and mGluRs are simultaneously activated by concurrent excitation and

Long-Term Control Medications for Lung Diseases

MedlinePlus

... Asthma Medications Long-Term Control Medications Long-Term Control Medications Make an Appointment Ask a Question Refer Patient Long-term control medications are taken daily to control and prevent ...

Stress and glucocorticoid receptor-dependent mechanisms in long-term memory: from adaptive responses to psychopathologies

PubMed Central

Finsterwald, Charles; Alberini, Cristina M.

2013-01-01

A proper response against stressors is critical for survival. In mammals, the stress response is primarily mediated by secretion of glucocorticoids via the hypothalamic-pituitaryadrenocortical (HPA) axis and release of catecholamines through adrenergic neurotransmission. Activation of these pathways results in a quick physical response to the stress and, in adaptive conditions, mediates long-term changes in the brain that lead to the formation of long-term memories of the experience. These long-term memories are an essential adaptive mechanism that allows an animal to effectively face similar demands again. Indeed, a moderate stress level has a strong positive effect on memory and cognition, as a single arousing or moderately stressful event can be remembered for up to a lifetime. Conversely, exposure to extreme, traumatic, or chronic stress can have the opposite effect and cause memory loss, cognitive impairments, and stress-related psychopathologies such as anxiety disorders, depression and post-traumatic stress disorder (PTSD). While more effort has been devoted to the understanding of the effects of the negative effects of chronic stress, much less has been done thus far on the identification of the mechanisms engaged in the brain when stress promotes long-term memory formation. Understanding these mechanisms will provide critical information for use in ameliorating memory processes in both normal and pathological conditions. Here, we will review the role of glucocorticoids and glucocorticoid receptors (GRs) in memory formation and modulation. Furthermore, we will discuss recent findings on the molecular cascade of events underlying the effect of GR activation in adaptive levels of stress that leads to strong, long-lasting memories. Our recent data indicate that the positive effects of GR activation on memory consolidation critically engage the brain-derived neurotrophic factor (BDNF) pathway. We propose and will discuss the hypothesis that stress promotes the

[Health-related long-term effects of adverse childhood experiences - an update].

PubMed

Egle, Ulrich T; Franz, Matthias; Joraschky, Peter; Lampe, Astrid; Seiffge-Krenke, Inge; Cierpka, Manfred

2016-10-01

In the last decade strong empirical evidence from several long-term studies supports the conclusion that physical and sexual abuse as well as emotional deprivation in childhood make people significantly more vulnerable to mental and functional disorders across their lifetime. Additionally, an increased vulnerability to several somatic disorders (cardiovascular disorders, type-2-diabetes, hepatitis, chronic obstructive pulmonary disease (COPD), immunological and pain disorders, pharynx and lung cancer) was demonstrated - most of them with a reduced life expectancy. A review of the current research will be presented that outlines the underlying developmental neurobiological and psychological mechanisms mediating these long-term effects. There is now sufficient evidence about familial risk constellations that demonstrates the well-documented impact of specific prevention strategies by several model projects. Only by establishing these strategies, future enormous health-related burdens and high economic costs (unfitness to work, early retirement) can presumably be limited.

Reforming Long-Term Care Funding in Alberta.

PubMed

Crump, R Trafford; Repin, Nadya; Sutherland, Jason M

2015-01-01

Like many provinces across Canada, Alberta is facing growing demand for long-term care. Issues with the mixed funding model used to pay long-term care providers had Alberta Health Services concerned that it was not efficiently meeting the demand for long-term care. Consequently, in 2010, Alberta Health Services introduced the patient/care-based funding (PCBF) model. PCBF is similar to activity-based funding in that it directly ties the complexity and care needs of long-term care residents to the payment received by long-term care providers. This review describes PCBF and discusses some of its strengths and weaknesses. In doing so, this review is intended to inform other provinces faced with similar long-term care challenges and contemplating their own funding reforms.

Aberrant cerebellar connectivity in bipolar disorder with psychosis.

PubMed

Shinn, Ann K; Roh, Youkyung S; Ravichandran, Caitlin T; Baker, Justin T; Öngür, Dost; Cohen, Bruce M

2017-07-01

The cerebellum, which modulates affect and cognition in addition to motor functions, may contribute substantially to the pathophysiology of mood and psychotic disorders, such as bipolar disorder. A growing literature points to cerebellar abnormalities in bipolar disorder. However, no studies have investigated the topographic representations of resting state cerebellar networks in bipolar disorder, specifically their functional connectivity to cerebral cortical networks. Using a well-defined cerebral cortical parcellation scheme as functional connectivity seeds, we compared ten cerebellar resting state networks in 49 patients with bipolar disorder and a lifetime history of psychotic features and 55 healthy control participants matched for age, sex, and image signal-to-noise ratio. Patients with psychotic bipolar disorder showed reduced cerebro-cerebellar functional connectivity in somatomotor A, ventral attention, salience, and frontoparietal control A and B networks relative to healthy control participants. These findings were not significantly correlated with current symptoms. Patients with psychotic bipolar disorder showed evidence of cerebro-cerebellar dysconnectivity in selective networks. These disease-related changes were substantial and not explained by medication exposure or substance use. Therefore, they may be mechanistically relevant to the underlying susceptibility to mood dysregulation and psychosis. Cerebellar mechanisms deserve further exploration in psychiatric conditions, and this study's findings may have value in guiding future studies on pathophysiology and treatment of mood and psychotic disorders, in particular.

Cerebellar contribution to locomotor behavior: A neurodevelopmental perspective.

PubMed

Sathyanesan, Aaron; Gallo, Vittorio

2018-04-30

The developmental trajectory of the formation of cerebellar circuitry has significant implications for locomotor plasticity and adaptive learning at later stages. While there is a wealth of knowledge on the development of locomotor behavior in human infants, children, and adolescents, pre-clinical animal models have fallen behind on the study of the emergence of behavioral motifs in locomotor function across postnatal development. Since cerebellar development is protracted, it is subject to higher risk of genetic or environmental disruption, potentially leading to abnormal behavioral development. This highlights the need for more sophisticated and specific functional analyses of adaptive cerebellar behavior within the context of whole-body locomotion across the entire span of postnatal development. Here we review evidence on cerebellar contribution to adaptive locomotor behavior, highlighting methodologies employed to quantify and categorize behavior at different developmental stages, with the ultimate goal of following the course of early behavioral alterations in neurodevelopmental disorders. Since experimental paradigms used to study cerebellar behavior are lacking in both specificity and applicability to locomotor contexts, we highlight the use of the Erasmus Ladder - an advanced, computerized, fully automated system to quantify adaptive cerebellar learning in conjunction with locomotor function. Finally, we emphasize the need to develop objective, quantitative, behavioral tasks which can track changes in developmental trajectories rather than endpoint measurement at the adult stage of behavior. Copyright © 2018 Elsevier Inc. All rights reserved.

T-Cell-Mediated Immune Responses in Patients with Cutaneous or Mucosal Leishmaniasis: Long-Term Evaluation after Therapy

PubMed Central

Da-Cruz, Alda Maria; Bittar, Rita; Mattos, Marise; Oliveira-Neto, Manuel P.; Nogueira, Ricardo; Pinho-Ribeiro, Vanessa; Azeredo-Coutinho, Rilza Beatriz; Coutinho, Sergio G.

2002-01-01

T-cell immune responses in patients with cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML) were studied during the active disease, at the end of therapy, and 1 to 17 years posttherapy (long-term follow-up). Lymphocyte proliferative responses, phenotypic characterization of CD4+ and CD8+ Leishmania-reactive T cells, and cytokine production were assayed. Patients with active ML and CL showed higher proportions of CD4+ than CD8+ T cells. In CL, the healing process was associated with a decrease of CD4+ and an increase of CD8+, leading to similar CD4+ and CD8+ proportions. This pattern was only seen in ML after long-term therapy. Long-term follow-up of patients with CL showed a positive CD4+/CD8+ ratio as observed during the active disease, although the percentages of these T cell subsets were significantly lower. Patients with CL did not show significant differences between gamma interferon (IFN-γ) and interleukin-5 (IL-5) production during the period of study. Patients with active ML presented higher IFN-γ and IL-5 levels compared to patients with active CL. IL-4 was only detected during active disease. Patients long term after cure from ML showed increasing production of IFN-γ, significant decrease of IL-5, and no IL-4 production. Two apparently beneficial immunological parameters were detected in tegumentary leishmaniasis: (i) decreasing proportions of CD4+ Leishmania-reactive T cells in the absence of IL-4 production associated with cure of CL and ML and (ii) decreasing levels of IL-5 long after cure, better detected in patients with ML. The observed T-cell responses maintained for a long period in healed patients could be relevant for immunoprotection against reinfection and used as a parameter for determining the prognosis of patients and selecting future vaccine preparations. PMID:11874860

Creature comforts: personal communities, pets and the work of managing a long-term condition.

PubMed

Brooks, Helen L; Rogers, Anne; Kapadia, Dharmi; Pilgrim, Jack; Reeves, David; Vassilev, Ivaylo

2013-06-01

To explore in the context of peoples' personal social networks, the contribution that pets make to 'the work' associated with the management of long-term conditions. Mixed methods survey with nested parallel qualitative study; 300 participants were drawn from diabetes and chronic heart disease registers of General Practices across Greater Manchester in the North West of England. Notions of 'work' were used to describe the illness and everyday activities associated with chronic illness. Nineteen percent of participants identified at least one pet within their network. Pets contributed mostly to managing emotions (emotional work), to enhancing a sense of self identity (biographical work) and to a lesser extent practical tasks (everyday work). There were indicators that pets mediated relationships for people living with a long-term condition through very weak ties with others in domestic and community settings. The findings suggest that pets have unique qualities and are not simply substitutes for human relationships in long-term condition management. The study has potential implications for furthering a social contextual analysis of chronic illness, the understanding of relationships, and the meaning and the role of companion animals in long-term condition management.

Creature comforts: personal communities, pets and the work of managing a long-term condition

PubMed Central

Brooks, Helen L; Rogers, Anne; Kapadia, Dharmi; Pilgrim, Jack; Reeves, David; Vassilev, Ivaylo

2013-01-01

Objectives: To explore in the context of peoples’ personal social networks, the contribution that pets make to ‘the work’ associated with the management of long-term conditions. Method: Mixed methods survey with nested parallel qualitative study; 300 participants were drawn from diabetes and chronic heart disease registers of General Practices across Greater Manchester in the North West of England. Notions of ‘work’ were used to describe the illness and everyday activities associated with chronic illness. Results: Nineteen percent of participants identified at least one pet within their network. Pets contributed mostly to managing emotions (emotional work), to enhancing a sense of self identity (biographical work) and to a lesser extent practical tasks (everyday work). There were indicators that pets mediated relationships for people living with a long-term condition through very weak ties with others in domestic and community settings. Conclusion: The findings suggest that pets have unique qualities and are not simply substitutes for human relationships in long-term condition management. The study has potential implications for furthering a social contextual analysis of chronic illness, the understanding of relationships, and the meaning and the role of companion animals in long-term condition management. PMID:22777565

Visuokinesthetic Perception of Hand Movement is Mediated by Cerebro–Cerebellar Interaction between the Left Cerebellum and Right Parietal Cortex

PubMed Central

Hagura, Nobuhiro; Oouchida, Yutaka; Aramaki, Yu; Okada, Tomohisa; Matsumura, Michikazu; Sadato, Norihiro

2009-01-01

Combination of visual and kinesthetic information is essential to perceive bodily movements. We conducted behavioral and functional magnetic resonance imaging experiments to investigate the neuronal correlates of visuokinesthetic combination in perception of hand movement. Participants experienced illusory flexion movement of their hand elicited by tendon vibration while they viewed video-recorded flexion (congruent: CONG) or extension (incongruent: INCONG) motions of their hand. The amount of illusory experience was graded by the visual velocities only when visual information regarding hand motion was concordant with kinesthetic information (CONG). The left posterolateral cerebellum was specifically recruited under the CONG, and this left cerebellar activation was consistent for both left and right hands. The left cerebellar activity reflected the participants' intensity of illusory hand movement under the CONG, and we further showed that coupling of activity between the left cerebellum and the “right” parietal cortex emerges during this visuokinesthetic combination/perception. The “left” cerebellum, working with the anatomically connected high-order bodily region of the “right” parietal cortex, participates in online combination of exteroceptive (vision) and interoceptive (kinesthesia) information to perceive hand movement. The cerebro–cerebellar interaction may underlie updating of one's “body image,” when perceiving bodily movement from visual and kinesthetic information. PMID:18453537

Network-targeted cerebellar transcranial magnetic stimulation improves attentional control

PubMed Central

Esterman, Michael; Thai, Michelle; Okabe, Hidefusa; DeGutis, Joseph; Saad, Elyana; Laganiere, Simon E.; Halko, Mark A.

2018-01-01

Developing non-invasive brain stimulation interventions to improve attentional control is extremely relevant to a variety of neurologic and psychiatric populations, yet few studies have identified reliable biomarkers that can be readily modified to improve attentional control. One potential biomarker of attention is functional connectivity in the core cortical network supporting attention - the dorsal attention network (DAN). We used a network-targeted cerebellar transcranial magnetic stimulation (TMS) procedure, intended to enhance cortical functional connectivity in the DAN. Specifically, in healthy young adults we administered intermittent theta burst TMS (iTBS) to the midline cerebellar node of the DAN and, as a control, the right cerebellar node of the default mode network (DMN). These cerebellar targets were localized using individual resting-state fMRI scans. Participants completed assessments of both sustained (gradual onset continuous performance task, gradCPT) and transient attentional control (attentional blink) immediately before and after stimulation, in two sessions (cerebellar DAN and DMN). Following cerebellar DAN stimulation, participants had significantly fewer attentional lapses (lower commission error rates) on the gradCPT. In contrast, stimulation to the cerebellar DMN did not affect gradCPT performance. Further, in the DAN condition, individuals with worse baseline gradCPT performance showed the greatest enhancement in gradCPT performance. These results suggest that temporarily increasing functional connectivity in the DAN via network-targeted cerebellar stimulation can enhance sustained attention, particularly in those with poor baseline performance. With regard to transient attention, TMS stimulation improved attentional blink performance across both stimulation sites, suggesting increasing functional connectivity in both networks can enhance this aspect of attention. These findings have important implications for intervention applications

Long-term nicotine exposure dampens LPS-induced nerve-mediated airway hyperreactivity in murine airways.

PubMed

Xu, Yuan; Cardell, Lars-Olaf

2017-09-01

Nicotine is a major component of cigarette smoke. It causes addiction and is used clinically to aid smoke cessation. The aim of the present study is to investigate the effect of nicotine on lipopolysaccharide (LPS)-induced airway hyperreactivity (AHR) and to explore the potential involvement of neuronal mechanisms behind nicotine's effects in murine models in vivo and in vitro. BALB/c mice were exposed to nicotine in vivo via subcutaneous Alzet osmotic minipumps containing nicotine tartate salt solution (24 mg·kg -1 ·day -1 ) for 28 days. LPS (0.1 mg/ml, 20 µl) was administered intranasally for 3 consecutive days during the end of this period. Lung functions were measured with flexiVent. For the in vitro experiments, mice tracheae were organcultured with either nicotine (10 μM) or vehicle (DMSO, 0.1%) for 4 days. Contractile responses of the tracheal segments were measured in myographs following electric field stimulation (EFS; increasing frequencies of 0.2 to 12.8 Hz) before and after incubation with 10 µg/ml LPS for 1 h. Results showed that LPS induced AHR to methacholine in vivo and increased contractile responses to EFS in vitro. Interestingly, long-term nicotine exposure markedly dampened this LPS-induced AHR both in vitro and in vivo. Tetrodotoxin (TTX) inhibited LPS-induced AHR but did not further inhibit nicotine-suppressed AHR in vivo. In conclusion, long-term nicotine exposure dampened LPS-induced AHR. The effect of nicotine was mimicked by TTX, suggesting the involvement of neuronal mechanisms. This information might be used for evaluating the long-term effects of nicotine and further exploring of how tobacco products interact with bacterial airway infections. Copyright © 2017 the American Physiological Society.

Postsynaptic N-type or P/Q-type calcium channels mediate long-term potentiation by group I metabotropic glutamate receptors in the trigeminal oralis.

PubMed

Weon, Haein; Kim, Tae Wan; Youn, Dong-Ho

2017-11-01

Both N-type and P/Q-type voltage-gated Ca 2+ channels (VGCCs) are involved in the induction of long-term potentiation (LTP), the long-lasting increase of synaptic strength, in the central nervous system. To provide further information on the roles of N-type and P/Q-type VGCCs in the induction of LTP at excitatory synapses of trigeminal primary afferents in the spinal trigeminal subnucleus oralis (Vo), we investigated whether they contribute to the induction of LTP by activation of group I metabotropic glutamate receptors (mGluRs). (S)-3,5-Dihydroxyphenylglycine (DHPG; 10μM for 5min), the group I mGluR agonist, was used to induce LTP of excitatory postsynaptic currents that were evoked in the Vo neurons by stimulating the trigeminal track. Weak blockade of the N-type or P/Q-type VGCCs by ω-conotoxin GVIA or ω-agatoxin IVA, respectively, which inhibited only 20-40% of Ca 2+ currents recorded in isolated trigeminal ganglion neurons but had no effect on the basal excitatory synaptic transmission, completely blocked the induction of LTP. In contrast, stronger blockade of the channels, which inhibited >50% of Ca 2+ currents and about 30% of basal synaptic transmission, resulted in the development of long-term depression (LTD), the long-lasting decrease of synaptic strength. Interestingly, the postsynaptic mechanism of DHPG-induced LTP, which was determined by paired-pulse ratio, disappeared when LTP was blocked, or LTD occurred, while a presynaptic mechanism still remained. Our data suggest that postsynaptic N-type and P/Q-type VGCCs mediate the DHPG-induced LTP at the trigeminal afferent synapses in the Vo. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Abstract 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

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…

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…

The Long-Term Budget Outlook

DTIC Science & Technology

2005-12-01

Revenues Under CBO’s Long-Term Budget Scenarios 56A-8. Real Gross Domestic Product Under CBO’s Long-Term Budget Scenarios 57A-9. Total Surplus or...scenarios suggest that total federal spending for Medicare and Medicaid in 2050 could range anywhere from 7 percent of gross domestic product (GDP)—a...see the Congressional Budget Office’s glossary of budgetary and economic terms, available at www.cbo.gov. 2. The future path of productivity growth

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

Microvascular anatomy of the cerebellar parafloccular perforating space.

PubMed

Sosa, Pablo; Dujovny, Manuel; Onyekachi, Ibe; Sockwell, Noressia; Cremaschi, Fabián; Savastano, Luis E

2016-02-01

The cerebellopontine angle is a common site for tumor growth and vascular pathologies requiring surgical manipulations that jeopardize cranial nerve integrity and cerebellar and brainstem perfusion. To date, a detailed study of vessels perforating the cisternal surface of the middle cerebellar peduncle-namely, the paraflocculus or parafloccular perforating space-has yet to be published. In this report, the perforating vessels of the anterior inferior cerebellar artery (AICA) in the parafloccular space, or on the cisternal surface of the middle cerebellar peduncle, are described to elucidate their relevance pertaining to microsurgery and the different pathologies that occur at the cerebellopontine angle. Fourteen cadaveric cerebellopontine cisterns (CPCs) were studied. Anatomical dissections and analysis of the perforating arteries of the AICA and posterior inferior cerebellar artery at the parafloccular space were recorded using direct visualization by surgical microscope, optical histology, and scanning electron microscope. A comprehensive review of the English-language and Spanish-language literature was also performed, and findings related to anatomy, histology, physiology, neurology, neuroradiology, microsurgery, and endovascular surgery pertaining to the cerebellar flocculus or parafloccular spaces are summarized. A total of 298 perforating arteries were found in the dissected specimens, with a minimum of 15 to a maximum of 26 vessels per parafloccular perforating space. The average outer diameter of the cisternal portion of the perforating arteries was 0.11 ± 0.042 mm (mean ± SD) and the average length was 2.84 ± 1.2 mm. Detailed schematics and the surgical anatomy of the perforating vessels at the CPC and their clinical relevance are reported. The parafloccular space is a key entry point for many perforating vessels toward the middle cerebellar peduncle and lateral brainstem, and it must be respected and protected during surgical approaches to the

The traumatized body: Long-term PTSD and its implications for the orientation towards bodily signals.

PubMed

Tsur, Noga; Defrin, Ruth; Lahav, Yael; Solomon, Zahava

2018-03-01

Orientation to bodily signals is defined as the way somatic sensations are attended, perceived and interpreted. Research suggests that trauma exposure, particularly the pathological reaction to trauma (i.e., PTSD), is associated with catastrophic and frightful orientation to bodily signals. However, little is known regarding the long-term ramifications of trauma exposure and PTSD for orientation to bodily signals. Less is known regarding which PTSD symptom cluster manifests in the 'somatic route' through which orientation to bodily signals is altered. The current study examined the long-term implications of trauma and PTSD trajectories on orientation to bodily signals. Fifty-nine ex-prisoners of war (ex-POWs) and 44 controls were assessed for PTSD along three time-points (18, 30 and 35 years post-war). Orientation to bodily signals (pain catastrophizing and anxiety sensitivity-physical concerns) was assessed at T3. Participants with a chronic PTSD trajectory had higher pain catastrophizing compared to participants with no PTSD. PTSD symptom severity at T2 and T3 mediated the association between captivity and orientation. Among PTSD symptom clusters, hyperarousal at two time-points and intrusion at three time-point mediated the association between captivity and orientation. These findings allude to the cardinal role of long-term PTSD in the subjective experience of the body following trauma. Copyright © 2018 Elsevier B.V. All rights reserved.

Long-term outcomes after severe shock.

PubMed

Pratt, Cristina M; Hirshberg, Eliotte L; Jones, Jason P; Kuttler, Kathryn G; Lanspa, Michael J; Wilson, Emily L; Hopkins, Ramona O; Brown, Samuel M

2015-02-01

Severe shock is a life-threatening condition with very high short-term mortality. Whether the long-term outcomes among survivors of severe shock are similar to long-term outcomes of other critical illness survivors is unknown. We therefore sought to assess long-term survival and functional outcomes among 90-day survivors of severe shock and determine whether clinical predictors were associated with outcomes. Seventy-six patients who were alive 90 days after severe shock (received ≥1 μg/kg per minute of norepinephrine equivalent) were eligible for the study. We measured 3-year survival and long-term functional outcomes using the Medical Outcomes Study 36-Item Short-Form Health Survey, the EuroQOL 5-D-3L, the Hospital Anxiety and Depression Scale, the Impact of Event Scale-Revised, and an employment instrument. We also assessed the relationship between in-hospital predictors and long-term outcomes. The mean long-term survival was 5.1 years; 82% (62 of 76) of patients survived, of whom 49 were eligible for follow-up. Patients who died were older than patients who survived. Thirty-six patients completed a telephone interview a mean of 5 years after hospital admission. The patients' Physical Functioning scores were below U.S. population norms (P < 0.001), whereas mental health scores were similar to population norms. Nineteen percent of the patients had symptoms of depression, 39% had symptoms of anxiety, and 8% had symptoms of posttraumatic stress disorder. Thirty-six percent were disabled, and 17% were working full-time. Early survivors of severe shock had a high 3-year survival rate. Patients' long-term physical and psychological outcomes were similar to those reported for cohorts of less severely ill intensive care unit survivors. Anxiety and depression were relatively common, but only a few patients had symptoms of posttraumatic stress disorder. This study supports the observation that acute illness severity does not determine long-term outcomes. Even extremely

Vertigo in brainstem and cerebellar strokes.

PubMed

Choi, Kwang-Dong; Lee, Hyung; Kim, Ji-Soo

2013-02-01

The aim of this study is to review the recent findings on the prevalence, clinical features, and diagnosis of vertigo from brainstem and cerebellar strokes. Patients with isolated vertigo are at higher risk for stroke than the general population. Strokes involving the brainstem and cerebellum may manifest as acute vestibular syndrome, and acute isolated audiovestibular loss may herald impending infarction in the territory of the anterior inferior cerebellar artery. Appropriate bedside evaluation is superior to MRI for detecting central vestibular syndromes. Recording of vestibular-evoked myogenic potentials is useful for evaluation of the central otolithic pathways in brainstem and cerebellar strokes. Accurate identification of isolated vascular vertigo is very important since misdiagnosis of acute stroke may result in significant morbidity and mortality, whereas overdiagnosis of vascular vertigo would lead to unnecessary costly work-ups and medication.

Short-term Action Intentions Overrule Long-Term Semantic Knowledge

ERIC Educational Resources Information Center

van Elk, M.; van Schie, H.T.; Bekkering, H.

2009-01-01

In the present study, we investigated whether the preparation of an unusual action with an object (e.g. bringing a cup towards the eye) could selectively overrule long-term semantic representations. In the first experiment it was found that unusual action intentions activated short-term semantic goal representations, rather than long-term…

Sex differences in cerebellar synaptic transmission and sex-specific responses to autism-linked Gabrb3 mutations in mice.

PubMed

Mercer, Audrey A; Palarz, Kristin J; Tabatadze, Nino; Woolley, Catherine S; Raman, Indira M

2016-04-14

Neurons of the cerebellar nuclei (CbN) transmit cerebellar signals to premotor areas. The cerebellum expresses several autism-linked genes, including GABRB3, which encodes GABAA receptor β3 subunits and is among the maternal alleles deleted in Angelman syndrome. We tested how this Gabrb3 m-/p+ mutation affects CbN physiology in mice, separating responses of males and females. Wild-type mice showed sex differences in synaptic excitation, inhibition, and intrinsic properties. Relative to females, CbN cells of males had smaller synaptically evoked mGluR1/5-dependent currents, slower Purkinje-mediated IPSCs, and lower spontaneous firing rates, but rotarod performances were indistinguishable. In mutant CbN cells, IPSC kinetics were unchanged, but mutant males, unlike females, showed enlarged mGluR1/5 responses and accelerated spontaneous firing. These changes appear compensatory, since mutant males but not females performed indistinguishably from wild-type siblings on the rotarod task. Thus, sex differences in cerebellar physiology produce similar behavioral output, but provide distinct baselines for responses to mutations.

Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice.

