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Activity-dependent changes in the dendritic distribution of hnRNP K : functional implications

Morais, Eduardo Manuel Firmo
Fonte: Universidade de Coimbra Publicador: Universidade de Coimbra
Tipo: Dissertação de Mestrado
Português
Relevância na Pesquisa
45.97%
Neurons communicate with each other through highly specialized structures, the synapses, and the synaptic strength can be bidirectionally modulated. Long-term potentiation (LTP) refers to a long-lasting enhancement of the excitatory synapse strength which may be induced by high-frequency presynaptic stimulation or by pairing low-frequency presynaptic stimulation with postsynaptic depolarization. Experimental evidence relates LTP to memory acquisition and learning, especially at the hippocampus. The late stages of LTP require local synthesis of specific proteins and, accordingly, the essential cellular machinery required for translation activity was found at the vicinities of synapses. Furthermore, LTP is associated with structural changes of dendritic spines, namely their enlargement. Brain-derived neurotrophic factor (BDNF) is a neurotrophin capable of modulating synaptic transmission and is a mediator of latephase LTP at hippocampal synapses. BDNF has been implicated, among other functions of the neurotrophin, in the control of mRNA localization in dendrites, in the regulation of translation machinery activity, as well as in spine plasticity. Heterogeneous nuclear Ribonucleoprotein K (hnRNP K) belongs to the heterogeneous nuclear ribonucleoprotein family of proteins and binds nascent transcripts. This ribonucleoprotein virtually regulates every step of mRNA biology and a recent study showed a role for hnRNP K in synaptic plasticity in the hippocampus. In this work we aimed at further characterizing the activity-dependent changes on hnRNP K levels in dendrites of cultured hippocampal neurons...

Neuropeptídeos GRP e BDNF como alvos moleculares em neoplasias femininas

Cornélio, Daniela Baumann
Fonte: Universidade Federal do Rio Grande do Sul Publicador: Universidade Federal do Rio Grande do Sul
Tipo: Tese de Doutorado Formato: application/pdf
Português
Relevância na Pesquisa
45.83%
Receptores de neuropeptídeos e neurotrofinas constituem importantes alvos moleculares no câncer. Fatores de crescimento como o peptídeo liberador da gastrina (GRP) e fator neurotrófico derivado do cérebro (BDNF) estão envolvidos na proliferação celular e progressão do câncer, influenciando na invasão local, angiogênese, metastatização e apoptose. O receptor de GRP (GRPR) tem sido identificado em muitos tumores humanos, mas até o presente trabalho não havia nenhuma informação na literatura quanto à sua expressão em câncer cervical. Nosso estudo inicial demonstrou pela primeira vez a expressão aberrante em GRPR em displasias e câncer do colo uterino, levantando a hipótese de que este receptor poderia estar implicado no processo carcinogênico destes tumores. Para explorar o papel de GRPR como um biomarcador de lesões de colo uterino, em nosso segundo estudo objetivamos avaliar o potencial diagnóstico da detecção de GRPR por imunocitoquímica, técnica que também não havia sido previamente descrita. Verificamos que este receptor foi fortemente associado com displasia e neoplasia cervical invasora. Além disso, o exame demonstrou elevada acurácia para lesões classificadas como células escamosas atípicas de significado indeterminado (ASCUS). Com base nestes resultados...

Enhanced nicotine-seeking behavior following pre-exposure to repeated cocaine is accompanied by changes in BDNF in the nucleus accumbens of rats

Leão, Rodrigo M.; Cruz, Fábio C.; Carneiro-De-Oliveira, Paulo E.; Rossetto, Daniella B.; Valentini, Sandro R.; Zanelli, Cleslei F.; Planeta, Cleopatra da Silva
Fonte: Universidade Estadual Paulista Publicador: Universidade Estadual Paulista
Tipo: Artigo de Revista Científica Formato: 169-176
Português
Relevância na Pesquisa
45.83%
We investigated the behavioral and molecular interactions between cocaine and nicotine, through evaluating locomotor activity, nicotine intravenous self-administration and gene expression. Locomotor sensitization was induced in male Wistar rats by repeated cocaine (20 mg/kg; i.p.) or saline injections once a day over 7 days. Three days after the last injection, rats were challenged with either saline or cocaine (15 mg/kg; i.p.) and the locomotor activity was measured. The very next day animals received either saline or nicotine (0.4 mg/kg; s.c.) and the locomotor cross-sensitization was tested. Animals were then prepared with intrajugular catheters for nicotine self-administration. Nicotine self-administration patterns were evaluated using fixed or progressive ratio schedules of reinforcement and a 24-h unlimited access binge. Immediately after the binge sessions animals were decapitated, the brains were removed and the nucleus accumbens was dissected. The dynorphin (DYN), μ-opioid receptor (mu opioid), neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), tropomyosin-related tyrosine kinase B receptor (TrkB) and corticotropin- releasing factor receptor type 1 (CRF-R1) gene expression were measured by the reverse transcription-polymerase chain reaction (RT-PCR). Pretreatment with cocaine caused sensitization of cocaine motor response and locomotor cross-sensitization with nicotine. In the self-administration experiments repeated cocaine administration caused an increase in the nicotine break point and nicotine intake during a 24 h binge session. © 2013 Elsevier Inc.

Ankyrin-rich Membrane Spanning Protein Plays a Critical Role in Nuclear Factor-κB Signaling

Sniderhan, Lynn F.; Stout, Angela; Lu, Yuanan; Chao, Moses V.; Maggirwar, Sanjay B.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
65.86%
Activation of nuclear factor-κB (NF-κB), a key feature of the neurotrophin signaling, has been shown to be critical for neuronal survival under pathologic settings. However, the precise mechanism by which neurotrophins activate NF-κB is not well understood. Here we report that the Ankyrin-rich Membrane Spanning (ARMS/Kidins220) protein, a novel transmembrane substrate of tropomyosin receptor kinase B (TrkB), plays an important role in NF-κB signaling elicited by brain-derived neurotrophic factor (BDNF). Accordingly, depletion of ARMS by specific RNA interference, or disruption of ARMS-TrkB interaction with expression of dominant-negative ARMS mutant, abolished BDNF-induced signaling to NF-κB. Our data further suggests that ARMS may promote NF-κB signaling via activation of mitogen-activated kinase (MAPK) and IκB kinase (IKK), thereby facilitating phosphorylation of RelA (major NF-κB subunit) at an IKK-sensitive site. The results shown here identify ARMS as a major factor that links neurotrophin signaling to NF-κB.

NEUROTOXIC (+)-METHAMPHETAMINE TREATMENT INCREASES BRAIN-DERIVED NEUROTROPHIC FACTOR AND TROPOMYOSIN RECEPTOR KINASE B (TrkB) EXPRESSION IN MULTIPLE BRAIN REGIONS

Braun, Amanda A.; Herring, Nicole R.; Schaefer, Tori L.; Hemmerle, Ann M.; Dickerson, Jonathan W.; Seroogy, Kim B.; Vorhees, Charles V.; Williams, Michael T.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
95.99%
Methamphetamine (MA) is an abused stimulant which can result in cognitive deficits and monoamine depletions. Animal models of neurotoxic MA exposure show reductions in dopamine, serotonin, and their associated transporters. MA abuse can result in long-term attention, working memory, and executive function deficits in humans and deficits in route-based egocentric learning, novel object recognition, and novel odor preference in rodents. MA has also been shown to affect brain-derived neurotrophic factor (BDNF) in humans and rodents. This experiment examined the effects of a MA binge dosing regimen (10 mg/kg × 4 at 2 h intervals, s.c.) in Sprague-Dawley rats on BDNF, tropomyosin receptor kinase B (TrkB), and tyrosine hydroxylase (TH) mRNA expression, and plasma corticosterone. Tissues were collected 1, 7, and 24 h following the last MA dose. Expression of BDNF and TrkB mRNA was analyzed using in situ hybridization with cRNA probes. Frontal, parietal, and entorhinal cortical BDNF mRNA expression were increased by MA exposure at all time-points. Increases in BDNF mRNA message were also seen in the hippocampal CA1, prefrontal cortex (PFC), piriform cortex, and locus coeruleus but only at specific times. TrkB mRNA expression was modified in several subregions of the hippocampus as well as in PFC and striatum. TH mRNA was increased at the 1 h time-point in the substantia nigra pars compacta with no differences noted at the other times. Corticosterone levels were increased at all three time-points. The findings suggest that BDNF and its receptor may be upregulated as a compensatory mechanism after MA exposure.

