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OBJECTIVE: To compare and analyze the feasibility of autologous facet joint bone block as an alternative to polyetheretherketone (PEEK) cage in lumbar intervertebral fusion surgery for patients with osteoporosis. METHODS: From December 2018 to June 2021, the case data of patients with osteoporosis (T value ≤ -2.5 on dual energy X-ray bone density) who underwent posterior lumbar interbody fusion in the Fourth Medical Center, Chinese PLA General Hospital were retrospectively reviewed. All the cases were followed up for no less than 12 months and were divided into two groups according to the differences of interbody fusion materials: the autologous facet joint bone block group (autogenous bone group) and the PEEK cage group (PEEK group). The general data [such as age, gender, body mass index (BMI), primary diagnosis, distribution of fusion segments, bone mineral density of lumbar (BMD), incidence of preoperative complications], the perioperative data (such as duration of operation, intraoperative blood loss, postoperative drainage, perioperative allogeneic blood transfusion rate), and the incidence of postoperative complications were compared between the two groups. Imaging parameters (disc height, lumbar lordosis angle, segment lordosis angle, segmental lordosis angle, disc height improvement rate, and fusion rate) and lumbar functional scores [visual analogue scale (VAS), Oswestry disability index (ODI), Japanese Orthopedics Association (JOA) score for lower back pain] were compared to evaluate the clinical efficacy between the kinds of intervertebral fusion materials 1 week, 3 months and 6 months postoperative and at the last follow-up. RESULTS: A total of 118 patients were enrolled, including 68 cases in the autogenous bone group and 50 cases in the PEEK group, there were no statistical differences in age, gender, BMI, primary diagnosis, distribution of fusion segments, BMD, incidence of preoperative complications, duration of operation, intraoperative blood loss, postoperative drainage, perioperative allogeneic blood transfusion rate, incidence of postoperative complications, all the preoperative imaging parameters and all the lumbar function scores between the two groups (P>0.05). Postoperative superficial surgical site infections occurred in 3 patients in the autogenous bone group and 2 patients in the PEEK group. At the last follow-up, 3 cases of intervertebral graft collapse occurred in the autogenous bone group and 5 cases in the PEEK group, 1 case of graft subsidence in the autogenous bone group and 1 case in the PEEK group. All the imaging parameters showed significant differences between postoperation and preoperation (P < 0.05), and all the imaging parameters showed significant differences between 1 week and 3 months postoperative in both groups (P < 0.05). The height, angle of fusion gap in the autogenous bone group were lower than those in the PEEK group 1 week postoperatively (P < 0.05), and the fusion gap height improvement rate in the autogenous bone group was lower than that in the PEEK group (P < 0.05). The cases in both groups started to show final fusion 3 months after surgery, and the fusion rate in the autogenous bone group was 75% 6 months postoperatively, which was significantly higher than the rate of 56% in the PEEK group (P < 0.05), and there was no statistically significant difference in the final fusion rate between the two groups (P>0.05). The ODI, the postoperative VAS score was significantly lower than that in preoperation, while the postoperative JOA score was significantly higher than that in preoperation (P < 0.05). The ODI was lower while the JOA score was higher of the autogenous bone group than that of the PEEK group 6 months postoperatively (P < 0.05). CONCLUSION: In osteoporosis patients, good interbody fusion rate and improvement of lumbar vertebral function can be obtained by using autologous facet joint bone block or PEEK cage, while the fusion rate and the improvement of lumbar function with autologous facet joint bone block are better than those with PEEK cage 6 months post-operatively. PEEK cage is superior to autologous facet joint bone block in intervertebral distraction and improvement of lumbar lordosis. Significant disc space subsidence occurred in osteoporotic patients within 3 months after lumbar interbody fusion, and the subsidence of PEEK cage was more obvious than that of autologous facet joint bone block.
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Lordosis , Osteoporosis , Fusión Vertebral , Articulación Cigapofisaria , Humanos , Estudios Retrospectivos , Fusión Vertebral/métodos , Polietilenglicoles/uso terapéutico , Resultado del Tratamiento , Cetonas , Vértebras Lumbares/cirugía , Pérdida de Sangre Quirúrgica , Complicaciones Posoperatorias , Hemorragia PosoperatoriaRESUMEN
Neurodevelopmental disorders (NDDs) are a widespread and growing public health challenge, affecting as many as 17% of children in the United States. Recent epidemiological studies have implicated ambient exposure to pyrethroid pesticides during pregnancy in the risk for NDDs in the unborn child. Using a litter-based, independent discovery-replication cohort design, we exposed mouse dams orally during pregnancy and lactation to the Environmental Protection Agency's reference pyrethroid, deltamethrin, at 3â mg/kg, a concentration well below the benchmark dose used for regulatory guidance. The resulting offspring were tested using behavioral and molecular methods targeting behavioral phenotypes relevant to autism and NDD, as well as changes to the striatal dopamine system. Low-dose developmental exposure to the pyrethroid deltamethrin (DPE) decreased pup vocalizations, increased repetitive behaviors, and impaired both fear conditioning and operant conditioning. Compared with control mice, DPE mice had greater total striatal dopamine, dopamine metabolites, and stimulated dopamine release, but no difference in vesicular dopamine capacity or protein markers of dopamine vesicles. Dopamine transporter protein levels were increased in DPE mice, but not temporal dopamine reuptake. Striatal medium spiny neurons showed changes in electrophysiological properties consistent with a compensatory decrease in neuronal excitability. Combined with previous findings, these results implicate DPE as a direct cause of an NDD-relevant behavioral phenotype and striatal dopamine dysfunction in mice and implicate the cytosolic compartment as the location of excess striatal dopamine.