PubMed

Tsokas, Panayiotis; Hsieh, Changchi; Yao, Yudong; Lesburguères, Edith; Wallace, Emma Jane Claire; Tcherepanov, Andrew; Jothianandan, Desingarao; Hartley, Benjamin Rush; Pan, Ling; Rivard, Bruno; Farese, Robert V; Sajan, Mini P; Bergold, Peter John; Hernández, Alejandro Iván; Cottrell, James E; Shouval, Harel Z; Fenton, André Antonio; Sacktor, Todd Charlton

2016-05-17

PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice.

Spillover-mediated feedforward-inhibition functionally segregates interneuron activity

PubMed Central

Coddington, Luke T.; Rudolph, Stephanie; Lune, Patrick Vande; Overstreet-Wadiche, Linda; Wadiche, Jacques I.

2013-01-01

Summary Neurotransmitter spillover represents a form of neural transmission not restricted to morphologically defined synaptic connections. Communication between climbing fibers (CFs) and molecular layer interneurons (MLIs) in the cerebellum is mediated exclusively by glutamate spillover. Here, we show how CF stimulation functionally segregates MLIs based on their location relative to glutamate release. Excitation of MLIs that reside within the domain of spillover diffusion coordinates inhibition of MLIs outside the diffusion limit. CF excitation of MLIs is dependent on extrasynaptic NMDA receptors that enhance the spatial and temporal spread of CF signaling. Activity mediated by functionally segregated MLIs converges onto neighboring Purkinje cells (PCs) to generate a long-lasting biphasic change in inhibition. These data demonstrate how glutamate release from single CFs modulates excitability of neighboring PCs, thus expanding the influence of CFs on cerebellar cortical activity in a manner not predicted by anatomical connectivity. PMID:23707614

Cerebellar contribution to higher and lower order rule learning and cognitive flexibility in mice.

PubMed

Dickson, P E; Cairns, J; Goldowitz, D; Mittleman, G

2017-03-14

Cognitive flexibility has traditionally been considered a frontal lobe function. However, converging evidence suggests involvement of a larger brain circuit which includes the cerebellum. Reciprocal pathways connecting the cerebellum to the prefrontal cortex provide a biological substrate through which the cerebellum may modulate higher cognitive functions, and it has been observed that cognitive inflexibility and cerebellar pathology co-occur in psychiatric disorders (e.g., autism, schizophrenia, addiction). However, the degree to which the cerebellum contributes to distinct forms of cognitive flexibility and rule learning is unknown. We tested lurcher↔wildtype aggregation chimeras which lose 0-100% of cerebellar Purkinje cells during development on a touchscreen-mediated attentional set-shifting task to assess the contribution of the cerebellum to higher and lower order rule learning and cognitive flexibility. Purkinje cells, the sole output of the cerebellar cortex, ranged from 0 to 108,390 in tested mice. Reversal learning and extradimensional set-shifting were impaired in mice with⩾95% Purkinje cell loss. Cognitive deficits were unrelated to motor deficits in ataxic mice. Acquisition of a simple visual discrimination and an attentional-set were unrelated to Purkinje cells. A positive relationship was observed between Purkinje cells and errors when exemplars from a novel, non-relevant dimension were introduced. Collectively, these data suggest that the cerebellum contributes to higher order cognitive flexibility, lower order cognitive flexibility, and attention to novel stimuli, but not the acquisition of higher and lower order rules. These data indicate that the cerebellar pathology observed in psychiatric disorders may underlie deficits involving cognitive flexibility and attention to novel stimuli. Copyright © 2016. Published by Elsevier Ltd.

Modeled changes of cerebellar activity in mutant mice are predictive of their learning impairments

NASA Astrophysics Data System (ADS)

Badura, Aleksandra; Clopath, Claudia; Schonewille, Martijn; de Zeeuw, Chris I.

2016-11-01

Translating neuronal activity to measurable behavioral changes has been a long-standing goal of systems neuroscience. Recently, we have developed a model of phase-reversal learning of the vestibulo-ocular reflex, a well-established, cerebellar-dependent task. The model, comprising both the cerebellar cortex and vestibular nuclei, reproduces behavioral data and accounts for the changes in neural activity during learning in wild type mice. Here, we used our model to predict Purkinje cell spiking as well as behavior before and after learning of five different lines of mutant mice with distinct cell-specific alterations of the cerebellar cortical circuitry. We tested these predictions by obtaining electrophysiological data depicting changes in neuronal spiking. We show that our data is largely consistent with the model predictions for simple spike modulation of Purkinje cells and concomitant behavioral learning in four of the mutants. In addition, our model accurately predicts a shift in simple spike activity in a mutant mouse with a brainstem specific mutation. This combination of electrophysiological and computational techniques opens a possibility of predicting behavioral impairments from neural activity.

Modeled changes of cerebellar activity in mutant mice are predictive of their learning impairments

PubMed Central

Badura, Aleksandra; Clopath, Claudia; Schonewille, Martijn; De Zeeuw, Chris I.

2016-01-01

Translating neuronal activity to measurable behavioral changes has been a long-standing goal of systems neuroscience. Recently, we have developed a model of phase-reversal learning of the vestibulo-ocular reflex, a well-established, cerebellar-dependent task. The model, comprising both the cerebellar cortex and vestibular nuclei, reproduces behavioral data and accounts for the changes in neural activity during learning in wild type mice. Here, we used our model to predict Purkinje cell spiking as well as behavior before and after learning of five different lines of mutant mice with distinct cell-specific alterations of the cerebellar cortical circuitry. We tested these predictions by obtaining electrophysiological data depicting changes in neuronal spiking. We show that our data is largely consistent with the model predictions for simple spike modulation of Purkinje cells and concomitant behavioral learning in four of the mutants. In addition, our model accurately predicts a shift in simple spike activity in a mutant mouse with a brainstem specific mutation. This combination of electrophysiological and computational techniques opens a possibility of predicting behavioral impairments from neural activity. PMID:27805050

Orthostatic tremor: a cerebellar pathology?

PubMed

Gallea, Cécile; 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

2016-08-01

SEE MUTHURAMAN ET AL DOI101093/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. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Exposure of rats to environmental tobacco smoke during cerebellar development alters behavior and perturbs mitochondrial energetics.

PubMed

Fuller, Brian F; Cortes, Diego F; Landis, Miranda K; Yohannes, Hiyab; Griffin, Hailey E; Stafflinger, Jillian E; Bowers, M Scott; Lewis, Mark H; Fox, Michael A; Ottens, Andrew K

2012-12-01

Environmental tobacco smoke (ETS) exposure is linked to developmental deficits and disorders with known cerebellar involvement. However, direct biological effects and underlying neurochemical mechanisms remain unclear. We sought to identify and evaluate underlying neurochemical change in the rat cerebellum with ETS exposure during critical period development. We exposed rats to daily ETS (300, 100, and 0 µg/m3 total suspended particulate) from postnatal day 8 (PD8) to PD23 and then assayed the response at the behavioral, neuroproteomic, and cellular levels. Postnatal ETS exposure induced heightened locomotor response in a novel environment on par initially with amphetamine stimulation. The cerebellar mitochondrial subproteome was significantly perturbed in the ETS-exposed rats. Findings revealed a dose-dependent up-regulation of aerobic processes through the modification and increased translocation of Hk1 to the mitochondrion with corresponding heightened ATP synthase expression. ETS exposure also induced a dose-dependent increase in total Dnm1l mitochondrial fission factor; although more active membrane-bound Dnm1l was found at the lower dose. Dnm1l activation was associated with greater mitochondrial staining, particularly in the molecular layer, which was independent of stress-induced Bcl-2 family dynamics. Further, electron microscopy associated Dnm1l-mediated mitochondrial fission with increased biogenesis, rather than fragmentation. The critical postnatal period of cerebellar development is vulnerable to the effects of ETS exposure, resulting in altered behavior. The biological effect of ETS is underlain in part by a Dnm1l-mediated mitochondrial energetic response at a time of normally tight control. These findings represent a novel mechanism by which environmental exposure can impact neurodevelopment and function.

Indoleamine 2,3-dioxygenase (IDO) and Treg Support are Critical for CTLA4Ig-Mediated Long-term Solid Organ Allograft Survival

PubMed Central

Sucher, Robert; Fischler, Klaus; Oberhuber, Rupert; Kronberger, Irmgard; Margreiter, Christian; Ollinger, Robert; Schneeberger, Stefan; Fuchs, Dietmar; Werner, Ernst R.; Watschinger, Katrin; Zelger, Bettina; Tellides, George; Pilat, Nina; Pratschke, Johann; Margreiter, Raimund; Wekerle, Thomas; Brandacher, Gerald

2011-01-01

Co-stimulatory blockade of CD28-B7 interaction with CTLA4Ig is a well-established strategy to induce transplantation tolerance. Although previous in vitro studies suggest that CTLA4Ig up-regulates expression of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in dendritic cells, the relationship of CTLA4Ig and IDO in in vivo organ transplantation remains unclear. Here we studied if concerted immunomodulation in vivo by CTLA4Ig depends on IDO. C57BL/6 recipients receiving a fully MHC-mismatched BALB/c heart graft treated with CTLA4Ig + donor specific transfusion (DST) showed indefinite graft survival [>100 days] without signs of chronic rejection or donor specific antibody formation. Recipients with long-term surviving grafts had significantly higher systemic IDO activity as compared to rejectors, which markedly correlated with intragraft IDO and Foxp3 levels. IDO inhibition with 1-methyl-DL-tryptophan, either at transplant or at POD 50, abrogated CTLA4Ig+DST-induced long-term graft survival. Importantly, IDO1 knock-out recipients experienced acute rejection and graft survival comparable to controls. In addition, αCD25 mAb-mediated depletion of Tregs resulted in decreased IDO activity and again prevented CTLA4Ig+DST induced indefinite graft survival. Our results suggest that CTLA4Ig-induced tolerance to murine cardiac allografts is critically dependent on synergistic cross-linked interplay of IDO and Tregs. These results have important implications for the clinical development of this co-stimulatory blocker. PMID:22131334

Numb deficiency in cerebellar Purkinje cells impairs synaptic expression of metabotropic glutamate receptor and motor coordination.

PubMed

Zhou, Liang; Yang, Dong; Wang, De-Juan; Xie, Ya-Jun; Zhou, Jia-Huan; Zhou, Lin; Huang, Hao; Han, Shuo; Shao, Chong-Yu; Li, Hua-Shun; Zhu, J Julius; Qiu, Meng-Sheng; De Zeeuw, Chris I; Shen, Ying

2015-12-15

Protein Numb, first identified as a cell-fate determinant in Drosophila, has been shown to promote the development of neurites in mammals and to be cotransported with endocytic receptors in clathrin-coated vesicles in vitro. Nevertheless, its function in mature neurons has not yet been elucidated. Here we show that cerebellar Purkinje cells (PCs) express high levels of Numb during adulthood and that conditional deletion of Numb in PCs is sufficient to impair motor coordination despite maintenance of a normal cerebellar cyto-architecture. Numb proved to be critical for internalization and recycling of metabotropic glutamate 1 receptor (mGlu1) in PCs. A significant decrease of mGlu1 and an inhibition of long-term depression at the parallel fiber-PC synapse were observed in conditional Numb knockout mice. Indeed, the trafficking of mGlu1 induced by agonists was inhibited significantly in these mutants, but the expression of ionotropic glutamate receptor subunits and of mGlu1-associated proteins was not affected by the loss of Numb. Moreover, transient and persistent forms of mGlu1 plasticity were robustly induced in mutant PCs, suggesting that they do not require mGlu1 trafficking. Together, our data demonstrate that Numb is a regulator for constitutive expression and dynamic transport of mGlu1.

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

Abdominal wall integrity after open abdomen: long-term results of vacuum-assisted wound closure and mesh-mediated fascial traction (VAWCM).

PubMed

Willms, A; Schaaf, S; Schwab, R; Richardsen, I; Bieler, D; Wagner, B; Güsgen, C

2016-12-01

The open abdomen has become a standard technique in the management of critically ill patients undergoing surgery for severe intra-abdominal conditions. Negative pressure and mesh-mediated fascial traction are commonly used and achieve low fistula rates and high fascial closure rates. In this study, long-term results of a standardised treatment approach are presented. Fifty-five patients who underwent OA management for different indications at our institution from 2006 to 2013 were enrolled. All patients were treated under a standardised algorithm that uses a combination of vacuum-assisted wound closure and mesh-mediated fascial traction. Structured follow-up assessments were offered to patients and included a medical history, a clinical examination and abdominal ultrasonography. The data obtained were statistically analysed. The fascial closure rate was 74 % in an intention-to-treat analysis and 89 % in a per-protocol analysis. The fistula rate was 1.8 %. Thirty-four patients attended follow-up. The median follow-up was 46 months (range 12-88 months). Incisional hernias developed in 35 %. Patients with hernias needed more operative procedures (10.3 vs 3.4, p = 0.03) than patients without hernia formation. A Patient Observer Scar Assessment Scale (POSAS) of 31.1 was calculated. Patients with symptomatic hernias (NAS of 2-10) had a significantly lower mean POSAS score (p = 0.04). Vacuum-assisted wound closure and mesh-mediated fascial traction (VAWCM) seem to result in low complication rates and high fascial closure rates. Abdominal wall reconstruction, which is a challenging and complex procedure and causes considerable patient discomfort, can thus be avoided in the majority of cases. Available results are based on studies involving only a small number of cases. Multi-centre studies and registry-based data are therefore needed to validate these findings.

Caffeine Modulates Vesicle Release and Recovery at Cerebellar Parallel Fibre Terminals, Independently of Calcium and Cyclic AMP Signalling

PubMed Central

Dobson, Katharine L.; Jackson, Claire; Balakrishnan, Saju; Bellamy, Tomas C.

2015-01-01

Background Cerebellar parallel fibres release glutamate at both the synaptic active zone and at extrasynaptic sites—a process known as ectopic release. These sites exhibit different short-term and long-term plasticity, the basis of which is incompletely understood but depends on the efficiency of vesicle release and recycling. To investigate whether release of calcium from internal stores contributes to these differences in plasticity, we tested the effects of the ryanodine receptor agonist caffeine on both synaptic and ectopic transmission. Methods Whole cell patch clamp recordings from Purkinje neurons and Bergmann glia were carried out in transverse cerebellar slices from juvenile (P16-20) Wistar rats. Key Results Caffeine caused complex changes in transmission at both synaptic and ectopic sites. The amplitude of postsynaptic currents in Purkinje neurons and extrasynaptic currents in Bergmann glia were increased 2-fold and 4-fold respectively, but paired pulse ratio was substantially reduced, reversing the short-term facilitation observed under control conditions. Caffeine treatment also caused synaptic sites to depress during 1 Hz stimulation, consistent with inhibition of the usual mechanisms for replenishing vesicles at the active zone. Unexpectedly, pharmacological intervention at known targets for caffeine—intracellular calcium release, and cAMP signalling—had no impact on these effects. Conclusions We conclude that caffeine increases release probability and inhibits vesicle recovery at parallel fibre synapses, independently of known pharmacological targets. This complex effect would lead to potentiation of transmission at fibres firing at low frequencies, but depression of transmission at high frequency connections. PMID:25933382

Estimating long-term multivariate progression from short-term data.

PubMed

Donohue, Michael C; Jacqmin-Gadda, Hélène; Le Goff, Mélanie; Thomas, Ronald G; Raman, Rema; Gamst, Anthony C; Beckett, Laurel A; Jack, Clifford R; Weiner, Michael W; Dartigues, Jean-François; Aisen, Paul S

2014-10-01

Diseases that progress slowly are often studied by observing cohorts at different stages of disease for short periods of time. The Alzheimer's Disease Neuroimaging Initiative (ADNI) follows elders with various degrees of cognitive impairment, from normal to impaired. The study includes a rich panel of novel cognitive tests, biomarkers, and brain images collected every 6 months for as long as 6 years. The relative timing of the observations with respect to disease pathology is unknown. We propose a general semiparametric model and iterative estimation procedure to estimate simultaneously the pathological timing and long-term growth curves. The resulting estimates of long-term progression are fine-tuned using cognitive trajectories derived from the long-term "Personnes Agées Quid" study. We demonstrate with simulations that the method can recover long-term disease trends from short-term observations. The method also estimates temporal ordering of individuals with respect to disease pathology, providing subject-specific prognostic estimates of the time until onset of symptoms. When the method is applied to ADNI data, the estimated growth curves are in general agreement with prevailing theories of the Alzheimer's disease cascade. Other data sets with common outcome measures can be combined using the proposed algorithm. Software to fit the model and reproduce results with the statistical software R is available as the grace package. ADNI data can be downloaded from the Laboratory of NeuroImaging. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Late-onset immune-mediated adverse effects after poly-L-lactic acid injection in non-HIV patients: clinical findings and long-term follow-up.

PubMed

Alijotas-Reig, Jaume; Garcia-Gimenez, Victor; Vilardell-Tarres, Miquel

2009-01-01

It has been thought that poly-L-lactic acid (PLLA) injections do not have inflammatory side effects. Recent evidence shows that local/regional/systemic delayed adverse effects may appear with its use. To evaluate the clinical complaints, treatment response and long-term follow-up of non-HIV patients with delayed immune-mediated adverse effects related to PLLA injections. Prospective, case series study of 10 patients with delayed adverse effects related to PLLA injections. The inclusion criterion was defined as the onset at least 6 months after PLLA use, with 1 or more of the following clinical signs: oedema, skin induration, swelling/tender nodules with or without discharge of pus or filler material. Several systemic manifestations were also included. Patients with immediate side effects were excluded. Patients underwent clinical management and long-term follow-up. The average latency period to the onset of symptoms was 19.2 months (range: 6-60). Tender, inflammatory nodules and facial oedema were commonly seen. One case presented a systemic granulomatous disorder as a complication. After 50.2 months of average follow-up (range: 38-78), 5 patients are in remission, 4 have recurrent bouts and the last case has been lost to follow-up. Although infrequently, local and/or regional and/or systemic delayed and recurrent granulomatous reactions may complicate PLLA gel injections. Copyright 2009 S. Karger AG, Basel.

Scientific Understanding from Long Term Observations: Insights from the Long Term Ecological Research (LTER) Program

NASA Astrophysics Data System (ADS)

Gosz, J.

2001-12-01

The network dedicated to Long Term Ecological Research (LTER) in the United States has grown to 24 sites since it was formed in 1980. Long-term research and monitoring are performed on parameters thatare basic to all ecosystems and are required to understand patterns, processes, and relationship to change. Collectively, the sites in the LTER Network provide opportunities to contrast marine, coastal, and continental regions, the full range of climatic gradients existing in North America, and aquatic and terrestrial habitats in a range of ecosystem types. The combination of common core areas and long-term research and monitoring in many habitats have allowed unprecedented abilities to understand and compare complex temporal and spatial dynamics associated with issues like climate change, effects of pollution, biodiversity and landuse. For example, McMurdo Dry Valley in the Antarctic has demonstrated an increase in glacier mass since 1993 which coincides with a period of cooler than normal summers and more than average snowfall. In contrast, the Bonanza Creek and Toolik Lake sites in Alaska have recorded a warming period unprecedented in the past 200 years. Nitrogen deposition effects have been identified through long-term watershed studies on biogeochemical cycles, especially at Coweeta Hydrological Lab, Harvard Forest, and the Hubbard Brook Experimental Forest. In aquatic systems, such as the Northern Temperate Lakes site, long-term data revealed time lags in effects of invaders and disturbance on lake communities. Biological recovery from an effect such as lake acidification was shown to lag behind chemical recovery. The long-term changes documented over 2 decades have been instrumental in influencing management practices in many of the LTER areas. In Puerto Rico, the Luquillo LTER demonstrated that dams obstruct migrations of fish and freshwater shrimp and water abstraction at low flows can completely obliterate downstream migration of juveniles and damage

Abnormal cerebellar development and Purkinje cell defects in Lgl1-Pax2 conditional knockout mice.

PubMed

Hou, Congzhe; Ding, Lingcui; Zhang, Jian; Jin, Yecheng; Sun, Chen; Li, Zhenzu; Sun, Xiaoyang; Zhang, Tingting; Zhang, Aizhen; Li, Huashun; Gao, Jiangang

2014-11-01

Lgl1 was initially identified as a tumour suppressor in flies and is characterised as a key regulator of epithelial polarity and asymmetric cell division. A previous study indicated that More-Cre-mediated Lgl1 knockout mice exhibited significant brain dysplasia and died within 24h after birth. To overcome early neonatal lethality, we generated Lgl1 conditional knockout mice mediated by Pax2-Cre, which is expressed in almost all cells in the cerebellum, and we examined the functions of Lgl1 in the cerebellum. Impaired motor coordination was detected in the mutant mice. Consistent with this abnormal behaviour, homozygous mice possessed a smaller cerebellum with fewer lobes, reduced granule precursor cell (GPC) proliferation, decreased Purkinje cell (PC) quantity and dendritic dysplasia. Loss of Lgl1 in the cerebellum led to hyperproliferation and impaired differentiation of neural progenitors in ventricular zone. Based on the TUNEL assay, we observed increased apoptosis in the cerebellum of mutant mice. We proposed that impaired differentiation and increased apoptosis may contribute to decreased PC quantity. To clarify the effect of Lgl1 on cerebellar granule cells, we used Math1-Cre to specifically delete Lgl1 in granule cells. Interestingly, the Lgl1-Math1 conditional knockout mice exhibited normal proliferation of GPCs and cerebellar development. Thus, we speculated that the reduction in the proliferation of GPCs in Lgl1-Pax2 conditional knockout mice may be secondary to the decreased number of PCs, which secrete the mitogenic factor Sonic hedgehog to regulate GPC proliferation. Taken together, these findings suggest that Lgl1 plays a key role in cerebellar development and folia formation by regulating the development of PCs. Copyright © 2014. Published by Elsevier Inc.

Long-Term Opioid Therapy Reconsidered

PubMed Central

Von Korff, Michael; Kolodny, Andrew; Deyo, Richard A.; Chou, Roger

2012-01-01

In the past 20 years, primary care physicians have greatly increased prescribing of long-term opioid therapy. However, the rise in opioid prescribing has outpaced the evidence regarding this practice. Increased opioid availability has been accompanied by an epidemic of opioid abuse and overdose. The rate of opioid addiction among patients receiving long-term opioid therapy remains unclear, but research suggests that opioid misuse is not rare. Recent studies report increased risks for serious adverse events, including fractures, cardiovascular events, and bowel obstruction, although further research on medical risks is needed. New data indicate that opioid-related risks may increase with dose. From a societal perspective, higher-dose regimens account for the majority of opioids dispensed, so cautious dosing may reduce both diversion potential and patient risks for adverse effects. Limiting long-term opioid therapy to patients for whom it provides decisive benefits could also reduce risks. Given the warning signs and knowledge gaps, greater caution and selectivity are needed in prescribing long-term opioid therapy. Until stronger evidence becomes available, clinicians should err on the side of caution when considering this treatment. PMID:21893626

Quick foot placement adjustments during gait are less accurate in individuals with focal cerebellar lesions.

PubMed

Hoogkamer, Wouter; Potocanac, Zrinka; Van Calenbergh, Frank; Duysens, Jacques

2017-10-01

Online gait corrections are frequently used to restore gait stability and prevent falling. They require shorter response times than voluntary movements which suggests that subcortical pathways contribute to the execution of online gait corrections. To evaluate the potential role of the cerebellum in these pathways we tested the hypotheses that online gait corrections would be less accurate in individuals with focal cerebellar damage than in neurologically intact controls and that this difference would be more pronounced for shorter available response times and for short step gait corrections. We projected virtual stepping stones on an instrumented treadmill while some of the approaching stepping stones were shifted forward or backward, requiring participants to adjust their foot placement. Varying the timing of those shifts allowed us to address the effect of available response time on foot placement error. In agreement with our hypothesis, individuals with focal cerebellar lesions were less accurate in adjusting their foot placement in reaction to suddenly shifted stepping stones than neurologically intact controls. However, the cerebellar lesion group's foot placement error did not increase more with decreasing available response distance or for short step versus long step adjustments compared to the control group. Furthermore, foot placement error for the non-shifting stepping stones was also larger in the cerebellar lesion group as compared to the control group. Consequently, the reduced ability to accurately adjust foot placement during walking in individuals with focal cerebellar lesions appears to be a general movement control deficit, which could contribute to increased fall risk. Copyright © 2017 Elsevier B.V. All rights reserved.

Understanding the Role of TSC1/2 in Cerebellar Purkinje Neurons

DTIC Science & Technology

2016-09-01

development of new pharmacotherapy for TSC-patients with autism . 15. SUBJECT TERMS autism , tuberous sclerosis, cerebellum 16. SECURITY CLASSIFICATION...patients with TSC display symptoms of autism spectrum disorder (ASD). Although much research has been conducted, the neural circuitry and molecular...mechanism underlying autism remain unclear. Specific cerebellar defects have been seen in TSC patients, suggesting a crucial role for the cerebellum

The role of poor sleep in the relation between workplace bullying/unwanted sexual attention and long-term sickness absence.

PubMed

Nabe-Nielsen, Kirsten; Grynderup, Matias Brødsgaard; Lange, Theis; Andersen, Johan Hviid; Bonde, Jens Peter; Conway, Paul Maurice; Garde, Anne Helene; Høgh, Annie; Kaerlev, Linda; Rugulies, Reiner; Hansen, Åse Marie

2016-08-01

While exposure to bullying and unwanted sexual attention was previously found to increase the risk of sickness absence, the underlying mechanisms are largely unknown. Poor sleep can be a consequence of stressful exposures and a cause of poor health, and poor sleep is also a determinant of insufficient recovery. Therefore, the present study investigated whether poor sleep mediates and/or moderates the association between bullying and unwanted sexual attention, on the one hand, and long-term sickness absence (LTSA), on the other hand. We used questionnaire data from 7650 individuals contributing with 15,040 2-year observation periods. Workplace bullying, unwanted sexual attention, disturbed sleep, and difficulties awakening were measured at three time points, and participants were followed in registers to measure the occurrence of LTSA, defined as ≥30 consecutive days of sickness absence during the subsequent 2 years. The odds of LTSA were significantly increased by workplace bullying (OR 1.77; 95 % CI 1.50-2.12) and unwanted sexual attention (OR 1.55; 95 % CI 1.06-2.29). Together, disturbed sleep and difficulties awakening mediated 12.8 % (95 % CI 8.1-19.8) of the association between bullying and long-term sickness absence, and 8.5 % (95 % CI -0.45 to 37.1) of the association between unwanted sexual attention and long-term sickness absence in the fully adjusted model. Neither disturbed sleep nor difficulties awakening moderated these associations. As expected, bullying and unwanted sexual attention were prospectively associated with long-term sickness absence. Only a small part of this association was mediated by poor sleep.

