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1.
J Neurosci ; 2022 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-35817577

RESUMEN

Spreading depolarization (SD), usually termed cortical spreading depression has been proposed as the pathophysiological substrate of migraine aura and as an endogenous trigger of headache pain. The links between neurovascular coupling and cortical craniofacial nociceptive activities modulated by SD were assessed by combining in vivo local field potential (LFPs) recordings in the primary somatosensory cortex (S1) with functional ultrasound (fUS) imaging of S1 and caudal insular (INS) cortices of anesthetized male rats. A single SD wave triggered in the primary visual cortex elicited an ipsilateral, quadriphasic hemodynamic and electrophysiological response in S1 with an early phase consisting of concomitant increases of relative cerebral blood volume (rCBV) and LFPs. A transient hypoperfusion was then correlated with the beginning of the neuronal silence, followed by a strong increase of rCBV while synaptic activities remained inhibited.LFPs and rCBV recovery period was followed by a progressive increase in S1 and INS baseline activities and facilitation of cortical responses evoked by periorbital cutaneous receptive fields stimulation. Sensitization of cortical ophthalmic fields by SD was bilateral, occurred with precise spatiotemporal profiles and was significantly reduced by pre-treatment with a NMDA antagonist. Combined high-resolution assessing of neurovascular coupling and electrophysiological activities has revealed a useful preclinical tool for deciphering central sensitization mechanisms involved in migraine attacks.SIGNIFICANCE STATEMENTA crucial unsolved issue is whether visual aura and migraine headache are parallel or sequential processes. Here we show that a single spreading depolarization (SD) wave triggered from the primary visual cortex is powerful enough to elicit progressive, sustained increases of hemodynamic and sensory responses to percutaneous periorbital noxious stimuli recorded in S1 and Insular ophthalmic fields. Sensitization of cortical ophthalmic fields by SD was bilateral, occurred with precise spatiotemporal profiles and was significantly reduced by pre-treatment with a NMDA antagonist. Combined high-resolution assessing of neurovascular coupling and electrophysiological activities has revealed a useful preclinical tool for deciphering central sensitization mechanisms involved in migraine attacks.

2.
PLoS Biol ; 16(10): e2006229, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30278045

RESUMEN

Exposure to man-made electromagnetic fields (EMFs), which increasingly pollute our environment, have consequences for human health about which there is continuing ignorance and debate. Whereas there is considerable ongoing concern about their harmful effects, magnetic fields are at the same time being applied as therapeutic tools in regenerative medicine, oncology, orthopedics, and neurology. This paradox cannot be resolved until the cellular mechanisms underlying such effects are identified. Here, we show by biochemical and imaging experiments that exposure of mammalian cells to weak pulsed electromagnetic fields (PEMFs) stimulates rapid accumulation of reactive oxygen species (ROS), a potentially toxic metabolite with multiple roles in stress response and cellular ageing. Following exposure to PEMF, cell growth is slowed, and ROS-responsive genes are induced. These effects require the presence of cryptochrome, a putative magnetosensor that synthesizes ROS. We conclude that modulation of intracellular ROS via cryptochromes represents a general response to weak EMFs, which can account for either therapeutic or pathological effects depending on exposure. Clinically, our findings provide a rationale to optimize low field magnetic stimulation for novel therapeutic applications while warning against the possibility of harmful synergistic effects with environmental agents that further increase intracellular ROS.


Asunto(s)
Campos Electromagnéticos/efectos adversos , Campos Magnéticos/efectos adversos , Animales , Aumento de la Célula , Proliferación Celular , Criptocromos , Drosophila , Células HEK293 , Humanos , Ratones , Especies Reactivas de Oxígeno/metabolismo
3.
Entropy (Basel) ; 23(11)2021 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-34828251

RESUMEN

This work addresses brain network analysis considering different clinical severity stages of cognitive dysfunction, based on resting-state electroencephalography (EEG). We use a cohort acquired in real-life clinical conditions, which contains EEG data of subjective cognitive impairment (SCI) patients, mild cognitive impairment (MCI) patients, and Alzheimer's disease (AD) patients. We propose to exploit an epoch-based entropy measure to quantify the connectivity links in the networks. This entropy measure relies on a refined statistical modeling of EEG signals with Hidden Markov Models, which allow a better estimation of the spatiotemporal characteristics of EEG signals. We also propose to conduct a comparative study by considering three other measures largely used in the literature: phase lag index, coherence, and mutual information. We calculated such measures at different frequency bands and computed different local graph parameters considering different proportional threshold values for a binary network analysis. After applying a feature selection procedure to determine the most relevant features for classification performance with a linear Support Vector Machine algorithm, our study demonstrates the effectiveness of the statistical entropy measure for analyzing the brain network in patients with different stages of cognitive dysfunction.

4.
Cereb Cortex ; 28(11): 3994-4007, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-29040410

RESUMEN

The retinoic acid-related orphan receptor alpha (RORα) is well-known for its role in cerebellar development and maturation as revealed in staggerer mice. However, its potential involvement in the development of other brain regions has hardly been assessed. Here, we describe a new role of RORα in the development of primary somatosensory maps. Staggerer mice showed a complete disruption of barrels in the somatosensory cortex and of barreloids in the thalamus. This phenotype results from a severe reduction of thalamocortical axon (TCA) branching and a defective maturation of layer IV cortical neurons during postnatal development. Conditional deletion of RORα was conducted in the thalamus or the cortex to determine the specific contribution of RORα in each of these structures to these phenotypes. This showed that RORα is cell-autonomously required in the thalamus for the organization of TCAs into periphery-related clusters and in the somatosensory cortex for the dendritic maturation of layer IV neurons. Microarray analyses revealed that Sema7a, Neph, and Adcy8 are RORα regulated genes that could be implicated in TCA and cortical maturation. Overall, our study outlines a new role of RORα for the coordinated maturation of the somatosensory thalamus and cortex during the assembly of columnar barrel structures.


Asunto(s)
Neuronas/fisiología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/fisiología , Corteza Somatosensorial/citología , Corteza Somatosensorial/crecimiento & desarrollo , Tálamo/citología , Tálamo/crecimiento & desarrollo , Animales , Dendritas , Ratones Endogámicos C57BL , Ratones Mutantes Neurológicos , Vías Nerviosas/citología , Vías Nerviosas/crecimiento & desarrollo , Neuronas/citología
5.
Cerebellum ; 17(1): 1-3, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29349629

RESUMEN

In recent years, there has been tremendous growth in research on cerebellar motor and non-motor functions. Cerebellum is particularly involved in the spectrum of neurodevelopmental diseases. The 8th International Symposium of the Society for Research on the Cerebellum and Ataxia (SRCA) was held in Winnipeg, Manitoba, (Canada) on May 24-26, 2017. The main theme of the 8th International Symposium was "Development of the Cerebellum and Neurodevelopmental Disorders." Advances in genetics, epigenetic, cerebellar neurogenesis, axonogenesis and gliogenesis, cerebellar developmental disorders including autism spectrum disorders (ASD), neuroimaging, cerebellar ataxias, medulloblastoma, and clinical investigation of cerebellar diseases were presented. The goal of this symposium was to provide a platform to discuss cutting-edge knowledge while allowing researchers and trainees the opportunity to share and discuss their front-line research and ideas with others in the field, make connections, and strengthen international collaborations. The Ferdinando Rossi lecture was delivered by Dr. Richard Hawkes on the topic of patterning of the cerebellar cortex. This symposium emphasized the major importance of the involvement of the cerebellum in neurodevelopmental diseases from the clinical, radiological, biological, and genetic standpoint.

6.
Cerebellum ; 15(6): 755-766, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-26607150

RESUMEN

Recent studies have found that in the cerebellum, the δ2 glutamate receptor (GluRδ2) plays a key role in regulating the differentiation of parallel fiber-Purkinje synapses and mediating key physiological functions in the granule cell-Purkinje cell circuit. In the hotfoot mutant or GluRδ2 knockout mice, the absence of GluRδ2 expression results in impaired motor-related tasks, ataxia, and disruption of long-term depression at parallel fiber-Purkinje cell synapses. The goal of this study was to determine the long-term consequences of deletion of GluRδ2 expression in the hotfoot mutant (GluRδ2 ho/ho ) on Purkinje and granule cell survival and Purkinje cell dendritic differentiation. Quantitative estimates of Purkinje and granule cell numbers in 3-, 12-, and 20-month-old hotfoot mutants and wild-type controls showed that Purkinje cell numbers are within control values at 3 and 12 months in the hotfoot mutant but reduced by 20 % at 20 months compared with controls. In contrast, the number of granule cells is significantly reduced from 3 months onwards in GluRδ2 ho/ho mutant mice compared to wild-type controls. Although the overall structure of Purkinje cell dendrites does not appear to be altered, there is a significant 27 % reduction in the cross-sectional area of Purkinje cell dendritic trees in the 20-month-old GluRδ2 ho/ho mutants. The interpretation of the results is that the GluRδ2 receptor plays an important role in the long-term organization of the granule-Purkinje cell circuit through its involvement in the regulation of parallel fiber-Purkinje cell synaptogenesis and in the normal functioning of this critical cerebellar circuit.