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Ghrelin is a circulating orexigenic hormone that promotes feeding behavior and regulates metabolism in humans and rodents. We previously reported that local infusion of ghrelin into the basolateral amygdala (BLA) blocked memory acquisition for conditioned taste aversion (CTA) by activating growth hormone secretagogue receptor 1a. In this study, we further explored the underlying mechanism and signaling pathways mediating ghrelin modulation of CTA memory in rats. Pharmacological agents targeting distinct signaling pathways were infused into the BLA during conditioning. We showed that preadministration of the PI3K inhibitor LY294002 abolished the repressive effect of ghrelin on CTA memory. Moreover, LY294002 pretreatment prevented ghrelin from inhibiting Arc and zif268 mRNA expression in the BLA triggered by CTA memory retrieval. Preadministration of rapamycin eliminated the repressive effect of ghrelin, while Gsk3 inhibitors failed to mimic ghrelin's effect. In addition, PLC and PKC inhibitors microinfused in the BLA blocked ghrelin's repression of CTA acquisition. These results demonstrate that ghrelin signaling in the BLA shapes CTA memory via the PI3K/Akt/mTOR and PLC/PKC pathways. We conducted in vivo multichannel recordings from mouse BLA neurons and found that microinjection of ghrelin (20 µM) suppressed intrinsic excitability. By means of whole-cell recordings from rat brain slices, we showed that bath application of ghrelin (200 nM) had no effect on basal synaptic transmission or synaptic plasticity of BLA pyramidal neurons. Together, this study reveals the mechanism underlying ghrelin-induced interference with CTA memory acquisition in rats, i.e., suppression of intrinsic excitability of BLA principal neurons via the PI3K/Akt/mTOR and PLC/PKC pathways.
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Complejo Nuclear Basolateral , Amígdala del Cerebelo/fisiología , Animales , Reacción de Prevención , Complejo Nuclear Basolateral/fisiología , Conducta Alimentaria , Ghrelina/farmacología , Ghrelina/fisiología , Glucógeno Sintasa Quinasa 3/farmacología , Humanos , Ratones , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Ratas , Transducción de Señal , Serina-Treonina Quinasas TOR , Fosfolipasas de Tipo C/metabolismoRESUMEN
Social relationships are dynamic and evolve with shared and personal experiences. Whether the functional role of social neuromodulators also evolves with experience to shape the trajectory of relationships is unknown. We utilized pair bonding in the socially monogamous prairie vole as an example of socio-sexual experience that dramatically alters behaviors displayed toward other individuals. We investigated oxytocin-dependent modulation of excitatory synaptic transmission in the nucleus accumbens as a function of pair-bonding status. We found that an oxytocin receptor agonist decreases the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in sexually naive virgin, but not pair-bonded, female voles, while it increases the amplitude of electrically evoked EPSCs in paired voles, but not in virgins. This oxytocin-induced potentiation of synaptic transmission relies on the de novo coupling between oxytocin receptor signaling and endocannabinoid receptor type 1 (CB1) receptor signaling in pair-bonded voles. Blocking CB1 receptors after pair-bond formation increases the occurrence of a specific form of social rejection-defensive upright response-that is displayed toward the partner, but not toward a novel individual. Altogether, our results demonstrate that oxytocin's action in the nucleus accumbens is changed through social experience in a way that regulates the trajectory of social interactions as the relationship with the partner unfolds, potentially promoting the maintenance of a pair bond by inhibiting aggressive responses. These results provide a mechanism by which social experience and context shift oxytocinergic signaling to impact neural and behavioral responses to social cues.
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Núcleo Accumbens , Receptores de Oxitocina , Animales , Arvicolinae/metabolismo , Femenino , Pradera , Humanos , Núcleo Accumbens/metabolismo , Oxitocina/farmacología , Apareamiento , Receptores de Oxitocina/metabolismo , Conducta SocialRESUMEN
Endothelial progenitor cells (EPCs) are immature endothelial cells (ECs) capable of proliferating and differentiating into mature ECs. These progenitor cells migrate from bone marrow (BM) after vascular injury to ischemic areas, where they participate in the repair of injured endothelium and new blood vessel formation. EPCs also secrete a series of protective cytokines and growth factors that support cell survival and tissue regeneration. Thus, EPCs provide novel and promising potential therapies to treat vascular disease, including ischemic stroke. However, EPCs are tightly regulated during the process of vascular repair and regeneration by numerous endogenous cytokines that are associated closely with the therapeutic efficacy of the progenitor cells. The regenerative capacity of EPCs also is affected by a range of exogenous factors and drugs as well as vascular risk factors. Understanding the functional properties of EPCs and the factors related to their regenerative capacity will facilitate better use of these progenitor cells in treating vascular disease. Here, we review the current knowledge of EPCs in cerebral neovascularization and tissue regeneration after cerebral ischemia and the factors associated with their regenerative function to better understand the underlying mechanisms and provide more effective strategies for the use of EPCs in treating ischemic stroke.
