Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Cell Physiol Biochem ; 35(5): 1905-23, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25871611

RESUMO

BACKGROUND: Accumulating evidence suggests that tinnitus may occur despite normal auditory sensitivity, probably linked to partial degeneration of the cochlear nerve and damage of the inner hair cell (IHC) synapse. Damage to the IHC synapses and deafferentation may occur even after moderate noise exposure. For both salicylate- and noise-induced tinnitus, aberrant N-methyl-d-aspartate (NMDA) receptor activation and related auditory nerve excitation have been suggested as origin of cochlear tinnitus. Accordingly, NMDA receptor inhibition has been proposed as a pharmacologic approach for treatment of synaptopathic tinnitus. METHODS: Round-window application of the NMDA receptor antagonist AM-101 (Esketamine hydrochloride gel; Auris Medical AG, Basel, Switzerland) was tested in an animal model of tinnitus induced by acute traumatic noise. The study included the quantification of IHC ribbon synapses as a correlate for deafferentation as well as the measurement of the auditory brainstem response (ABR) to close-threshold sensation level stimuli as an indication of sound-induced auditory nerve activity. RESULTS: We have shown that AM-101 reduced the trauma-induced loss of IHC ribbons and counteracted the decline of ABR wave I amplitude generated in the cochlea/auditory nerve. CONCLUSION: Local round-window application of AM-101 may be a promising therapeutic intervention for the treatment of synaptopathic tinnitus.


Assuntos
Cóclea/metabolismo , Ruído , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Anestesia , Animais , Proteínas Reguladoras de Apoptose/uso terapêutico , Proteínas Reguladoras de Apoptose/toxicidade , Limiar Auditivo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Cóclea/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Zumbido/tratamento farmacológico , Zumbido/etiologia
2.
Cell Tissue Res ; 361(1): 77-93, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25843689

RESUMO

Before hearing onset, inner hair cell (IHC) maturation proceeds under the influence of spontaneous Ca(2+) action potentials (APs). The temporal signature of the IHC Ca(2+) AP is modified through an efferent cholinergic feedback from the medial olivocochlear bundle (MOC) and drives the IHC pre- and post-synapse phenotype towards low spontaneous (spike) rate (SR), high-threshold characteristics. With sensory experience, the IHC pre- and post-synapse phenotype matures towards the instruction of low-SR, high-threshold and of high-SR, low-threshold auditory fiber characteristics. Corticosteroid feedback together with local brain-derived nerve growth factor (BDNF) and catecholaminergic neurotransmitters (dopamine) might be essential for this developmental step. In this review, we address the question of whether the control of low-SR and high-SR fiber characteristics is linked to various degrees of vulnerability of auditory fibers in the mature system. In particular, we examine several IHC synaptopathies in the context of various hearing disorders and exemplified shortfalls before and after hearing onset.


Assuntos
Cóclea/crescimento & desenvolvimento , Células Ciliadas Auditivas Internas/metabolismo , Transtornos da Audição/genética , Perda Auditiva Central/genética , Células Ciliadas Auditivas Internas/citologia , Humanos
3.
Mol Pharmacol ; 73(4): 1085-91, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18198284

