scholarly journals A novel inhibitory nucleo-cortical circuit controls cerebellar Golgi cell activity

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Lea Ankri ◽  
Zoé Husson ◽  
Katarzyna Pietrajtis ◽  
Rémi Proville ◽  
Clément Léna ◽  
...  
Keyword(s):  
Cerebellar Cortex ◽  
Motor Coordination ◽  
Granule Cells ◽  
Cell Activity ◽  
Cerebellar Nuclei ◽  
Golgi Cell ◽  
Main Mode ◽  
Golgi Cells

The cerebellum, a crucial center for motor coordination, is composed of a cortex and several nuclei. The main mode of interaction between these two parts is considered to be formed by the inhibitory control of the nuclei by cortical Purkinje neurons. We now amend this view by showing that inhibitory GABA-glycinergic neurons of the cerebellar nuclei (CN) project profusely into the cerebellar cortex, where they make synaptic contacts on a GABAergic subpopulation of cerebellar Golgi cells. These spontaneously firing Golgi cells are inhibited by optogenetic activation of the inhibitory nucleo-cortical fibers both in vitro and in vivo. Our data suggest that the CN may contribute to the functional recruitment of the cerebellar cortex by decreasing Golgi cell inhibition onto granule cells.

Feedforward Inhibition Controls the Spread of Granule Cell–Induced Purkinje Cell Activity in the Cerebellar Cortex

2007 ◽  
Vol 97 (1) ◽  
pp. 248-263 ◽  
Author(s):  
Fidel Santamaria ◽  
Patrick G. Tripp ◽  
James M. Bower
Keyword(s):  
Cerebellar Cortex ◽  
Granule Cells ◽  
Functional Organization ◽  
Cerebellar Granule Cells ◽  
Molecular Layer ◽  
Cell Activity ◽  
Excitatory Input ◽  
Cortical Inhibition ◽  
Before And After

Synapses associated with the parallel fiber (pf) axons of cerebellar granule cells constitute the largest excitatory input onto Purkinje cells (PCs). Although most theories of cerebellar function assume these synapses produce an excitatory sequential “beamlike” activation of PCs, numerous physiological studies have failed to find such beams. Using a computer model of the cerebellar cortex we predicted that the lack of PCs beams is explained by the concomitant pf activation of feedforward molecular layer inhibition. This prediction was tested, in vivo, by recording PCs sharing a common set of pfs before and after pharmacologically blocking inhibitory inputs. As predicted by the model, pf-induced beams of excitatory PC responses were seen only when inhibition was blocked. Blocking inhibition did not have a significant effect in the excitability of the cerebellar cortex. We conclude that pfs work in concert with feedforward cortical inhibition to regulate the excitability of the PC dendrite without directly influencing PC spiking output. This conclusion requires a significant reassessment of classical interpretations of the functional organization of the cerebellar cortex.

Dynamic Synchronization of Purkinje Cell Simple Spikes

2006 ◽  
Vol 96 (6) ◽  
pp. 3485-3491 ◽  
Author(s):  
Soon-Lim Shin ◽  
Erik De Schutter
Keyword(s):  
Purkinje Cell ◽  
Firing Rate ◽  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Cerebellar Nuclei ◽  
Temporal Coding ◽  
Sharp Peak ◽  
Deep Cerebellar Nuclei

Purkinje cells (PCs) integrate all computations performed in the cerebellar cortex to inhibit neurons in the deep cerebellar nuclei (DCN). Simple spikes recorded in vivo from pairs of PCs separated by <100 μm are known to be synchronized with a sharp peak riding on a broad peak, but the significance of this finding is unclear. We show that the sharp peak consists exclusively of simple spikes associated with pauses in firing. The broader, less precise peak was caused by firing-rate co-modulation of faster firing spikes. About 13% of all pauses were synchronized, and these pauses had a median duration of 20 ms. As in vitro studies have reported that synchronous pauses can reliably trigger spikes in DCN neurons, we suggest that the subgroup of spikes causing the sharp peak is important for precise temporal coding in the cerebellum.

scholarly journals Accounting for uncertainty: inhibition for neural inference in the cerebellum

2021 ◽  
Vol 288 (1947) ◽  
Author(s):  
Ensor Rafael Palacios ◽  
Conor Houghton ◽  
Paul Chadderton
Keyword(s):  
State Estimation ◽  
Cerebellar Cortex ◽  
Granular Layer ◽  
Granule Cells ◽  
Neural Mechanisms ◽  
Golgi Cell ◽  
Golgi Cells ◽  
Neural Representations ◽  
Cell Inhibition ◽  
Specific Contribution