Brain-derived Neurotrophic Factor-Tropomyosin-related Kinase B Signaling Contributes to Activity-dependent Changes in Synaptic Proteins*

Jia, Jie-Min; Chen, Qian; Zhou, Yang; Miao, Sheng; Zheng, Jing; Zhang, Chi; Xiong, Zhi-Qi
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em 25/07/2008 Português
Relevância na Pesquisa
65.95%
The ability of synapses to undergo changes in structure and function in response to alterations of neuronal activity is an essential property of neural circuits. One way that this is achieved is through global changes in the molecular composition of the synapse; however, it is not clear how these changes are coupled to the dynamics of neuronal activity. Here we found that, in cultured rat cortical neurons, bidirectional changes of neuronal activity led to corresponding alterations in the expression of brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor tropomyosin-related kinase B (TrkB), as well as in the level of synaptic proteins. Exogenous BDNF reversed changes in synaptic proteins induced by chronic activity blockade, while inhibiting Trk kinase activity or depleting endogenous BDNF abolished the concentration changes induced by chronic activity elevation. Both tetrodotoxin and bicuculline had significant, but opposite, effects on synaptic protein ubiquitination in a time-dependent manner. Furthermore, exogenous BDNF was sufficient to increase ubiquitination of synaptic proteins, whereas scavenging endogenous BDNF or inhibiting Trk kinase activity prevented the ubiquitination of synaptic proteins induced by chronic elevation of neuronal activity. Inhibiting the proteasome or blocking protein polyubiquitination mimicked the effect of tetrodotoxin on the levels of synaptic proteins and canceled the effects of BDNF. Our study indicates that BDNF-TrkB signaling acts upstream of the ubiquitin proteasome system...

The novel TrkB receptor agonist 7,8-dihydroxyflavone enhances neuromuscular transmission

Mantilla, Carlos B.; Ermilov, Leonid G.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/2012 Português
Relevância na Pesquisa
45.77%
Neurotrophin signaling at the neuromuscular junction modulates cholinergic transmission and enhances neuromuscular transmission via the tropomyosin-related kinase receptor subtype B (TrkB). A novel flavonoid, 7,8-dihydroxyflavone (7,8-DHF), selectively activates TrkB receptors. Using TrkBF616A mice that are susceptible to specific inhibition of TrkB activity by 1NMPP1, we show that neuromuscular transmission is enhanced by 7,8-DHF (~32%) via activation of TrkB in diaphragm muscle. The small molecule 7,8-DHF may constitute a novel therapy to improve neuromuscular function.

Imbalance of neurotrophin receptor isoforms TrkB-FL/TrkB-T1 induces neuronal death in excitotoxicity

Vidaurre, Ó G; Gascón, S; Deogracias, R; Sobrado, M; Cuadrado, E; Montaner, J; Rodríguez-Peña, Á; Díaz-Guerra, M
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
45.82%
A better understanding of the mechanisms underlying neuronal death in cerebral ischemia is required for the development of stroke therapies. Here we analyze the contribution of the tropomyosin-related kinase B (TrkB) neurotrophin receptor to excitotoxicity, a primary pathological mechanism in ischemia, which is induced by overstimulation of glutamate receptors of the N-methyl-D-aspartate type. We demonstrate a significant modification of TrkB expression that is strongly associated with neurodegeneration in models of ischemia and in vitro excitotoxicity. Two mechanisms cooperate for TrkB dysregulation: (1) calpain-processing of full-length TrkB (TrkB-FL), high-affinity receptor for brain-derived neurotrophic factor, which produces a truncated protein lacking the tyrosine-kinase domain and strikingly similar to the inactive TrkB-T1 isoform and (2) reverse regulation of the mRNA of these isoforms. Collectively, excitotoxicity results in a decrease of TrkB-FL, the production of truncated TrkB-FL and the upregulation of TrkB-T1. A similar neuro-specific increase of the TrkB-T1 isoform is also observed in stroke patients. A lentivirus designed for both neuro-specific TrkB-T1 interference and increased TrkB-FL expression allows recovery of the TrkB-FL/TrkB-T1 balance and protects neurons from excitotoxic death. These data implicate a combination of TrkB-FL downregulation and TrkB-T1 upregulation as significant causes of neuronal death in excitotoxicity...

Targeted Delivery of TrkB Receptor to Phrenic Motoneurons Enhances Functional Recovery of Rhythmic Phrenic Activity after Cervical Spinal Hemisection

Gransee, Heather M.; Zhan, Wen-Zhi; Sieck, Gary C.; Mantilla, Carlos B.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 28/05/2013 Português
Relevância na Pesquisa
45.77%
Progressive recovery of rhythmic phrenic activity occurs over time after a spinal cord hemisection involving unilateral transection of anterolateral funiculi at C2 (SH). Brain-derived neurotrophic factor (BDNF) acting through its full-length tropomyosin related kinase receptor subtype B (TrkB.FL) contributes to neuroplasticity after spinal cord injury, but the specific cellular substrates remain unclear. We hypothesized that selectively targeting increased TrkB.FL expression to phrenic motoneurons would be sufficient to enhance recovery of rhythmic phrenic activity after SH. Several adeno-associated virus (AAV) serotypes expressing GFP were screened to determine specificity for phrenic motoneuron transduction via intrapleural injection in adult rats. GFP expression was present in the cervical spinal cord 3 weeks after treatment with AAV serotypes 7, 8, and 9, but not with AAV2, 6, or rhesus-10. Overall, AAV7 produced the most consistent GFP expression in phrenic motoneurons. SH was performed 3 weeks after intrapleural injection of AAV7 expressing human TrkB.FL-FLAG or saline. Delivery of TrkB.FL-FLAG to phrenic motoneurons was confirmed by FLAG protein expression in the phrenic motor nucleus and human TrkB.FL mRNA expression in microdissected phrenic motoneurons. In all SH rats...

Brimonidine promotes axon growth after optic nerve injury through Erk phosphorylation

Fujita, Y; Sato, A; Yamashita, T
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
45.76%
It is well known that axons of the adult mammalian central nervous system have a very limited ability to regenerate after injury. Therefore, the neurodegenerative process of glaucoma results in irreversible functional deficits, such as blindness. Brimonidine (BMD) is an alpha2-adrenergic receptor agonist that is used commonly to lower intraocular pressure in glaucoma. Although it has been suggested that BMD has neuroprotective effects, the underlying mechanism remains unknown. In this study, we explored the molecular mechanism underlying the neuroprotective effect of BMD in an optic nerve injury (ONI) model. BMD treatment promoted optic nerve regeneration by inducing Erk1/2 phosphorylation after ONI. In addition, an Erk1/2 antagonist suppressed BMD-mediated axonal regeneration. A gene expression analysis revealed that the expression of the neurotrophin receptor gene p75 was increased and that the expression of the tropomyosin receptor kinase B (TrkB) gene was decreased after ONI. BMD treatment abrogated the changes in the expression of these genes. These results indicate that BMD promotes optic nerve regeneration via the activation of Erk1/2.

Taste Neurons Consist of Both a Large TrkB-Receptor-Dependent and a Small TrkB-Receptor-Independent Subpopulation

Fei, Da; Krimm, Robin F.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 27/12/2013 Português
Relevância na Pesquisa
45.79%
Brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) are two neurotrophins that play distinct roles in geniculate (taste) neuron survival, target innervation, and taste bud formation. These two neurotrophins both activate the tropomyosin-related kinase B (TrkB) receptor and the pan-neurotrophin receptor p75. Although the roles of these neurotrophins have been well studied, the degree to which BDNF and NT-4 act via TrkB to regulate taste development in vivo remains unclear. In this study, we compared taste development in TrkB−/− and Bdnf−/−/Ntf4−/− mice to determine if these deficits were similar. If so, this would indicate that the functions of both BDNF and NT-4 can be accounted for by TrkB-signaling. We found that TrkB−/− and Bdnf−/−/Ntf4−/− mice lose a similar number of geniculate neurons by E13.5, which indicates that both BDNF and NT-4 act primarily via TrkB to regulate geniculate neuron survival. Surprisingly, the few geniculate neurons that remain in TrkB−/− mice are more successful at innervating the tongue and taste buds compared with those neurons that remain in Bdnf−/−/Ntf4−/− mice. The remaining neurons in TrkB−/− mice support a significant number of taste buds. In addition...

A Monoclonal Antibody TrkB Receptor Agonist as a Potential Therapeutic for Huntington’s Disease

Todd, Daniel; Gowers, Ian; Dowler, Simon J.; Wall, Michael D.; McAllister, George; Fischer, David F.; Dijkstra, Sipke; Fratantoni, Silvina A.; van de Bospoort, Rhea; Veenman-Koepke, Jessica; Flynn, Geraldine; Arjomand, Jamshid; Dominguez, Celia; Munoz-San
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 04/02/2014 Português
Relevância na Pesquisa
55.78%
Huntington’s disease (HD) is a devastating, genetic neurodegenerative disease caused by a tri-nucleotide expansion in exon 1 of the huntingtin gene. HD is clinically characterized by chorea, emotional and psychiatric disturbances and cognitive deficits with later symptoms including rigidity and dementia. Pathologically, the cortico-striatal pathway is severely dysfunctional as reflected by striatal and cortical atrophy in late-stage disease. Brain-derived neurotrophic factor (BDNF) is a neuroprotective, secreted protein that binds with high affinity to the extracellular domain of the tropomyosin-receptor kinase B (TrkB) receptor promoting neuronal cell survival by activating the receptor and down-stream signaling proteins. Reduced cortical BDNF production and transport to the striatum have been implicated in HD pathogenesis; the ability to enhance TrkB signaling using a BDNF mimetic might be beneficial in disease progression, so we explored this as a therapeutic strategy for HD. Using recombinant and native assay formats, we report here the evaluation of TrkB antibodies and a panel of reported small molecule TrkB agonists, and identify the best candidate, from those tested, for in vivo proof of concept studies in transgenic HD models.

Brain-derived neurotrophic factor rapidly increases AMPA receptor surface expression in rat nucleus accumbens

Li, Xuan; Wolf, Marina E.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.82%
In the rodent nucleus accumbens (NAc), cocaine elevates levels of brain-derived neurotrophic factor (BDNF). Conversely, BDNF can augment cocaine-related behavioral responses. The latter could reflect enhancement of AMPA receptor (AMPAR) transmission, because AMPARs in the NAc mediate some cocaine-induced behaviors. Furthermore, in vitro studies in other cell types show that BDNF can promote AMPAR synaptic delivery. In this study, we investigated whether BDNF similarly promotes AMPAR trafficking in the adult rat NAc. After unilateral intracranial injection of BDNF into NAc core or shell, rats were killed at post-injection times ranging from 30 min to 3 days. NAc core or shell tissue from both injected and non-injected hemispheres was analyzed by Western blotting. A protein crosslinking assay was used to measure AMPAR surface expression. Assessment of tropomyosin receptor kinase B (TrkB) signaling demonstrated that injected BDNF was biologically active. BDNF injection into NAc core, but not NAc shell, led to a protein synthesis and extracellular signal-regulated kinase (ERK) dependent increase in cell surface GluA1 and a trend towards increased total GluA1. This was detected 30 min post-injection but not at longer time-points. GluA2 and GluA3 were unaffected...

Brain-Derived Neurotrophic Factor (BDNF)-Induced Tropomyosin-Related Kinase B (Trk B) Signaling Is a Potential Therapeutic Target for Peritoneal Carcinomatosis Arising from Colorectal Cancer

Tanaka, Koji; Okugawa, Yoshinaga; Toiyama, Yuji; Inoue, Yasuhiro; Saigusa, Susumu; Kawamura, Mikio; Araki, Toshimitsu; Uchida, Keiichi; Mohri, Yasuhiko; Kusunoki, Masato
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 06/05/2014 Português
Relevância na Pesquisa
65.91%
Tropomyosin-related receptor kinase B (TrkB) signaling, stimulated by brain-derived neurotrophic factor (BDNF) ligand, promotes tumor progression, and is related to the poor prognosis of various malignancies. We sought to examine the clinical relevance of BDNF/TrkB expression in colorectal cancer (CRC) tissues, its prognostic value for CRC patients, and its therapeutic potential in vitro and in vivo. Two hundred and twenty-three CRC patient specimens were used to determine both BDNF and TrkB mRNA levels. The expression of these proteins in their primary and metastatic tumors was investigated by immunohistochemistry. CRC cell lines and recombinant BDNF and K252a (a selective pharmacological pan-Trk inhibitor) were used for in vitro cell viability, migration, invasion, anoikis resistance and in vivo peritoneal metastasis assays. Tissue BDNF mRNA was associated with liver and peritoneal metastasis. Tissue TrkB mRNA was also associated with lymph node metastasis. The co-expression of BDNF and TrkB was associated with liver and peritoneal metastasis. Patients with higher BDNF, TrkB, and co-expression of BDNF and TrkB had a significantly poor prognosis. BDNF increased tumor cell viability, migration, invasion and inhibited anoikis in the TrkB-expressing CRC cell lines. These effects were suppressed by K252a. In mice injected with DLD1 co-expressing BDNF and TrkB...

5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation

Samarajeewa, Anshula; Goldemann, Lolita; Vasefi, Maryam S.; Ahmed, Nawaz; Gondora, Nyasha; Khanderia, Chandni; Mielke, John G.; Beazely, Michael A.
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 07/11/2014 Português
Relevância na Pesquisa
45.88%
The serotonin (5-HT) type 7 receptor is expressed throughout the CNS including the cortex and hippocampus. We have previously demonstrated that the application of 5-HT7 receptor agonists to primary hippocampal neurons and SH-SY5Y cells increases platelet-derived growth factor (PDGF) receptor expression and promotes neuroprotection against N-methyl-D-aspartate-(NMDA)-induced toxicity. The tropomyosin-related kinase B (TrkB) receptor is one of the receptors for brain-derived neurotrophic factor (BDNF) and is associated with neurodevelopmental and neuroprotective effects. Application of LP 12 to primary cerebral cortical cultures, SH-SY5Y cells, as well as the retinal ganglion cell line, RGC-5, increased both the expression of full length TrkB as well as its basal phosphorylation state at tyrosine 816. The increase in TrkB expression and phosphorylation was observed as early as 30 min after 5-HT7 receptor activation. In addition to full-length TrkB, kinase domain-deficient forms may be expressed and act as dominant-negative proteins toward the full length receptor. We have identified distinct patterns of TrkB isoform expression across our cell lines and cortical cultures. Although TrkB receptor expression is regulated by cyclic AMP and Gαs-coupled GPCRs in several systems...

Enhanced brain-derived neurotrophic factor signaling in the nucleus accumbens of juvenile rats

Perreault, Melissa L.; Fan, Theresa; O’Dowd, Brian F.; George, Susan R.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
45.79%
Brain-derived neurotrophic factor (BDNF) signaling through its receptor, tropomyosin receptor kinase B (TrkB), plays a critical role in neural plasticity and its dysregulation in striatum and prefrontal cortex (PFC) has been implicated in the etiology of mental health disorders such schizophrenia and drug addiction. In the present study we characterized age-dependent differences in BDNF signaling and TrkB expression within the nucleus accumbens (NAc), caudate putamen (CP) and PFC in rats and determined the effects of administration of the dopamine agonist, SKF 83959, previously which selectively activates the Gq-coupled dopamine receptors, the dopamine D5 receptor and the D1-D2 receptor heteromer. As proBDNF binds with high affinity to the p75 neurotrophin receptor (p75NTR), expression levels of these proteins were also assessed. The present findings showed that juvenile rats (age-26-28 days) exhibited significantly elevated basal BDNF expression and activation of full length TrkB (TrkBfull) in NAc compared to their adult counterparts, as evidence by increased TrkBfull phosphorylation. These changes were concomitant with an increase in the relative expression of TrkBfull compared to the truncated isoform, TrkB.T1, in NAc and CP. Conversely...

Motor and Sensory Deficits in the teetering Mice Result from Mutation of the ESCRT Component HGS

Watson, Jennifer A.; Bhattacharyya, Bula J.; Vaden, Jada H.; Wilson, Julie A.; Icyuz, Mert; Howard, Alan D.; Phillips, Edward; DeSilva, Tara M.; Siegal, Gene P.; Bean, Andrew J.; King, Gwendalyn D.; Phillips, Scott E.; Miller, Richard J.; Wilson, Scott M.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 26/06/2015 Português
Relevância na Pesquisa
45.83%
Neurons are particularly vulnerable to perturbations in endo-lysosomal transport, as several neurological disorders are caused by a primary deficit in this pathway. In this report, we used positional cloning to show that the spontaneously occurring neurological mutation teetering (tn) is a single nucleotide substitution in hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs/Hrs), a component of the endosomal sorting complex required for transport (ESCRT). The tn mice exhibit hypokenesis, muscle weakness, reduced muscle size and early perinatal lethality by 5-weeks of age. Although HGS has been suggested to be essential for the sorting of ubiquitinated membrane proteins to the lysosome, there were no alterations in receptor tyrosine kinase levels in the central nervous system, and only a modest decrease in tropomyosin receptor kinase B (TrkB) in the sciatic nerves of the tn mice. Instead, loss of HGS resulted in structural alterations at the neuromuscular junction (NMJ), including swellings and ultra-terminal sprouting at motor axon terminals and an increase in the number of endosomes and multivesicular bodies. These structural changes were accompanied by a reduction in spontaneous and evoked release of acetylcholine, indicating a deficit in neurotransmitter release at the NMJ. These deficits in synaptic transmission were associated with elevated levels of ubiquitinated proteins in the synaptosome fraction. In addition to the deficits in neuronal function...

Low-frequency transcranial magnetic stimulation is beneficial for enhancing synaptic plasticity in the aging brain

Zhang, Zhan-chi; Luan, Feng; Xie, Chun-yan; Geng, Dan-dan; Wang, Yan-yong; Ma, Jun
Fonte: Medknow Publications & Media Pvt Ltd Publicador: Medknow Publications & Media Pvt Ltd
Tipo: Artigo de Revista Científica
Publicado em /06/2015 Português
Relevância na Pesquisa
45.75%
In the aging brain, cognitive function gradually declines and causes a progressive reduction in the structural and functional plasticity of the hippocampus. Transcranial magnetic stimulation is an emerging and novel neurological and psychiatric tool used to investigate the neurobiology of cognitive function. Recent studies have demonstrated that low-frequency transcranial magnetic stimulation (≤1 Hz) ameliorates synaptic plasticity and spatial cognitive deficits in learning-impaired mice. However, the mechanisms by which this treatment improves these deficits during normal aging are still unknown. Therefore, the current study investigated the effects of transcranial magnetic stimulation on the brain-derived neurotrophic factor signal pathway, synaptic protein markers, and spatial memory behavior in the hippocampus of normal aged mice. The study also investigated the downstream regulator, Fyn kinase, and the downstream effectors, synaptophysin and growth-associated protein 43 (both synaptic markers), to determine the possible mechanisms by which transcranial magnetic stimulation regulates cognitive capacity. Transcranial magnetic stimulation with low intensity (110% average resting motor threshold intensity, 1 Hz) increased mRNA and protein levels of brain-derived neurotrophic factor...

Développement et radiosynthèse de ligands du récepteur tyrosine kinase neurotrophique type 2 (TrkB) marqués aux carbone-11 et fluor-18 pour l’imagerie cérébrale par tomographie d’émission de positons

Bernard-Gauthier, Vadim
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
Português
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75.96%
Ce mémoire présente mes travaux ayant menés au développement d’une première génération de radioligands marqués au fluor-18 (t1/2 = 110 min) et au carbone-11 (t1/2 = 20.4 min) destinés à l’imagerie cérébrale in vivo du récepteur tyrosine kinase neurotrophique de type 2 (TrkB) en tomographie par émission de positons (TEP). Ces travaux reposent sur l’identification récente de ligands de TrkB non peptidiques à hautes affinités dérivés du 7,8-dihydroxyflavone. La synthèse d’une série de dérivés du 7,8-dihydroxyflavone non-radioactifs de même que des précuseurs à l’incorporation du fluro-18 et du carbone-11 a d’abord été effectuée. Partant des précurseurs adéquats synthétisés, la radiosynthèse de deux radioligands, l’un marqué au fluor-18 et l’autre au carbone-11, a été développée. Ces radiosynthèses reposent respectivement sur une 18F-radiofluorination nucléophile aromatique nouvelle et hautement efficace et sur une 11C-méthylation N-sélective. Les radiotraceurs de TrkB ainsi obtenus ont ensuite été évalués in vitro en autoradiographie et in vivo en tant que traceurs TEP dans des rats. L’évaluation des propriétés physico-chimique de même que de la stabilité in vitro des radiotraceurs sont présentées. Partant d’une série d’analogues cristallisés de ces flavones synthétiques...

Changes in expression of BDNF and its receptors TrkB and p75NTR in the hippocampus of a dog model of chronic alcoholism and abstinence

Xu,R.; Duan,S.R.; Zhao,J.W.; Wang,C.Y.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/08/2015 Português
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Chronic ethanol consumption can produce learning and memory deficits. Brain-derived neurotrophic factor (BDNF) and its receptors affect the pathogenesis of alcoholism. In this study, we examined the expression of BDNF, tropomyosin receptor kinase B (TrkB) and p75 neurotrophin receptor (p75NTR) in the hippocampus of a dog model of chronic alcoholism and abstinence. Twenty domestic dogs (9-10 months old, 15-20 kg; 10 males and 10 females) were obtained from Harbin Medical University. A stable alcoholism model was established through ad libitum feeding, and anti-alcohol drug treatment (Zhong Yao Jie Jiu Ling, the main ingredient was the stems of watermelon; developed in our laboratory), at low- and high-doses, was carried out. The Zhong Yao Jie Jiu Ling was effective for the alcoholism in dogs. The morphology of hippocampal neurons was evaluated using hematoxylin-eosin staining. The number and morphological features of BDNF, TrkB and p75NTR-positive neurons in the dentate gyrus (DG), and the CA1, CA3 and CA4 regions of the hippocampus were observed using immunohistochemistry. One-way ANOVA was used to determine differences in BDNF, TrkB and p75NTR expression. BDNF, TrkB and p75NTR-positive cells were mainly localized in the granular cell layer of the DG and in the pyramidal cell layer of the CA1...