RESUMO

Brain-derived neurotrophic factor (BDNF) is a key neurotrophin whose expression is altered in response to neurological activity, influencing both short- and long-term synaptic changes. The BDNF gene consists of eight upstream exons (I-VII), each of which has a distinct promoter and can be independently spliced to the ninth coding exon (IX). We showed recently that the expression of BDNF exon IV in the cochlea is altered after exposure to salicylate, an ototoxic drug that in high doses is able to induce hearing loss and tinnitus. These changes were a crucial trigger for plasticity changes in the central auditory system. BDNF exon IV expression is regulated via interaction between calcium-response elements CaRE1, CaRE2, and CaRE3/Cre (CaREs) that are bound by the transcription factors CaRF1, upstream stimulatory factors 1 and 2 (USF1/2), and cAMP/Ca(2+) response element-binding protein (CREB), respectively. To determine whether the salicylate-induced changes in cochlear BDNF exon IV expression include a differential use of the CaRE binding proteins, we studied the level of the corresponding binding proteins in the spiral ganglion neurons before and after systemic application of concentrated salicylate using in situ hybridization and RT-PCR. BDNF exon IV and CaRF1 expression were up-regulated after application of salicylate, whereas USF1/2 and CREB mRNA expression remained unaffected. The changes in BDNF exon IV and CaRF1 expression were also dose-dependent. The data show Ca(2+) and CaRF1 as messengers of trauma (salicylate)-induced altered BDNF levels in the cochlea. Furthermore, they also provide the first evidence that a differential regulation of BDNF transcription factors might participate in BDNF-mediated plasticity changes.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cóclea/efeitos dos fármacos , Cóclea/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Salicilatos/farmacologia , Fatores de Transcrição/genética , Transcrição Gênica/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Cóclea/citologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Éxons/genética , Feminino , Hibridização In Situ , Injeções , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Elementos de Resposta , Fatores de Transcrição/metabolismo
4.
Mol Pharmacol ; 74(3): 595-604, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18524887

RESUMO

Tinnitus is a phantom auditory perception, which can be induced via application of concentrated sodium salicylate, and is known to be associated with hearing loss and altered neuronal excitability in peripheral and central auditory neurons. The molecular features of this excitability, however, has been poorly characterized to date. Brain-derived neurotrophic factor (BDNF), the activity-dependent cytoskeletal protein (Arg3.1, also known as Arc), and c-Fos are known to be affected by changes in excitability and plasticity. Using reverse transcription-polymerase chain reaction, in situ hybridization, and immunohistochemistry, the expression of these genes was monitored in the rat auditory system after local (cochlear) and systemic application of salicylate. Induction of tinnitus and hearing loss was verified in a behavioral model. Regardless of the mode of salicylate application, a common pattern became evident: 1) BDNF mRNA expression was increased in the spiral ganglion neurons of the cochlea; and 2) Arg3.1 expression was significantly reduced in the auditory cortex. Local application of the GABA(A) receptor modulator midazolam resulted in the reversal not only of salicylate-induced changes in cochlear BDNF expression, but also in cortical Arg3.1 expression, indicating that the tinnitus-associated changes in cochlear BDNF expression trigger the decline of cortical Arg3.1 expression. Furthermore, local midazolam application reduced tinnitus perception in the animal model. These findings support Arg3.1 and BDNF as markers for activity changes in the auditory system and suggest a role of GABAergic inhibition of cochlear neurons in the modulation of Arg3.1 plasticity changes in the auditory cortex and tinnitus perception.


Assuntos
Percepção Auditiva/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Proteínas do Citoesqueleto/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Midazolam/farmacologia , Proteínas do Tecido Nervoso/genética , Salicilatos/farmacologia , Zumbido/metabolismo , Animais , Córtex Auditivo/efeitos dos fármacos , Córtex Auditivo/metabolismo , Vias Auditivas/efeitos dos fármacos , Vias Auditivas/metabolismo , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cóclea/efeitos dos fármacos , Cóclea/metabolismo , Proteínas do Citoesqueleto/metabolismo , Feminino , Perda Auditiva/induzido quimicamente , Midazolam/administração & dosagem , Modelos Biológicos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de GABA/metabolismo , Salicilatos/administração & dosagem , Zumbido/patologia
5.
Front Mol Neurosci ; 11: 260, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30127717

RESUMO

Activity-dependent BDNF (brain-derived neurotrophic factor) expression is hypothesized to be a cue for the context-specificity of memory formation. So far, activity-dependent BDNF cannot be explicitly monitored independently of basal BDNF levels. We used the BLEV ( B DNF- live-exon- visualization) reporter mouse to specifically detect activity-dependent usage of Bdnf exon-IV and -VI promoters through bi-cistronic co-expression of CFP and YFP, respectively. Enriching acoustic stimuli led to improved peripheral and central auditory brainstem responses, increased Schaffer collateral LTP, and enhanced performance in the Morris water maze. Within the brainstem, neuronal activity was increased and accompanied by a trend for higher expression levels of Bdnf exon-IV-CFP and exon-VI-YFP transcripts. In the hippocampus BDNF transcripts were clearly increased parallel to changes in parvalbumin expression and were localized to specific neurons and capillaries. Severe acoustic trauma, in contrast, elevated neither Bdnf transcript levels, nor auditory responses, parvalbumin or LTP. Together, this suggests that critical sensory input is essential for recruitment of activity-dependent auditory-specific BDNF expression that may shape network adaptation.