Sensorimotor coordination is thought to rely on cerebellar-based internal models for state estimation, but the underlying neural mechanisms and specific contribution of the cerebellar components is unknown. A central aspect of any inferential process is the representation of uncertainty or conversely precision characterizing the ensuing estimates. Here, we discuss the possible contribution of inhibition to the encoding of precision of neural representations in the granular layer of the cerebellar cortex. Within this layer, Golgi cells influence excitatory granule cells, and their action is critical in shaping information transmission downstream to Purkinje cells. In this review, we equate the ensuing excitation–inhibition balance in the granular layer with the outcome of a precision-weighted inferential process, and highlight the physiological characteristics of Golgi cell inhibition that are consistent with such computations.

scholarly journals Osseointegrating and phase-oriented micro-arc-oxidized titanium dioxide bone implants

2021 ◽  
Vol 19 ◽  
pp. 228080002110068
Author(s):  
Hsien-Te Chen ◽  
Hsin-I Lin ◽  
Chi-Jen Chung ◽  
Chih-Hsin Tang ◽  
Ju-Liang He
Keyword(s):  
Titanium Dioxide ◽  
High Surface ◽  
Cell Activity ◽  
Active Surface ◽  
Rutile Phase ◽  
Hydroxyl Groups ◽  
Bone Implant ◽  
Implant System

Here, we present a bone implant system of phase-oriented titanium dioxide (TiO2) fabricated by the micro-arc oxidation method (MAO) on β-Ti to facilitate improved osseointegration. This (101) rutile-phase-dominant MAO TiO2 (R-TiO2) is biocompatible due to its high surface roughness, bone-mimetic structure, and preferential crystalline orientation. Furthermore, (101) R-TiO2 possesses active and abundant hydroxyl groups that play a significant role in enhancing hydroxyapatite formation and cell adhesion and promote cell activity leading to osseointegration. The implants had been elicited their favorable cellular behavior in vitro in the previous publications; in addition, they exhibit excellent shear strength and promote bone–implant contact, osteogenesis, and tissue formation in vivo. Hence, it can be concluded that this MAO R-TiO2 bone implant system provides a favorable active surface for efficient osseointegration and is suitable for clinical applications.

scholarly journals In VitroandIn VivoCharacterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase

2016 ◽  
Vol 60 (8) ◽  
pp. 4830-4839 ◽  
Author(s):  
Christopher M. Tan ◽  
Charles J. Gill ◽  
Jin Wu ◽  
Nathalie Toussaint ◽  
Jingjun Yin ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Antibacterial Agents ◽  
Cell Activity ◽  
Dna Gyrase ◽  
Topoisomerase Iv ◽  
Bacterial Dna ◽  
Whole Cell ◽  
Content Type

ABSTRACTOxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, andin vivocharacterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV fromStaphylococcus aureusandEscherichia coliand displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergencein vitroat concentrations 16- to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activityin vitroandin vivo.

Preclinical Evaluation of a Bone-Marrow Autograft Culture Procedure for Generating Lymphokine-Activated Killer Cells in Vitro

1992 ◽  
Vol 3 (suppl b) ◽  
pp. 123-127 ◽  
Author(s):  
Hans-Georg Klingemann ◽  
Heather Deal ◽  
Dianne Reid ◽  
Connie J Eaves
Keyword(s):  
Bone Marrow ◽  
Calf Serum ◽  
Cell Activity ◽  
Hematopoietic Cells ◽  
Lak Cells ◽  
High Dose ◽  
Lymphokine Activated Killer Cells ◽  
Lak Cell

Despite the use of high dose chemoradiotherapy for the treatment of acute leukemia. relapse continues to be a major cause of death in patients given an autologous bone marrow transplant. Further augmentation of pretransplant chemotherapy causes life threatening toxicity to nonhematopoietic tissues and the effectiveness of currently available ex vivo purging methods in reducing the relapse rate is unclear. Recently, data from experimental models have suggested that bone marrow-derived lymphokine (IL-2)-activated killer (BM-LAK) cells might be used to eliminate residual leukemic cells both in vivo and in vitro. To evaluate this possibility clinically, a procedure was developed for culturing whole marrow harvests with IL-2 prior to use as autografts, and a number of variables examined that might affect either the generation of BM-LAK cells or the recovery of the primitive hematopoietic cells. The use of Dexter long term culture (LTC) conditions, which expose the cells to horse serum and hydrocortisone. supported LAK cell generation as effectively as fetal calf serum (FCS) -containing medium in seven-day cultures. Maintenance of BM-LAK cell activity after a further seven days of culture in the presence of IL-2 was also tested. As in the clinical setting. patients would receive IL-2 in vivo for an additional week immediately following infusion of the cultured marrow autograft. Generation ofBM-LAK activity was dependent on the presence of IL-2 and could be sustained by further incubation in medium containing IL-2. Primitive hematopoietic cells were quantitated by measuring the number of in vitro colony-forming progenitors produced after five weeks in secondary Dexter-type LTC. Maintenance of these 'LTC-initiating cells' was unaffected by lL-2 in the culture medium. These results suggest that LAK cells can be generated efficien tly in seven-day marrow autograft cultures containing IL-2 under conditions that allow the most primitive human hematopoietic cells currently detectable to be maintained.