School Engagement Mediates Long Term Prevention Effects for Mexican American Adolescents

PubMed Central

Gonzales, Nancy A.; Wong, Jessie J.; Toomey, Russell B.; Millsap, Roger; Dumka, Larry E.; Mauricio, Anne M.

2014-01-01

This five year follow-up of a randomized clinical trial evaluated the efficacy of a family-focused intervention delivered in middle school to increase school engagement following transition to high school (2 years posttest), and also evaluated mediated effects through school engagement on multiple problem outcomes in late adolescence (5 years posttest). The study sample included 516 Mexican American adolescents who participated in a randomized trial of the Bridges to High School Program (Bridges/ Puentes). Path models representing the direct and indirect effects of the program on four outcome variables were evaluated using school engagement measured in the 9th grade as a mediator. The program significantly increased school engagement, with school engagement mediating intervention effects on internalizing symptoms, adolescent substance use, and school dropout in late adolescence when most adolescents were in the 12th grade. Effects on substance use were stronger for youth at higher risk based on pretest report of substance use initiation. There were no direct or indirect intervention effects on externalizing symptoms. Findings support that school engagement is an important prevention target for Mexican American adolescents. PMID:24398825

Temporal Coupling with Cortex Distinguishes Spontaneous Neuronal Activities in Identified Basal Ganglia-Recipient and Cerebellar-Recipient Zones of the Motor Thalamus

PubMed Central

Nakamura, Kouichi C.; Sharott, Andrew; Magill, Peter J.

2014-01-01

Neurons of the motor thalamus mediate basal ganglia and cerebellar influences on cortical activity. To elucidate the net result of γ-aminobutyric acid-releasing or glutamatergic bombardment of the motor thalamus by basal ganglia or cerebellar afferents, respectively, we recorded the spontaneous activities of thalamocortical neurons in distinct identified “input zones” in anesthetized rats during defined cortical activity states. Unexpectedly, the mean rates and brain state dependencies of the firing of neurons in basal ganglia-recipient zone (BZ) and cerebellar-recipient zone (CZ) were matched during slow-wave activity (SWA) and cortical activation. However, neurons were distinguished during SWA by their firing regularities, low-threshold spike bursts and, more strikingly, by the temporal coupling of their activities to ongoing cortical oscillations. The firing of neurons across the BZ was stronger and more precisely phase-locked to cortical slow (∼1 Hz) oscillations, although both neuron groups preferentially fired at the same phase. In contrast, neurons in BZ and CZ fired at different phases of cortical spindles (7–12 Hz), but with similar strengths of coupled firing. Thus, firing rates do not reflect the predicted inhibitory–excitatory imbalance across the motor thalamus, and input zone-specific temporal coding through oscillatory synchronization with the cortex could partly mediate the different roles of basal ganglia and cerebellum in behavior. PMID:23042738

Neurotrophins play differential roles in short and long-term recognition memory.

PubMed

Callaghan, Charlotte K; Kelly, Aine M

2013-09-01

The neurotrophin family of proteins are believed to mediate various forms of synaptic plasticity in the adult brain. Here we have assessed the roles of these proteins in object recognition memory in the rat, using icv infusions of function-blocking antibodies or the tyrosine kinase antagonist, tyrphostin AG879, to block Trk receptors. We report that tyrphostin AG879 impairs both short-term and long-term recognition memory, indicating a requirement for Trk receptor activation in both processes. The effect of inhibition of each of the neurotrophins with activity-blocking neutralising antibodies was also tested. Treatment with anti-BDNF, anti-NGF or anti-NT4 had no effect on short-term memory, but blocked long-term recognition memory. Treatment with anti-NT3 had no effect on either process. We also assessed changes in expression of neurotrophins and their respective receptors in the hippocampus, dentate gyrus and perirhinal cortex over a 24 h period following training in the object recognition task. We observed time-dependent changes in expression of the Trk receptors and their ligands in the dentate gyrus and perirhinal cortex. The data are consistent with a pivotal role for neurotrophic factors in the expression of recognition memory. Copyright © 2013 Elsevier Inc. All rights reserved.

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.

Very long-term sequelae of craniopharyngioma.

PubMed

Wijnen, Mark; van den Heuvel-Eibrink, Marry M; Janssen, Joseph A M J L; Catsman-Berrevoets, Coriene E; Michiels, Erna M C; van Veelen-Vincent, Marie-Lise C; Dallenga, Alof H G; van den Berge, J Herbert; van Rij, Carolien M; van der Lely, Aart-Jan; Neggers, Sebastian J C M M

2017-06-01

Studies investigating long-term health conditions in patients with craniopharyngioma are limited by short follow-up durations and generally do not compare long-term health effects according to initial craniopharyngioma treatment approach. In addition, studies comparing long-term health conditions between patients with childhood- and adult-onset craniopharyngioma report conflicting results. The objective of this study was to analyse a full spectrum of long-term health effects in patients with craniopharyngioma according to initial treatment approach and age group at craniopharyngioma presentation. Cross-sectional study based on retrospective data. We studied a single-centre cohort of 128 patients with craniopharyngioma treated from 1980 onwards (63 patients with childhood-onset disease). Median follow-up since craniopharyngioma presentation was 13 years (interquartile range: 5-23 years). Initial craniopharyngioma treatment approaches included gross total resection ( n  = 25), subtotal resection without radiotherapy ( n  = 44), subtotal resection with radiotherapy ( n  = 25), cyst aspiration without radiotherapy ( n  = 8), and 90 Yttrium brachytherapy ( n  = 21). Pituitary hormone deficiencies (98%), visual disturbances (75%) and obesity (56%) were the most common long-term health conditions observed. Different initial craniopharyngioma treatment approaches resulted in similar long-term health effects. Patients with childhood-onset craniopharyngioma experienced significantly more growth hormone deficiency, diabetes insipidus, panhypopituitarism, morbid obesity, epilepsy and psychiatric conditions compared with patients with adult-onset disease. Recurrence-/progression-free survival was significantly lower after initial craniopharyngioma treatment with cyst aspiration compared with other therapeutic approaches. Survival was similar between patients with childhood- and adult-onset craniopharyngioma. Long-term health conditions were comparable after

Long-term care in international perspective.

PubMed

Doty, P

1988-12-01

The findings of a study of long-term care policies in 18 countries are reported in this article. Initial data were collected by a questionnaire survey under the auspices of the International Social Security Association. These data were supplemented by published documents and government statistics obtained while researching long-term care for the International Social Security Association and, subsequently, for the Organization for Economic Cooperation and Development. The principal focus is a cross-national comparison of institutionalization rates for the elderly. Differences in use rates for medically oriented facilities are less than those for nonmedical residential long-term care facilities. Only a small amount of variation is related to demographic differences, such as older or more female elderly populations in those countries with higher institutionalization rates. Included also is a description of the modes of financing long-term care.

Anticoagulation therapy is harmful to large-sized cerebellar infarction.

PubMed

Zhang, She-Qing; Wang, Wei; Ma, Xiao-Long; Xia, Yu-Ye; Liu, Ai-Jun

2014-09-01

Anticoagulants are commonly used to treat ischemic stroke. Its impact on cerebellar infarction has not been fully understood. In the clinical study, we reviewed a consecutive series of patients with large-sized cerebellar infarction (diameter > 3 cm, n = 30) treated with or without anticoagulation. In animal study, cerebellar infarction operation was performed in 12 Cynomolgus monkeys. Then the animals were administrated with low molecular weight heparin (LMWH) or vehicle for 14 days. Six patients died during the following treatment. All the subjects that died received anticoagulation therapy, while nobody in the survival group received such a therapy. Compared with sham-operated animals, all monkeys with cerebellar infarction have obvious neurological deficits. The number and size of the Purkinje cells in the cerebellar area were also reduced. Two animals in the LMWH group (33%) died, while all animals in the vehicle control group survived. Compared with the vehicle group, the neurological score in the LMWH group was significantly increased (P < 0.05). The water content in the cerebella was also significantly higher (P < 0.05). Edema, hemorrhage, and subarachnoid hemorrhage occurred in the cerebella as well as brainstem of all the LMWH treated animals. These results indicated the harmful effects of anticoagulation therapy on large-sized cerebellar infarction. © 2014 John Wiley & Sons Ltd.

Cerebellar blood flow in methylmercury poisoning (Minamata disease).

PubMed

Itoh, K; Korogi, Y; Tomiguchi, S; Takahashi, M; Okajima, T; Sato, H

2001-04-01

We looked at regional cerebellar blood flow in patients with Minamata disease (MD) using technetium-99m ethyl cysteinate dimer (99m-Tc-ECD). We carried out single-photon emission computed tomography (SPECT) on 15 patients with MD (eight men, seven women, aged 51-78 years, mean 70.5 years) and 11 control subjects (eight men, three women, aged 62-80 years, mean 72.5 years). Regional blood flow was measured in the superior, middle, and inferior portions of the cerebellar hemispheres, and the frontal, temporal and occipital cerebral lobes. The degree of cerebellar atrophy was assessed on MRI. There were significant differences in regional blood flow in all parts of the cerebellum between patients and control, but no significant decrease was observed in the cerebrum. Blood flow was lower in the inferior cerebellum than in the other parts. Even in patients without cerebellar atrophy, flow was significantly decreased regional blood flow in the inferior part.

Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice

PubMed Central

Tsokas, Panayiotis; Hsieh, Changchi; Yao, Yudong; Lesburguères, Edith; Wallace, Emma Jane Claire; Tcherepanov, Andrew; Jothianandan, Desingarao; Hartley, Benjamin Rush; Pan, Ling; Rivard, Bruno; Farese, Robert V; Sajan, Mini P; Bergold, Peter John; Hernández, Alejandro Iván; Cottrell, James E; Shouval, Harel Z; Fenton, André Antonio; Sacktor, Todd Charlton

2016-01-01

PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice. DOI: http://dx.doi.org/10.7554/eLife.14846.001 PMID:27187150

Competitive short-term and long-term memory processes in spatial habituation.

PubMed

Sanderson, David J; Bannerman, David M

2011-04-01

Exposure to a spatial location leads to habituation of exploration such that, in a novelty preference test, rodents subsequently prefer exploring a novel location to the familiar location. According to Wagner's (1981) theory of memory, short-term and long-term habituation are caused by separate and sometimes opponent processes. In the present study, this dual-process account of memory was tested. Mice received a series of exposure training trials to a location before receiving a novelty preference test. The novelty preference was greater when tested after a short, rather than a long, interval. In contrast, the novelty preference was weaker when exposure training trials were separated by a short, rather than a long interval. Furthermore, it was found that long-term habituation was determined by the independent effects of the amount of exposure training and the number of exposure training trials when factors such as the intertrial interval and the cumulative intertrial interval were controlled. A final experiment demonstrated that a long-term reduction of exploration could be caused by a negative priming effect due to associations formed during exploration. These results provide evidence against a single-process account of habituation and suggest that spatial habituation is determined by both short-term, recency-based memory and long-term, incrementally strengthened memory.

Mechanisms of human cerebellar dysmetria: experimental evidence and current conceptual bases

PubMed Central

Manto, Mario

2009-01-01

The human cerebellum contains more neurons than any other region in the brain and is a major actor in motor control. Cerebellar circuitry is unique by its stereotyped architecture and its modular organization. Understanding the motor codes underlying the organization of limb movement and the rules of signal processing applied by the cerebellar circuits remains a major challenge for the forthcoming decades. One of the cardinal deficits observed in cerebellar patients is dysmetria, designating the inability to perform accurate movements. Patients overshoot (hypermetria) or undershoot (hypometria) the aimed target during voluntary goal-directed tasks. The mechanisms of cerebellar dysmetria are reviewed, with an emphasis on the roles of cerebellar pathways in controlling fundamental aspects of movement control such as anticipation, timing of motor commands, sensorimotor synchronization, maintenance of sensorimotor associations and tuning of the magnitudes of muscle activities. An overview of recent advances in our understanding of the contribution of cerebellar circuitry in the elaboration and shaping of motor commands is provided, with a discussion on the relevant anatomy, the results of the neurophysiological studies, and the computational models which have been proposed to approach cerebellar function. PMID:19364396

Brief, pre-retrieval stress differentially influences long-term memory depending on sex and corticosteroid response.

PubMed

Zoladz, Phillip R; Kalchik, Andrea E; Hoffman, Mackenzie M; Aufdenkampe, Rachael L; Burke, Hanna M; Woelke, Sarah A; Pisansky, Julia M; Talbot, Jeffery N

2014-03-01

Previous work has indicated that stress generally impairs memory retrieval. However, little research has addressed discrepancies that exist in this line of work and the factors that could explain why stress can exert differential effects on retrieval processes. Therefore, we examined the influence of brief, pre-retrieval stress that was administered immediately before testing on long-term memory in males and females. Participants learned a list of 42 words varying in emotional valence and arousal. Following the learning phase, participants were given an immediate free recall test. Twenty-four hours later, participants submerged their non-dominant hand in a bath of ice cold (Stress) or warm (No Stress) water for 3 min. Immediately following this manipulation, participants' memory for the word list was assessed via free recall and recognition tests. We observed no group differences on short-term memory. However, male participants who showed a robust cortisol response to the stress exhibited enhanced long-term recognition memory, while male participants who demonstrated a blunted cortisol response to the stress exhibited impaired long-term recall and recognition memory. These findings suggest that the effects of brief, pre-retrieval stress on long-term memory are sex-specific and mediated by corticosteroid mechanisms. Copyright © 2014 Elsevier Inc. All rights reserved.

Altered soleus responses to magnetic stimulation in pure cerebellar ataxia.

PubMed

Kurokawa-Kuroda, Tomomi; Ogata, Katsuya; Suga, Rie; Goto, Yoshinobu; Taniwaki, Takayuki; Kira, Jun-Ichi; Tobimatsu, Shozo

2007-06-01

Transcranial magnetic stimulation (TMS) over the leg motor area elicits a soleus primary response (SPR) and a soleus late response (SLR). We evaluated the influence of the cerebellofugal pathway on the SPR and SLR in patients with 'pure' cerebellar ataxia. SPRs and SLRs were recorded from 11 healthy subjects and 9 patients with 'pure' cerebellar cortical degeneration; 5 with spinocerebellar ataxia type 6 (SCA6), and 4 with late cortical cerebellar ataxia (LCCA). In addition, three patients with localized cerebellar lesions were tested. The SPR latency was significantly longer in patients than in controls, but primary responses in the tibialis anterior muscle were normal. The frequency of abnormal SLR was 38.9% in the supine position and 83.3% in the standing position. Two out of three patients with localized cerebellar lesions also showed abnormal SLR. Altered SPRs in patients may result from a dysfunction of the primary motor cortex caused by crossed cerebello-cerebral diaschisis. In addition, our results suggest that 'pure' cerebellar degeneration involves the mechanism responsible for evoking SLR which is related to the control of posture. SLR can be a useful neurophysiological parameter for evaluating cerebellofugal function.

Differentiating Cerebellar Impact on Thalamic Nuclei.

PubMed

Gornati, Simona V; Schäfer, Carmen B; Eelkman Rooda, Oscar H J; Nigg, Alex L; De Zeeuw, Chris I; Hoebeek, Freek E

2018-05-29

The cerebellum plays a role in coordination of movements and non-motor functions. Cerebellar nuclei (CN) axons connect to various parts of the thalamo-cortical network, but detailed information on the characteristics of cerebello-thalamic connections is lacking. Here, we assessed the cerebellar input to the ventrolateral (VL), ventromedial (VM), and centrolateral (CL) thalamus. Confocal and electron microscopy showed an increased density and size of CN axon terminals in VL compared to VM or CL. Electrophysiological recordings in vitro revealed that optogenetic CN stimulation resulted in enhanced charge transfer and action potential firing in VL neurons compared to VM or CL neurons, despite that the paired-pulse ratio was not significantly different. Together, these findings indicate that the impact of CN input onto neurons of different thalamic nuclei varies substantially, which highlights the possibility that cerebellar output differentially controls various parts of the thalamo-cortical network. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Postnatal Migration of Cerebellar Interneurons

PubMed Central

Galas, Ludovic; Bénard, Magalie; Lebon, Alexis; Komuro, Yutaro; Schapman, Damien; Vaudry, Hubert; Vaudry, David; Komuro, Hitoshi

2017-01-01

Due to its continuing development after birth, the cerebellum represents a unique model for studying the postnatal orchestration of interneuron migration. The combination of fluorescent labeling and ex/in vivo imaging revealed a cellular highway network within cerebellar cortical layers (the external granular layer, the molecular layer, the Purkinje cell layer, and the internal granular layer). During the first two postnatal weeks, saltatory movements, transient stop phases, cell-cell interaction/contact, and degradation of the extracellular matrix mark out the route of cerebellar interneurons, notably granule cells and basket/stellate cells, to their final location. In addition, cortical-layer specific regulatory factors such as neuropeptides (pituitary adenylate cyclase-activating polypeptide (PACAP), somatostatin) or proteins (tissue-type plasminogen activator (tPA), insulin growth factor-1 (IGF-1)) have been shown to inhibit or stimulate the migratory process of interneurons. These factors show further complexity because somatostatin, PACAP, or tPA have opposite or no effect on interneuron migration depending on which layer or cell type they act upon. External factors originating from environmental conditions (light stimuli, pollutants), nutrients or drug of abuse (alcohol) also alter normal cell migration, leading to cerebellar disorders. PMID:28587295

Business Students' Choice of Short-Term or Long-Term Study Abroad Opportunities

ERIC Educational Resources Information Center

Fitzsimmons, Stacey R.; Flanagan, David J.; Wang, Xiaodan

2013-01-01

Recent years have seen a proliferation of short-term study abroad opportunities. Although they are both supplementing and replacing semester-long study abroad programs, research has focused primarily on semester (long-term) programs. We draw on the theory of planned behavior (TPB) to explore factors that predict why students choose long-term and…

Cerebellar abiotrophy in a family of Border Collie dogs.

PubMed

Sandy, J R; Slocombe, R E; Mitten, R W; Jedwab, D

2002-11-01

Cerebellar abiotrophies have a nonsex-linked, autosomal, recessively inherited basis in a number of species, and lesions typically reflect profound and progressive loss of Purkinje cells. In this report, an unusual form of abiotrophy is described for two sibling Border Collies. Extensive loss of the cerebellar granular cell layer was present with relative sparing of Purkinje cells of two female pups. The biochemical basis for this form of cerebellar abiotrophy is unknown, but the lack of disease in other siblings supports an autosomal recessive mode of inheritance.

Short and Long-Term Sunlight Radiation and Stroke Incidence

PubMed Central

McClure, Leslie A.; Judd, Suzanne E.; Howard, Virginia J.; Crosson, William L.; Al-Hamdan, Mohammad Z.; Wadley, Virginia G.; Peace, Fredrick; Kabagambe, Edmond K.

2012-01-01

OBJECTIVE Examine whether long and short-term sunlight radiation is related to stroke incidence. METHODS Fifteen-year residential histories merged with satellite, ground monitor, and model reanalysis data were used to determine sunlight radiation (insolation) and temperature exposure for a cohort of 16,606 stroke and coronary artery disease free black and white participants aged 45+ from the 48 contiguous United States. Fifteen, ten, five, two and one-year exposures were used to predict stroke incidence during follow-up in Cox proportional hazard models. Potential confounders and mediators were included during model-building. RESULTS Shorter exposure periods exhibited similar, but slightly stronger relationships than longer exposure periods. After adjustment for other covariates, the previous year’s monthly average insolation exposure below the median gave an HR=1.61 (95% CI: 1.15, 2.26) and the previous year’s highest compared to the second highest quartile of monthly average maximum temperature exposure gave an HR=1.92 (1.27, 2.92). INTERPRETATION These results indicate a relationship between lower levels of sunlight radiation and higher stroke incidence. The biological pathway of this relationship is not clear. Future research will show whether this finding stands, the pathway for this relationship, and if it is due to short or long-term exposures. PMID:23225379

Transplantation of Embryonic Cerebellar Grafts Improves Gait Parameters in Ataxic Lurcher Mice.

PubMed

Babuska, Vaclav; Houdek, Zbynek; Tuma, Jan; Purkartova, Zdenka; Tumova, Jana; Kralickova, Milena; Vozeh, Frantisek; Cendelin, Jan

2015-12-01

Hereditary cerebellar ataxias are severe diseases for which therapy is currently not sufficiently effective. One of the possible therapeutic approaches could be neurotransplantation. Lurcher mutant mice are a natural model of olivocerebellar degeneration representing a tool to investigate its pathogenesis as well as experimental therapies for hereditary cerebellar ataxias. The effect of intracerebellar transplantation of embryonic cerebellar solid tissue or cell suspension on motor performance in adult Lurcher mutant and healthy wild-type mice was studied. Brain-derived neurotrophic factor level was measured in the graft and adult cerebellar tissue. Gait analysis and rotarod, horizontal wire, and wooden beam tests were carried out 2 or 6 months after the transplantation. Higher level of the brain-derived neurotrophic factor was found in the Lurcher cerebellum than in the embryonic and adult wild-type tissue. A mild improvement of gait parameters was found in graft-treated Lurcher mice. The effect was more marked in cell suspension grafts than in solid transplants and after the longer period than after the short one. Lurcher mice treated with cell suspension and examined 6 months later had a longer hind paw stride (4.11 vs. 3.73 mm, P < 0.05) and higher swing speed for both forepaws (52.46 vs. 32.79 cm/s, P < 0.01) and hind paws (63.46 vs. 43.67 cm/s, P < 0.001) than controls. On the other hand, classical motor tests were not capable of detecting clearly the change in the motor performance. No strong long-lasting negative effect of the transplantation was seen in wild-type mice, suggesting that the treatment has no harmful impact on the healthy cerebellum.

Blood harmane is correlated with cerebellar metabolism in essential tremor: a pilot study.

PubMed

Louis, Elan D; Zheng, Wei; Mao, Xiangling; Shungu, Dikoma C

2007-08-07

On proton magnetic resonance spectroscopic imaging ((1)H MRSI), there is a decrease in cerebellar N-acetylaspartate/total creatine (NAA/tCr) in essential tremor (ET), signifying cerebellar neuronal dysfunction or degeneration. Harmane, which is present in the human diet, is a potent tremor-producing neurotoxin. Blood harmane concentrations seem to be elevated in ET. To assess in patients with ET whether blood harmane concentration is correlated with cerebellar NAA/tCR, a neuroimaging measure of neuronal dysfunction or degeneration. Twelve patients with ET underwent (1)H MRSI. The major neuroanatomic structure of interest was the cerebellar cortex. Secondary regions were the central cerebellar white matter, cerebellar vermis, thalamus, and basal ganglia. Blood concentrations of harmane and another neurotoxin, lead, were also assessed. Mean +/- SD cerebellar NAA/tCR was 1.52 +/- 0.41. In a linear regression model that adjusted for age and gender, log blood harmane concentration was a predictor of cerebellar NAA/tCR (beta = -0.41, p = 0.009); every 1 g(-10)/mL unit increase in log blood harmane concentration was associated with a 0.41 unit decrease in cerebellar NAA/tCR. The association between blood harmane concentration and brain NAA/tCR only occurred in the cerebellar cortex; it was not observed in secondary brain regions of interest. Furthermore, the association was specific to harmane and not another neurotoxin, lead. This study provides additional support for the emerging link between harmane, a neurotoxin, and ET. Further studies are warranted to address whether cerebellar harmane concentrations are associated with cerebellar pathology in postmortem studies of the ET brain.

Early nutrition programming of long-term health.

PubMed

Koletzko, Berthold; Brands, Brigitte; Poston, Lucilla; Godfrey, Keith; Demmelmair, Hans

2012-08-01

Increasing evidence from the EU Project EARNEST and many other investigators demonstrates that early nutrition and lifestyle have long-term effects on later health and the risk of common non-communicable diseases (known as 'developmental programming'). Because of the increasing public health importance and the transgenerational nature of the problem, obesity and associated disorders are the focus of the new EU funded project 'EarlyNutrition'. Currently, three key hypotheses have been defined: the fuel mediated 'in utero' hypothesis suggests that intrauterine exposure to an excess of fuels, most notably glucose, causes permanent changes of the fetus that lead to obesity in postnatal life; the accelerated postnatal weight gain hypothesis proposes an association between rapid weight gain in infancy and an increased risk of later obesity and adverse outcomes; and the mismatch hypothesis suggests that experiencing a developmental 'mismatch' between a sub-optimal perinatal and an obesogenic childhood environment is related to a particular predisposition to obesity and corresponding co-morbidities. Using existing cohort studies, ongoing and novel intervention studies and a basic science programme to investigate those key hypotheses, project EarlyNutrition will provide the scientific foundations for evidence-based recommendations for optimal nutrition considering long-term health outcomes, with a focus on obesity and related disorders. Scientific and technical expertise in placental biology, epigenetics and metabolomics will provide understanding at the cellular and molecular level of the relationships between early life nutritional status and the risk of later adiposity. This will help refine strategies for intervention in early life to prevent obesity.

A Long-Term BCI Study With ECoG Recordings in Freely Moving Rats.

PubMed

Costecalde, Thomas; Aksenova, Tetiana; Torres-Martinez, Napoleon; Eliseyev, Andriy; Mestais, Corinne; Moro, Cecile; Benabid, Alim Louis

2018-02-01

Brain Computer Interface (BCI) studies are performed in an increasing number of applications. Questions are raised about electrodes, data processing and effectors. Experiments are needed to solve these issues. To develop a simple BCI set-up to easier studies for improving the mathematical tools to process the ECoG to control an effector. We designed a simple BCI using transcranial electrodes (17 screws, three mechanically linked to create a common reference, 14 used as recording electrodes) to record Electro-Cortico-Graphic (ECoG) neuronal activities in rodents. The data processing is based on an online self-paced non-supervised (asynchronous) BCI paradigm. N-way partial least squares algorithm together with Continuous Wavelet Transformation of ECoG recordings detect signatures related to motor activities. Signature detection in freely moving rats may activate external effectors during a behavioral task, which involved pushing a lever to obtain a reward. After routine training, we showed that peak brain activity preceding a lever push (LP) to obtain food reward was located mostly in the cerebellar cortex with a higher correlation coefficient, suggesting a strong postural component and also in the occipital cerebral cortex. Analysis of brain activities provided a stable signature in the high gamma band (∼180Hz) occurring within 1500 msec before the lever push approximately around -400 msec to -500 msec. Detection of the signature from a single cerebellar cortical electrode triggers the effector with high efficiency (68% Offline and 30% Online) and rare false positives per minute in sessions about 30 minutes and up to one hour (∼2 online and offline). In summary, our results are original as compared to the rest of the literature, which involves rarely rodents, a simple BCI set-up has been developed in rats, the data show for the first time long-term, up to one year, unsupervised online control of an effector. © 2017 International Neuromodulation Society.