6.
Front Mol Neurosci ; 11: 325, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319348

RESUMO

Bdnf exon-IV and exon-VI transcripts are driven by neuronal activity and are involved in pathologies related to sleep, fear or memory disorders. However, how their differential transcription translates activity changes into long-lasting network changes is elusive. Aiming to trace specifically the network controlled by exon-IV and -VI derived BDNF during activity-dependent plasticity changes, we generated a transgenic reporter mouse for B DNF- l ive- e xon- v isualization (BLEV), in which expression of Bdnf exon-IV and -VI can be visualized by co-expression of CFP and YFP. CFP and YFP expression was differentially activated and targeted in cell lines, primary cultures and BLEV reporter mice without interfering with BDNF protein synthesis. CFP and YFP expression, moreover, overlapped with BDNF protein expression in defined hippocampal neuronal, glial and vascular locations in vivo. So far, activity-dependent BDNF cannot be explicitly monitored independent of basal BDNF levels. The BLEV reporter mouse therefore provides a new model, which can be used to test whether stimulus-induced activity-dependent changes in BDNF expression are instrumental for long-lasting plasticity modifications.

7.
Methods Mol Biol ; 1427: 263-76, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27259932

RESUMO

In sensory systems, a balanced excitatory and inhibitory circuit along the ascending pathway is not only important for the establishment of topographically ordered connections from the periphery to the cortex but also for temporal precision of signal processing. The accomplishment of spatial and temporal cortical resolution in the central nervous system is a process that is likely initiated by the first sensory experiences that drive a period of increased intracortical inhibition. In the auditory system, the time of first sensory experience is also the period in which a reorganization of cochlear efferent and afferent fibers occurs leading to the mature innervation of inner and outer hair cells. This mature hair cell innervation is the basis of accurate sound processing along the ascending pathway up to the auditory cortex. We describe here, a protocol for detecting excitatory and inhibitory marker proteins along the ascending auditory pathway, which could be a useful tool for detecting changes in auditory signal processing during various forms of hearing disorders. Our protocol uses fluorescence immunohistochemistry in combination with high-resolution fluorescence microscopy in cochlear and brain tissue.


Assuntos
Cóclea/metabolismo , Sinapses/metabolismo , Animais , Vias Auditivas/metabolismo , Encéfalo/metabolismo , Imuno-Histoquímica , Camundongos , Microscopia de Fluorescência , Ratos
8.
Mol Neurobiol ; 53(8): 5607-27, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26476841

RESUMO

For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF-dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNF (Pax2) -KO) versus the auditory cortex and hippocampus (BDNF (TrkC) -KO). We demonstrate that BDNF (Pax2) -KO but not BDNF (TrkC) -KO mice exhibit reduced sound-evoked suprathreshold ABR waves at the level of the auditory nerve (wave I) and inferior colliculus (IC) (wave IV), indicating that BDNF in lower brain regions but not in the auditory cortex improves sound sensitivity during hearing onset. Extracellular recording of IC neurons of BDNF (Pax2) mutant mice revealed that the reduced sensitivity of auditory fibers in these mice went hand in hand with elevated thresholds, reduced dynamic range, prolonged latency, and increased inhibitory strength in IC neurons. Reduced parvalbumin-positive contacts were found in the ascending auditory circuit, including the auditory cortex and hippocampus of BDNF (Pax2) -KO, but not of BDNF (TrkC) -KO mice. Also, BDNF (Pax2) -WT but not BDNF (Pax2) -KO mice did lose basal inhibitory strength in IC neurons after acoustic trauma. These findings suggest that BDNF in the lower parts of the auditory system drives auditory fidelity along the entire ascending pathway up to the cortex by increasing inhibitory strength in behaviorally relevant frequency regions. Fidelity and inhibitory strength can be lost following auditory nerve injury leading to diminished sensory outcome and increased central noise.