scholarly journals Antiepileptic and Antioxidant Activity of Some Medicinal Plants: A Review

2017 ◽  
Vol 9 (10) ◽  
Author(s):  
Jeenu Joseph ◽  
Lincy Joseph ◽  
Mathew George
Keyword(s):  
Medicinal Plants ◽  
Cell Activity ◽  
Acorus Calamus ◽  
Herbal Drugs ◽  
Clinical Testing ◽  
Bacopa Monniera ◽  
Ficus Religiosa ◽  
Antiepileptic Agents

Medicinal plants are the oldest form of healthcare known to mankind. Antioxidants are considered to be important in fighting against the damages done by the free radicals produced due to oxidative stress. Antiepileptic drugs help to minimize or to irradiate the convulsive shocks and seizures as a result of abnormal and excessive nerve cell activity. Standardized, well established in vitro and in vivo methods are available for experimental evaluation of antioxidant and antiepileptic agents. A step wise procedure from in vitro and in vivo seems reasonable to reduce the large quantity of potential drugs to a few promising agents for further clinical testing. This review has focused on some herbal drugs with both antioxidant and antiepileptic property such as Brassica nigra, Bacopa monniera, Ficus religiosa, Convolvulus pluricalis, Jatamansi and Acorus calamus.

scholarly journals Deletion of Jdp2 enhances Slc7a11 expression in Atoh-1 positive cerebellum granule cell progenitors in vivo

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chia-Chen Ku ◽  
Kenly Wuputra ◽  
Kohsuke Kato ◽  
Jia-Bin Pan ◽  
Chia-Pei Li ◽  
...  
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Apoptotic Cell ◽  
Redox Homeostasis ◽  
Critical Role ◽  
Glutamate Transporter ◽  
Developmental Abnormalities ◽  
Oxidative Stresses

Abstract Background The cerebellum is the sensitive region of the brain to developmental abnormalities related to the effects of oxidative stresses. Abnormal cerebellar lobe formation, found in Jun dimerization protein 2 (Jdp2)-knockout (KO) mice, is related to increased antioxidant formation and a reduction in apoptotic cell death in granule cell progenitors (GCPs). Here, we aim that Jdp2 plays a critical role of cerebellar development which is affected by the ROS regulation and redox control. Objective Jdp2-promoter-Cre transgenic mouse displayed a positive signal in the cerebellum, especially within granule cells. Jdp2-KO mice exhibited impaired development of the cerebellum compared with wild-type (WT) mice. The antioxidation controlled gene, such as cystine-glutamate transporter Slc7a11, might be critical to regulate the redox homeostasis and the development of the cerebellum. Methods We generated the Jdp2-promoter-Cre mice and Jdp2-KO mice to examine the levels of Slc7a11, ROS levels and the expressions of antioxidation related genes were examined in the mouse cerebellum using the immunohistochemistry. Results The cerebellum of Jdp2-KO mice displayed expression of the cystine-glutamate transporter Slc7a11, within the internal granule layer at postnatal day 6; in contrast, the WT cerebellum mainly displayed Sla7a11 expression in the external granule layer. Moreover, development of the cerebellar lobes in Jdp2-KO mice was altered compared with WT mice. Expression of Slc7a11, Nrf2, and p21Cip1 was higher in the cerebellum of Jdp2-KO mice than in WT mice. Conclusion Jdp2 is a critical regulator of Slc7a11 transporter during the antioxidation response, which might control the growth, apoptosis, and differentiation of GCPs in the cerebellar lobes. These observations are consistent with our previous study in vitro.

scholarly journals Stereotyped spatial patterns of functional synaptic connectivity in the cerebellar cortex

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Antoine M Valera ◽  
Francesca Binda ◽  
Sophie A Pawlowski ◽  
Jean-Luc Dupont ◽  
Jean-François Casella ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Granule Cell ◽  
Motor Coordination ◽  
Molecular Layer ◽  
Granule Cell Layer ◽  
Synaptic Organization ◽  
Cerebellar Modules ◽  
Activity Dependent

Motor coordination is supported by an array of highly organized heterogeneous modules in the cerebellum. How incoming sensorimotor information is channeled and communicated between these anatomical modules is still poorly understood. In this study, we used transgenic mice expressing GFP in specific subsets of Purkinje cells that allowed us to target a given set of cerebellar modules. Combining in vitro recordings and photostimulation, we identified stereotyped patterns of functional synaptic organization between the granule cell layer and its main targets, the Purkinje cells, Golgi cells and molecular layer interneurons. Each type of connection displayed position-specific patterns of granule cell synaptic inputs that do not strictly match with anatomical boundaries but connect distant cortical modules. Although these patterns can be adjusted by activity-dependent processes, they were found to be consistent and predictable between animals. Our results highlight the operational rules underlying communication between modules in the cerebellar cortex.

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