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Isquemia Encefálica , Células Progenitoras Endoteliales , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Isquemia Encefálica/terapia , Humanos , Neovascularización Patológica , Neovascularización Fisiológica , Accidente Cerebrovascular/terapiaRESUMEN
Soluble amyloid ß (Aß)-induced synaptic dysfunction is an early event in the pathogenesis of Alzheimer's disease (AD) that precedes the deposition of insoluble Aß and correlates with the development of cognitive deficits better than the number of plaques. The mammalian plasminogen activation (PA) system catalyzes the generation of plasmin via two activators: tissue-type (tPA) and urokinase-type (uPA). A dysfunctional tPA-plasmin system causes defective proteolytic degradation of Aß plaques in advanced stages of AD. In contrast, it is unknown whether uPA and its receptor (uPAR) contribute to the pathogenesis of this disease. Neuronal cadherin (NCAD) plays a pivotal role in the formation of synapses and dendritic branches, and Aß decreases its expression in cerebral cortical neurons. Here we show that neuronal uPA protects the synapse from the harmful effects of soluble Aß. However, Aß-induced inactivation of the eukaryotic initiation factor 2α halts the transcription of uPA mRNA, leaving unopposed the deleterious effects of Aß on the synapse. In line with these observations, the synaptic abundance of uPA, but not uPAR, is decreased in the frontal cortex of AD patients and 5xFAD mice, and in cerebral cortical neurons incubated with soluble Aß. We found that uPA treatment increases the synaptic expression of NCAD by a uPAR-mediated plasmin-independent mechanism, and that uPA-induced formation of NCAD dimers protects the synapse from the harmful effects of soluble Aß oligomers. These data indicate that Aß-induced decrease in the synaptic abundance of uPA contributes to the development of synaptic damage in the early stages of AD.SIGNIFICANCE STATEMENT Soluble amyloid ß (Aß)-induced synaptic dysfunction is an early event in the pathogenesis of cognitive deficits in Alzheimer's disease (AD). We found that neuronal urokinase-type (uPA) protects the synapse from the deleterious effects of soluble Aß. However, Aß-induced inactivation of the eukaryotic initiation factor 2α decreases the synaptic abundance of uPA, leaving unopposed the harmful effects of Aß on the synapse. In line with these observations, the synaptic expression of uPA is decreased in the frontal cortex of AD brains and 5xFAD mice, and uPA treatment abrogates the deleterious effects of Aß on the synapse. These results unveil a novel mechanism of Aß-induced synaptic dysfunction in AD patients, and indicate that recombinant uPA is a potential therapeutic strategy to protect the synapse before the development of irreversible brain damage.
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Péptidos beta-Amiloides/farmacología , Corteza Cerebral/efectos de los fármacos , Neuronas/efectos de los fármacos , Sinapsis/efectos de los fármacos , Activador de Plasminógeno de Tipo Uroquinasa/genética , Activador de Plasminógeno de Tipo Uroquinasa/farmacología , Animales , Células Cultivadas , Corteza Cerebral/metabolismo , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismoRESUMEN
Oxidative stress is increasingly recognized as a central event contributing to the degeneration of dopaminergic neurons in the pathogenesis of Parkinson's disease (PD). Although reactive oxygen species (ROS) production is implicated as a causative factor in PD, the cellular and molecular mechanisms linking oxidative stress with dopaminergic neuron death are complex and not well characterized. The primary insults cause the greatest production of ROS, which contributes to oxidative damage by attacking all macromolecules, including lipids, proteins and nucleic acids, leading to defects in their physiological function. Consequently, the defects in these macromolecules result in mitochondrial dysfunction and neuroinflammation, which subsequently enhance the production of ROS and ultimately neuronal damage. The interaction between these various mechanisms forms a positive feedback loop that drives the progressive loss of dopaminergic neurons in PD, and oxidative stressmediated neuron damage appears to serve a central role in the neurodegenerative process. Thus, understanding the cellular and molecular mechanisms by which oxidative stress contributes to the loss of dopaminergic neurons may provide a promising therapeutic approach in PD treatment.
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Neuronas Dopaminérgicas/patología , Mitocondrias/patología , Estrés Oxidativo , Enfermedad de Parkinson/patología , Animales , Muerte Celular , Neuronas Dopaminérgicas/metabolismo , Humanos , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Enfermedad de Parkinson/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The basolateral amygdala (BLA) is a key site for crossmodal association of sensory stimuli and an important relay in the neural circuitry of emotion. Indeed, the BLA receives substantial glutamatergic inputs from multiple brain regions including the prefrontal cortex and thalamic nuclei. Modulation of glutamatergic transmission in the BLA regulates stress- and anxiety-related behaviors. Serotonin (5-HT) also plays an important role in regulating stress-related behavior through activation of both pre- and postsynaptic 5-HT receptors. Multiple 5-HT receptors are expressed in the BLA, where 5-HT has been reported to modulate glutamatergic transmission. However, the 5-HT receptor subtype mediating this effect is not yet clear. The aim of this study was to use patch-clamp recordings from BLA neurons in an ex vivo slice preparation to examine 1) the effect of 5-HT on extrinsic sensory inputs, and 2) to determine if any pathway specificity exists in 5-HT regulation of glutamatergic transmission. Two independent input pathways into the BLA were stimulated: the external capsule to mimic cortical input, and the internal capsule to mimic thalamic input. Bath application of 5-HT reversibly reduced the amplitude of evoked excitatory postsynaptic currents (eEPSCs) induced by stimulation of both pathways. The decrease was associated with an increase in the paired-pulse ratio and coefficient of variation of eEPSC amplitude, suggesting 5-HT acts presynaptically. Moreover, the effect of 5-HT in both pathways was mimicked by the selective 5-HT1B receptor agonist CP93129, but not by the 5-HT1A receptor agonist 8-OH DPAT. Similarly the effect of exogenous 5-HT was blocked by the 5-HT1B receptor antagonist GR55562, but not affected by the 5-HT1A receptor antagonist WAY 100635 or the 5-HT2 receptor antagonists pirenperone and MDL 100907. Together these data suggest 5-HT gates cortical and thalamic glutamatergic inputs into the BLA by activating presynaptic 5-HT1B receptors.
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Complejo Nuclear Basolateral/fisiología , Corteza Cerebral/fisiología , Ácido Glutámico/fisiología , Neuronas/fisiología , Serotonina/fisiología , Tálamo/fisiología , Animales , Benzamidas/administración & dosificación , Potenciales Postsinápticos Excitadores , Cápsula Externa/fisiología , Cápsula Interna/fisiología , Masculino , Vías Nerviosas/fisiología , Piridinas/administración & dosificación , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1B/fisiología , Antagonistas del Receptor de Serotonina 5-HT1RESUMEN
Recently we determined that activation of the tachykinin 2 (Tac2) pathway in the central amygdala (CeA) is necessary and sufficient for the modulation of fear memories. The Tac2 pathway includes the Tac2 gene, which encodes the neuropeptide neurokinin B and its corresponding receptor neurokinin 3 receptor (NK3R). In this study, using Tac2-cre and Tac2-GFP mice, we applied a combination of in vivo (optogenetics) and multiple in vitro techniques to further explore the mechanisms of action within the Tac2 pathway. In transgenic mice that express ChR2 solely in Tac2 neurons, in vivo optogenetic stimulation of CeA Tac2-expressing neurons during fear acquisition enhanced fear memory consolidation and drove action potential firing in vitro. In addition, Tac2-CeA neurons were shown to co-express striatal-enriched protein tyrosine phosphatase, which may have an important role in regulating Nk3R signaling during fear conditioning. These data extend our current understanding for the underlying mechanism(s) for the role of the Tac2 pathway in the regulation of fear memory, which may serve as a new therapeutic target in the treatment of fear-related disorders.
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Amígdala del Cerebelo/fisiología , Miedo , Aprendizaje/fisiología , Precursores de Proteínas/genética , Transducción de Señal/genética , Taquicininas/genética , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Amígdala del Cerebelo/efectos de los fármacos , Animales , Antipsicóticos/farmacología , Channelrhodopsins , Condicionamiento Clásico/fisiología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Locomoción/genética , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Organofosfatos/metabolismo , Piperidinas/farmacología , Polímeros/metabolismo , Proteína Quinasa C-delta/metabolismo , Precursores de Proteínas/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/genética , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Receptores de Neuroquinina-3/genética , Receptores de Neuroquinina-3/metabolismo , Taquicininas/metabolismoRESUMEN
OBJECTIVE: To evaluate the preliminary curative effect of interspinous injections for the diagnosis and treatment of back pain caused by lumbar kissing spine (Baastrup's disease) under fluoroscopically guiding. METHODS: From November 2011 to March 2013,17 patients with back pain caused by Baastrup's disease were treated with fluoroscopically-guided interspinous injections, including 7 males and 10 females with an average age of 49.6 years old ranging from 40 to 71 years old; the duration of the disease ranged from 2 to 5 years with a mean of 3.7 years. The visual analogue scale (VAS) and the lumbar segments range of motion (ROM) was analyzed at pre-operation, 2 days, 3 months and final followed-up after operation, the effects were evaluated with modified Macnab standard. RESULTS: All patients were follow-up from 6 to 10 months with an average of 7.6 months. The pre-operative VAS was 6.41 +/- 0.94, the postoperative VAS at different time points improved significantly comparing with pre-operation,and the differences were statistically significant (P < 0.01). There was no significant difference in VAS at different time points after operation (P > 0.05). The ROM of operated segment and adjacent segment was (4.88 +/- 0.86) degrees and (6.82 +/- 0.73) degrees respectively at pre-operation. The postoperative operated segment ROM at different time points improved significantly comparing with pre-operation, and the differences were statistically significant (P < 0.05). Compared with pre-operation, there was no significant difference in adjacent segment ROM at different time points after operation (P > 0.05). According to modified Macnab, the result was excellent in 6 cases, good in 7 cases, fair in 3 cases and poor in 1 case. CONCLUSION: Fluoroscopically-guided interspinous injections is an effective method for the diagnosis and treatment of Baastrup's disease. The method has advantages of simple operation, minimal invasion and safety, satisfactory short-term and medium-term therapeutic effect; it can also effectively lessen the pain of lumbar and back.
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Anestésicos Locales/administración & dosificación , Dolor de la Región Lumbar/tratamiento farmacológico , Vértebras Lumbares/efectos de los fármacos , Enfermedades de la Columna Vertebral/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Dolor de la Región Lumbar/diagnóstico , Dolor de la Región Lumbar/diagnóstico por imagen , Vértebras Lumbares/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Bloqueo Nervioso , Enfermedades de la Columna Vertebral/diagnóstico , Enfermedades de la Columna Vertebral/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
Spinal cord injury (SCI) results in a loss of normal motor and sensory function, leading to severe disability and reduced quality of life. The aim of this work was to investigate the effect of receptor for advanced glycation end products (RAGE) deficiency on the function recovery in a mouse model of SCI. Mice received a mid-thoracic spinal contusion injury. Upregulation of RAGE protein expression in spinal cord tissue was evident at 12 h after SCI and continued at 2 and 5 days. Furthermore, we showed that locomotor recovery was improved and lesion pathology was reduced after SCI in RAGE-deficient mice. RAGE deficiency in mice attenuated apoptosis after SCI through inhibiting p53/Bax/caspase-3 pathway. RAGE deficiency in mice inhibited inflammation after SCI, marked by reduced myeloperoxidase activity, NFκB nuclear translocation, and TNF-α, IL-1ß, and IL-6 mRNA and protein levels. RAGE deficiency in mice exposed to SCI suppressed the upregulation of inducible nitric oxide synthase (iNOS) and gp91-phox and attenuated oxidative and nitrosative stresses, marked by reduced formation of malondialdehyde, reactive oxygen species, peroxynitrite (OONO(-)), and 3-nitrotyrosine. RAGE deficiency in mice exposed to SCI attenuated glial scar at the injury site, marked by decreased expression of glial fibrillary acidic protein. These data indicate that the RAGE plays an important role in the development of SCI and might provide a therapeutic target to promote recovery from SCI.
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Regulación de la Expresión Génica/genética , Inflamación/genética , Estrés Oxidativo/genética , Receptores Inmunológicos/biosíntesis , Traumatismos de la Médula Espinal/genética , Animales , Caspasa 3/metabolismo , Modelos Animales de Enfermedad , Humanos , Inflamación/patología , Interleucina-6/metabolismo , Ratones , Óxido Nítrico Sintasa de Tipo II/genética , Especies Reactivas de Oxígeno/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Recuperación de la Función , Traumatismos de la Médula Espinal/patologíaRESUMEN
Regulation of BNSTALG neuronal firing activity is tightly regulated by the opposing actions of the fast outward potassium current, IA , mediated by α subunits of the Kv4 family of ion channels, and the transient inward calcium current, IT . Together, these channels play a critical role in regulating the latency to action potential onset, duration, and frequency, as well as dendritic back-propagation and synaptic plasticity. Previously we have shown that Type I-III BNSTALG neurons express mRNA transcripts for each of the Kv4 α subunits. However, the biophysical properties of native IA channels are critically dependent on the formation of macromolecular complexes of Kv4 channels with a family of chaperone proteins, the potassium channel-interacting proteins (KChIP1-4). Here we used a multidisciplinary approach to investigate the expression and function of Kv4 channels and KChIPs in neurons of the rat BNSTALG . Using immunofluorescence we demonstrated the pattern of localization of Kv4.2, Kv4.3, and KChIP1-4 proteins in the BNSTALG . Moreover, our single-cell reverse-transcription polymerase chain reaction (scRT-PCR) studies revealed that mRNA transcripts for Kv4.2, Kv4.3, and all four KChIPs were differentially expressed in Type I-III BNSTALG neurons. Furthermore, immunoelectron microscopy revealed that Kv4.2 and Kv4.3 channels were primarily localized to the dendrites and spines of BNSTALG neurons, and are thus ideally situated to modulate synaptic transmission. Consistent with this observation, in vitro patch clamp recordings showed that reducing postsynaptic IA in these neurons lowered the threshold for long-term potentiation (LTP) induction. These results are discussed in relation to potential modulation of IA channels by chronic stress.
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Proteínas de Interacción con los Canales Kv/metabolismo , Neuronas/metabolismo , Núcleos Septales/anatomía & histología , Núcleos Septales/metabolismo , Canales de Potasio Shal/metabolismo , 4-Aminopiridina/farmacología , Análisis de Varianza , Animales , Biofisica , Estimulación Eléctrica , Técnicas In Vitro , Proteínas de Interacción con los Canales Kv/genética , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Microscopía Inmunoelectrónica , Neuronas/clasificación , Neuronas/efectos de los fármacos , Neuronas/ultraestructura , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , ARN Mensajero , Ratas , Ratas Sprague-Dawley , Canales de Potasio Shal/genética , Fracciones Subcelulares/metabolismo , Fracciones Subcelulares/ultraestructuraRESUMEN
Corticotrophin-releasing factor (CRF) plays a key role in initiating many of the endocrine, autonomic, and behavioral responses to stress. CRF-containing neurons of the paraventricular nucleus of the hypothalamus (PVN) are classically involved in regulating endocrine function through activation of the stress axis. However, CRF is also thought to play a critical role in mediating anxiety-like responses to environmental stressors, and dysfunction of the CRF system in extra-hypothalamic brain regions, like the bed nucleus of stria terminalis (BNST), has been linked to the etiology of many psychiatric disorders including anxiety and depression. Thus, although CRF neurons of the PVN and BNST share a common neuropeptide phenotype, they may represent two functionally diverse neuronal populations. Here, we employed dual-immunofluorescence, single-cell RT-PCR, and electrophysiological techniques to further examine this question and report that CRF neurons of the PVN and BNST are fundamentally different such that PVN CRF neurons are glutamatergic, whereas BNST CRF neurons are GABAergic. Moreover, these two neuronal populations can be further distinguished based on their electrophysiological properties, their co-expression of peptide neurotransmitters such as oxytocin and arginine-vasopressin, and their cognate receptors. Our results suggest that CRF neurons in the PVN and the BNST would not only differ in their response to local neurotransmitter release, but also in their action on downstream target structures.
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BACKGROUND: Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific protein tyrosine phosphatase that opposes the development of synaptic strengthening and the consolidation of fear memories. In contrast, stress facilitates fear memory formation, potentially by activating corticotrophin releasing factor (CRF) neurons in the anterolateral cell group of the bed nucleus of the stria terminalis (BNSTALG). METHODS: Here, using dual-immunofluorescence, single-cell reverse transcriptase polymerase chain reaction, quantitative reverse transcriptase polymerase chain reaction, Western blot, and whole-cell patch-clamp electrophysiology, we examined the expression and role of STEP in regulating synaptic plasticity in rat BNSTALG neurons and its modulation by stress. RESULTS: Striatal-enriched protein tyrosine phosphatase was selectively expressed in CRF neurons in the oval nucleus of the BNSTALG. Following repeated restraint stress (RRS), animals displayed a significant increase in anxiety-like behavior, which was associated with a downregulation of STEP messenger RNA and protein expression in the BNSTALG, as well as selectively enhancing the magnitude of long-term potentiation (LTP) induced in Type III, putative CRF neurons. To determine if the changes in STEP expression following RRS were mechanistically related to LTP facilitation, we examined the effects of intracellular application of STEP on the induction of LTP. STEP completely blocked the RRS-induced facilitation of LTP in BNSTALG neurons. CONCLUSIONS: Hence, STEP acts to buffer CRF neurons against excessive activation, while downregulation of STEP after chronic stress may result in pathologic activation of CRF neurons in the BNSTALG and contribute to prolonged states of anxiety. Thus, targeted manipulations of STEP activity might represent a novel treatment strategy for stress-induced anxiety disorders.
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Hormona Liberadora de Corticotropina/metabolismo , Neuronas/enzimología , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Núcleos Septales/enzimología , Estrés Fisiológico , Animales , Masculino , Proteínas Tirosina Fosfatasas no Receptoras/fisiología , Ratas , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
BACKGROUND AND PURPOSE: Sublesional osteoporosis predisposes individuals with spinal cord injury (SCI) to an increased risk of low-trauma fracture. The aim of the present work was to investigate the effect of treatment with resveratrol (RES) on sublesional bone loss in spinal cord-injured rats. EXPERIMENTAL APPROACH: Complete SCI was generated by surgical transaction of the cord at the T10-12 level. Treatment with RES (400 mg·kg(-1) body mass per day(-1) , intragastrically) was initiated 12 h after the surgery for 10 days. Then, blood was collected and femurs and tibiae were removed for evaluation of the effects of RES on bone tissue after SCI. KEY RESULTS: Treatment of SCI rats with RES prevented the reduction of bone mass including bone mineral content and bone mineral density in tibiae, preserved bone structure including trabecular bone volume fraction, trabecular number, and trabecular thickness in tibiae, and preserved mechanical strength including ultimate load, stiffness, and energy in femurs. Treatment of SCI rats with RES enhanced femoral total sulfhydryl content, reduced femoral malondialdehyde and IL-6 mRNA levels. Treatment of SCI rats with RES suppressed the up-regulation of mRNA levels of PPARγ, adipose-specific fatty-acid-binding protein and lipoprotein lipase, and restored mRNA levels of Wnt1, low-density lipoprotein-related protein 5, Axin2, ctnnb1, insulin-like growth factor 1 (IGF-1) and receptor for IGF-1 in femurs and tibiae. CONCLUSIONS AND IMPLICATIONS: Treatment with RES attenuated sublesional bone loss in spinal-cord-injured rats, associated with abating oxidative stress, attenuating inflammation, depressing PPARγ signalling, and restoring Wnt/ß-catenin and IGF-1 signalling.
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Conservadores de la Densidad Ósea/farmacología , Fémur/efectos de los fármacos , Osteoporosis/prevención & control , Traumatismos de la Médula Espinal/tratamiento farmacológico , Estilbenos/farmacología , Tibia/efectos de los fármacos , Animales , Densidad Ósea/efectos de los fármacos , Modelos Animales de Enfermedad , Fémur/diagnóstico por imagen , Fémur/metabolismo , Regulación de la Expresión Génica , Mediadores de Inflamación/metabolismo , Masculino , Malondialdehído/metabolismo , Osteoporosis/diagnóstico por imagen , Osteoporosis/etiología , Osteoporosis/genética , Osteoporosis/metabolismo , Estrés Oxidativo/efectos de los fármacos , ARN Mensajero/metabolismo , Radiografía , Ratas , Ratas Sprague-Dawley , Resveratrol , Transducción de Señal/efectos de los fármacos , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/diagnóstico por imagen , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/metabolismo , Compuestos de Sulfhidrilo/metabolismo , Tibia/diagnóstico por imagen , Tibia/metabolismoRESUMEN
Many psychiatric disorders, including anxiety and autism spectrum disorders, have early ages of onset and high incidence in juveniles. To better treat and prevent these disorders, it is important to first understand normal development of brain circuits that process emotion. Healthy and maladaptive emotional processing involve the basolateral amygdala (BLA), dysfunction of which has been implicated in numerous psychiatric disorders. Normal function of the adult BLA relies on a fine balance of glutamatergic excitation and GABAergic inhibition. Elsewhere in the brain GABAergic transmission changes throughout development, but little is known about the maturation of GABAergic transmission in the BLA. Here we used whole cell patch-clamp recording and single-cell RT-PCR to study GABAergic transmission in rat BLA principal neurons at postnatal day (P)7, P14, P21, P28, and P35. GABAA currents exhibited a significant twofold reduction in rise time and nearly 25% reduction in decay time constant between P7 and P28. This corresponded with a shift in expression of GABAA receptor subunit mRNA from the α2- to the α1-subunit. The reversal potential for GABAA receptors transitioned from depolarizing to hyperpolarizing with age, from around -55 mV at P7 to -70 mV by P21. There was a corresponding shift in expression of opposing chloride pumps that influence the reversal, from NKCC1 to KCC2. Finally, we observed short-term depression of GABAA postsynaptic currents in immature neurons that was significantly and gradually abolished by P28. These findings reveal that in the developing BLA GABAergic transmission is highly dynamic, reaching maturity at the end of the first postnatal month.
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Amígdala del Cerebelo/crecimiento & desarrollo , Potenciales Postsinápticos Inhibidores , Neuronas/fisiología , Receptores de GABA-A/metabolismo , Ácido gamma-Aminobutírico/fisiología , Amígdala del Cerebelo/fisiología , Animales , Femenino , Técnicas In Vitro , Masculino , Plasticidad Neuronal , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: To investigate retrospectively the clinical effects and recurrence rate of 143 cases who underwent one level discectomy and followed up more than 10 years. To evaluate the outcome of patients in groups of different operating age and extents of disc herniation, and analyse whether difference exists in each group. METHODS: There were 143 patients (operation time from January 1996 to December 2000) including 80 males and 63 females, aged from 18 to 66 years old with an average of 37.85 years. The followed-up time was 10 to 15 years with an average of 12.7 years. Patients were divided into 3 groups depends on operating age: < 30 years old, 30 to 50 years old and > 50 years old; 87 patients who's pre-operative CT scan could be collected among 143 cases were divided into 3 groups depends on extents of disc herniation: I degree, II degrees, and III degrees. The final followed-up was obtained in 2011, to evaluate each group and the holistic clincal outcome with JOA scores and ODI scores, and observe whether there were difference between every groups; to judge the effects by patient himself with modified Macnab Criteria. RESULTS: (1) JOA scores pre-operation and final followed-up was 5.11 +/- 2.02 and 12.51 +/- 2.35 respectively; ODI scores pre-operation and final followed-up was 33.98 +/- 7.42 and 13.39 +/- 6.79 respectively. There were significant differences between pre-operative and final followed-up in JOA and ODI (P < 0.01). The excellent-good rate was 83.2% (119/143 ) according to modified Macnab Classification with recurrence rate of 6.3% at final follow-up. (2) Obvious difference was found in JOA scores in group who's age at operation less than 30 years old compared with other 2 groups at followed-up time, and no significant difference was found in JOA scores between other two groups ; no significant difference was found in ODI scores among the three groups. (3) Significant difference was found in JOA and ODI scores in group with III degrees lumbar disc herniation group compared with other 2 groups, and no statistical difference was found in clincal scores between other 2 groups. CONCLUSION: (1) Long-term followed-up of 143 cases prove mono-level lumbar discectomy is an option for disc herniation with good curative effect and lower recurrent rate, the technique should be the prior selection in dealing with patients with lumbar disc herniation. (2) 51% patients (19/37) in group under 30 years old endure persistent low back pain. (3) The long-term clinical effects in patients with severe disc protrution who underwent lumbar discectomy is worse than those patients with mild lumbar disc herniation.
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Desplazamiento del Disco Intervertebral/cirugía , Disco Intervertebral/cirugía , Laminectomía/métodos , Vértebras Lumbares/cirugía , Adolescente , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND AND PURPOSE: Accumulating evidence indicates an important role of oxidative stress in the progression of osteoporosis. Recently, it was demonstrated that hydrogen gas, as a novel antioxidant, could selectively reduce hydroxyl radicals and peroxynitrite anion to exert potent therapeutic antioxidant activity. The aim of the present work was to investigate the effect of hydrogen water (HW) consumption on ovariectomy-induced osteoporosis. EXPERIMENTAL APPROACH: Ovariectomized rats were fed with HW (1.3 ± 0.2 mg·L⻹) for 3 months. Then, blood was collected and femur and vertebrae were removed for evaluation of the effect of HW on bone. KEY RESULTS: HW consumption in ovariectomized rats had no significant effect on oestrogen production, but prevented the reduction of bone mass including bone mineral content and bone mineral density in femur and vertebrae, and preserved mechanical strength including ultimate load, stiffness, and energy, and bone structure including trabecular bone volume fraction, trabecular number, and trabecular thickness in femur, and preserved mechanical strength including ultimate load and stiffness, and bone structure including trabecular bone volume fraction and trabecular number in vertebrae. In addition, treatment with HW abated oxidative stress and suppressed IL-6 and TNF-α mRNA expressions in femur of ovariectomized rats; treatment with HW increased femur endothelial NOS activity and enhanced circulating NO level in ovariectomized rats. CONCLUSIONS AND IMPLICATIONS: HW consumption prevents osteopenia in ovariectomized rats possibly through the ablation of oxidative stress induced by oestrogen withdrawal.
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Antioxidantes/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Enfermedades Óseas Metabólicas/prevención & control , Huesos/química , Hidrógeno/uso terapéutico , Estrés Oxidativo , Animales , Densidad Ósea , Enfermedades Óseas Metabólicas/etiología , Enfermedades Óseas Metabólicas/metabolismo , Enfermedades Óseas Metabólicas/patología , Huesos/metabolismo , Huesos/patología , Fenómenos Químicos , Femenino , Regulación de la Expresión Génica , Interleucina-6/antagonistas & inhibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Fenómenos Mecánicos , Óxido Nítrico/sangre , Óxido Nítrico Sintasa de Tipo III/biosíntesis , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ovariectomía/efectos adversos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Transcripción ReIA/antagonistas & inhibidores , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismoRESUMEN
Corticotropin-releasing factor (CRF) is critical for the endocrine, autonomic, and behavioral responses to stressors, and it has been shown to modulate fear and anxiety. The CRF receptor is widely expressed across a variety of cell types, impeding progress toward understanding the contribution of specific CRF-containing neurons to fear dysregulation. We used a unique CRF-Cre driver transgenic mouse line to remove floxed GABA(A)α1 subunits specifically from CRF neurons [CRF-GABA(A)α1 KO]. This process resulted in mice with decreased GABA(A)α1 expression only in CRF neurons and increased CRF mRNA within the amygdala, bed nucleus of the stria terminalis (BNST) and paraventricular nucleus of the hypothalamus. These mice show normal locomotor and pain responses and no difference in depressive-like behavior or Pavlovian fear conditioning. However, CRF-GABA(A)α1 KO increased anxiety-like behavior and impaired extinction of conditioned fear, coincident with an increase in plasma corticosterone concentration. These behavioral impairments were rescued with systemic or BNST infusion of the CRF antagonist R121919. Infusion of Zolpidem, a GABA(A)α1-preferring benzodiazepine-site agonist, into the BNST of the CRF-GABA(A)α1 KO was ineffective at decreasing anxiety. Electrophysiological findings suggest a disruption in inhibitory current may play a role in these changes. These data indicate that disturbance of CRF containing GABA(A)α1 neurons causes increased anxiety and impaired fear extinction, both of which are symptoms diagnostic for anxiety disorders, such as posttraumatic stress disorder.
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Ansiedad/fisiopatología , Hormona Liberadora de Corticotropina/metabolismo , Extinción Psicológica/fisiología , Miedo/fisiología , Neuronas/metabolismo , Receptores de GABA-A/deficiencia , Análisis de Varianza , Animales , Ansiedad/metabolismo , Condicionamiento Psicológico/fisiología , Corticosterona/sangre , Cartilla de ADN/genética , Hibridación in Situ , Hibridación Fluorescente in Situ , Aprendizaje por Laberinto , Ratones , Ratones Transgénicos , Neuronas/fisiología , Técnicas de Placa-Clamp , Piridinas , Pirimidinas , Receptores de GABA-A/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , ZolpidemRESUMEN
The anterolateral cell group of the bed nucleus of the stria terminalis (BNST(ALG)) serves as an important relay station in stress circuitry. Limbic inputs to the BNST(ALG) are primarily glutamatergic and activity-dependent changes in this input have been implicated in abnormal behaviors associated with chronic stress and addiction. Significantly, local infusion of acetylcholine (ACh) receptor agonists into the BNST trigger stress-like cardiovascular responses, however, little is known about the effects of these agents on glutamatergic transmission in the BNST(ALG). Here, we show that glutamate- and ACh-containing fibers are found in close association in the BNST(ALG). Moreover, in the presence of the acetylcholinesterase inhibitor, eserine, endogenous ACh release evoked a long-lasting reduction of the amplitude of stimulus-evoked EPSCs. This effect was mimicked by exogenous application of the ACh analog, carbachol, which caused a reversible, dose-dependent, reduction of the evoked EPSC amplitude, and an increase in both the paired-pulse ratio and coefficient of variation, suggesting a presynaptic site of action. Uncoupling of postsynaptic G-proteins with intracellular GDP-ß-S, or application of the nicotinic receptor antagonist, tubocurarine, failed to block the carbachol effect. In contrast, the carbachol effect was blocked by prior application of atropine or M(2) receptor-preferring antagonists, and was absent in M(2)/M(4) receptor knockout mice, suggesting that presynaptic M(2) receptors mediate the effect of ACh. Immunoelectron microscopy studies further revealed the presence of M(2) receptors on axon terminals that formed asymmetric synapses with BNST neurons. Our findings suggest that presynaptic M(2) receptors might be an important modulator of the stress circuit and hence a novel target for drug development.