Assuntos
Córtex Auditivo/patologia , Córtex Auditivo/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ruído , Animais , Córtex Auditivo/metabolismo , Limiar Auditivo , Cóclea/metabolismo , Potenciais Evocados Auditivos do Tronco Encefálico , Deleção de Genes , Audição , Colículos Inferiores/patologia , Colículos Inferiores/fisiopatologia , Integrases/metabolismo , Camundongos Knockout , Regiões Promotoras Genéticas/genética , Receptor trkC/metabolismo , Fatores de Risco
9.
Neuropharmacology ; 76 Pt C: 719-28, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23688926

RESUMO

The inner ear of vertebrates is specialized to perceive sound, gravity and movements. Each of the specialized sensory organs within the cochlea (sound) and vestibular system (gravity, head movements) transmits information to specific areas of the brain. During development, brain-derived neurotrophic factor (BDNF) orchestrates the survival and outgrowth of afferent fibers connecting the vestibular organ and those regions in the cochlea that map information for low frequency sound to central auditory nuclei and higher-auditory centers. The role of BDNF in the mature inner ear is less understood. This is mainly due to the fact that constitutive BDNF mutant mice are postnatally lethal. Only in the last few years has the improved technology of performing conditional cell specific deletion of BDNF in vivo allowed the study of the function of BDNF in the mature developed organ. This review provides an overview of the current knowledge of the expression pattern and function of BDNF in the peripheral and central auditory system from just prior to the first auditory experience onwards. A special focus will be put on the differential mechanisms in which BDNF drives refinement of auditory circuitries during the onset of sensory experience and in the adult brain. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.


Assuntos
Vias Auditivas/metabolismo , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Animais , Vias Auditivas/anatomia & histologia , Humanos , Camundongos , Plasticidade Neuronal/fisiologia , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/patologia
10.
PLoS One ; 8(3): e57247, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23516401

RESUMO

Tinnitus is proposed to be caused by decreased central input from the cochlea, followed by increased spontaneous and evoked subcortical activity that is interpreted as compensation for increased responsiveness of central auditory circuits. We compared equally noise exposed rats separated into groups with and without tinnitus for differences in brain responsiveness relative to the degree of deafferentation in the periphery. We analyzed (1) the number of CtBP2/RIBEYE-positive particles in ribbon synapses of the inner hair cell (IHC) as a measure for deafferentation; (2) the fine structure of the amplitudes of auditory brainstem responses (ABR) reflecting differences in sound responses following decreased auditory nerve activity and (3) the expression of the activity-regulated gene Arc in the auditory cortex (AC) to identify long-lasting central activity following sensory deprivation. Following moderate trauma, 30% of animals exhibited tinnitus, similar to the tinnitus prevalence among hearing impaired humans. Although both tinnitus and no-tinnitus animals exhibited a reduced ABR wave I amplitude (generated by primary auditory nerve fibers), IHCs ribbon loss and high-frequency hearing impairment was more severe in tinnitus animals, associated with significantly reduced amplitudes of the more centrally generated wave IV and V and less intense staining of Arc mRNA and protein in the AC. The observed severe IHCs ribbon loss, the minimal restoration of ABR wave size, and reduced cortical Arc expression suggest that tinnitus is linked to a failure to adapt central circuits to reduced cochlear input.