Physical activity enhances long-term quality of life in older adults: efficacy, esteem, and affective influences.

PubMed

Elavsky, Steriani; McAuley, Edward; Motl, Robert W; Konopack, James F; Marquez, David X; Hu, Liang; Jerome, Gerald J; Diener, Ed

2005-10-01

Physical activity has been effective in enhancing quality of life (QOL) of older adults over relatively short periods of time. However, little is known about the long-term effects of physical activity and even less about the possible mediators of this relationship. We examined the mediating effects of psychological variables on the relationship between physical activity and global QOL (satisfaction with life) in older adults over a 4-year period. Participants (N = 174, M age = 66.7 years) completed a battery of psychosocial measures at 1 and 5 years following enrollment in a 6-month randomized controlled exercise trial. Panel analysis conducted within a covariance modeling framework indicated that physical activity was related to self-efficacy, physical self-esteem, and positive affect at 1 year, and in turn, greater levels of self-efficacy and positive affect were associated with higher levels of QOL. Analyses indicated that changes in physical activity over the 4-year period were related to increases in physical self-esteem and positive affect, but only positive affect directly influenced improvements in QOL. The findings lend support to the position that physical activity effects on QOL are in part mediated by intermediate psychological outcomes and that physical activity can have long-term effects on well-being.

Long Periodic Terms in the Solar System

NASA Technical Reports Server (NTRS)

Bretagnon, P.

1982-01-01

The long period variations of the first eight planets in the solar system are studied. First, the Lagrangian solution is calculated and then the long period terms with fourth order eccentricities and inclinations are introduced into the perturbation function. A second approximation was made taking into account the short period terms' contribution, namely the perturbations of first order with respect to the masses. Special attention was paid to the determination of the integration constants. The relative importance of the different contributions is shown. It is useless, for example, to introduce the long period terms of fifth order if no account has been taken of the short period terms. Meanwhile, the terms that have been neglected would not introduce large changes in the integration constants. Even so, the calculation should be repeated with higher order short period terms and fifth order long periods.

Long-Term Hearing Results After Ossiculoplasty.

PubMed

Cox, Matthew D; Trinidade, Aaron; Russell, James Shep; Dornhoffer, John L

2017-04-01

To determine if the OOPS index is predictive of long-term hearing results after ossiculoplasty. Case series with retrospective chart review. Tertiary care otology practice. Adult and pediatric patients (3-88 years of age). Ossiculoplasty with cartilage tympanoplasty, with or without mastoidectomy. Primary outcome measures included short-term hearing results (pure-tone average air-bone gap [PTA-ABG] measured between 60 days and 1 year after surgery), long-term hearing results (PTA-ABG measured ≥5 years after surgery), and the rate of successful ABG closure to ≤20 dB. Secondary measures included the need for revision surgery, delayed tympanic membrane graft failure, worsening conductive hearing loss (after an initially satisfactory hearing result), and recurrence of cholesteatoma. There was no significant difference between adults and children for short-term hearing results (average post-op PTA-ABG was 18.9 dB vs. 19.8 dB, respectively; p = 0.544), long-term hearing results (average final PTA-ABG was 19.3 dB vs. 19.4 dB, respectively; p = 0.922), or rate of ABG closure to less than 20 dB (63.1% vs. 58.0%, p = 0.282). Spearman's rank-order correlation (ρ) identified a strong positive correlation between OOPS index score and average post-operative PTA-ABG (ρ = 0.983; p < 0.001; 2-tailed), as well as average long-term PTA-ABG (ρ = 0.950, p < 0.001; 2-tailed). The OOPS index makes it possible to accurately prognosticate hearing outcomes in adult and pediatric patients undergoing ossiculoplasty in both the short term and the long term.

Friedreich and dominant ataxias: quantitative differences in cerebellar dysfunction measurements.

PubMed

Tanguy Melac, Audrey; Mariotti, Caterina; Filipovic Pierucci, Antoine; Giunti, Paola; Arpa, Javier; Boesch, Sylvia; Klopstock, Thomas; Müller Vom Hagen, Jennifer; Klockgether, Thomas; Bürk, Katrin; Schulz, Jörg B; Reetz, Kathrin; Pandolfo, Massimo; Durr, Alexandra; Tezenas du Montcel, Sophie

2018-06-01

Sensitive outcome measures for clinical trials on cerebellar ataxias are lacking. Most cerebellar ataxias progress very slowly and quantitative measurements are required to evaluate cerebellar dysfunction. We evaluated two scales for rating cerebellar ataxias: the Composite Cerebellar Functional Severity (CCFS) Scale and Scale for the Assessment and Rating of Ataxia (SARA), in patients with spinocerebellar ataxia (SCA) and controls. We evaluated these scales for different diseases and investigated the factors governing the scores obtained. All patients were recruited prospectively. There were 383 patients with Friedreich's ataxia (FRDA), 205 patients with SCA and 168 controls. In FRDA, 31% of the variance of cerebellar signs with the CCFS and 41% of that with SARA were explained by disease duration, age at onset and the shorter abnormal repeat in the FXN gene. Increases in CCFS and SARA scores per year were lower for FRDA than for SCA (CCFS index: 0.123±0.123 per year vs 0.163±0.179, P<0.001; SARA index: 1.5±1.2 vs 1.7±1.7, P<0.001), indicating slower cerebellar dysfunction indexes for FRDA than for SCA. Patients with SCA2 had higher CCFS scores than patients with SCA1 and SCA3, but similar SARA scores. Cerebellar dysfunction, as measured with the CCFS and SARA scales, was more severe in FRDA than in patients with SCA, but with lower progression indexes, within the limits of these types of indexes. Ceiling effects may occur at late stages, for both scales. The CCFS scale is rater-independent and could be used in a multicentre context, as it is simple, rapid and fully automated. ClinicalTrials.gov: NCT02069509. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Short-term memory and long-term memory are still different.

PubMed

Norris, Dennis

2017-09-01

A commonly expressed view is that short-term memory (STM) is nothing more than activated long-term memory. If true, this would overturn a central tenet of cognitive psychology-the idea that there are functionally and neurobiologically distinct short- and long-term stores. Here I present an updated case for a separation between short- and long-term stores, focusing on the computational demands placed on any STM system. STM must support memory for previously unencountered information, the storage of multiple tokens of the same type, and variable binding. None of these can be achieved simply by activating long-term memory. For example, even a simple sequence of digits such as "1, 3, 1" where there are 2 tokens of the digit "1" cannot be stored in the correct order simply by activating the representations of the digits "1" and "3" in LTM. I also review recent neuroimaging data that has been presented as evidence that STM is activated LTM and show that these data are exactly what one would expect to see based on a conventional 2-store view. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Short-Term Memory and Long-Term Memory are Still Different

PubMed Central

2017-01-01

A commonly expressed view is that short-term memory (STM) is nothing more than activated long-term memory. If true, this would overturn a central tenet of cognitive psychology—the idea that there are functionally and neurobiologically distinct short- and long-term stores. Here I present an updated case for a separation between short- and long-term stores, focusing on the computational demands placed on any STM system. STM must support memory for previously unencountered information, the storage of multiple tokens of the same type, and variable binding. None of these can be achieved simply by activating long-term memory. For example, even a simple sequence of digits such as “1, 3, 1” where there are 2 tokens of the digit “1” cannot be stored in the correct order simply by activating the representations of the digits “1” and “3” in LTM. I also review recent neuroimaging data that has been presented as evidence that STM is activated LTM and show that these data are exactly what one would expect to see based on a conventional 2-store view. PMID:28530428

Cerebellar ataxia: abnormal control of interaction torques across multiple joints.

PubMed

Bastian, A J; Martin, T A; Keating, J G; Thach, W T

1996-07-01

1. We studied seven subjects with cerebellar lesions and seven control subjects as they made reaching movements in the sagittal plane to a target directly in front of them. Reaches were made under three different conditions: 1) "slow-accurate," 2) "fast-accurate," and 3) "fast as possible." All subjects were videotaped moving in a sagittal plane with markers on the index finger, wrist, elbow, and shoulder. Marker positions were digitized and then used to calculate joint angles. For each of the shoulder, elbow and wrist joints, inverse dynamics equations based on a three-segment limb model were used to estimate the net torque (sum of components) and each of the component torques. The component torques consisted of the torque due to gravity, the dynamic interaction torques induced passively by the movement of the adjacent joint, and the torque produced by the muscles and passive tissue elements (sometimes called "residual" torque). 2. A kinematic analysis of the movement trajectory and the change in joint angles showed that the reaches of subjects with cerebellar lesions were abnormal compared with reaches of control subjects. In both the slow-accurate and fast-accurate conditions the cerebellar subjects made abnormally curved wrist paths; the curvature was greater in the slow-accurate condition. During the slow-accurate condition, cerebellar subjects showed target undershoot and tended to move one joint at a time (decomposition). During the fast-accurate reaches, the cerebellar subjects showed target overshoot. Additionally, in the fast-accurate condition, cerebellar subjects moved the joints at abnormal rates relative to one another, but the movements were less decomposed. Only three subjects were tested in the fast as possible condition; this condition was analyzed only to determine maximal reaching speeds of subjects with cerebellar lesions. Cerebellar subjects moved more slowly than controls in all three conditions. 3. A kinetic analysis of torques generated at

Remote cerebellar hemorrhage following supratentorial craniotomy.

PubMed

Huang, Chih-Yuan; Lee, Po-Hsuan; Lin, Sheng-Hsiang; Chuang, Ming-Tsung; Sun, Yuan-Ting; Hung, Yu-Chang; Lee, E-Jian

2012-06-01

Cerebellar hemorrhage remote from the site of surgery may complicate neurosurgical procedure. The exact pathophysiology of this type of hemorrhage is poorly understood. We retrospectively compared 16 patients who had remote cerebellar hemorrhage (RCH) with a case-matched control cohort, to determine the significance of perisurgical and surgical factors that may predispose patients to such bleeding events. From 1 June 2005 to 31 December 2008, postoperative routine head computed tomographic (CT) scan was performed in our institution and 16 patients with RCH after supratentorial neurosurgical procedure were identified. The medical charts of these 16 cases and a control cohort of 64 patients were recorded. All parameters were analyzed with regards to various variables. The incidence RCH after supratentorial craniotomy increased after postoperative computed tomographic scan. The mechanism of cerebellar hemorrhage in this series of patients is most likely multifactorial. Several variables showed a significant association with the occurrence of RCH. Multivariate analysis indicated that the following two factors independently correlated with occurrence of RCH: (1) postoperative epidural drainage amount; and (2) history of previous cerebrovascular accident (CVA) with cerebral atrophy. All cases with RCH underwent medical treatment and no neurological sequelae associated with RCH. Postoperative epidural drainage amount and history of previous CVA with cerebral atrophy can reliably predict the occurrence of cerebellar hemorrhage after supratentorial craniotomy. One of the most important strategies to minimize hazardous complications is to be aware of these potential risk factors and to take action to prevent them.

Long-term failure of alveologenesis after an early short-term exposure to a PDGF-receptor antagonist.

PubMed

Lau, Mandy; Masood, Azhar; Yi, Man; Belcastro, Rosetta; Li, Jun; Tanswell, A Keith

2011-04-01

Survivors of moderate-to-severe bronchopulmonary dysplasia have impaired alveologenesis lasting at least into early adult life. The mechanisms underlying this long-term effect are unknown. We hypothesized that short-term inhibition of growth factor-mediated early alveolar formation would result in a long-term impairment of subsequent alveologenesis. Neonatal rats were injected daily with the platelet-derived growth factor (PDGF) receptor antagonist, imatinib mesylate, from day 1-7 of life, to inhibit the early alveolar formation occurring by in-growth of secondary crests into precursor saccules. The pups were then allowed to recover for 7, 14, 21, or 58 days. In imatinib-treated pups, DNA synthesis in total lung cells, and specifically in cells of secondary crests, was reduced at day 8 of life, had rebounded on day 14 of life but was then again reduced by day 28 of life. At day 8 of life, imatinib-treated pups had impaired alveologenesis as reflected by a decrease in secondary crests, an increase in alveolar size, and an overall decrease in both estimated alveolar number and generations compared with age-matched controls. No meaningful recovery was observed, even after a 21- or 58-day recovery period. The lungs of imatinib-treated pups had increased fibulin-5 content and an abnormal deposition of elastin. We conclude that reduced signaling through the PDGF pathways, at an early stage of alveologenesis, can result in long-lasting changes in lung architecture. A likely mechanism is through impaired formation of the elastin scaffold required for alveolarization.

The Calmodulin-Binding Transcription Activator CAMTA1 Is Required for Long-Term Memory Formation in Mice

ERIC Educational Resources Information Center

Bas-Orth, Carlos; Tan, Yan-Wei; Oliveira, Ana M. M.; Bengtson, C. Peter; Bading, Hilmar

2016-01-01

The formation of long-term memory requires signaling from the synapse to the nucleus to mediate neuronal activity-dependent gene transcription. Synapse-to-nucleus communication is initiated by influx of calcium ions through synaptic NMDA receptors and/or L-type voltage-gated calcium channels and involves the activation of transcription factors by…

Anti-Hu Antibody Associated Paraneoplastic Cerebellar Degeneration in Head and Neck Cancer.

PubMed

Huemer, Florian; Melchardt, Thomas; Tränkenschuh, Wolfgang; Neureiter, Daniel; Moser, Gerhard; Magnes, Teresa; Weiss, Lukas; Schlattau, Alexander; Hufnagl, Clemens; Ricken, Gerda; Höftberger, Romana; Greil, Richard; Egle, Alexander

2015-12-22

Paraneoplastic syndromes are most frequently associated with small cell lung carcinoma, hematologic and gynecologic malignancies while reports in head and neck cancer are rare. We present the case of a 60-year old female patient who developed paraneoplastic cerebellar degeneration upon locoregional recurrence of a poorly differentiated spindle cell carcinoma of the nasal cavity and paranasal sinus. The neurological symptoms, especially ataxia, stabilized after resection of tumor recurrence and concomitant chemoradiotherapy whereas anti-Hu-antibodies remained positive. Despite the unfavorable prognosis of paraneoplastic neurological disorders associated with onconeural antibodies, the patient achieved long-standing stabilization of neurological symptoms. We report the first patient with anti-Hu antibodies and paraneoplastic cerebellar degeneration associated with a spindle cell carcinoma of the head and neck. We recommend that evaluation of neurological symptoms in patients with this tumor entity should also include paraneoplastic syndromes as differential diagnoses and suggest early extensive screening for onconeural antibodies.

Heat stroke induced cerebellar dysfunction: A “forgotten syndrome”

PubMed Central

Kosgallana, Athula D; Mallik, Shreyashee; Patel, Vishal; Beran, Roy G

2013-01-01

We report a case of heat stroke induced acute cerebellar dysfunction, a rare neurological disease characterized by gross cerebellar dysfunction with no acute radiographic changes, in a 61 years old ship captain presenting with slurred speech and gait ataxia. A systematic review of the literature on heat stroke induced cerebellar dysfunction was performed, with a focus on investigations, treatment and outcomes. After review of the literature and detailed patient investigation it was concluded that this patient suffered heat stroke at a temperature less than that quoted in the literature. PMID:24340279

Five-year Survival After Surgical Removal and Gamma Knife Stereotactic Radiosurgery for a Cerebellar Metastasis from an Esophagogastric Junction Cancer: A Case Report and Literature Review

PubMed Central

KANAZAWA, YOSHIKAZU; FUJITA, ITSUO; KAKINUMA, DAISUKE; AOKI, YUTO; KANNO, HITOSHI; ARAI, HIROKI; MATSUNO, KUNIHIKO; SHIMODA, TOMOHIRO; MATSUTANI, TAKESHI; HAGIWARA, NOBUTOSHI; NOMURA, TSUTOMU; YAMADA, TAKESHI; KATO, SHUNJI; NAITO, ZENYA; TAKASAKI, HIDEAKI; UCHIDA, EIJI

2017-01-01

Brain metastases originating from esophageal or gastric cancer are rare, accounting for 2.1-3.3% of all brain tumors registered in Japan. There are no established therapeutic measures for brain metastases, which accordingly have a poor prognosis. We present here a patient who survived for 5 years after surgery and gamma knife treatment of a cerebellar metastasis from esophagogastric adenocarcinoma. The primary gastric cancer was treated by laparotomy with total gastrectomy, splenectomy, and D2 lymphadenectomy. It was diagnosed as a esophagogastric junction Siewert type II tumor, type 3, tub1-2, pT3 (SS), pN1, and stage IIB on histopathological examination of the surgical specimen. Five months postoperatively, a solitary cerebellar metastasis was identified and surgically removed, followed by 20 Gy administered by gamma knife stereotactic radiosurgery; the patient received no subsequent treatment such as chemotherapy. Five years after the primary surgery, there have been no recurrences and the patient has a good quality of life. There are very few case reports of long-term survival after surgical treatment of cerebellar metastases from esophagogastric junction cancer. We report our experience and review published case reports of surgical treatment of brain metastases from gastric cancer. PMID:29102948

Sex differences in cerebellar synaptic transmission and sex-specific responses to autism-linked Gabrb3 mutations in mice

PubMed Central

Mercer, Audrey A; Palarz, Kristin J; Tabatadze, Nino; Woolley, Catherine S; Raman, Indira M

2016-01-01

Neurons of the cerebellar nuclei (CbN) transmit cerebellar signals to premotor areas. The cerebellum expresses several autism-linked genes, including GABRB3, which encodes GABAA receptor β3 subunits and is among the maternal alleles deleted in Angelman syndrome. We tested how this Gabrb3 m-/p+ mutation affects CbN physiology in mice, separating responses of males and females. Wild-type mice showed sex differences in synaptic excitation, inhibition, and intrinsic properties. Relative to females, CbN cells of males had smaller synaptically evoked mGluR1/5-dependent currents, slower Purkinje-mediated IPSCs, and lower spontaneous firing rates, but rotarod performances were indistinguishable. In mutant CbN cells, IPSC kinetics were unchanged, but mutant males, unlike females, showed enlarged mGluR1/5 responses and accelerated spontaneous firing. These changes appear compensatory, since mutant males but not females performed indistinguishably from wild-type siblings on the rotarod task. Thus, sex differences in cerebellar physiology produce similar behavioral output, but provide distinct baselines for responses to mutations. DOI: http://dx.doi.org/10.7554/eLife.07596.001 PMID:27077953

Diffusion tensor imaging of the human cerebellar pathways and their interplay with cerebral macrostructure

PubMed Central

Keser, Zafer; Hasan, Khader M.; Mwangi, Benson I.; Kamali, Arash; Ucisik-Keser, Fehime Eymen; Riascos, Roy F.; Yozbatiran, Nuray; Francisco, Gerard E.; Narayana, Ponnada A.

2015-01-01

Cerebellar white matter (WM) connections to the central nervous system are classified functionally into the Spinocerebellar (SC), vestibulocerebellar (VC), and cerebrocerebellar subdivisions. The SC pathways project from spinal cord to cerebellum, whereas the VC pathways project from vestibular organs of the inner ear. Cerebrocerebellar connections are composed of feed forward and feedback connections between cerebrum and cerebellum including the cortico-ponto-cerebellar (CPC) pathways being of cortical origin and the dentate-rubro-thalamo-cortical (DRTC) pathway being of cerebellar origin. In this study we systematically quantified the whole cerebellar system connections using diffusion tensor magnetic resonance imaging (DT-MRI). Ten right-handed healthy subjects (7 males and 3 females, age range 20–51 years) were studied. DT-MRI data were acquired with a voxel size = 2 mm × 2 mm × 2 mm at a 3.0 Tesla clinical MRI scanner. The DT-MRI data were prepared and analyzed using anatomically-guided deterministic tractography methods to reconstruct the SC, DRTC, fronto-ponto-cerebellar (FPC), parieto-ponto-cerebellar (PPC), temporo-ponto-cerebellar (TPC) and occipito-ponto-cerebellar (OPC). The DTI-attributes or the cerebellar tracts along with their cortical representation (Brodmann areas) were presented in standard Montréal Neurological Institute space. All cerebellar tract volumes were quantified and correlated with volumes of cerebral cortical, subcortical gray matter (GM), cerebral WM and cerebellar GM, and cerebellar WM. On our healthy cohort, the ratio of total cerebellar GM-to-WM was ~3.29 ± 0.24, whereas the ratio of cerebral GM-to-WM was approximately 1.10 ± 0.11. The sum of all cerebellar tract volumes is ~25.8 ± 7.3 mL, or a percentage of 1.6 ± 0.45 of the total intracranial volume (ICV). PMID:25904851

Cerebellar Structure and Function in Male Wistar-Kyoto Hyperactive Rats

PubMed Central

Thanellou, Alexandra; Green, John T.

2014-01-01

Previous research has suggested that the Wistar-Kyoto Hyperactive (WKHA) rat strain may model some of the behavioral features associated with attention-deficit/hyperactivity disorder (ADHD). We have shown that, in cerebellar-dependent eyeblink conditioning, WKHA emit eyeblink CRs with shortened onset latencies. To further characterize the shortened CR onset latencies seen in WKHA rats, we examined 750-ms delay conditioning with either a tone CS or a light CS, we extended acquisition training, and we included Wistar rats as an additional, outbred control strain. Our results indicated that WKHAs learned more quickly and showed a shortened CR onset latency to a tone CS compared to both Wistar-Kyoto Hypertensive (WKHT) and Wistars. WKHAs and Wistars show a lengthening of CR onset latency over conditioning with a tone CS and an increasing confinement of CRs to the later part of the tone CS (inhibition of delay). WKHAs learned more quickly to a light CS only in comparison to WKHTs and showed a shortened CR onset latency only in comparison to Wistars. Wistars showed an increasing confinement of CRs to the late part of the light CS over conditioning. We used unbiased stereology to estimate the number of Purkinje and granule cells in the cerebellar cortex of the three strains. Our results indicated that WKHAs have more granule cells than Wistars and WKHTs and more Purkinje cells than Wistars. Results are discussed in terms of CS processing and cerebellar cortical contributions to EBC. PMID:23398437

Improved segmentation of cerebellar structures in children

PubMed Central

Narayanan, Priya Lakshmi; Boonazier, Natalie; Warton, Christopher; Molteno, Christopher D; Joseph, Jesuchristopher; Jacobson, Joseph L; Jacobson, Sandra W; Zöllei, Lilla; Meintjes, Ernesta M

2016-01-01

Background Consistent localization of cerebellar cortex in a standard coordinate system is important for functional studies and detection of anatomical alterations in studies of morphometry. To date, no pediatric cerebellar atlas is available. New method The probabilistic Cape Town Pediatric Cerebellar Atlas (CAPCA18) was constructed in the age-appropriate National Institute of Health Pediatric Database asymmetric template space using manual tracings of 16 cerebellar compartments in 18 healthy children (9–13 years) from Cape Town, South Africa. The individual atlases of the training subjects were also used to implement multi atlas label fusion using multi atlas majority voting (MAMV) and multi atlas generative model (MAGM) approaches. Segmentation accuracy in 14 test subjects was compared for each method to ‘gold standard’ manual tracings. Results Spatial overlap between manual tracings and CAPCA18 automated segmentation was 73% or higher for all lobules in both hemispheres, except VIIb and X. Automated segmentation using MAGM yielded the best segmentation accuracy over all lobules (mean Dice Similarity Coefficient 0.76; range 0.55–0.91). Comparison with existing methods In all lobules, spatial overlap of CAPCA18 segmentations with manual tracings was similar or higher than those obtained with SUIT (spatially unbiased infra-tentorial template), providing additional evidence of the benefits of an age appropriate atlas. MAGM segmentation accuracy was comparable to values reported recently by Park et al. (2014) in adults (across all lobules mean DSC = 0.73, range 0.40–0.89). Conclusions CAPCA18 and the associated multi atlases of the training subjects yield improved segmentation of cerebellar structures in children. PMID:26743973

Long-Term Memory Performance in Adult ADHD.

PubMed

Skodzik, Timo; Holling, Heinz; Pedersen, Anya

2017-02-01

Memory problems are a frequently reported symptom in adult ADHD, and it is well-documented that adults with ADHD perform poorly on long-term memory tests. However, the cause of this effect is still controversial. The present meta-analysis examined underlying mechanisms that may lead to long-term memory impairments in adult ADHD. We performed separate meta-analyses of measures of memory acquisition and long-term memory using both verbal and visual memory tests. In addition, the influence of potential moderator variables was examined. Adults with ADHD performed significantly worse than controls on verbal but not on visual long-term memory and memory acquisition subtests. The long-term memory deficit was strongly statistically related to the memory acquisition deficit. In contrast, no retrieval problems were observable. Our results suggest that memory deficits in adult ADHD reflect a learning deficit induced at the stage of encoding. Implications for clinical and research settings are presented.

Electrophysiological evidence of cerebellar fiber system involvement in the Miller Fisher syndrome.

PubMed

Lo, Y L; Fook-Chong, S; Chan, L L; Ong, W Y; Ratnagopal, P

2010-01-15

In the Miller Fisher syndrome (MFS), ataxia may be due involvement of Ia afferents and the cerebellum. Transcranial magnetic stimulation (TMS) over the cerebellum is known to interfere transiently with normal function. In this study, we utilized a previously described TMS protocol over the cerebellum in combination with ballistic movements to investigate cerebellar dysfunction in MFS patients. The agonist (biceps) reaction time in MFS patients during a motor cancellation task was not significantly reduced during the initial TMS study. However, during the repeat TMS study, significant reduction was seen for all patients, in tandem with clinical recovery. There was significant correlation between anti-GQ1b IgG titers and change in agonist reaction time between the initial and repeat TMS studies. TMS likely affected horizontally orientated parallel fibers in the cerebellar molecular layer. During disease onset, antibody binding may have interfered with facilitation of reaction time during motor cancellation tasks seen in normal subjects. Normalization of reaction time facilitation corresponded to resolution of antibody-mediated interference in the molecular layer. Our study has provided evidence suggesting parallel fiber involvement in MFS, and suggested a role of anti-GQ1b IgG antibody in these changes.

Defective cerebellar control of cortical plasticity in writer’s cramp

PubMed Central

Hubsch, Cecile; Roze, Emmanuel; Popa, Traian; Russo, Margherita; Balachandran, Ammu; Pradeep, Salini; Mueller, Florian; Brochard, Vanessa; Quartarone, Angelo; Degos, Bertrand; Vidailhet, Marie; Kishore, Asha

2013-01-01

A large body of evidence points to a role of basal ganglia dysfunction in the pathophysiology of dystonia, but recent studies indicate that cerebellar dysfunction may also be involved. The cerebellum influences sensorimotor adaptation by modulating sensorimotor plasticity of the primary motor cortex. Motor cortex sensorimotor plasticity is maladaptive in patients with writer’s cramp. Here we examined whether putative cerebellar dysfunction in dystonia is linked to these patients’ maladaptive plasticity. To that end we compared the performances of patients and healthy control subjects in a reaching task involving a visuomotor conflict generated by imposing a random deviation (−40° to 40°) on the direction of movement of the mouse/cursor. Such a task is known to involve the cerebellum. We also compared, between patients and healthy control subjects, how the cerebellum modulates the extent and duration of an ongoing sensorimotor plasticity in the motor cortex. The cerebellar cortex was excited or inhibited by means of repeated transcranial magnetic stimulation before artificial sensorimotor plasticity was induced in the motor cortex by paired associative stimulation. Patients with writer’s cramp were slower than the healthy control subjects to reach the target and, after having repeatedly adapted their trajectories to the deviations, they were less efficient than the healthy control subjects to perform reaching movement without imposed deviation. It was interpreted as impaired washing-out abilities. In healthy subjects, cerebellar cortex excitation prevented the paired associative stimulation to induce a sensorimotor plasticity in the primary motor cortex, whereas cerebellar cortex inhibition led the paired associative stimulation to be more efficient in inducing the plasticity. In patients with writer’s cramp, cerebellar cortex excitation and inhibition were both ineffective in modulating sensorimotor plasticity. In patients with writer’s cramp, but not

Cerebro-cerebellar interactions underlying temporal information processing.

PubMed

Aso, Kenji; Hanakawa, Takashi; Aso, Toshihiko; Fukuyama, Hidenao

2010-12-01

The neural basis of temporal information processing remains unclear, but it is proposed that the cerebellum plays an important role through its internal clock or feed-forward computation functions. In this study, fMRI was used to investigate the brain networks engaged in perceptual and motor aspects of subsecond temporal processing without accompanying coprocessing of spatial information. Direct comparison between perceptual and motor aspects of time processing was made with a categorical-design analysis. The right lateral cerebellum (lobule VI) was active during a time discrimination task, whereas the left cerebellar lobule VI was activated during a timed movement generation task. These findings were consistent with the idea that the cerebellum contributed to subsecond time processing in both perceptual and motor aspects. The feed-forward computational theory of the cerebellum predicted increased cerebro-cerebellar interactions during time information processing. In fact, a psychophysiological interaction analysis identified the supplementary motor and dorsal premotor areas, which had a significant functional connectivity with the right cerebellar region during a time discrimination task and with the left lateral cerebellum during a timed movement generation task. The involvement of cerebro-cerebellar interactions may provide supportive evidence that temporal information processing relies on the simulation of timing information through feed-forward computation in the cerebellum.

Variation in short-term and long-term responses of photosynthesis and isoprenoid-mediated photoprotection to soil water availability in four Douglas-fir provenances

DOE PAGES

Junker, Laura Verena; Kleiber, Anita; Jansen, Kirstin; ...

2017-01-10

For long-lived forest tree species, the understanding of intraspecific variation among populations and their response to water availability can reveal their ability to cope with and adapt to climate change. Dissipation of excess excitation energy, mediated by photoprotective isoprenoids, is an important defense mechanism against drought and high light when photosynthesis is hampered. We used 50-year-old Douglas-fir trees of four provenances at two common garden experiments to characterize provenance-specific variation in photosynthesis and photoprotective mechanisms mediated by essential and non-essential isoprenoids in response to soil water availability and solar radiation. All provenances revealed uniform photoprotective responses to high solar radiation,more » including increased de-epoxidation of photoprotective xanthophyll cycle pigments and enhanced emission of volatile monoterpenes. In contrast, we observed differences between provenances in response to drought, where provenances sustaining higher CO2 assimilation rates also revealed increased water-use efficiency, carotenoid-chlorophyll ratios, pools of xanthophyll cycle pigments, β-carotene and stored monoterpenes. Our results demonstrate that local adaptation to contrasting habitats affected chlorophyll-carotenoid ratios, pool sizes of photoprotective xanthophylls, β-carotene, and stored volatile isoprenoids. We conclude that intraspecific variation in isoprenoid-mediated photoprotective mechanisms contributes to the adaptive potential of Douglas-fir provenances to climate change.« less

Variation in short-term and long-term responses of photosynthesis and isoprenoid-mediated photoprotection to soil water availability in four Douglas-fir provenances

DOE Office of Scientific and Technical Information (OSTI.GOV)

Junker, Laura Verena; Kleiber, Anita; Jansen, Kirstin

For long-lived forest tree species, the understanding of intraspecific variation among populations and their response to water availability can reveal their ability to cope with and adapt to climate change. Dissipation of excess excitation energy, mediated by photoprotective isoprenoids, is an important defense mechanism against drought and high light when photosynthesis is hampered. We used 50-year-old Douglas-fir trees of four provenances at two common garden experiments to characterize provenance-specific variation in photosynthesis and photoprotective mechanisms mediated by essential and non-essential isoprenoids in response to soil water availability and solar radiation. All provenances revealed uniform photoprotective responses to high solar radiation,more » including increased de-epoxidation of photoprotective xanthophyll cycle pigments and enhanced emission of volatile monoterpenes. In contrast, we observed differences between provenances in response to drought, where provenances sustaining higher CO2 assimilation rates also revealed increased water-use efficiency, carotenoid-chlorophyll ratios, pools of xanthophyll cycle pigments, β-carotene and stored monoterpenes. Our results demonstrate that local adaptation to contrasting habitats affected chlorophyll-carotenoid ratios, pool sizes of photoprotective xanthophylls, β-carotene, and stored volatile isoprenoids. We conclude that intraspecific variation in isoprenoid-mediated photoprotective mechanisms contributes to the adaptive potential of Douglas-fir provenances to climate change.« less

Variation in short-term and long-term responses of photosynthesis and isoprenoid-mediated photoprotection to soil water availability in four Douglas-fir provenances

PubMed Central

Junker, Laura Verena; Kleiber, Anita; Jansen, Kirstin; Wildhagen, Henning; Hess, Moritz; Kayler, Zachary; Kammerer, Bernd; Schnitzler, Jörg-Peter; Kreuzwieser, Jürgen; Gessler, Arthur; Ensminger, Ingo

2017-01-01

For long-lived forest tree species, the understanding of intraspecific variation among populations and their response to water availability can reveal their ability to cope with and adapt to climate change. Dissipation of excess excitation energy, mediated by photoprotective isoprenoids, is an important defense mechanism against drought and high light when photosynthesis is hampered. We used 50-year-old Douglas-fir trees of four provenances at two common garden experiments to characterize provenance-specific variation in photosynthesis and photoprotective mechanisms mediated by essential and non-essential isoprenoids in response to soil water availability and solar radiation. All provenances revealed uniform photoprotective responses to high solar radiation, including increased de-epoxidation of photoprotective xanthophyll cycle pigments and enhanced emission of volatile monoterpenes. In contrast, we observed differences between provenances in response to drought, where provenances sustaining higher CO2 assimilation rates also revealed increased water-use efficiency, carotenoid-chlorophyll ratios, pools of xanthophyll cycle pigments, β-carotene and stored monoterpenes. Our results demonstrate that local adaptation to contrasting habitats affected chlorophyll-carotenoid ratios, pool sizes of photoprotective xanthophylls, β-carotene, and stored volatile isoprenoids. We conclude that intraspecific variation in isoprenoid-mediated photoprotective mechanisms contributes to the adaptive potential of Douglas-fir provenances to climate change. PMID:28071755

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.

Epigenetics as a mechanism linking developmental exposures to long-term toxicity.

PubMed

Barouki, R; Melén, E; Herceg, Z; Beckers, J; Chen, J; Karagas, M; Puga, A; Xia, Y; Chadwick, L; Yan, W; Audouze, K; Slama, R; Heindel, J; Grandjean, P; Kawamoto, T; Nohara, K

2018-05-01

A variety of experimental and epidemiological studies lend support to the Developmental Origin of Health and Disease (DOHaD) concept. Yet, the actual mechanisms accounting for mid- and long-term effects of early-life exposures remain unclear. Epigenetic alterations such as changes in DNA methylation, histone modifications and the expression of certain RNAs have been suggested as possible mediators of long-term health effects of environmental stressors. This report captures discussions and conclusions debated during the last Prenatal Programming and Toxicity meeting held in Japan. Its first aim is to propose a number of criteria that are critical to support the primary contribution of epigenetics in DOHaD and intergenerational transmission of environmental stressors effects. The main criteria are the full characterization of the stressors, the actual window of exposure, the target tissue and function, the specificity of the epigenetic changes and the biological plausibility of the linkage between those changes and health outcomes. The second aim is to discuss long-term effects of a number of stressors such as smoking, air pollution and endocrine disruptors in order to identify the arguments supporting the involvement of an epigenetic mechanism. Based on the developed criteria, missing evidence and suggestions for future research will be identified. The third aim is to critically analyze the evidence supporting the involvement of epigenetic mechanisms in intergenerational and transgenerational effects of environmental exposure and to particularly discuss the role of placenta and sperm. While the article is not a systematic review and is not meant to be exhaustive, it critically assesses the contribution of epigenetics in the long-term effects of environmental exposures as well as provides insight for future research. Copyright © 2018 Elsevier Ltd. All rights reserved.

Virtual Models of Long-Term Care

ERIC Educational Resources Information Center

Phenice, Lillian A.; Griffore, Robert J.

2012-01-01

Nursing homes, assisted living facilities and home-care organizations, use web sites to describe their services to potential consumers. This virtual ethnographic study developed models representing how potential consumers may understand this information using data from web sites of 69 long-term-care providers. The content of long-term-care web…

Ethyl pyruvate protects against blood-brain barrier damage and improves long-term neurological outcomes in a rat model of traumatic brain injury.

PubMed

Shi, Hong; Wang, Hai-Lian; Pu, Hong-Jian; Shi, Ye-Jie; Zhang, Jia; Zhang, Wen-Ting; Wang, Guo-Hua; Hu, Xiao-Ming; Leak, Rehana K; Chen, Jun; Gao, Yan-Qin

2015-04-01

Many traumatic brain injury (TBI) survivors sustain neurological disability and cognitive impairments due to the lack of defined therapies to reduce TBI-induced long-term brain damage. Ethyl pyruvate (EP) has shown neuroprotection in several models of acute brain injury. The present study therefore investigated the potential beneficial effect of EP on long-term outcomes after TBI and the underlying mechanisms. Male adult rats were subjected to unilateral controlled cortical impact injury. EP was injected intraperitoneally 15 min after TBI and again at 12, 24, 36, 48, and 60 h after TBI. Neurological deficits, blood-brain barrier (BBB) integrity, and neuroinflammation were assessed. Ethyl pyruvate improved sensorimotor and cognitive functions and ameliorated brain tissue damage up to 28 day post-TBI. BBB breach and brain edema were attenuated by EP at 48 h after TBI. EP suppressed matrix metalloproteinase (MMP)-9 production from peripheral neutrophils and reduced the number of MMP-9-overproducing neutrophils in the spleen, and therefore mitigated MMP-9-mediated BBB breakdown. Moreover, EP exerted potent antiinflammatory effects in cultured microglia and inhibited the elevation of inflammatory mediators in the brain after TBI. Ethyl pyruvate confers long-term neuroprotection against TBI, possibly through breaking the vicious cycle among MMP-9-mediated BBB disruption, neuroinflammation, and long-lasting brain damage. © 2014 John Wiley & Sons Ltd.

Impaired Cerebellar Maturation, Growth Restriction, and Circulating Insulin-Like Growth Factor 1 in Preterm Rabbit Pups

PubMed Central

Sveinsdóttir, Kristbjörg; Länsberg, John-Kalle; Sveinsdóttir, Snjólaug; Garwicz, Martin; Ohlsson, Lennart; Hellström, Ann; Smith, Lois; Gram, Magnus; Ley, David

2018-01-01

Cerebellar growth is impeded following very preterm birth in human infants and the observed reduction in cerebellar volume is associated with neurodevelopmental impairment. Decreased levels of circulating insulin-like growth factor 1 (IGF-1) are associated with decreased cerebellar volume. The relationship between preterm birth, circulating IGF-1, and key cell populations supporting cerebellar proliferation is unknown. The aim of this study was to evaluate the effect of preterm birth on postnatal growth, circulating IGF-1, and cerebellar maturation in a preterm rabbit pup model. Preterm rabbit pups (PT) were delivered by cesarean section at day 29 of gestation, cared for in closed incubators with humidified air, and gavage fed with formula. Control term pups (T) delivered by spontaneous vaginal delivery at day 32 of gestation were housed and fed by their lactating doe. In vivo perfusion-fixation for immunohistochemical evaluation of cerebellar proliferation, cell maturation, and apoptosis was performed at repeated time points in PT and T pups. Results show that the mean weight of the pups and circulating IGF-1 protein levels were lower in the PT group at all time points (p < 0.05) than in the T group. Postnatal weight development correlated with circulating IGF-1 (r2 = 0.89) independently of gestational age at birth and postnatal age. The proliferative (Ki-67-positive) portion of the external granular layer (EGL) was decreased in the PT group at postnatal day 2 (P2) compared to in the T group (p = 0.01). Purkinje cells exhibited decreased calbindin staining at P0 (p = 0.003), P2 (p = 0.004), and P5 (p = 0.04) in the PT group compared to in the T group. Staining for sonic hedgehog was positive in neuronal EGL progenitors and Purkinje cells at early time points but was restricted to a well-defined Purkinje cell monolayer at later time points. Preterm birth in rabbit pups is associated with lower circulating levels of IGF-1, decreased postnatal growth, and decreased

In and out of the loop: external and internal modulation of the olivo-cerebellar loop

PubMed Central

Libster, Avraham M.; Yarom, Yosef

2013-01-01

Cerebellar anatomy is known for its crystal like structure, where neurons and connections are precisely and repeatedly organized with minor variations across the Cerebellar Cortex. The olivo-cerebellar loop, denoting the connections between the Cerebellar cortex, Inferior Olive and Cerebellar Nuclei (CN), is also modularly organized to form what is known as the cerebellar module. In contrast to the relatively organized and static anatomy, the cerebellum is innervated by a wide variety of neuromodulator carrying axons that are heterogeneously distributed along the olivo-cerebellar loop, providing heterogeneity to the static structure. In this manuscript we review modulatory processes in the olivo-cerebellar loop. We start by discussing the relationship between neuromodulators and the animal behavioral states. This is followed with an overview of the cerebellar neuromodulatory signals and a short discussion of why and when the cerebellar activity should be modulated. We then devote a section for three types of neurons where we briefly review its properties and propose possible neuromodulation scenarios. PMID:23626524

Prevalence of Long-Term Opioid Use in Long-Stay Nursing Home Residents.

PubMed

Hunnicutt, Jacob N; Chrysanthopoulou, Stavroula A; Ulbricht, Christine M; Hume, Anne L; Tjia, Jennifer; Lapane, Kate L

2018-01-01

Overall and long-term opioid use among older adults have increased since 1999. Less is known about opioid use in older adults in nursing homes (NHs). Cross-sectional. U.S. NHs (N = 13,522). Long-stay NH resident Medicare beneficiaries with a Minimum Data Set 3.0 (MDS) assessment between April 1, 2012, and June 30, 2012, and 120 days of follow-up (N = 315,949). We used Medicare Part D claims to measure length of opioid use in the 120 days from the index assessment (short-term: ≤30 days, medium-term: >30-89 days, long-term: ≥90 days), adjuvants (e.g., anticonvulsants), and other pain medications (e.g., corticosteroids). MDS assessments in the follow-up period were used to measure nonpharmacological pain management use. Modified Poisson models were used to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for age, gender, race and ethnicity, cognitive and physical impairment, and long-term opioid use. Of all long-stay residents, 32.4% were prescribed any opioid, and 15.5% were prescribed opioids long-term. Opioid users (versus nonusers) were more commonly prescribed pain adjuvants (32.9% vs 14.9%), other pain medications (25.5% vs 11.0%), and nonpharmacological pain management (24.5% vs 9.3%). Long-term opioid use was higher in women (aPR = 1.21, 95% CI = 1.18-1.23) and lower in racial and ethnic minorities (non-Hispanic blacks vs whites: APR = 0.93, 95% CI = 0.90-0.94) and those with severe cognitive impairment (vs no or mild impairment, aPR = 0.82, 95% CI = 0.79-0.83). One in seven NH residents was prescribed opioids long-term. Recent guidelines on opioid prescribing for pain recommend reducing long-term opioid use, but this is challenging in NHs because residents may not benefit from nonpharmacological and nonopioid interventions. Studies to address concerns about opioid safety and effectiveness (e.g., on pain and functional status) in NHs are needed. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics

Partial diel migration: A facultative migration underpinned by long-term inter-individual variation.

PubMed

Harrison, Philip M; Gutowsky, Lee F G; Martins, Eduardo G; Patterson, David A; Cooke, Steven J; Power, Michael

2017-09-01

The variations in migration that comprise partial diel migrations, putatively occur entirely as a consequence of behavioural flexibility. However, seasonal partial migrations are increasingly recognised to be mediated by a combination of reversible plasticity in response to environmental variation and individual variation due to genetic and environmental effects. Here, we test the hypothesis that while partial diel migration heterogeneity occurs primarily due to short-term within-individual flexibility in behaviour, long-term individual differences in migratory behaviour also underpin this migration variation. Specifically, we use a hierarchical behavioural reaction norm approach to partition within- and among-individual variation in depth use and diel plasticity in depth use, across short- and long-term time-scales, in a group of 47 burbot (Lota lota) tagged with depth-sensing acoustic telemetry transmitters. We found that within-individual variation at the among-dates-within-seasons and among-seasons scale, explained the dominant proportion of phenotypic variation. However, individuals also repeatedly differed in their expression of migration behaviour over the 2 year study duration. These results reveal that diel migration variation occurs primarily due to short-term within-individual flexibility in depth use and diel migration behaviour. However, repeatable individual differences also played a key role in mediating partial diel migration. These findings represent a significant advancement of our understanding of the mechanisms generating the important, yet poorly understood phenomena of partial diel migration. Moreover, given the pervasive occurrence of diel migrations across aquatic taxa, these findings indicate that individual differences have an important, yet previously unacknowledged role in structuring the temporal and vertical dynamics of aquatic ecosystems. © 2017 The Authors. Journal of Animal Ecology © 2017 British Ecological Society.

Heterosynaptic changes accompany long-term but not short-term potentiation of the perforant path in the anaesthetized rat.

PubMed

Abraham, W C; Bliss, T V; Goddard, G V

1985-06-01

Brief high-frequency trains of electrical stimulation delivered to the perforant path result in long-term potentiation (l.t.p.) of field potentials recorded extracellularly from granule cells of the dentate gyrus. L.t.p. of the population spike is often disproportionately greater than l.t.p. of the population excitatory post-synaptic potential (e.p.s.p.). We have investigated the basis of this effect in rats anaesthetized with sodium pentobarbitone. A series of graded stimuli were given before and after tetanization of the perforant path. From data obtained in this way, we plotted stimulus-response curves, and the relation (E-S curve) between the slope of the population e.p.s.p. (E) and the amplitude of the population spike (S). Curves relating spike onset latency to the slope of the e.p.s.p. were also constructed. Tetanization of the combined medial and lateral components of the perforant path led to long-term changes in the relation between the e.p.s.p. and the population spike. For a given e.p.s.p., the corresponding population spike was of greater amplitude and earlier onset. This E-S potentiation was marked by a shift to the left of the E-S amplitude curve and a downward displacement of the E-S latency curve. Tetanization of the lateral component of the perforant path had two long-term effects on responses evoked by test stimuli to the untetanized medial component: (1) long-term depression of the medial e.p.s.p. and (2) long-term E-S potentiation. The net result of these two heterosynaptically induced effects was to leave unaltered information transfer across medial perforant path-granule cell synapses; for a given test volley the e.p.s.p. was smaller, but because of E-S potentiation the population spike remained relatively unaffected. Short-term potentiation, which has a time course of only a few minutes and is presumed to be mediated by presynaptic mechanisms, was not accompanied by E-S potentiation or by corresponding changes in spike latency. Possible

Late Onset of Cerebellar Abiotrophy in a Boxer Dog

PubMed Central

Gumber, Sanjeev; Cho, Doo-Youn; Morgan, Timothy W.

2010-01-01

Cerebellar abiotrophy is a degenerative disorder of the central nervous system and has been reported in humans and animals. This case report documents clinical, histopathological, and immunohistochemical findings of cerebellar abiotrophy in an adult Boxer dog. A 3.5-year-old, female, tan Boxer dog presented with a six-week history of left-sided head tilt. Neurological examination and additional diagnostics during her three subsequent visits over 4.5 months revealed worsening of neurological signs including marked head pressing, severe proprioceptive deficits in all the four limbs, loss of menace response and palpebral reflex in the left eye, and a gradual seizure lasting one hour at her last visit. Based on the immunohistochemical staining for glial fibrillary acidic protein and histopathological examination of cerebellum, cerebellar cortical abiotrophy was diagnosed. This is the first reported case of cerebellar abiotrophy in a Boxer dog to our knowledge. PMID:21151662

Cerebellar theta-burst stimulation selectively enhances lexical associative priming.

PubMed

Argyropoulos, Giorgos P

2011-09-01

Recent research in cerebellar cognitive and linguistic functions makes plausible the idea that the cerebellum is involved in processing temporally contiguous linguistic input. In order to assess this hypothesis, a simple lexical decision task was constructed to study whether the effect of transcranial magnetic stimulation on two different cerebellar sites would have a selective impact on associative as opposed to semantic priming. This is the first experiment applying transcranial magnetic stimulation of the cerebellum to a linguistic task. The results show a selective drop in lexical decision accuracy after stimulation of a medial cerebellar site in the first session of participation. Most importantly, they also demonstrate a selective increase of associative priming sizes after stimulation of the same site that cannot be attributed to changes in sensorimotor performance or in accuracy rates. The finding is discussed within the context of domain-general associative cerebellar computations.

Homolateral ataxia and crural paresis: a crossed cerebral-cerebellar diaschisis.

PubMed Central

Giroud, M; Creisson, E; Fayolle, H; Gras, P; Vion, P; Brunotte, F; Dumas, R

1994-01-01

A patient developed weakness of the right leg and homolateral ataxia of the arm, caused by a subcortical infarct in the area supplied by the anterior cerebral artery in the left paracentral region, demonstrated by CT and MRI. Cerebral blood flow studied by technetium-labelled hexamethyl-propylene-amine oxime using single photon emission computed tomography showed decreased blood flow in the left lateral frontal cortex and in the right cerebellar hemisphere ("crossed cerebral-cerebellar diaschisis"). The homolateral ataxia of the arm may be caused by decreased function of the right cerebellar hemisphere, because of a lesion of the corticopontine-cerebellar tracts, whereas crural hemiparesis is caused by a lesion of the upper part of the corona radiata. Images PMID:8126511

Complex network structure influences processing in long-term and short-term memory.

PubMed

Vitevitch, Michael S; Chan, Kit Ying; Roodenrys, Steven

2012-07-01

Complex networks describe how entities in systems interact; the structure of such networks is argued to influence processing. One measure of network structure, clustering coefficient, C, measures the extent to which neighbors of a node are also neighbors of each other. Previous psycholinguistic experiments found that the C of phonological word-forms influenced retrieval from the mental lexicon (that portion of long-term memory dedicated to language) during the on-line recognition and production of spoken words. In the present study we examined how network structure influences other retrieval processes in long- and short-term memory. In a false-memory task-examining long-term memory-participants falsely recognized more words with low- than high-C. In a recognition memory task-examining veridical memories in long-term memory-participants correctly recognized more words with low- than high-C. However, participants in a serial recall task-examining redintegration in short-term memory-recalled lists comprised of high-C words more accurately than lists comprised of low-C words. These results demonstrate that network structure influences cognitive processes associated with several forms of memory including lexical, long-term, and short-term.

Long-term effects of bariatric surgery on peripheral endothelial function and coronary microvascular function.

PubMed

Tarzia, Pierpaolo; Lanza, Gaetano A; Sestito, Alfonso; Villano, Angelo; Russo, Giulio; Figliozzi, Stefano; Lamendola, Priscilla; De Vita, Antonio; Crea, Filippo

We previously demonstrated that bariatric surgery (BS) leads to a short-term significant improvement of endothelial function and coronary microvascular function. In this study we assessed whether BS maintains its beneficial effect at long-term follow up. We studied 19 morbidly obese patients (age 43±9years, 12 women) without any evidence of cardiovascular disease who underwent BS. Patients were studied before BS, at 3 months and at 4.0±1.5years follow up. Peripheral vascular function was assessed by flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD), i.e., brachial artery diameter changes in response to post-ischemic forearm hyperhaemia and to nitroglycerin administration, respectively. Coronary microvascular function was assessed by measuring coronary blood flow (CBF) response to intravenous adenosine and to cold pressor test (CPT) in the left anterior descending coronary artery. Together with improvement of anthropometric and metabolic profile, at long-term follow-up patients showed a significant improvement of FMD (6.43±2.88 vs. 8.21±1.73%, p=0.018), and CBF response to both adenosine (1.73±0.48 vs. 2.58±0.54; p<0.01) and CPT (1.43±0.30 vs. 2.23±0.48; p<0.01), compared to basal values. No differences in vascular end-points were shown at 3-month and 4-year follow-up after BS. Our data show that, in morbidly obese patients, BS exerts beneficial and long lasting effects on peripheral endothelial function and on coronary microvascular dilator function. Copyright © 2016 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Long-term priority effects among insects and fungi colonizing decaying wood.

PubMed

Weslien, Jan; Djupström, Line B; Schroeder, Martin; Widenfalk, Olof

2011-11-01

1. Priority effects have been hypothesized to have long-lasting impact on community structure in natural ecosystems. Long-term studies of priority effects in natural ecosystems are however sparse, especially in terrestrial ecosystems. 2. Wood decay is a slow process involving a high diversity of insect and fungus species. Species interactions that drive change in communities of insects and fungi during wood decay are poorly understood because of a lack of sufficient long-term studies. 3. In this paper, we followed the colonization and succession of wood-living insects and fungi on cut trees during 15 years, from tree death and onwards, in a boreal forest landscape. We test the long-term priority effects hypothesis that the identity and abundance of species that colonize first affect the colonization success of later-arriving species. We also hypothesize that species interact in both facilitative and inhibitory ways, which ultimately affect habitat quality for a red-listed late-succession beetle species. 4. Possible causal associations between species were explored by path analysis. The results indicate that one bark beetle species, Hylurgops palliatus, and one wood-borer species, Monochamus sutor, which colonized the wood during the first year after cutting, influenced the occurrence of a rare, wood-living beetle, Peltis grossa, that started to emerge from the stumps about 10 years later. The positive effects of Hylurgops palliatus and negative effects of M. sutor were largely mediated through the wood-decaying fungus species Fomitopsis pinicola. 5. The study shows that variable priority effects may have long-lasting impact on community assembly in decaying wood. The study also exemplifies new possibilities for managing populations of threatened species by exploring links between early, well-understood species guilds and late, more poorly understood species guilds. © 2011 The Authors. Journal of Animal Ecology © 2011 British Ecological Society.

Long-term outcomes of acute kidney injury.

PubMed

Coca, Steven G

2010-05-01

The goal of this review is to summarize the recent plethora of data that relate to long-term outcomes after acute kidney injury (AKI). Surviving patients with AKI are still at high risk for long-term adverse outcomes, even if serum creatinine returns to normal. After adjusting for potential confounders, many recent studies have demonstrated that AKI is independently associated with chronic kidney disease, end-stage renal disease, and premature death. Unfortunately, definitive evidence from randomized controlled trials demonstrating that prevention or treatment of AKI prevents long-term adverse outcomes is not yet available. AKI is clearly a prognostic marker for poor long-term outcomes, but more studies will be needed to determine whether AKI is truly causal and whether or not the risk is modifiable.

Cerebellar Alterations and Gait Defects as Therapeutic Outcome Measures for Enzyme Replacement Therapy in α-Mannosidosis

PubMed Central

Damme, Markus; Stroobants, Stijn; Walkley, Steven U.; Lüllmann-Rauch, Renate; D`Hooge, Rudi; Fogh, Jens; Saftig, Paul; Lübke, Torben; Blanz, Judith

2011-01-01

α-Mannosidosis is a rare lysosomal storage disease with accumulation of undegraded mannosyl-linked oligosaccharides in cells throughout the body, most notably in the CNS. This leads to a broad spectrum of neurological manifestations, including progressive intellectual impairment, disturbed motor functions and cerebellar atrophy. To develop therapeutic outcome measures for enzyme replacement therapy (ERT) that could be used for human patients, a gene knockout model of α-mannosidosis in mice was analyzed for CNS pathology and motor deficits. In the cerebellar molecular layer, α-mannosidosis mice display clusters of activated Bergman glia, infiltration of phagocytic macrophages and accumulation of free cholesterol and gangliosides (GM1), notably in regions lacking Purkinje cells. α-mannosidosis brain lysates also displayed increased expression of Lamp1 and hyperglycosylation of the cholesterol binding protein NPC2. Detailed assessment of motor function revealed age-dependent gait defects in the mice that resemble the disturbed motor function in human patients. Short-term ERT partially reversed the observed cerebellar pathology with fewer activated macrophages and astrocytes but unchanged levels of hyperglycosylated NPC2, gangliosides and cholesterol. The present study demonstrates cerebellar alterations in α-mannosidosis mice that relate to the motor deficits and pathological changes seen in human patients and can be used as therapeutic outcome measures. PMID:21157375

Cerebellar malformations alter regional cerebral development.

PubMed

Bolduc, Marie-Eve; Du Plessis, Adre J; Evans, Alan; Guizard, Nicolas; Zhang, Xun; Robertson, Richard L; Limperopoulos, Catherine

2011-12-01

The aim of this study was to compare total and regional cerebral volumes in children with isolated cerebellar malformations (CBMs) with those in typically developing children, and to examine the extent to which cerebellar volumetric reductions are associated with total and regional cerebral volumes. This is a case-control study of children diagnosed with isolated CBMs. Each child was matched on age and sex to two typically developing children. Using advanced three-dimensional volumetric magnetic resonance imaging, the cerebrum was segmented into tissue classes and partitioned into eight regions. Analysis of variance was used to compare cerebral volumes between children with CBMs and control children, and linear regressions to examine the impact of cerebellar volume reduction on cerebral volumes. Magnetic resonance imaging was performed at a mean age of 27 months in 20 children (10 males, 10 females) with CBMs and 40 typically developing children. Children with CBMs showed significantly smaller deep grey matter nuclei (p < 0.001), subgenual white matter (p = 0.03), midtemporal white matter (p = 0.02), and inferior occipital grey matter (p = 0.03) volumes than typically developing children. Greater cerebellar volumetric reduction in children with CBMs was associated with decreased total cerebral volume and deep grey matter nuclei (p = 0.02), subgenual white/grey matter (p = 0.001), midtemporal white (p = 0.02) and grey matter (p = 0.01), and parieto-occipital grey matter (p = 0.004). CBMs are associated with impaired regional cerebral growth, suggesting deactivation of principal cerebello-cerebral pathways. © The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.

Aryl Hydrocarbon Receptor (AhR) Deletion in Cerebellar Granule Neuron Precursors Impairs Neurogenesis

PubMed Central

Dever, Daniel P.; Adham, Zachariah O.; Thompson, Bryan; Genestine, Matthieu; Cherry, Jonathan; Olschowka, John A.; DiCicco-Bloom, Emanuel; Opanashuk, Lisa A.

2015-01-01

The aryl hydrocarbon receptor (AhR) is a ligand-activated member of the basic-helix-loop-helix (bHLH)/PER-ARNT-SIM(PAS) transcription factor superfamily that also mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increasing evidence suggests that AhR influences the development of many tissues, including the central nervous system. Our previous studies suggest that sustained AhR activation by TCDD and/or AhR deletion disrupts cerebellar granule neuron precursor (GNP) development. In the current study, to determine whether endogenous AhR controls GNP development in a cell autonomous manner, we created a GNP-specific AhR deletion mouse, AhRfx/fx/Math1CRE/+ (AhR CKO). Selective AhR deletion in GNPs produced abnormalities in proliferation and differentiation. Specifically, fewer GNPs were engaged in S-phase, as demonstrated by ~25% reductions in thymidine (in vitro) and BrdU (in vivo) incorporation. Furthermore, total granule neuron numbers in the IGL at PND21 and PND60 were diminished in AhR CKO mice compared to controls. On the other hand, differentiation was enhanced, including ~40% increase in neurite outgrowth and 50% increase in GABARα6 receptor expression in deletion mutants. Our results suggest that AhR activity plays a role in regulating granule neuron number and differentiation, possibly by coordinating this GNP developmental transition. These studies provide novel insights for understanding the normal roles of AhR signaling during cerebellar granule cell neurogenesis, and may have important implications for the effects of environmental factors in cerebellar dysgenesis. PMID:26243376

Primary Cerebellar Gliosarcoma with Extracranial Metastases: An Orphan Differential Diagnosis.

PubMed

Ben Nsir, Atef; Thai, Quoc-Anh; Kassar, Alia Zhani; Ben Said, Imed; Jemel, Hafedh

2015-12-01

Gliosarcomas are rare, malignant primary brain tumors, most commonly located in the temporal lobe, that contain both glial and mesenchymal elements. Gliosarcomas located within the cerebellum are exceedingly rare. The previously unreported finding of a cerebellar gliosarcoma concurrently with an extracranial metastasis to the lungs is discussed here. A 57-year-old man presented with a 3-month history of chest pain, weight loss, headaches, and vomiting. Physical examination revealed a left cerebellar dysfunction, and the radiological work-up revealed a 6 × 6-cm right apical pulmonary tumor and a 4 × 3.5 × 3.8-cm peripherally enhancing left cerebellar mass. On the basis of a smoking history in the setting of a lung lesion and cerebellar mass, the presumptive diagnosis was primary lung cancer with metastasis to the cerebellum. Gross total resection of a firm pseudo-encapsulated cerebellar mass was performed. The microscopic features and the immunohistochemical profile confirmed the diagnosis of Gliosarcoma. The thoracic lesion was removed subsequently, and pathology confirmed it as an extracranial metastasis from the cerebellar gliosarcoma. Adjuvant radiation and chemotherapy were then administered. No clinical or radiographic evidence of recurrence was observed during one year of follow-up monitoring. To the best of our knowledge, a primary infratentorial gliosarcoma with extracranial metastases has not been previously described. Copyright © 2015 Elsevier Inc. All rights reserved.

Cerebellar Volume in Children With Attention-Deficit Hyperactivity Disorder (ADHD).

PubMed

Wyciszkiewicz, Aleksandra; Pawlak, Mikolaj A; Krawiec, Krzysztof

2017-02-01

Attention Deficit Hyperactivity Disorder (ADHD) is associated with altered cerebellar volume and cerebellum is associated with cognitive performance. However there are mixed results regarding the cerebellar volume in young patients with ADHD. To clarify the size and direction of this effect, we conducted the analysis on the large public database of brain images. The aim of this study was to confirm that cerebellar volume in ADHD is smaller than in control subjects in currently the largest publicly available cohort of ADHD subjects.We applied cross-sectional case control study design by comparing 286 ADHD patients (61 female) with age and gender matched control subjects. Volumetric measurements of cerebellum were obtained using automated segmentation with FreeSurfer 5.1. Statistical analysis was performed in R-CRAN statistical environment. Patients with ADHD had significantly smaller total cerebellar volumes (134.5±17.11cm 3 vs.138.90±15.32 cm 3 ). The effect was present in both females and males (males 136.9±14.37 cm 3 vs. 141.20±14.75 cm 3 ; females 125.7±12.34 cm 3 vs. 131.20±15.03 cm 3 ). Age was positively and significantly associated with the cerebellar volumes. These results indicate either delayed or disrupted cerebellar development possibly contributing to ADHD pathophysiology.

Cerebellar stroke presenting with isolated dizziness: Brain MRI in 136 patients.

PubMed

Perloff, Michael D; Patel, Nimesh S; Kase, Carlos S; Oza, Anuja U; Voetsch, Barbara; Romero, Jose R

2017-11-01

To evaluate occurrence of cerebellar stroke in Emergency Department (ED) presentations of isolated dizziness (dizziness with a normal exam and negative neurological review of systems). A 5-year retrospective study of ED patients presenting with a chief complaint of "dizziness or vertigo", without other symptoms or signs in narrative history or on exam to suggest a central nervous system lesion, and work-up included a brain MRI within 48h. Patients with symptoms commonly peripheral in etiology (nystagmus, tinnitus, gait instability, etc.) were included in the study. Patient demographics, stroke risk factors, and gait assessments were recorded. One hundred and thirty-six patients, who had a brain MRI for isolated dizziness, were included. There was a low correlation of gait assessment between ED physician and Neurologist (49 patients, Spearman's correlation r 2 =0.17). Based on MRI DWI sequence, 3.7% (5/136 patients) had acute cerebellar strokes, limited to or including, the medial posterior inferior cerebellar artery vascular territory. In the 5 cerebellar stroke patients, mean age, body mass index (BMI), hemoglobin A1c, gender distribution, and prevalence of hypertension were similar to the non-cerebellar stroke patient group. Mean LDL/HDL ratio was 3.63±0.80 and smoking prevalence was 80% in the cerebellar stroke group compared to 2.43±0.79 and 22% (respectively, p values<0.01) in the non-cerebellar stroke group. Though there was preselection bias for stroke risk factors, our study suggests an important proportion of cerebellar stroke among ED patients with isolated dizziness, considering how common this complaint is. Copyright © 2017 Elsevier Inc. All rights reserved.

Acute Ethanol Exposure Prevents PMA-mediated Augmentation of N-methyl-d-aspartate Receptor Function in Primary Cultured Cerebellar Granule Cells

PubMed Central

Reneau, Jason; Reyland, Mary E.; Popp, R. Lisa

2011-01-01

Many intracellular proteins and signaling cascades contribute to the ethanol sensitivity of native N-methyl-d-aspartate receptors (NMDARs). One putative protein is the serine / threonine kinase, Protein kinase C (PKC). The purpose of this study was to assess if PKC modulates the ethanol sensitivity of native NMDARs expressed in primary cultured cerebellar granule cells (CGCs). With the whole-cell patch-clamp technique, we assessed if ethanol inhibition of NMDA-induced currents (INMDA) (100 μM NMDA plus 10 μM glycine) were altered in CGCs in which the novel and classical PKC isoforms were activated by phorbol-12-myristate-13-acetate (PMA). Percent inhibition by 10, 50 or 100 mM ethanol of NMDA-induced steady-state (ISS) or peak current amplitudes (IPk) of NMDARs expressed in CGCs in which PKC was activated by a 12.5 min, 100 nM PMA exposure at 37° C did not differ from currents obtained from receptors contained in control cells. However, PMA-mediated augmentation of IPk in the absence of ethanol was abolished after brief applications of 10 or 1 mM ethanol co-applied with agonists, and this suppression of enhanced receptor function was observed for up to eight minutes post-ethanol exposure. Because we had previously shown that PMA-mediated augmentation of INMDA of NMDARs expressed in these cells is by activation of PKCα, we assessed the effect of ethanol (1, 10, 50 and 100 mM) on PKCα activity. Ethanol decreased PKCα activity by 18% for 1 mM ethanol and activity decreased with increasing ethanol concentrations with a 50% inhibition observed with 100 mM ethanol. The data suggest that ethanol disruption of PMA-mediated augmentation of INMDA may be due to a decrease in PKCα activity by ethanol. However, given the incomplete blockade of PKCα activity and the low concentration of ethanol at which this phenomenon is observed, other ethanol-sensitive signaling cascades must also be involved. PMID:21624785

Long-term metapopulation study of the Glanville fritillary butterfly (Melitaea cinxia): survey methods, data management, and long-term population trends.

PubMed

Ojanen, Sami P; Nieminen, Marko; Meyke, Evgeniy; Pöyry, Juha; Hanski, Ilkka

2013-10-01

Long-term observational studies conducted at large (regional) spatial scales contribute to better understanding of landscape effects on population and evolutionary dynamics, including the conditions that affect long-term viability of species, but large-scale studies are expensive and logistically challenging to keep running for a long time. Here, we describe the long-term metapopulation study of the Glanville fritillary butterfly (Melitaea cinxia) that has been conducted since 1991 in a large network of 4000 habitat patches (dry meadows) within a study area of 50 by 70 km in the Åland Islands in Finland. We explain how the landscape structure has been described, including definition, delimitation, and mapping of the habitat patches; methods of field survey, including the logistics, cost, and reliability of the survey; and data management using the EarthCape biodiversity platform. We describe the long-term metapopulation dynamics of the Glanville fritillary based on the survey. There has been no long-term change in the overall size of the metapopulation, but the level of spatial synchrony and hence the amplitude of fluctuations in year-to-year metapopulation dynamics have increased over the years, possibly due to increasing frequency of exceptional weather conditions. We discuss the added value of large-scale and long-term population studies, but also emphasize the need to integrate more targeted experimental studies in the context of long-term observational studies. For instance, in the case of the Glanville fritillary project, the long-term study has produced an opportunity to sample individuals for experiments from local populations with a known demographic history. These studies have demonstrated striking differences in dispersal rate and other life-history traits of individuals from newly established local populations (the offspring of colonizers) versus individuals from old, established local populations. The long-term observational study has stimulated the

Long-term metapopulation study of the Glanville fritillary butterfly (Melitaea cinxia): survey methods, data management, and long-term population trends

PubMed Central

Ojanen, Sami P; Nieminen, Marko; Meyke, Evgeniy; Pöyry, Juha; Hanski, Ilkka

2013-01-01

Long-term observational studies conducted at large (regional) spatial scales contribute to better understanding of landscape effects on population and evolutionary dynamics, including the conditions that affect long-term viability of species, but large-scale studies are expensive and logistically challenging to keep running for a long time. Here, we describe the long-term metapopulation study of the Glanville fritillary butterfly (Melitaea cinxia) that has been conducted since 1991 in a large network of 4000 habitat patches (dry meadows) within a study area of 50 by 70 km in the Åland Islands in Finland. We explain how the landscape structure has been described, including definition, delimitation, and mapping of the habitat patches; methods of field survey, including the logistics, cost, and reliability of the survey; and data management using the EarthCape biodiversity platform. We describe the long-term metapopulation dynamics of the Glanville fritillary based on the survey. There has been no long-term change in the overall size of the metapopulation, but the level of spatial synchrony and hence the amplitude of fluctuations in year-to-year metapopulation dynamics have increased over the years, possibly due to increasing frequency of exceptional weather conditions. We discuss the added value of large-scale and long-term population studies, but also emphasize the need to integrate more targeted experimental studies in the context of long-term observational studies. For instance, in the case of the Glanville fritillary project, the long-term study has produced an opportunity to sample individuals for experiments from local populations with a known demographic history. These studies have demonstrated striking differences in dispersal rate and other life-history traits of individuals from newly established local populations (the offspring of colonizers) versus individuals from old, established local populations. The long-term observational study has stimulated the

Effect of Valsartan on Cerebellar Adrenomedullin System Dysregulation During Hypertension.

PubMed

Figueira, Leticia; Israel, Anita

2017-02-01

Adrenomedullin (AM) and its receptors components, calcitonin-receptor-like receptor (CRLR), and receptor activity-modifying protein (RAMP1, RAMP2, and RAMP3) are expressed in cerebellum. Cerebellar AM, AM binding sites and receptor components are altered during hypertension, suggesting a role for cerebellar AM in blood pressure regulation. Thus, we assessed the effect of valsartan, on AM and its receptor components expression in the cerebellar vermis of Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Additionally, we evaluated AM action on superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activity, and thiobarbituric acid reactive substances (TBARS) production in cerebellar vermis. Animals were treated with valsartan or vehicle for 11 days. Rats were sacrificed by decapitation; cerebellar vermis was dissected; and AM, CRLR, RAMP1, RAMP2, and RAMP3 expression was quantified by Western blot analysis. CAT, SOD, and GPx activity was determined spectrophotometrically and blood pressure by non-invasive plethysmography. We demonstrate that AM and RAMP2 expression was lower in cerebellum of SHR rats, while CRLR, RAMP1, and RAMP3 expression was higher than those of WKY rats. AM reduced cerebellar CAT, SOD, GPx activities, and TBARS production in WKY rats, but not in SHR rats. Valsartan reduced blood pressure and reversed the altered expression of AM and its receptors components, as well the loss of AM capacity to reduce antioxidant enzyme activity and TBARS production in SHR rats. These findings demonstrate that valsartan is able to reverse the dysregulation of cerebellar adrenomedullinergic system; and they suggest that altered AM system in the cerebellum could represent the primary abnormality leading to hypertension.

Optimization of cerebellar purkinje neuron cultures and development of a plasmid-based method for purkinje neuron-specific, miRNA-mediated protein knockdown.

PubMed

Alexander, C J; Hammer, J A

2016-01-01

We present a simple and efficient method to knock down proteins specifically in Purkinje neurons (PN) present in mixed mouse primary cerebellar cultures. This method utilizes the introduction via nucleofection of a plasmid encoding a specific miRNA downstream of the L7/Pcp2 promoter, which drives PN-specific expression. As proof-of-principle, we used this plasmid to knock down the motor protein myosin Va, which is required for the targeting of smooth endoplasmic reticulum (ER) into PN spines. Consistent with effective knockdown, transfected PNs robustly phenocopied PNs from dilute-lethal (myosin Va-null) mice with regard to the ER targeting defect. Importantly, our plasmid-based approach is less challenging technically and more specific to PNs than several alternative methods (e.g., biolistic- and lentiviral-based introduction of siRNAs). We also present a number of improvements for generating mixed cerebellar cultures that shorten the procedure and improve the total yield of PNs, and of transfected PNs, considerably. Finally, we present a method to rescue cerebellar cultures that develop large cell aggregates, a common problem that otherwise precludes the further use of the culture. Copyright © 2016 Elsevier Inc. All rights reserved.

Long-Term Dynamics of Autonomous Fractional Differential Equations

NASA Astrophysics Data System (ADS)

Liu, Tao; Xu, Wei; Xu, Yong; Han, Qun

This paper aims to investigate long-term dynamic behaviors of autonomous fractional differential equations with effective numerical method. The long-term dynamic behaviors predict where systems are heading after long-term evolution. We make some modification and transplant cell mapping methods to autonomous fractional differential equations. The mapping time duration of cell mapping is enlarged to deal with the long memory effect. Three illustrative examples, i.e. fractional Lotka-Volterra equation, fractional van der Pol oscillator and fractional Duffing equation, are studied with our revised generalized cell mapping method. We obtain long-term dynamics, such as attractors, basins of attraction, and saddles. Compared with some existing stability and numerical results, the validity of our method is verified. Furthermore, we find that the fractional order has its effect on the long-term dynamics of autonomous fractional differential equations.

Enhanced long-term and impaired short-term spatial memory in GluA1 AMPA receptor subunit knockout mice: evidence for a dual-process memory model.

PubMed

Sanderson, David J; Good, Mark A; Skelton, Kathryn; Sprengel, Rolf; Seeburg, Peter H; Rawlins, J Nicholas P; Bannerman, David M

2009-06-01

The GluA1 AMPA receptor subunit is a key mediator of hippocampal synaptic plasticity and is especially important for a rapidly-induced, short-lasting form of potentiation. GluA1 gene deletion impairs hippocampus-dependent, spatial working memory, but spares hippocampus-dependent spatial reference memory. These findings may reflect the necessity of GluA1-dependent synaptic plasticity for short-term memory of recently visited places, but not for the ability to form long-term associations between a particular spatial location and an outcome. This hypothesis is in concordance with the theory that short-term and long-term memory depend on dissociable psychological processes. In this study we tested GluA1-/- mice on both short-term and long-term spatial memory using a simple novelty preference task. Mice were given a series of repeated exposures to a particular spatial location (the arm of a Y-maze) before their preference for a novel spatial location (the unvisited arm of the maze) over the familiar spatial location was assessed. GluA1-/- mice were impaired if the interval between the trials was short (1 min), but showed enhanced spatial memory if the interval between the trials was long (24 h). This enhancement was caused by the interval between the exposure trials rather than the interval prior to the test, thus demonstrating enhanced learning and not simply enhanced performance or expression of memory. This seemingly paradoxical enhancement of hippocampus-dependent spatial learning may be caused by GluA1 gene deletion reducing the detrimental effects of short-term memory on subsequent long-term learning. Thus, these results support a dual-process model of memory in which short-term and long-term memory are separate and sometimes competitive processes.

The Womanly World of Long Term Care: The Plight of the Long Term Care Worker. Gray Paper.

ERIC Educational Resources Information Center

Older Women's League, Washington, DC.

Long-term care workers (those who are paid to provide custodial care for long-term patients in nursing homes or at home) must care for a growing number of increasingly disabled or dependent persons. They are working for agencies and institutions under growing pressure to increase productivity. They face new training and competency requirements,…

Involvement of N-methyl-D-aspartate receptor subunits in zinc-mediated modification of CA1 long-term potentiation in the developing hippocampus.

PubMed

Takeda, Atsushi; Itagaki, Kosuke; Ando, Masaki; Oku, Naoto

2012-03-01

Zinc is an endogenous N-methyl-D-aspartate (NMDA) receptor blocker. It is possible that zinc-mediated modification of hippocampal CA1 long-term potentiation (LTP) is linked to the expression of NMDA receptor subunits, which varies with postnatal development. In the present study, the effect of ZnCl(2) and CaEDTA, a membrane-impermeable zinc chelator, on CA1 LTP induction was examined in hippocampal slices from immature (3-week-old) and young (6-week-old) rats. Tetanus (10-100 Hz, 1 sec)-induced CA1 LTP was more greatly enhanced in 3-week-old rats. CA1 LTP was inhibited in the presence of 2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, and CaEDTA in 3-week-old rats, as in the case of 6-week-old rats reported previously. In 3-week-old rats, on the other hand, 5 μM ZnCl(2) attenuated NMDA receptor-mediated EPSPs more than in 6-week-old rats and significantly attenuated CA1 LTP. Moreover, 5 μM ZnCl(2) significantly attenuated CA1 LTP in the presence of (2R,4S)-4-(3-phosphonopropyl)-2-piperidinecarboxylic acid (PPPA), an NR2A antagonist, in 3-week-old rats, but not that in the presence of ifenprodil, an NR2B antagonist, suggesting that zinc-mediated attenuation of CA1 LTP is associated with the preferential expression of NR2B subunit in 3-week-old rats. In 6-week-old rats, however, 5 μM ZnCl(2) significantly potentiated CA1 LTP and also CA1 LTP in the presence of PPPA. The present study demonstrates that endogenous zinc may participate in the induction of CA1 LTP. It is likely that the changes in expression of NMDA receptor subunits are involved in the zinc-mediated modification of CA1 LTP in the developing hippocampus. Copyright © 2011 Wiley Periodicals, Inc.

Long-term studies of dopamine agonists.

PubMed

Hubble, Jean P

2002-02-26

Dopamine agonists have long been used as adjunctive therapy for the treatment of Parkinson's disease (PD). In more recent years these drugs have also been proved safe and effective as initial therapy in lieu of levodopa in the treatment of PD. Long-term levodopa therapy is associated with motor complications, including fluctuating response patterns and dyskinesia. By initially introducing a dopamine agonist as symptomatic drug therapy, it may be possible to postpone the use of levodopa and delay or prevent the development of motor complications. Recently, four clinical trials have explored this hypothesis by comparing the long-term response and side effects of levodopa with dopamine agonist therapy. The drugs studied have included ropinirole, pramipexole, cabergoline, and pergolide. In each of these projects, the occurrence of motor complications, such as wearing off and dyskinesia, was significantly less in the subjects assigned to initiation of therapy with a dopamine agonist. The addition of levodopa could be postponed by many months or even several years. Therefore, these long-term studies of dopamine agonists support the initiation of a dopamine agonist instead of levodopa in an effort to postpone levodopa-related motor complications. This therapeutic approach may be particularly appropriate in PD patients with a long treatment horizon on the basis of age and general good health. The extension phase of the long-term study comparing pramipexole with levodopa is ongoing, and follow-up information may help to establish the value of this treatment strategy.

Increased cerebellar PET glucose metabolism corresponds to ataxia in Wernicke-Korsakoff syndrome.

PubMed

Fellgiebel, Andreas; Siessmeier, Thomas; Winterer, Georg; Lüddens, Hartmut; Mann, Klaus; Schmidt, Lutz G; Bartenstein, Peter

2004-01-01

To investigate a possible relationship between cerebellar glucose metabolism and recovery from ataxia in the first months of acute Wernicke-Korsakoff syndrome. Two cases of alcoholic Wernicke-Korsakoff syndrome were followed up with the clinical status and cerebral glucose metabolism over a 4- and 9-month period. Initially both patients showed severe ataxia and elevated cerebellar glucose metabolism that decreased corresponding to the restitution of stance and gait. Increased cerebellar glucose metabolism at the onset of the illness may reflect the reorganization process of disturbed motor skills and may indicate cerebellar plasticity.

Lissencephaly with brainstem and cerebellar hypoplasia and congenital cataracts.

PubMed

Abumansour, Iman S; Wrogemann, Jens; Chudley, Albert E; Chodirker, Bernard N; Salman, Michael S

2014-06-01

Classical lissencephaly may be associated with cerebellar hypoplasia and when significant cerebellar abnormalities occur, defects in proteins encoded by TUBA1A, RELN, and very-low-density lipoprotein receptor (VLDLR) genes have been reported. We present a neonate with a severe neurologic phenotype associated with hypotonia, oropharyngeal incoordination that required a gastric tube for feeding, intractable epilepsy, and congenital cataracts. Her brain magnetic resonance imaging (MRI) showed classical lissencephaly, ventriculomegaly, absent corpus callosum, globular and vertical hippocampi, and severe cerebellar and brainstem hypoplasia. She died at 6 weeks of age. No specific molecular diagnosis was made. This likely represents a previously undescribed genetic lissencephaly syndrome. © The Author(s) 2013.

Cerebellar contribution to feedforward control of locomotion.

PubMed

Pisotta, Iolanda; Molinari, Marco

2014-01-01

The cerebellum is an important contributor to feedforward control mechanisms of the central nervous system, and sequencing-the process that allows spatial and temporal relationships between events to be recognized-has been implicated as the fundamental cerebellar mode of operation. By adopting such a mode and because cerebellar activity patterns are sensitive to a variety of sensorimotor-related tasks, the cerebellum is believed to support motor and cognitive functions that are encoded in the frontal and parietal lobes of the cerebral cortex. In this model, the cerebellum is hypothesized to make predictions about the consequences of a motor or cognitive command that originates from the cortex to prepare the entire system to cope with ongoing changes. In this framework, cerebellar predictive mechanisms for locomotion are addressed, focusing on sensorial and motoric sequencing. The hypothesis that sequence recognition is the mechanism by which the cerebellum functions in gait control is presented and discussed.

Cerebellar contribution to feedforward control of locomotion

PubMed Central

Pisotta, Iolanda; Molinari, Marco

2014-01-01

The cerebellum is an important contributor to feedforward control mechanisms of the central nervous system, and sequencing—the process that allows spatial and temporal relationships between events to be recognized—has been implicated as the fundamental cerebellar mode of operation. By adopting such a mode and because cerebellar activity patterns are sensitive to a variety of sensorimotor-related tasks, the cerebellum is believed to support motor and cognitive functions that are encoded in the frontal and parietal lobes of the cerebral cortex. In this model, the cerebellum is hypothesized to make predictions about the consequences of a motor or cognitive command that originates from the cortex to prepare the entire system to cope with ongoing changes. In this framework, cerebellar predictive mechanisms for locomotion are addressed, focusing on sensorial and motoric sequencing. The hypothesis that sequence recognition is the mechanism by which the cerebellum functions in gait control is presented and discussed. PMID:25009490

Gaze holding deficits discriminate early from late onset cerebellar degeneration.

PubMed

Tarnutzer, Alexander A; Weber, K P; Schuknecht, B; Straumann, D; Marti, S; Bertolini, G

2015-08-01

The vestibulo-cerebellum calibrates the output of the inherently leaky brainstem neural velocity-to-position integrator to provide stable gaze holding. In healthy humans small-amplitude centrifugal nystagmus is present at extreme gaze-angles, with a non-linear relationship between eye-drift velocity and eye eccentricity. In cerebellar degeneration this calibration is impaired, resulting in pathological gaze-evoked nystagmus (GEN). For cerebellar dysfunction, increased eye drift may be present at any gaze angle (reflecting pure scaling of eye drift found in controls) or restricted to far-lateral gaze (reflecting changes in shape of the non-linear relationship) and resulting eyed-drift patterns could be related to specific disorders. We recorded horizontal eye positions in 21 patients with cerebellar neurodegeneration (gaze-angle = ±40°) and clinically confirmed GEN. Eye-drift velocity, linearity and symmetry of drift were determined. MR-images were assessed for cerebellar atrophy. In our patients, the relation between eye-drift velocity and gaze eccentricity was non-linear, yielding (compared to controls) significant GEN at gaze-eccentricities ≥20°. Pure scaling was most frequently observed (n = 10/18), followed by pure shape-changing (n = 4/18) and a mixed pattern (n = 4/18). Pure shape-changing patients were significantly (p = 0.001) younger at disease-onset compared to pure scaling patients. Atrophy centered around the superior/dorsal vermis, flocculus/paraflocculus and dentate nucleus and did not correlate with the specific drift behaviors observed. Eye drift in cerebellar degeneration varies in magnitude; however, it retains its non-linear properties. With different drift patterns being linked to age at disease-onset, we propose that the gaze-holding pattern (scaling vs. shape-changing) may discriminate early- from late-onset cerebellar degeneration. Whether this allows a distinction among specific cerebellar disorders remains to be determined.

Assessing the value of post-processed state-of-the-art long-term weather forecast ensembles for agricultural water management mediated by farmers' behaviours

NASA Astrophysics Data System (ADS)

Li, Yu; Giuliani, Matteo; Castelletti, Andrea

2016-04-01

Recent advances in modelling of coupled ocean-atmosphere dynamics significantly improved skills of long-term climate forecast from global circulation models (GCMs). These more accurate weather predictions are supposed to be a valuable support to farmers in optimizing farming operations (e.g. crop choice, cropping and watering time) and for more effectively coping with the adverse impacts of climate variability. Yet, assessing how actually valuable this information can be to a farmer is not straightforward and farmers' response must be taken into consideration. Indeed, in the context of agricultural systems potentially useful forecast information should alter stakeholders' expectation, modify their decisions, and ultimately produce an impact on their performance. Nevertheless, long-term forecast are mostly evaluated in terms of accuracy (i.e., forecast quality) by comparing hindcast and observed values and only few studies investigated the operational value of forecast looking at the gain of utility within the decision-making context, e.g. by considering the derivative of forecast information, such as simulated crop yields or simulated soil moisture, which are essential to farmers' decision-making process. In this study, we contribute a step further in the assessment of the operational value of long-term weather forecasts products by embedding these latter into farmers' behavioral models. This allows a more critical assessment of the forecast value mediated by the end-users' perspective, including farmers' risk attitudes and behavioral patterns. Specifically, we evaluate the operational value of thirteen state-of-the-art long-range forecast products against climatology forecast and empirical prediction (i.e. past year climate and historical average) within an integrated agronomic modeling framework embedding an implicit model of the farmers' decision-making process. Raw ensemble datasets are bias-corrected and downscaled using a stochastic weather generator, in

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome.

PubMed

Whittaker, Danielle E; Kasah, Sahrunizam; Donovan, Alex P A; Ellegood, Jacob; Riegman, Kimberley L H; Volk, Holger A; McGonnell, Imelda; Lerch, Jason P; Basson, M Albert

2017-12-01

Mutations in the gene encoding the ATP dependent chromatin-remodeling factor, CHD7 are the major cause of CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital-urinary anomalies, and Ear defects) syndrome. Neurodevelopmental defects and a range of neurological signs have been identified in individuals with CHARGE syndrome, including developmental delay, lack of coordination, intellectual disability, and autistic traits. We previously identified cerebellar vermis hypoplasia and abnormal cerebellar foliation in individuals with CHARGE syndrome. Here, we report mild cerebellar hypoplasia and distinct cerebellar foliation anomalies in a Chd7 haploinsufficient mouse model. We describe specific alterations in the precise spatio-temporal sequence of fissure formation during perinatal cerebellar development responsible for these foliation anomalies. The altered cerebellar foliation pattern in Chd7 haploinsufficient mice show some similarities to those reported in mice with altered Engrailed, Fgf8 or Zic1 gene expression and we propose that mutations or polymorphisms in these genes may modify the cerebellar phenotype in CHARGE syndrome. Our findings in a mouse model of CHARGE syndrome indicate that a careful analysis of cerebellar foliation may be warranted in patients with CHARGE syndrome, particularly in patients with cerebellar hypoplasia and developmental delay. © 2017 The Authors. American Journal of Medical Genetics Part C Published by Wiley Periodicals, Inc.

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

PubMed Central

Whittaker, Danielle E.; Kasah, Sahrunizam; Donovan, Alex P. A.; Ellegood, Jacob; Riegman, Kimberley L. H.; Volk, Holger A.; McGonnell, Imelda; Lerch, Jason P.

2017-01-01

Mutations in the gene encoding the ATP dependent chromatin‐remodeling factor, CHD7 are the major cause of CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital‐urinary anomalies, and Ear defects) syndrome. Neurodevelopmental defects and a range of neurological signs have been identified in individuals with CHARGE syndrome, including developmental delay, lack of coordination, intellectual disability, and autistic traits. We previously identified cerebellar vermis hypoplasia and abnormal cerebellar foliation in individuals with CHARGE syndrome. Here, we report mild cerebellar hypoplasia and distinct cerebellar foliation anomalies in a Chd7 haploinsufficient mouse model. We describe specific alterations in the precise spatio‐temporal sequence of fissure formation during perinatal cerebellar development responsible for these foliation anomalies. The altered cerebellar foliation pattern in Chd7 haploinsufficient mice show some similarities to those reported in mice with altered Engrailed, Fgf8 or Zic1 gene expression and we propose that mutations or polymorphisms in these genes may modify the cerebellar phenotype in CHARGE syndrome. Our findings in a mouse model of CHARGE syndrome indicate that a careful analysis of cerebellar foliation may be warranted in patients with CHARGE syndrome, particularly in patients with cerebellar hypoplasia and developmental delay. PMID:29168327

Long Term TOA - M Data and Information

Atmospheric Science Data Center

2017-09-06

... A Long-Term TOA and Constrained Surface Radiation Budget Project A Long-Term TOA and Constrained Surface Readiation ... Budget Experiment (ERBE) and Clouds and the Earth's Radiant Energy System (CERES), that span nearly 30 years to date.   The ...

Incidence and anatomy of gaze-evoked nystagmus in patients with cerebellar lesions.

PubMed

Baier, Bernhard; Dieterich, Marianne

2011-01-25

Disorders of gaze-holding--organized by a neural network located in the brainstem or the cerebellum--may lead to nystagmus. Based on previous animal studies it was concluded that one key player of the cerebellar part of this gaze-holding neural network is the flocculus. Up to now, in humans there are no systematic studies in patients with cerebellar lesions examining one of the most common forms of nystagmus: gaze-evoked nystagmus (GEN). The aim of our present study was to clarify which cerebellar structures are involved in the generation of GEN. Twenty-one patients with acute unilateral cerebellar stroke were analyzed by means of modern MRI-based voxel-wise lesion-behavior mapping. Our data indicate that cerebellar structures such as the vermal pyramid, the uvula, and the tonsil, but also parts of the biventer lobule and the inferior semilunar lobule, were affected in horizontal GEN. It seems that these structures are part of a gaze-holding neural integrator control system. Furthermore, GEN might present a diagnostic sign pointing toward ipsilesionally located lesions of midline and lower cerebellar structures.

Long-term biological investigations in space.

PubMed

Lotz, R G; Fuchs, H; Bertsche, U

1975-01-01

Missions in space within the next two decades will be of longer duration than those carried out up to the present time, and the effects of such long-term flights on biological organisms are unknown. Results of biological experiments that have been performed to date cannot be extrapolated to results in future flights because of the unknown influence of adaptation over a long period of time. Prior experiments with Axolotl, fishes, and vertebrates by our research team (in part with sounding rockets) showed that these specimens did not appear to be suitable for long-term missions on which minimization of expense, technique, and energy is required. Subsequent investigations have shown the suitability of the leech (Hirudo medicinalis), which consumes blood of mammals up to ten times its own weight (1 g) and can live more than 2 years without further food supply. Emphasis in the experiments with Hirudo medicinalis is placed on metabolic rhythm and motility. Resorption and diffusion in tissue, development, and growth under long-term effects of cosmic proton radiation and zero-gravity are other focal points. The constancy of cellular life in the mature animals is a point in favor of these specimens. We have also taken into account the synergistic effects of the space environment on the problems just mentioned. The life-support system constructed for the leech has been tested successfully in four sounding rocket flights and, on that basis, has been prepared for a long-term mission. Long-term investigations out of the terrestrial biosphere will provide us with information concerning the degree of adaptation of certain physiological and biochemical functions and as to what extent biological readjustment or repair processes can occur under the specific stress conditions of space flight.

miR-191 and miR-135 are required for long-lasting spine remodelling associated with synaptic long-term depression

NASA Astrophysics Data System (ADS)

Hu, Zhonghua; Yu, Danni; Gu, Qin-Hua; Yang, Yanqin; Tu, Kang; Zhu, Jun; Li, Zheng

2014-02-01

Activity-dependent modification of dendritic spines, subcellular compartments accommodating postsynaptic specializations in the brain, is an important cellular mechanism for brain development, cognition and synaptic pathology of brain disorders. NMDA receptor-dependent long-term depression (NMDAR-LTD), a prototypic form of synaptic plasticity, is accompanied by prolonged remodelling of spines. The mechanisms underlying long-lasting spine remodelling in NMDAR-LTD, however, are largely unclear. Here we show that LTD induction causes global changes in miRNA transcriptomes affecting many cellular activities. Specifically, we show that expression changes of miR-191 and miR-135 are required for maintenance but not induction of spine restructuring. Moreover, we find that actin depolymerization and AMPA receptor exocytosis are regulated for extended periods of time by miRNAs to support long-lasting spine plasticity. These findings reveal a miRNA-mediated mechanism and a role for AMPA receptor exocytosis in long-lasting spine plasticity, and identify a number of candidate miRNAs involved in LTD.

Ultastructural analysis on acetylcholinesterase localization in the cerebellar cortex of teleosts.

PubMed

Contestabile, A; Villani, L; Ciani, F

1977-12-28

The histochemical localization of acetylcholinesterase (AChE) was studied by electron microscopy in the cerebellar cortex of the goldfish and the catfish. The patterns of enzyme distribution show noticeable differences in the two teleost species at the level of the corresponding cerebellar structures. Among the most distinctive features is the prevailing intracellular localization of enzyme activity in the goldfish and the prevailing extracellular localization in the catfish in the molecular layer and, to a lesser extent, the granular layer. Only quantitative differences in the ability to synthesize AChE can be recorded among the different cerebellar neurons in the two species, since all these neurons exhibit different amounts of enzyme activity linked to their cytoplasmic structures. Comparing the results obtained with those of previous histochemical, experimental and developmental researches, the hypothesis seems well founded that the embryonic pool of cerebellar neurons is made up of AChE-synthesizing nruroblasts which, during development, loss or maintain to a different the mechanisms for AChE synthesis. In addition the light and electron microscope histochemistry reveals at different levels of resolution that the final pattern of AChE distribution in the cerebellar cortex is the sum of different degress of AChE synthesis by cerebellar neurons and different degrees of enzyme release in extracellular spaces.

Landscape context and long-term tree influences shape the dynamics of forest-meadow ecotones in mountain ecosystems

Treesearch

R.E. Haugo; C.B. Halpern; J.D. Bakker

2011-01-01

Forest-meadow ecotones are prominent and dynamic features of mountain ecosystems. Understanding how vegetation changes are shaped by long-term interactions with trees and are mediated by the physical environment is critical to predicting future trends in biological diversity across these landscapes. We examined 26 yr of vegetation change (1983-2009) across 20 forest-...

Embolization of renal angiomyolipomas: short-term and long-term outcomes, complications, and tumor shrinkage.

PubMed

Lee, Shen-Yang; Hsu, Hsiang-Hao; Chen, Yung-Chang; Huang, Chen-Chih; Wong, Yon-Cheong; Wang, Li-Jen; Chuang, Cheng-Keng; Yang, Chih-Wei

2009-11-01

This study retrospectively evaluated outcomes, complications, and tumor shrinkage in renal angiomyolipomas after transcatheter arterial embolization (TAE). All renal angiomyolipoma patients who underwent TAE between August 2000 and December 2008 and had short-term (long-term (>6 months) follow-up images were evaluated. Complications and tumor relapse after TAE were reviewed. The sizes of embolized tumors were measured to calculate size reductions and reduction rates after TAE. Differences in tumor size, size reduction, and reduction rate between different time points (pre-TAE, short-term follow-up, and long-term follow-up) and groups (completely and incompletely embolized) were determined. Eleven renal angiomyolipoma patients who had undergone TAE were included. Seven (63.6%) patients had postembolization syndrome and one had abscess formation following TAE. Two patients had a tumor relapse (18.2%). The mean tumor size was 8.57+/-2.66 cm on pre-TAE images. The mean size reduction was 3.1 cm (33.3%) and 3.8 cm (43.0%) at short-term and long-term follow-up. Tumor sizes differed significantly between pre-TAE and short-term (p=0.004) or long-term images (p=0.022) but not between short-term and long-term images (p=0.059). Results stratified by the completeness of embolization indicate that only the short-term size reduction rate differed significantly (p=0.025), while the long-term reduction rate and short- and long-term follow-up tumor size and size reduction were comparable between the two groups. In conclusion, selective TAE is effective for tumor shrinkage in most renal angiomyolipomas, with acceptable complication and relapse rates. Tumor shrinkage occurring within 6 months after TAE may reflect the long-term effect of TAE.

Maturation and long-term hypoxia-induced acclimatization responses in PKC-mediated signaling pathways in ovine cerebral arterial contractility

PubMed Central

Goyal, Ravi; Mittal, Ashwani; Chu, Nina; Arthur, Rebecca Afiba; Zhang, Lubo

2010-01-01

In the developing fetus, cerebral arteries (CA) show striking differences in signal transduction mechanisms compared with the adult, and these differences are magnified in response to high-altitude long-term hypoxia (LTH). In addition, in the mature organism, cerebrovascular acclimatization to LTH may be associated with several clinical problems, the mechanisms of which are unknown. Because PKC plays a key role in regulating CA contractility, in fetal and adult cerebral arteries, we tested the hypothesis that LTH differentially regulates the PKC-mediated Ca2+ sensitization pathways and contractility. In four groups of sheep [fetal normoxic (FN), fetal hypoxic (FH), adult normoxic (AN), and adult hypoxic (AH)], we examined, simultaneously, responses of CA tension and intracellular Ca2+ concentration and measured CA levels of PKC, ERK1/2, RhoA, 20-kDa myosin light chain, and the 17-kDa PKC-potentiated myosin phosphatase inhibitor CPI-17. The PKC activator phorbol 12,13-dibutyrate (PDBu) produced robust contractions in all four groups. However, PDBu-induced contractions were significantly greater in AH CA than in the other groups. In all CA groups except AH, in the presence of MEK inhibitor (U-0126), the PDBu-induced contractions were increased a further 20–30%. Furthermore, in adult CA, PDBu led to increased phosphorylation of ERK1, but not ERK2; in fetal CA, the reverse was the case. PDBu-stimulated ERK2 phosphorylation also was significantly greater in FH than FN CA. Also, although RhoA/Rho kinase played a significant role in PDBu-mediated contractions of FN CA, this was not the case in FH or either adult group. Also, whereas CPI-17 had a significant role in adult CA contractility, this was not the case for the fetus. Overall, in ovine CA, the present study demonstrates several important maturational and LTH acclimatization changes in PKC-induced contractile responses and downstream pathways. The latter may play a key role in the pathophysiologic disorders

Maturation and long-term hypoxia-induced acclimatization responses in PKC-mediated signaling pathways in ovine cerebral arterial contractility.

PubMed

Goyal, Ravi; Mittal, Ashwani; Chu, Nina; Arthur, Rebecca Afiba; Zhang, Lubo; Longo, Lawrence D

2010-11-01

In the developing fetus, cerebral arteries (CA) show striking differences in signal transduction mechanisms compared with the adult, and these differences are magnified in response to high-altitude long-term hypoxia (LTH). In addition, in the mature organism, cerebrovascular acclimatization to LTH may be associated with several clinical problems, the mechanisms of which are unknown. Because PKC plays a key role in regulating CA contractility, in fetal and adult cerebral arteries, we tested the hypothesis that LTH differentially regulates the PKC-mediated Ca(2+) sensitization pathways and contractility. In four groups of sheep [fetal normoxic (FN), fetal hypoxic (FH), adult normoxic (AN), and adult hypoxic (AH)], we examined, simultaneously, responses of CA tension and intracellular Ca(2+) concentration and measured CA levels of PKC, ERK1/2, RhoA, 20-kDa myosin light chain, and the 17-kDa PKC-potentiated myosin phosphatase inhibitor CPI-17. The PKC activator phorbol 12,13-dibutyrate (PDBu) produced robust contractions in all four groups. However, PDBu-induced contractions were significantly greater in AH CA than in the other groups. In all CA groups except AH, in the presence of MEK inhibitor (U-0126), the PDBu-induced contractions were increased a further 20-30%. Furthermore, in adult CA, PDBu led to increased phosphorylation of ERK1, but not ERK2; in fetal CA, the reverse was the case. PDBu-stimulated ERK2 phosphorylation also was significantly greater in FH than FN CA. Also, although RhoA/Rho kinase played a significant role in PDBu-mediated contractions of FN CA, this was not the case in FH or either adult group. Also, whereas CPI-17 had a significant role in adult CA contractility, this was not the case for the fetus. Overall, in ovine CA, the present study demonstrates several important maturational and LTH acclimatization changes in PKC-induced contractile responses and downstream pathways. The latter may play a key role in the pathophysiologic disorders

Long-term neuropathologic changes associated with cerebral palsy in a nonhuman primate model of hypoxic-ischemic encephalopathy

PubMed Central

McAdams, Ryan M.; Fleiss, Bobbi; Traudt, Christopher; Schwendimann, Leslie; Snyder, Jessica M.; Haynes, Robin L.; Natarajan, Niranjana; Gressens, Pierre; Juul, Sandra E.

2017-01-01

Background Cerebral palsy (CP) is the most common motor disability in childhood with a worldwide prevalence of ranging between 1.5 to >4 per 1000 live births. Hypoxic ischemic encephalopathy (HIE) contributes to the burden of CP, but the long-term neuropathological findings of this association remain limited. Methodology Thirty-four term Macaca nemestrina were included in this long-term neuropathologic study: 9 control animals delivered by Cesarean section, and 25 animals with perinatal asphyxia who delivered by cesarean section after 15–18 minutes of umbilical cord occlusion (UCO). UCO animals were randomized to saline (n = 11), therapeutic hypothermia (TH) only (n = 6), or TH+erythropoietin (Epo; n = 8). Epo was given on days 1, 2, 3, and 7. Animals had serial developmental assessments and underwent MRI with diffusion tensor imaging at 9 months of age followed by necropsy. Histology and immunohistochemical staining of brain and brainstem sections was performed. Results All UCO animals demonstrated and met standard diagnostic criteria for human neonates with moderate-to-severe HIE. Four animals developed moderate-to-severe CP (3 UCO, 1 UCO+TH), 9 had mild CP (2 UCO, 3 UCO+TH, 3 UCO+TH+Epo, 1 control) and 2 UCO animals died. None of the animals treated with TH+Epo died, had moderate-to-severe CP, or demonstrated signs of long-term neuropathological toxicity. Compared to animals grouped together as non-CP (controls and mild CP only), animals with CP (moderate & severe) demonstrated decreased fractional anisotropy of multiple white matter tracks including corpus callosum and internal capsule on using track based special statistics (TBSS). Animals with CP had decreased staining for cortical neurons, and increased brainstem glial scarring compared to animals without CP. Cerebellar cell density of the internal granular layer and white matter was decreased in CP animals compared to control animals without CP. Conclusions/Significance In this nonhuman primate HIE model

Predictors of Long-Term Victimization After Early Pediatric Traumatic Brain Injury.

PubMed

Hung, Anna H; Cassedy, Amy; Schultz, Hanna M; Yeates, Keith Owen; Taylor, Hudson Gerry; Stancin, Terry; Walz, Nicolay Chertkoff; Wade, Shari L

2017-01-01

Pediatric traumatic brain injuries (TBIs) adversely affect long-term functional and social outcomes. Limited research suggests children with TBI are more likely to be victimized by peers than noninjured children. Deficits in social information processing (SIP), cognitive ability, and executive functioning (EF) may contribute to increased victimization risk. This study examined rates of peer victimization/bullying in children with early TBI compared with children with orthopedic injuries (OIs) and the role of processing speed, executive function (EF), and SIP as mediators of the association of TBI and peer victimization. Children ages 10 to 14 years who sustained a complicated mild/moderate or severe TBI (N = 58) or OI (N = 72) during early childhood (ages 3-7 yr) and their parents participated in a longitudinal prospective follow-up 6.8 years postinjury. SIP, EF and processing speed, and peer victimization were assessed. Parents of children with severe TBI reported greater rates of peer victimization than parents of children with OIs. Children with severe TBI demonstrated greater EF deficits than children with complicated mild/moderate TBI or OI and poorer processing speed than children with OI. No significant indirect relationships were found between groups and any outcome variables to indicate mediation. Based on parent report, children with severe TBI have higher risk of peer victimization than those with less severe injuries. In addition, children with severe TBI have more impaired EF and cognitive ability than counterparts with less severe TBI. Further research is needed to explore predictors of long-term victimization after early TBI to create interventions aimed at providing social, emotional, and behavioral skill building for victimized youth.

Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation.

PubMed

Garcia, I; Crowther, A J; Gama, V; Miller, C R; Miller, C Ryan; Deshmukh, M; Gershon, T R

2013-05-02

Neurogenesis requires negative regulation through differentiation of progenitors or their programmed cell death (PCD). Growth regulation is particularly important in the postnatal cerebellum, where excessive progenitor proliferation promotes medulloblastoma, the most common malignant brain tumor in children. We present evidence that PCD operates alongside differentiation to regulate cerebellar granule neuron progenitors (CGNPs) and to prevent medulloblastoma. Here, we show that genetic deletion of pro-apoptotic Bax disrupts regulation of cerebellar neurogenesis and promotes medulloblastoma formation. In Bax(-/-) mice, the period of neurogenesis was extended into the third week of postnatal life, and ectopic neurons and progenitors collected in the molecular layer of the cerebellum and adjacent tectum. Importantly, genetic deletion of Bax in medulloblastoma-prone ND2:SmoA1 transgenic mice greatly accelerated tumorigenesis. Bax-deficient medulloblastomas exhibited strikingly distinct pathology, with reduced apoptosis, increased neural differentiation and tectal migration. Comparing Bax(+/+) and Bax(-/-) medulloblastomas, we were able to identify upregulation of Bcl-2 and nuclear exclusion of p27 as tumorigenic changes that are required to mitigate the tumor suppressive effect of Bax. Studies on human tumors confirmed the importance of modulating Bax in medulloblastoma pathogenesis. Our results demonstrate that Bax-dependent apoptosis regulates postnatal cerebellar neurogenesis, suppresses medulloblastoma formation and imposes selective pressure on tumors that form. Functional resistance to Bax-mediated apoptosis, required for medulloblastoma tumorigenesis, may be a tumor-specific vulnerability to be exploited for therapeutic benefit.

Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome

PubMed Central

Thomas, Anna C.; Williams, Hywel; Setó-Salvia, Núria; Bacchelli, Chiara; Jenkins, Dagan; O’Sullivan, Mary; Mengrelis, Konstantinos; Ishida, Miho; Ocaka, Louise; Chanudet, Estelle; James, Chela; Lescai, Francesco; Anderson, Glenn; Morrogh, Deborah; Ryten, Mina; Duncan, Andrew J.; Pai, Yun Jin; Saraiva, Jorge M.; Ramos, Fabiana; Farren, Bernadette; Saunders, Dawn; Vernay, Bertrand; Gissen, Paul; Straatmaan-Iwanowska, Anna; Baas, Frank; Wood, Nicholas W.; Hersheson, Joshua; Houlden, Henry; Hurst, Jane; Scott, Richard; Bitner-Glindzicz, Maria; Moore, Gudrun E.; Sousa, Sérgio B.; Stanier, Philip

2014-01-01

Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum. PMID:25439728

Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome.

PubMed

Thomas, Anna C; Williams, Hywel; Setó-Salvia, Núria; Bacchelli, Chiara; Jenkins, Dagan; O'Sullivan, Mary; Mengrelis, Konstantinos; Ishida, Miho; Ocaka, Louise; Chanudet, Estelle; James, Chela; Lescai, Francesco; Anderson, Glenn; Morrogh, Deborah; Ryten, Mina; Duncan, Andrew J; Pai, Yun Jin; Saraiva, Jorge M; Ramos, Fabiana; Farren, Bernadette; Saunders, Dawn; Vernay, Bertrand; Gissen, Paul; Straatmaan-Iwanowska, Anna; Baas, Frank; Wood, Nicholas W; Hersheson, Joshua; Houlden, Henry; Hurst, Jane; Scott, Richard; Bitner-Glindzicz, Maria; Moore, Gudrun E; Sousa, Sérgio B; Stanier, Philip

2014-11-06

Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Excitotoxicity through NMDA receptors mediates cerebellar granule neuron apoptosis induced by prion protein 90-231 fragment.

PubMed

Thellung, Stefano; Gatta, Elena; Pellistri, Francesca; Corsaro, Alessandro; Villa, Valentina; Vassalli, Massimo; Robello, Mauro; Florio, Tullio

2013-05-01

Prion diseases recognize, as a unique molecular trait, the misfolding of CNS-enriched prion protein (PrP(C)) into an aberrant isoform (PrP(Sc)). In this work, we characterize the in vitro toxicity of amino-terminally truncated recombinant PrP fragment (amino acids 90-231, PrP90-231), on rat cerebellar granule neurons (CGN), focusing on glutamatergic receptor activation and Ca(2+) homeostasis impairment. This recombinant fragment assumes a toxic conformation (PrP90-231(TOX)) after controlled thermal denaturation (1 h at 53 °C) acquiring structural characteristics identified in PrP(Sc) (enrichment in β-structures, increased hydrophobicity, partial resistance to proteinase K, and aggregation in amyloid fibrils). By annexin-V binding assay, and evaluation of the percentage of fragmented and condensed nuclei, we show that treatment with PrP90-231(TOX), used in pre-fibrillar aggregation state, induces CGN apoptosis. This effect was associated with a delayed, but sustained elevation of [Ca(2+)]i. Both CGN apoptosis and [Ca(2+)]i increase were not observed using PrP90-231 in PrP(C)-like conformation. PrP90-231(TOX) effects were significantly reduced in the presence of ionotropic glutamate receptor antagonists. In particular, CGN apoptosis and [Ca(2+)]i increase were largely reduced, although not fully abolished, by pre-treatment with the NMDA antagonists APV and memantine, while the AMPA antagonist CNQX produced a lower, although still significant, effect. In conclusion, we report that CGN apoptosis induced by PrP90-231(TOX) correlates with a sustained elevation of [Ca(2+)]i mediated by the activation of NMDA and AMPA receptors.

Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice.

PubMed

Tsai, Peter T; Hull, Court; Chu, YunXiang; Greene-Colozzi, Emily; Sadowski, Abbey R; Leech, Jarrett M; Steinberg, Jason; Crawley, Jacqueline N; Regehr, Wade G; Sahin, Mustafa

2012-08-30

Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss, and isolated cerebellar injury has been associated with a higher incidence of ASDs. However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology and correlate cerebellar pathology with increased ASD symptomatology. Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs. However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism.

Cerebellar Abiotrophy Across Domestic Species.

PubMed

Scott, Erica Yuki; Woolard, Kevin Douglas; Finno, Carrie J; Murray, James D

2018-06-01

Cerebellar abiotrophy (CA) is a neurodegenerative disorder affecting the cerebellum and occurs in multiple species. Although CA is well researched in humans and mice, domestic species such as the dog, cat, sheep, cow, and horse receive little recognition. This may be due to few studies addressing the mechanism of CA in these species. However, valuable information can still be extracted from these cases. A review of the clinicohistologic phenotype of CA in these species and determining the various etiologies of CA may aid in determining conserved and required pathways necessary for proper cerebellar development and function. This review outlines research approaches of studies of CA in domestic species, compared to the approaches used in mice, with the objective of comparing CA in domestic species while identifying areas for further research efforts.

Clinical features and long term outcome of epilepsy in periventricular nodular heterotopia. Simple compared with plus forms

PubMed Central

d'Orsi, G; Tinuper, P; Bisulli, F; Zaniboni, A; Bernardi, B; Rubboli, G; Riva, R; Michelucci, R; Volpi, L; Tassinari, C; Baruzzi, A

2004-01-01

Objectives: Little is known about the long term outcome of patients with periventricular nodular heterotopia (PNH) and epilepsy, particularly the course of seizures. This study investigated the electroclinical and prognostic features of 16 patients with PNH. Methods: Of 120 patients with epilepsy and malformations of cortical development, 16 had PNH. Of these, eight patients had periventricular nodules only (simple PNH) and eight also presented with other cortical or cerebral malformations (subcortical heterotopia; polymicrogyria; focal dysplasia; schizencephaly; cortical infolding; agenesis of the corpus callosum; mega cisterna magna and cerebellar atrophy) (PNH plus). All patients underwent clinical, neurophysiological, and MRI investigation. The mean follow up was 17.3 years (2–40 years). Results: Two electroclinical patterns emerged: (1) The first pattern, associated with simple PNH, was characterised by normal intelligence and seizures, usually partial, which began during the second decade of life. The seizures never became frequent and tended to disappear or become very rare. The EEG showed focal abnormalities. (2) The second pattern, associated with PNH plus, was characterised by mental retardation and seizures that began during the first decade of life. The seizures were very frequent in most cases and sudden drops were observed in six patients. Seizures were medically refractory in four patients. The EEG showed focal and bisynchronous abnormalities. Conclusions: Two groups of PNH patients with different electroclinical and neuroradiological features can be identified after a long term follow up. The presence of other types of cortical or cerebral malformations, in addition to periventricular nodules, determines a poor prognosis. PMID:15146004

BDNF is essential to promote persistence of long-term memory storage

PubMed Central

Bekinschtein, Pedro; Cammarota, Martín; Katche, Cynthia; Slipczuk, Leandro; Rossato, Janine I.; Goldin, Andrea; Izquierdo, Ivan; Medina, Jorge H.

2008-01-01

Persistence is a characteristic attribute of long-term memories (LTMs). However, little is known about the molecular mechanisms that mediate this process. We recently showed that persistence of LTM requires a late protein synthesis- and BDNF-dependent phase in the hippocampus. Here, we show that intrahippocampal delivery of BDNF reverses the deficit in memory persistence caused by inhibition of hippocampal protein synthesis. Importantly, we demonstrate that BDNF induces memory persistence by itself, transforming a nonlasting LTM trace into a persistent one in an ERK-dependent manner. Thus, BDNF is not only necessary, but sufficient to induce a late postacquisition phase in the hippocampus essential for persistence of LTM storage. PMID:18263738

Anti-Hebbian long-term potentiation in the hippocampal feedback inhibitory circuit.

PubMed

Lamsa, Karri P; Heeroma, Joost H; Somogyi, Peter; Rusakov, Dmitri A; Kullmann, Dimitri M

2007-03-02

Long-term potentiation (LTP), which approximates Hebb's postulate of associative learning, typically requires depolarization-dependent glutamate receptors of the NMDA (N-methyl-D-aspartate) subtype. However, in some neurons, LTP depends instead on calcium-permeable AMPA-type receptors. This is paradoxical because intracellular polyamines block such receptors during depolarization. We report that LTP at synapses on hippocampal interneurons mediating feedback inhibition is "anti-Hebbian":Itis induced by presynaptic activity but prevented by postsynaptic depolarization. Anti-Hebbian LTP may occur in interneurons that are silent during periods of intense pyramidal cell firing, such as sharp waves, and lead to their altered activation during theta activity.

Role of Plasticity at Different Sites across the Time Course of Cerebellar Motor Learning

PubMed Central

Lisberger, Stephen G.

2014-01-01

Learning comprises multiple components that probably involve cellular and synaptic plasticity at multiple sites. Different neural sites may play their largest roles at different times during behavioral learning. We have used motor learning in smooth pursuit eye movements of monkeys to determine how and when different components of learning occur in a known cerebellar circuit. The earliest learning occurs when one climbing-fiber response to a learning instruction causes simple-spike firing rate of Purkinje cells in the floccular complex of the cerebellum to be depressed transiently at the time of the instruction on the next trial. Trial-over-trial depression and the associated learning in eye movement are forgotten in <6 s, but facilitate long-term behavioral learning over a time scale of ∼5 min. During 100 repetitions of a learning instruction, simple-spike firing rate becomes progressively depressed in Purkinje cells that receive climbing-fiber inputs from the instruction. In Purkinje cells that prefer the opposite direction of pursuit and therefore do not receive climbing-fiber inputs related to the instruction, simple-spike responses undergo potentiation, but more weakly and more slowly. Analysis of the relationship between the learned changes in simple-spike firing and learning in eye velocity suggests an orderly progression of plasticity: first on Purkinje cells with complex-spike (CS) responses to the instruction, later on Purkinje cells with CS responses to the opposite direction of instruction, and last in sites outside the cerebellar cortex. Climbing-fiber inputs appear to play a fast and primary, but nonexclusive, role in pursuit learning. PMID:24849344

Absence of oncogenic transformation despite acquisition of cytogenetic aberrations in long-term cultured telomerase-immortalized human fetal hepatocytes.

PubMed

Haker, Björn; Fuchs, Sigrid; Dierlamm, Judith; Brümmendorf, Tim H; Wege, Henning

2007-10-18

As a culture model to study hepatocarcinogenesis, telomerase-immortalized human fetal hepatocytes were monitored for karyotype changes evolving in long-term culture and development of functional defects in DNA damage response. G-banding revealed acquisition of characteristic karyotype abnormalities, e.g., trisomy 7 and monosomy X, in two independently immortalized and cultured populations after 80-100 population doublings. Interestingly, the detected aneuploidies resemble some of the genetic events observed in hepatocellular cancer. However, these genetic changes were not sufficient to induce oncogenic transformation reflected by absence of anchorage-independent growth. Furthermore, long-term cultured telomerase-immortalized cells preserved p53 expression levels and effective p53-mediated damage response.

Alterations to global but not local motion processing in long-term ecstasy (MDMA) users.

PubMed

White, Claire; Brown, John; Edwards, Mark

2014-07-01

Growing evidence indicates that the main psychoactive ingredient in the illegal drug "ecstasy" (methylendioxymethamphetamine) causes reduced activity in the serotonin and gamma-aminobutyric acid (GABA) systems in humans. On the basis of substantial serotonin input to the occipital lobe, recent research investigated visual processing in long-term users and found a larger magnitude of the tilt aftereffect, interpreted to reflect broadened orientation tuning bandwidths. Further research found higher orientation discrimination thresholds and reduced long-range interactions in the primary visual area of ecstasy users. The aim of the present research was to investigate whether serotonin-mediated V1 visual processing deficits in ecstasy users extend to motion processing mechanisms. Forty-five participants (21 controls, 24 drug users) completed two psychophysical studies: A direction discrimination study directly measured local motion processing in V1, while a motion coherence task tested global motion processing in area V5/MT. "Primary" ecstasy users (n = 18), those without substantial polydrug use, had significantly lower global motion thresholds than controls [p = 0.027, Cohen's d = 0.78 (large)], indicating increased sensitivity to global motion stimuli, but no difference in local motion processing (p = 0.365). These results extend on previous research investigating the long-term effects of illicit drugs on visual processing. Two possible explanations are explored: defuse attentional processes may be facilitating spatial pooling of motion signals in users. Alternatively, it may be that a GABA-mediated disruption to V5/MT processing is reducing spatial suppression and therefore improving global motion perception in ecstasy users.

42 CFR 412.536 - Special payment provisions for long-term care hospitals and satellites of long-term care...

Code of Federal Regulations, 2010 CFR

2010-10-01

... December 29, 2007, was co-located with an entity that is a provider-based, off-campus location of a... hospital or the satellite facility from any individual hospital not co-located with the long-term care... from any individual hospital not co-located with the long-term care hospital or with the satellite of a...

SPIN90 Modulates Long-Term Depression and Behavioral Flexibility in the Hippocampus

PubMed Central

Kim, Dae Hwan; Kang, Minkyung; Kim, Chong-Hyun; Huh, Yun Hyun; Cho, In Ha; Ryu, Hyun-Hee; Chung, Kyung Hwun; Park, Chul-Seung; Rhee, Sangmyung; Lee, Yong-Seok; Song, Woo Keun

2017-01-01

The importance of actin-binding proteins (ABPs) in the regulation of synapse morphology and plasticity has been well established. SH3 protein interacting with Nck, 90 kDa (SPIN90), an Nck-interacting protein highly expressed in synapses, is essential for actin remodeling and dendritic spine morphology. Synaptic targeting of SPIN90 to spine heads or dendritic shafts depends on its phosphorylation state, leading to blockage of cofilin-mediated actin depolymerization and spine shrinkage. However, the physiological role of SPIN90 in long-term plasticity, learning and memory are largely unknown. In this study, we demonstrate that Spin90-knockout (KO) mice exhibit substantial deficits in synaptic plasticity and behavioral flexibility. We found that loss of SPIN90 disrupted dendritic spine density in CA1 neurons of the hippocampus and significantly impaired long-term depression (LTD), leaving basal synaptic transmission and long-term potentiation (LTP) intact. These impairments were due in part to deficits in AMPA receptor endocytosis and its pre-requisites, GluA1 dephosphorylation and postsynaptic density (PSD) 95 phosphorylation, but also by an intrinsic activation of Akt-GSK3β signaling as a result of Spin90-KO. In accordance with these defects, mice lacking SPIN90 were found to carry significant deficits in object-recognition and behavioral flexibility, while learning ability was largely unaffected. Collectively, these findings demonstrate a novel modulatory role for SPIN90 in hippocampal LTD and behavioral flexibility. PMID:28979184

Fast convergence of learning requires plasticity between inferior olive and deep cerebellar nuclei in a manipulation task: a closed-loop robotic simulation

PubMed Central

Luque, Niceto R.; Garrido, Jesús A.; Carrillo, Richard R.; D'Angelo, Egidio; Ros, Eduardo

2014-01-01

The cerebellum is known to play a critical role in learning relevant patterns of activity for adaptive motor control, but the underlying network mechanisms are only partly understood. The classical long-term synaptic plasticity between parallel fibers (PFs) and Purkinje cells (PCs), which is driven by the inferior olive (IO), can only account for limited aspects of learning. Recently, the role of additional forms of plasticity in the granular layer, molecular layer and deep cerebellar nuclei (DCN) has been considered. In particular, learning at DCN synapses allows for generalization, but convergence to a stable state requires hundreds of repetitions. In this paper we have explored the putative role of the IO-DCN connection by endowing it with adaptable weights and exploring its implications in a closed-loop robotic manipulation task. Our results show that IO-DCN plasticity accelerates convergence of learning by up to two orders of magnitude without conflicting with the generalization properties conferred by DCN plasticity. Thus, this model suggests that multiple distributed learning mechanisms provide a key for explaining the complex properties of procedural learning and open up new experimental questions for synaptic plasticity in the cerebellar network. PMID:25177290

RNP-Granule Assembly via Ataxin-2 Disordered Domains Is Required for Long-Term Memory and Neurodegeneration.

PubMed

Bakthavachalu, Baskar; Huelsmeier, Joern; Sudhakaran, Indulekha P; Hillebrand, Jens; Singh, Amanjot; Petrauskas, Arnas; Thiagarajan, Devasena; Sankaranarayanan, M; Mizoue, Laura; Anderson, Eric N; Pandey, Udai Bhan; Ross, Eric; VijayRaghavan, K; Parker, Roy; Ramaswami, Mani

2018-05-16

Human Ataxin-2 is implicated in the cause and progression of amyotrophic lateral sclerosis (ALS) and type 2 spinocerebellar ataxia (SCA-2). In Drosophila, a conserved atx2 gene is essential for animal survival as well as for normal RNP-granule assembly, translational control, and long-term habituation. Like its human homolog, Drosophila Ataxin-2 (Atx2) contains polyQ repeats and additional intrinsically disordered regions (IDRs). We demonstrate that Atx2 IDRs, which are capable of mediating liquid-liquid phase transitions in vitro, are essential for efficient formation of neuronal mRNP assemblies in vivo. Remarkably, ΔIDR mutants that lack neuronal RNP granules show normal animal development, survival, and fertility. However, they show defects in long-term memory formation/consolidation as well as in C9ORF72 dipeptide repeat or FUS-induced neurodegeneration. Together, our findings demonstrate (1) that higher-order mRNP assemblies contribute to long-term neuronal plasticity and memory, and (2) that a targeted reduction in RNP-granule formation efficiency can alleviate specific forms of neurodegeneration. Copyright © 2018 Elsevier Inc. All rights reserved.

Short-term and long-term treatment outcomes with Class III activator

PubMed Central

Ryu, Hyo-kyung; Chong, Hyun-Jeong; An, Ki-Yong

2015-01-01

Objective The purpose of this retrospective study was to investigate short-term and long-term skeletodental outcomes of Class III activator treatment. Methods A Class III activator treatment group (AG) comprised of 22 patients (9 boys, 13 girls) was compared with a Class III control group (CG) comprised of 17 patients (6 boys, 11 girls). The total treatment period was divided into three stages; the initial stage (T1), the post-activator treatment or post-mandibular growth peak stage (T2), and the long-term follow-up stage (T3). Cephalometric changes were evaluated statistically via the Mann-Whitney U-test and the Friedman test. Results The AG exhibited significant increases in the SNA angle, ANB angle, Wits appraisal, A point-N perpendicular, Convexity of A point, and proclination of the maxillary incisors, from T1 to T2. In the long-term follow-up (T1-T3), the AG exhibited significantly greater increases in the ANB angle, Wits appraisal, and Convexity of A point than the CG. Conclusions Favorable skeletal outcomes induced during the Class III activator treatment period were generally maintained until the long-term follow-up period of the post-mandibular growth peak stage. PMID:26445717

[Psychosocial issues of long-term cancer survivors].

PubMed

Weis, J; Faller, H

2012-04-01

Although cancer incidence rates are increasing, recent statistical studies suggest that cancer patients are showing higher cure rates as well as improved overall survival rates for most cancer locations. These advances are explained by improved strategies in early diagnoses as well as improved cancer therapies. Therefore, the number of long-term cancer survivors has also increased, but only few studies, especially within the last years, have focused on psychosocial issues of this subgroup. Some studies show that overall quality of life of long-term cancer survivors is quite high and comparable to that of the normal population. Nevertheless, a substantial percentage of former patients shows reduced quality of life and suffers from various sequelae of cancer and its treatment. This review focuses on the most common psychosocial issue of long-term survivors such as reduced psychological wellbeing, neuropsychological deficits and cancer-related fatigue syndrome. Finally, recommendations for problem-oriented interventions as well as improvement of psychosocial care of long-term survivors are given.

A security/safety survey of long term care facilities.

PubMed

Acorn, Jonathan R

2010-01-01

What are the major security/safety problems of long term care facilities? What steps are being taken by some facilities to mitigate such problems? Answers to these questions can be found in a survey of IAHSS members involved in long term care security conducted for the IAHSS Long Term Care Security Task Force. The survey, the author points out, focuses primarily on long term care facilities operated by hospitals and health systems. However, he believes, it does accurately reflect the security problems most long term facilities face, and presents valuable information on security systems and practices which should be also considered by independent and chain operated facilities.

Mechanisms of hippocampal long-term depression are required for memory enhancement by novelty exploration.

PubMed

Dong, Zhifang; Gong, Bo; Li, Hongjie; Bai, Yanrui; Wu, Xiaoyan; Huang, Yan; He, Wenting; Li, Tingyu; Wang, Yu Tian

2012-08-29

It is well known that novel environments can enhance learning and memory. However, the underlying mechanisms remain poorly understood. Here, we report that, in freely moving rats, novelty exploration facilitates the production of hippocampal CA1 long-term depression (LTD), a well characterized form of synaptic plasticity believed to be a cellular substrate of spatial learning, and thereby converts short-term memory (STM) into long-term memory (LTM) in an inhibitory avoidance learning procedure. Blocking the induction or the expression of CA1 LTD with two mechanistically and structurally distinct inhibitors prevents not only novelty acquisition but also the novelty exploration-promoted conversion of STM into LTM. Moreover, production of LTD with a strong electrical stimulation induction protocol or facilitation of hippocampal LTD by pharmacological inhibition of glutamate transporter activity mimics the behavioral effects of novelty exploration, sufficiently promoting the conversion of STM into LTM. Together, our findings suggest that induction of LTD may play an essential role not only in novelty acquisition but also in novelty-mediated memory enhancement.

Long-Term Care Financing: Lessons From France

PubMed Central

Doty, Pamela; Nadash, Pamela; Racco, Nathalie

2015-01-01

Context An aging population leads to a growing demand for long-term services and supports (LTSS). In 2002, France introduced universal, income-adjusted, public long-term care coverage for adults 60 and older, whereas the United States funds means-tested benefits only. Both countries have private long-term care insurance (LTCI) markets: American policies create alternatives to out-of-pocket spending and protect purchasers from relying on Medicaid. Sales, however, have stagnated, and the market's viability is uncertain. In France, private LTCI supplements public coverage, and sales are growing, although its potential to alleviate the long-term care financing problem is unclear. We explore whether France's very different approach to structuring public and private financing for long-term care could inform the United States’ long-term care financing reform efforts. Methods We consulted insurance experts and conducted a detailed review of public reports, academic studies, and other documents to understand the public and private LTCI systems in France, their advantages and disadvantages, and the factors affecting their development. Findings France provides universal public coverage for paid assistance with functional dependency for people 60 and older. Benefits are steeply income adjusted and amounts are low. Nevertheless, expenditures have exceeded projections, burdening local governments. Private supplemental insurance covers 11% of French, mostly middle-income adults (versus 3% of Americans 18 and older). Whether policyholders will maintain employer-sponsored coverage after retirement is not known. The government's interest in pursuing an explicit public/private partnership has waned under President François Hollande, a centrist socialist, in contrast to the previous center-right leader, President Nicolas Sarkozy, thereby reducing the prospects of a coordinated public/private strategy. Conclusions American private insurers are showing increasing interest in long-term

Motion perception without Nystagmus--a novel manifestation of cerebellar stroke.

PubMed

Shaikh, Aasef G

2014-01-01

The motion perception and the vestibulo-ocular reflex (VOR) each serve distinct functions. The VOR keeps the gaze steady on the target of interest, whereas vestibular perception serves a number of tasks, including awareness of self-motion and orientation in space. VOR and motion perception might abide the same neurophysiological principles, but their distinct anatomical correlates were proposed. In patients with cerebellar stroke in distribution of medial division of posterior inferior cerebellar artery, we asked whether specific location of the focal lesion in vestibulocerebellum could cause impaired perception of motion but normal eye movements. Thirteen patients were studied, 5 consistently perceived spinning of surrounding environment (vertigo), but the eye movements were normal. This group was called "disease model." Remaining 8 patients were also symptomatic for vertigo, but they had spontaneous nystagmus. The latter group was called "disease control." Magnetic resonance imaging in both groups consistently revealed focal cerebellar infarct affecting posterior cerebellar vermis (lobule IX). In the "disease model" group, only part of lobule IX was affected. In the disease control group, however, complete lobule IX was involved. This study discovered a novel presentation of cerebellar stroke where only motion perception was affected, but there was an absence of objective neurologic signs. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.