Asunto(s)
Cerebelo/metabolismo , Cerebelo/patología , Neuronas/metabolismo , Neuronas/patología , Receptores de Glutamato/metabolismo , Envejecimiento/metabolismo , Envejecimiento/patología , Análisis de Varianza , Animales , Calbindinas/metabolismo , Recuento de Células , Muerte Celular/fisiología , Tamaño de la Célula , Supervivencia Celular/fisiología , Cerebelo/crecimiento & desarrollo , Femenino , Inmunohistoquímica , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Fotomicrografía , Receptores de Glutamato/genética
7.
J Pathol ; 237(1): 111-22, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25953430

RESUMEN

Genetic studies have added to the understanding of complex diseases. Here, we used a combined genetic approach for risk-loci identification in a prototypic, organ-specific, autoimmune disease, namely experimental epidermolysis bullosa acquisita (EBA), in which autoantibodies to type VII collagen (COL7) and neutrophil activation cause mucocutaneous blisters. Anti-COL7 IgG induced moderate blistering in most inbred mouse strains, while some showed severe disease or were completely protected. Using publicly available genotyping data, we identified haplotype blocks that control blistering and confirmed two haplotype blocks in outbred mice. To identify the blistering-associated genes, haplotype blocks encoding genes that are differentially expressed in EBA-affected skin were considered. This procedure identified nine genes, including retinoid-related orphan receptor alpha (RORα), known to be involved in neurological development and function. After anti-COL7 IgG injection, RORα+/- mice showed reduced blistering and homozygous mice were completely resistant to EBA induction. Furthermore, pharmacological RORα inhibition dose-dependently blocked reactive oxygen species (ROS) release from activated neutrophils but did not affect migration or phagocytosis. Thus, forward genomics combined with multiple validation steps identifies RORα to be essential to drive inflammation in experimental EBA.


Asunto(s)
Epidermólisis Ampollosa Adquirida/metabolismo , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Piel/metabolismo , Animales , Autoanticuerpos/inmunología , Colágeno Tipo VII/inmunología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Agonismo Parcial de Drogas , Epidermólisis Ampollosa Adquirida/genética , Epidermólisis Ampollosa Adquirida/inmunología , Epidermólisis Ampollosa Adquirida/patología , Predisposición Genética a la Enfermedad , Genómica/métodos , Haplotipos , Heterocigoto , Homocigoto , Inmunoglobulina G/inmunología , Ratones Noqueados , Activación Neutrófila , Neutrófilos/inmunología , Neutrófilos/metabolismo , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/deficiencia , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Piel/efectos de los fármacos , Piel/inmunología , Piel/patología , Especificidad de la Especie , Sulfonamidas/farmacología , Tiofenos/farmacología , Factores de Tiempo
8.
J Neurosci ; 33(22): 9546-62, 2013 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-23719821

RESUMEN

Neuronal maturation during development is a multistep process regulated by transcription factors. The transcription factor RORα (retinoic acid-related orphan receptor α) is necessary for early Purkinje cell (PC) maturation but is also expressed throughout adulthood. To identify the role of RORα in mature PCs, we used Cre-lox mouse genetic tools in vivo that delete it specifically from PCs between postnatal days 10-21. Up to 14 d of age, differences between mutant and control PCs were not detectable: both were mono-innervated by climbing fibers (CFs) extending along their well-developed dendrites with spiny branchlets. By week 4, mutant mice were ataxic, some PCs had died, and remaining PC soma and dendrites were atrophic, with almost complete disappearance of spiny branchlets. The innervation pattern of surviving RORα-deleted PCs was abnormal with several immature characteristics. Notably, multiple functional CF innervation was reestablished on these mature PCs, simultaneously with the relocation of CF contacts to the PC soma and their stem dendrite. This morphological modification of CF contacts could be induced even later, using lentivirus-mediated depletion of rora from adult PCs. These data show that the late postnatal expression of RORα cell-autonomously regulates the maintenance of PC dendritic complexity, and the CF innervation status of the PC (dendritic vs somatic contacts, and mono-innervation vs multi-innervation). Thus, the differentiation state of adult neurons is under the control of transcription factors; and in their absence, adult neurons lose their mature characteristics and acquire some characteristics of an earlier developmental stage.


Asunto(s)
Fibras Nerviosas/fisiología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/fisiología , Células de Purkinje/fisiología , Animales , Axones/fisiología , Axones/ultraestructura , Conducta Animal/fisiología , Recuento de Células , Diferenciación Celular/genética , Diferenciación Celular/fisiología , ADN/genética , Factores de Transcripción Forkhead/genética , Vectores Genéticos , Humanos , Inmunohistoquímica , Relaciones Interpersonales , Lentivirus/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica , Fuerza Muscular/genética , Fuerza Muscular/fisiología , Mutación/genética , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Reacción en Cadena de la Polimerasa , Equilibrio Postural/fisiología , Desempeño Psicomotor/fisiología , Proteínas Represoras/genética , Proteína 1 de Transporte Vesicular de Glutamato/genética , Proteína 2 de Transporte Vesicular de Glutamato/genética
9.
J Biol Chem ; 288(29): 21433-21447, 2013 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-23760501

RESUMEN

The N-acyl chain length of ceramides is determined by the specificity of different ceramide synthases (CerS). The CerS family in mammals consists of six members with different substrate specificities and expression patterns. We have generated and characterized a mouse line harboring an enzymatically inactive ceramide synthase 6 (CerS6KO) gene and lacz reporter cDNA coding for ß-galactosidase directed by the CerS6 promoter. These mice display a decrease in C16:0 containing sphingolipids. Relative to wild type tissues the amount of C16:0 containing sphingomyelin in kidney is ∼35%, whereas we find a reduction of C16:0 ceramide content in the small intestine to about 25%. The CerS6KO mice show behavioral abnormalities including a clasping abnormality of their hind limbs and a habituation deficit. LacZ reporter expression in the brain reveals CerS6 expression in hippocampus, cortex, and the Purkinje cell layer of the cerebellum. Using newly developed antibodies that specifically recognize the CerS6 protein we show that the endogenous CerS6 protein is N-glycosylated and expressed in several tissues of mice, mainly kidney, small and large intestine, and brain.


Asunto(s)
Conducta Animal , Esfingolípidos/metabolismo , Esfingosina N-Aciltransferasa/metabolismo , Animales , Ansiedad/patología , Ansiedad/fisiopatología , Encéfalo/metabolismo , Encéfalo/patología , Activación Enzimática , Pruebas de Enzimas , Conducta Exploratoria , Técnica del Anticuerpo Fluorescente , Glicosilación , Células HEK293 , Habituación Psicofisiológica , Humanos , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Glomérulos Renales/ultraestructura , Espectrometría de Masas , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Especificidad de Órganos , Fenotipo , Esfingolípidos/química , Esfingosina N-Aciltransferasa/deficiencia , beta-Galactosidasa/metabolismo
10.
Prog Neurobiol ; 232: 102560, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38097036

RESUMEN

Damaged or dysfunctional neural circuits can be replaced after a lesion by axon sprouting and collateral growth from undamaged neurons. Unfortunately, these new connections are often disorganized and rarely produce clinical improvement. Here we investigate how to promote post-lesion axonal collateral growth, while retaining correct cellular targeting. In the mouse olivocerebellar path, brain-derived neurotrophic factor (BDNF) induces correctly-targeted post-lesion cerebellar reinnervation by remaining intact inferior olivary axons (climbing fibers). In this study we identified cellular processes through which BDNF induces this repair. BDNF injection into the denervated cerebellum upregulates the transcription factor Pax3 in inferior olivary neurons and induces rapid climbing fiber sprouting. Pax3 in turn increases polysialic acid-neural cell adhesion molecule (PSA-NCAM) in the sprouting climbing fiber path, facilitating collateral outgrowth and pathfinding to reinnervate the correct targets, cerebellar Purkinje cells. BDNF-induced reinnervation can be reproduced by olivary Pax3 overexpression, and abolished by olivary Pax3 knockdown, suggesting that Pax3 promotes axon growth and guidance through upregulating PSA-NCAM, probably on the axon's growth cone. These data indicate that restricting growth-promotion to potential reinnervating afferent neurons, as opposed to stimulating the whole circuit or the injury site, allows axon growth and appropriate guidance, thus accurately rebuilding a neural circuit.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Moléculas de Adhesión de Célula Nerviosa , Animales , Ratones , Axones/fisiología , Cerebelo
11.
EClinicalMedicine ; 68: 102383, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38545090

RESUMEN

Background: SARS-CoV-2 binding to ACE2 is potentially associated with severe pneumonia due to COVID-19. The aim of the study was to test whether Mas-receptor activation by 20-hydroxyecdysone (BIO101) could restore the Renin-Angiotensin System equilibrium and limit the frequency of respiratory failure and mortality in adults hospitalized with severe COVID-19. Methods: Double-blind, randomized, placebo-controlled phase 2/3 trial. Randomization: 1:1 oral BIO101 (350 mg BID) or placebo, up to 28 days or until an endpoint was reached. Primary endpoint: mortality or respiratory failure requiring high-flow oxygen, mechanical ventilation, or extra-corporeal membrane oxygenation. Key secondary endpoint: hospital discharge following recovery (ClinicalTrials.gov Number, NCT04472728). Findings: Due to low recruitment the planned sample size of 310 was not reached and 238 patients were randomized between August 26, 2020 and March 8, 2022. In the modified ITT population (233 patients; 126 BIO101 and 107 placebo), respiratory failure or early death by day 28 was 11.4% lower in the BIO101 (13.5%) than in the placebo (24.3%) group, (p = 0.0426). At day 28, proportions of patients discharged following recovery were 80.1%, and 70.9% in the BIO101 and placebo group respectively, (adjusted difference 11.0%, 95% CI [-0.4%, 22.4%], p = 0.0586). Hazard Ratio for time to death over 90 days: 0.554 (95% CI [0.285, 1.077]), a 44.6% mortality reduction in the BIO101 group (not statistically significant). Treatment emergent adverse events of respiratory failure were more frequent in the placebo group. Interpretation: BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19. Funding: Biophytis.

12.
J Neuroinflammation ; 10: 65, 2013 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-23672668

RESUMEN

BACKGROUND: There is growing evidence that the death receptor CD95 has a wider role in non-apoptotic functions. In the brain, it may contribute to neural death and to the associated inflammatory reaction via a non-apoptotic pathway. Brain injury triggers an inflammatory reaction in which the CD95/CD95L system acts principally through peripheral cells recruited to the lesion. In cases of inflammation within the brain, with no blood-brain barrier leakage, the role of the CD95/CD95L system is thus unclear. We investigated the possible role of CD95 and CD95L in such conditions, by studying the relationships between glial cell activation, neuron death and CD95/CD95L expression in the cerebellum of the Lurcher (Grid2(Lc/+)) mutant mouse, a model of cerebellar neurodegeneration. METHODS: Glial cells in slices of wild-type and Lurcher mouse cerebella were observed by light microscopy at various ages overlapping periods of neuron loss and of pre- and post-neurodegeneration. Subcellular organization was studied by electron microscopy. We assessed CD95 levels by western blotting, RT-PCR and glial cell cultures. The levels of CD95L and IL-6 were studied by ELISA and a biological assay, respectively. RESULTS: In the Grid2(Lc/+)cerebellum, neuron loss triggers a typical, but abnormally persistent, inflammatory reaction. We identified two phases of astrogliosis: an early burst of large glial cell activation, peaking at postnatal days 25 to 26, coinciding with peak cerebellar neuron loss, followed by a long period of slow decline indicating that the strength of the glial reaction is modulated by neuron mortality rates. Comparisons of time-courses of glial cell activation, cytokine production and neuron loss revealed that the number of surviving neurons decreased as CD95 increased. Thus, CD95 cannot be directly involved in neuron death, and its role must be limited to a contribution to the inflammatory reaction. The upregulation of CD95 likely on astrocytes coincides with increases in the levels of IL-6, a cytokine produced principally by astrocytes, and soluble CD95L. CONCLUSIONS: These results suggest that CD95 and soluble CD95L contribute, via non-apoptotic signaling, to the inflammatory reaction initiated early in neuron death within the Grid2(Lc/+) cerebellum.


Asunto(s)
Cerebelo/patología , Proteína Ligando Fas/fisiología , Inmunidad Innata/fisiología , Neuronas/patología , Receptores de Glutamato/fisiología , Degeneraciones Espinocerebelosas/patología , Receptor fas/fisiología , Animales , Astrocitos/fisiología , Western Blotting , Muerte Celular/fisiología , Células Cultivadas , Citocinas/metabolismo , Femenino , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes Neurológicos , Microscopía Electrónica , Neuronas/ultraestructura , Reacción en Cadena en Tiempo Real de la Polimerasa , Degeneraciones Espinocerebelosas/genética , Degeneraciones Espinocerebelosas/inmunología
13.
Cerebellum ; 12(3): 319-21, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23325508

RESUMEN

The assembly of neural circuits involves multiple sequential steps, in particular the formation and maturation of synaptic connections. This often prolonged process involves several stages including the appropriate morphological and physiological maturation of each synaptic partner as well as their mutual interaction in order to ensure correct cellular and subcellular targeting. Understanding the processes involved becomes critical if neural circuits are to be appropriately reassembled following lesion, atrophy or neurodegeneration. We study the climbing fibre to Purkinje cell synapse as an example of a neural circuit which undergoes initial synaptic formation, selective stabilisation and elimination of redundant connections, in order to better understand the relative roles of each synaptic partner in the process of synaptogenesis and post-lesion synapse reformation. In particular, we are interested in the molecules which may underlie these processes. Here, we present data showing that the maturational state of both the target Purkinje cell and the climbing fibre axon influence their capacity for synapse formation. The climbing fibre retains some ability to recapitulate developmental processes irrespective of its maturational state. In contrast, the experience of synaptic formation and selective stabilisation/elimination permanently changes the Purkinje cell so that it cannot be repeated. Thus, if the climbing fibre-Purkinje cell synapse is recreated after the period of normal maturation, the process of synaptic competition, involving the gradual weakening of one climbing fibre synapse and stabilisation of another, no longer takes place. Moreover, we show that these processes of synaptic competition can only proceed during a specific developmental phase. To understand why these changes occur, we have investigated the role of molecules involved in the development of the olivocerebellar path and show that brain-derived neurotrophic factor, through activation of its receptor TrkB, as well as polysialated neural cell adhesion molecule and the transcription factor RORα regulate these processes.


Asunto(s)
Cerebelo/citología , Fibras Nerviosas/fisiología , Células de Purkinje/fisiología , Sinapsis/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Ácidos Siálicos/metabolismo
14.
Cerebellum ; 12(3): 377-89, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23136008

RESUMEN

Recent studies using both dissociated and organotypic cell cultures have shown that heterozygous Lurcher (Lc/+) Purkinje cells (PCs) grown in vitro share many of the same survival and morphological characteristics as Lc/+ PCs in vivo. We have used this established tissue culture system as a valuable model for studying cell death mechanisms in a relatively simple system where neurodegeneration is induced by a constitutive cation leak mediated by the Lurcher mutation in the δ2 glutamate receptor (GluRδ2). In this study, Ca(++) imaging and immunocytochemistry studies indicate that intracellular levels of Ca(++) are chronically increased in Lc/+ PCs and the concentration and/or distribution of the conventional PKCγ isoform is altered in degenerating Lc/+ PCs. To begin to characterize the molecular mechanisms that regulate Lc/+ PC death, the contributions of conventional PKC pathways and of two MAP kinase family members, JNK and p38, were examined in slice cultures from wild-type and Lc/+ mutant mouse cerebellum. Cerebellar slice cultures from P0 pups were treated with either a conventional PKC inhibitor, a JNK inhibitor, or a p38 inhibitor either from 0 to 14 or 7 to 14 DIV. Treatment with either of the three inhibitors from 0 DIV significantly increased wild type and Lc/+ PC survival through 14 DIV, but only Lc/+ PC survival was significantly increased following treatments from 7 to 14 DIV. The results suggest that multiple PC death pathways are induced by the physical trauma of making organotypic slice cultures, naturally-occurring postnatal cell death, and the GluRδ2 (Lc) mutation.


Asunto(s)
Cerebelo/citología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteína Quinasa C/metabolismo , Células de Purkinje/efectos de los fármacos , Receptores de Glutamato/genética , Transducción de Señal/efectos de los fármacos , Análisis de Varianza , Animales , Animales Recién Nacidos , Calbindinas/metabolismo , Calcio/metabolismo , Caspasa 3/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Inhibidores Enzimáticos/farmacología , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/genética , Masculino , Ratones , Ratones Endogámicos CBA , Ratones Transgénicos , Técnicas de Cultivo de Órganos , Transducción de Señal/genética
15.
J Gerontol A Biol Sci Med Sci ; 78(Suppl 1): 44-52, 2023 06 16.
Artículo en Inglés | MEDLINE | ID: mdl-37325960

RESUMEN

In recent years, several new classes of therapies have been investigated with their potential for restoring or improving physical functioning in older adults. These have included Mas receptor agonists, regulators of mitophagy, skeletal muscle troponin activators, anti-inflammatory compounds, and targets of orphan nuclear receptors. The present article summarizes recent developments of the function-promoting effects of these exciting new compounds and shares relevant preclinical and clinical data related to their safety and efficacy. The development of novel compounds in this area is expanding and likely will need the advent of a new treatment paradigm for age-associated mobility loss and disability.


Asunto(s)
Antiinflamatorios , Receptores Nucleares Huérfanos
16.
J Neurosci ; 31(40): 14314-23, 2011 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-21976517

RESUMEN

There is increasing evidence to suggest that the neuronal response to hypoxia is regulated through their interactions with astrocytes. However, the hypoxia-induced molecular mechanisms within astrocytes which influence neuronal death have yet to be characterized. In this study, we investigated the roles of the nuclear receptor RORα (retinoid-related orphan receptor-α) respectively in neurons and astrocytes during hypoxia using cultures and cocultures of neurons and astrocytes obtained from RORα-deficient mice. We found that loss of RORα function in neuronal cultures increases neuronal death after hypoxia, suggesting a cell-autonomous neuroprotective effect of RORα. Moreover, wild-type neurons cocultured with RORα-deficient astrocytes are characterized by a higher death rate after hypoxia than neurons cocultured with wild-type astrocytes, suggesting that RORα also has a non-cell-autonomous action. By using cocultures of neurons and astrocytes of different genotypes, we showed that this neuroprotective effect of RORα in astrocytes is additive to its effect in neurons, and is mediated in part by cell-to-cell interactions between neurons and astrocytes. We also found that RORα is upregulated by hypoxia in both neurons and astrocytes. Furthermore, our data showed that RORα does not alter oxidative mechanisms during hypoxia but regulates hypoxic inducible factor 1α (HIF-1α) expression, a major regulator of hypoxia sensing, in a cell-specific manner. Indeed, the neuroprotective function of RORα in astrocytes correlates with a downregulation of HIF-1α selectively in these cells. Altogether, our results show that RORα is a key molecular player in hypoxia, protecting neurons through its dual action in neurons and astrocytes.


Asunto(s)
Astrocitos/fisiología , Supervivencia Celular/fisiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Neuronas/fisiología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/fisiología , Animales , Astrocitos/metabolismo , Muerte Celular/fisiología , Hipoxia de la Célula/fisiología , Células Cultivadas , Técnicas de Cocultivo , Regulación hacia Abajo/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes Neurológicos , Neuronas/metabolismo
17.
J Neurochem ; 122(5): 1032-46, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22708926

RESUMEN

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of mice is a standard model of Parkinson's disease (PD). However, it does not reproduce functionally PD. Given the occurrence of PD during aging, symptoms might only be detected in MPTP-intoxicated mice after aging. To address this, mice injected with MPTP at 2.5 months were followed up to a maximum age of 21 months. There was no loss of dopamine cells with aging in control mice; moreover, the initial post-MPTP intoxication decrease in dopamine cell was no longer significant at 21 months. With aging, striatal dopamine level remained constant, but concentrations of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were markedly reduced in both groups. There was also a late impairment of fine motor skills. After MPTP intoxication, hyperactivity was immediately detected and it became greater than in control mice from 14 months of age; fine motor skills were also more impaired; both these symptoms were correlated with striatal dopamine, DOPAC and HVA concentrations. In bothgroups, neither motor symptoms nor dopamine changes worsened with age. These findings do not support the notion that PD develops with age in mice after MPTP intoxication and that the motor deficits seen are because of an aging process.


Asunto(s)
Envejecimiento , Conducta Animal/fisiología , Encéfalo/patología , Dopamina/metabolismo , Intoxicación por MPTP , Actividad Motora/fisiología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Factores de Edad , Envejecimiento/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Ácido Homovanílico/metabolismo , Intoxicación por MPTP/inducido químicamente , Intoxicación por MPTP/patología , Intoxicación por MPTP/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Neurotoxinas/farmacología , Prueba de Desempeño de Rotación con Aceleración Constante , Estadística como Asunto , Tirosina 3-Monooxigenasa/metabolismo
18.
Neurobiol Dis ; 46(3): 710-21, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22426389

RESUMEN

Limiting the development of secondary damage represents one of the major goals of neuroprotective therapies after spinal cord injury. Here, we demonstrate that specific JNK inhibition via a single intraperitoneal injection of the cell permeable peptide D-JNKI1 6h after lesion improves locomotor recovery assessed by both the footprint and the BMS tests up to 4 months post-injury in mice. JNK inhibition prevents c-jun phosphorylation and caspase-3 cleavage, has neuroprotective effects and results in an increased sparing of white matter at the lesion site. Lastly, D-JNKI1 treated animals show a lower increase of erythrocyte extravasation and blood brain barrier permeability, thus indicating protection of the vascular system. In total, these results clearly point out JNK inhibition as a promising neuroprotective strategy for preventing the evolution of secondary damage after spinal cord injury.


Asunto(s)
Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Locomoción/efectos de los fármacos , Fármacos Neuroprotectores , Péptidos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Recuperación de la Función/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/fisiología , Western Blotting , Caspasa 3/metabolismo , Miembro Posterior/fisiología , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Inmunohistoquímica , Inyecciones Intraperitoneales , Masculino , Ratones , Fibras Nerviosas/fisiología , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-jun/metabolismo , Serotonina/fisiología , Médula Espinal/patología , Traumatismos de la Médula Espinal/enzimología , Traumatismos de la Médula Espinal/fisiopatología
19.
Cerebellum ; 11(2): 451-2, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22223133

RESUMEN

Studies of staggerer mice, in which retinoid-related orphan receptor-alpha (RORα) is mutated, have provided new insights into the critical functions of RORα in various physiological processes in peripheral tissues and in the brain. Staggerer mice present an ataxic phenotype caused by a massive neurodegeneration in the cerebellum. As a result, most of studies have focused on the role of RORα in the development of the cerebellum. Recent studies have expanded the role of RORα to other structures and functions in the brain. RORα was considered to be exclusively expressed in neurons in the brain. Recently, it has been shown that, in addition to its neuronal expression, RORα is expressed in glial cells and particularly in astrocytes in different brain regions. Moreover, RORα has been implicated in the regulation of some astrocyte functions such as the inflammatory function. Several reports have also presented evidence for a role of RORα in diverse pathological processes including oxidative stress-induced apoptosis and cerebral hypoxia. This review therefore focuses on the emerging roles of RORα in the brain and particularly in astrocytes.


Asunto(s)
Encéfalo/crecimiento & desarrollo , Encéfalo/fisiología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/fisiología , Animales , Astrocitos/metabolismo , Humanos , Ratones , Ratones Mutantes Neurológicos , Neuronas/fisiología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/biosíntesis
20.
Proc Natl Acad Sci U S A ; 106(33): 14102-7, 2009 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-19666592

RESUMEN

During developmental synaptogenesis, the pre- and postsynaptic cells undergo specific interactions that lead to the establishment of the mature circuit. We have studied the roles of the pre- and postsynaptic cells in establishing this mature innervation by using an in vitro model of synaptic development. We describe climbing fiber (CF)-Purkinje cell (PC) synaptogenesis in cultured mouse hindbrain explants and show that synaptic competition occurs during early development in vitro. By manipulating the maturation stage of each of the synaptic partners in a coculture experimental paradigm, we found that multi-innervation does not occur when both synaptic partners are mature and have already experienced synapse elimination; in contrast, mature PCs can be multi-innervated when they have never experienced synapse elimination and/or when CFs are immature. However in these cases, the normal process of synapse elimination is impaired. These results show that CF-synapse elimination occurs only during a PC-dependant critical period and triggers indelible signals that prevent synapse competition in the mature system.


Asunto(s)
Cerebelo/metabolismo , Células de Purkinje/metabolismo , Sinapsis/fisiología , Animales , Encéfalo/metabolismo , Técnicas de Cocultivo , Electrofisiología/métodos , Proteínas Fluorescentes Verdes/metabolismo , Ratones , Modelos Biológicos , Modelos Neurológicos , Fibras Nerviosas/metabolismo , Neurogénesis , Técnicas de Placa-Clamp , Sinapsis/metabolismo , Factores de Tiempo
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