Assuntos
Adaptação Fisiológica , Cóclea/fisiopatologia , Potenciais Evocados Auditivos do Tronco Encefálico , Ruído/efeitos adversos , Zumbido/etiologia , Animais , Córtex Auditivo/metabolismo , Limiar Auditivo , Comportamento Animal , Cóclea/metabolismo , Proteínas do Citoesqueleto/metabolismo , Feminino , Células Ciliadas Auditivas Internas/metabolismo , Perda Auditiva Provocada por Ruído/fisiopatologia , Imuno-Histoquímica , Proteínas do Tecido Nervoso/metabolismo , Ratos , Zumbido/metabolismo
11.
Mol Neurobiol ; 47(1): 261-79, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23154938

RESUMO

Increasing evidence shows that hearing loss is a risk factor for tinnitus and hyperacusis. Although both often coincide, a causal relationship between tinnitus and hyperacusis has not been shown. Currently, tinnitus and hyperacusis are assumed to be caused by elevated responsiveness in subcortical circuits. We examined both the impact of different degrees of cochlear damage and the influence of stress priming on tinnitus induction. We used (1) a behavioral animal model for tinnitus designed to minimize stress, (2) ribbon synapses in inner hair cells (IHCs) as a measure for deafferentation, (3) the integrity of auditory brainstem responses (ABR) to detect differences in stimulus-evoked neuronal activity, (4) the expression of the activity-regulated cytoskeletal protein, Arc, to identify long-lasting changes in network activity within the basolateral amygdala (BLA), hippocampal CA1, and auditory cortex (AC), and (5) stress priming to investigate the influence of corticosteroid on trauma-induced brain responses. We observed that IHC ribbon loss (deafferentation) leads to tinnitus when ABR functions remain reduced and Arc is not mobilized in the hippocampal CA1 and AC. If, however, ABR waves are functionally restored and Arc is mobilized, tinnitus does not occur. Both central response patterns were found to be independent of a profound threshold loss and could be shifted by the corticosterone level at the time of trauma. We, therefore, discuss the findings in the context of a history of stress that can trigger either an adaptive or nonadaptive brain response following injury.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Células Ciliadas Auditivas Internas/patologia , Proteínas do Tecido Nervoso/metabolismo , Ruído/efeitos adversos , Zumbido/metabolismo , Zumbido/patologia , Estimulação Acústica , Animais , Córtex Auditivo/metabolismo , Córtex Auditivo/patologia , Córtex Auditivo/fisiopatologia , Limiar Auditivo , Proteínas do Citoesqueleto/genética , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Células Ciliadas Auditivas Internas/metabolismo , Perda Auditiva/complicações , Perda Auditiva/metabolismo , Perda Auditiva/patologia , Perda Auditiva/fisiopatologia , Modelos Biológicos , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Estresse Psicológico/complicações , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologia , Zumbido/complicações , Zumbido/fisiopatologia
12.
Neurobiol Aging ; 28(4): 586-601, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16580094

RESUMO

A decline in neuronal plasticity during the adult life span has been proposed to be associated with a reduced level of the effectors of plasticity responses (e.g., BDNF). Alteration of plasticity is also correlated with age-related hearing loss (presbycusis), but to date no detailed studies of BDNF expression have been performed in the young or aging mature cochlea. We have used rat and gerbil animal models for presbycusis, which displayed hearing loss in the final third of the animals' natural life span. We demonstrate for the first time a co-localization of BDNF protein, transcripts III and IV in cochlear neurons with a declining distribution towards low-frequency processing cochlear turns. BDNF protein was also found within the neuronal projections of the cochlea. A significant reduction of BDNF transcripts in high-frequency processing cochlear neurons was observed during aging, though this did not coincide with a major reduction of BDNF protein. In contrast, BDNF protein in peripheral and central projections was drastically reduced. Our results suggest that reduced BDNF protein levels in auditory nerves over age may be a crucial factor in the altered brainstem plasticity observed during presbycusis.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Regulação da Expressão Gênica/fisiologia , Presbiacusia/metabolismo , RNA Mensageiro/metabolismo , Fatores Etários , Animais , Contagem de Células/métodos , Cóclea/patologia , Modelos Animais de Doenças , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Imunofluorescência/métodos , Gerbillinae , Hibridização In Situ/métodos , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Presbiacusia/genética , Presbiacusia/patologia , Presbiacusia/fisiopatologia , Ratos , Ratos Endogâmicos F344 , Receptor trkB/deficiência , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Gânglio Espiral da Cóclea/patologia
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa