RESUMO
Retinoic acid (RA), a vitamin A (retinol) derivative, has pleiotropic functions during embryonic development. The synthesis of RA requires two enzymatic reactions: oxidation of retinol into retinaldehyde by alcohol dehydrogenases (ADHs) or retinol dehydrogenases (RDHs); and oxidation of retinaldehyde into RA by aldehyde dehydrogenases family 1, subfamily A (ALDH1as), such as ALDH1a1, ALDH1a2 and ALDH1a3. Levels of RA in tissues are regulated by spatiotemporal expression patterns of genes encoding RA-synthesizing and -degrading enzymes, such as cytochrome P450â 26 (Cyp26 genes). Here, we show that RDH10 is important for both sensory and non-sensory formation of the vestibule of the inner ear. Mice deficient in Rdh10 exhibit failure of utricle-saccule separation, otoconial formation and zonal patterning of vestibular sensory organs. These phenotypes are similar to those of Aldh1a3 knockouts, and the sensory phenotype is complementary to that of Cyp26b1 knockouts. Together, these results demonstrate that RDH10 and ALDH1a3 are the key RA-synthesis enzymes involved in vestibular development. Furthermore, we discovered that RA induces Cyp26b1 expression in the developing vestibular sensory organs, which generates the differential RA signaling required for zonal patterning.
Assuntos
Homeostase , Organogênese , Tretinoína/metabolismo , Vestíbulo do Labirinto/embriologia , Oxirredutases do Álcool/genética , Oxirredutases do Álcool/metabolismo , Animais , Camundongos , Camundongos Knockout , Retinal Desidrogenase/genética , Retinal Desidrogenase/metabolismo , Ácido Retinoico 4 Hidroxilase/genética , Ácido Retinoico 4 Hidroxilase/metabolismo , Vestíbulo do Labirinto/citologiaRESUMO
The mechanism by which nutrients in the deep ocean are uplifted to maintain nutrient-rich surface waters in the subarctic Pacific has not been properly described. The iron (Fe) supply processes that control biological production in the nutrient-rich waters are also still under debate. Here, we report the processes that determine the chemical properties of intermediate water and the uplift of Fe and nutrients to the main thermocline, which eventually maintains surface biological productivity. Extremely nutrient-rich water is pooled in intermediate water (26.8 to 27.6 σθ) in the western subarctic area, especially in the Bering Sea basin. Increases of two to four orders in the upward turbulent fluxes of nutrients were observed around the marginal sea island chains, indicating that nutrients are uplifted to the surface and are returned to the subarctic intermediate nutrient pool as sinking particles through the biological production and microbial degradation of organic substances. This nutrient circulation coupled with the dissolved Fe in upper-intermediate water (26.6 to 27.0 σθ) derived from the Okhotsk Sea evidently constructs an area that has one of the largest biological CO2 drawdowns in the world ocean. These results highlight the pivotal roles of the marginal seas and the formation of intermediate water at the end of the ocean conveyor belt.
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Cell transplantation therapy has long been investigated as a therapeutic intervention for neurodegenerative disorders, including spinal cord injury, Parkinson's disease, and amyotrophic lateral sclerosis. Indeed, patients have high hopes for a cell-based therapy. However, there are numerous practical challenges for clinical translation. One major problem is that only very low numbers of donor cells survive and achieve functional integration into the host. Glial scar tissue in chronic neurodegenerative disorders strongly inhibits regeneration, and this inhibition must be overcome to accomplish successful cell transplantation. Intraneural cell transplantation is considered to be the best way to deliver cells to the host. We questioned this view with experiments in vivo on a rat glial scar model of the auditory system. Our results show that intraneural transplantation to the auditory nerve, preceded by chondroitinase ABC (ChABC)-treatment, is ineffective. There is no functional recovery, and almost all transplanted cells die within a few weeks. However, when donor cells are placed on the surface of a ChABC-treated gliotic auditory nerve, they autonomously migrate into it and recapitulate glia- and neuron-guided cell migration modes to repair the auditory pathway and recover auditory function. Surface transplantation may thus pave the way for improved functional integration of donor cells into host tissue, providing a less invasive approach to rescue clinically important neural tracts.
Assuntos
Proliferação de Células , Nervo Coclear/patologia , Regeneração Nervosa , Neuroglia/patologia , Animais , Condroitina ABC Liase/administração & dosagem , Modelos Animais de Doenças , Humanos , Masculino , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/terapia , Ratos , Ratos Sprague-DawleyRESUMO
Inner ear mechanosensory hair cells transduce sound and balance information. Auditory hair cells emerge from a Sox2-positive sensory patch in the inner ear epithelium, which is progressively restricted during development. This restriction depends on the action of signaling molecules. Fibroblast growth factor (FGF) signalling is important during sensory specification: attenuation of Fgfr1 disrupts cochlear hair cell formation; however, the underlying mechanisms remain unknown. Here we report that in the absence of FGFR1 signaling, the expression of Sox2 within the sensory patch is not maintained. Despite the down-regulation of the prosensory domain markers, p27(Kip1), Hey2, and Hes5, progenitors can still exit the cell cycle to form the zone of non-proliferating cells (ZNPC), however the number of cells that form sensory cells is reduced. Analysis of a mutant Fgfr1 allele, unable to bind to the adaptor protein, Frs2/3, indicates that Sox2 maintenance can be regulated by MAP kinase. We suggest that FGF signaling, through the activation of MAP kinase, is necessary for the maintenance of sensory progenitors and commits precursors to sensory cell differentiation in the mammalian cochlea.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Orelha Interna/crescimento & desenvolvimento , Células Ciliadas Auditivas Internas/citologia , Proteínas de Membrana/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Ciclo Celular , Diferenciação Celular/genética , Cóclea/crescimento & desenvolvimento , Cóclea/metabolismo , Orelha Interna/citologia , Epitélio/crescimento & desenvolvimento , Epitélio/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Membrana/metabolismo , Ligação Proteica , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Fatores de Transcrição SOXB1/genética , Transdução de SinaisRESUMO
Hearing loss is a pivotal risk factor for dementia. It has recently emerged that a disruption in the intercommunication between the cochlea and brain is a key process in the initiation and progression of this disease. However, whether the cochlear properties can be influenced by pathological signals associated with dementia remains unclear. In this study, using a mouse model of Alzheimer's disease (AD), we investigated the impacts of the AD-like amyloid ß (Aß) pathology in the brain on the cochlea. Despite little detectable change in the age-related shift of the hearing threshold, we observed quantitative and qualitative alterations in the protein profile in perilymph, an extracellular fluid that fills the path of sound waves in the cochlea. Our findings highlight the potential contribution of Aß pathology in the brain to the disturbance of cochlear homeostasis.
Assuntos
Doença de Alzheimer , Cóclea , Modelos Animais de Doenças , Perilinfa , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Camundongos , Perilinfa/metabolismo , Cóclea/metabolismo , Cóclea/patologia , Peptídeos beta-Amiloides/metabolismo , Camundongos Transgênicos , Perda Auditiva/metabolismo , Perda Auditiva/patologiaRESUMO
OBJECTIVES: This study validated the Japanese version of the Attention-Deficit/Hyperactivity Disorder-Rating Scale-5 (ADHD-RS-5) and the Disruptive Behavior Disorders Rating Scale. We extended the ADHD-RS-5 by adding the oppositional defiant disorder and conduct disorder subscales to compare the two rating scales psychometrically. METHODS: We examined the internal consistency, test-retest reliability, construct validity and criterion validity of the two rating scales in 135 Japanese outpatients aged 6-18 years. RESULTS: The internal consistency and test-retest reliability were good for all the subscales of the two rating scales except for the conduct disorder subscale of the ADHD-RS-5 extended. Good construct validity was revealed by expected correlational patterns between subscales from the two rating scales and the Children Behavior Checklist. The criterion validity was good for all the subscales of the two rating scales rated by parents, while teacher-ratings revealed substantially lower predictive ability for all the subscales. Agreement between parent- and teacher-ratings of the two rating scales was generally moderate and using predictive ratings alone of both ratings showed the best predictive ability among the integration methods examined. CONCLUSION: The two rating scales have sound psychometric properties and will aid in screening and severity assessment of externalizing disorders in Japanese clinical settings.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Comportamento Problema , Criança , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Psicometria/métodos , Reprodutibilidade dos Testes , Japão , Pacientes Ambulatoriais , Escalas de Graduação PsiquiátricaRESUMO
The Totten Glacier in East Antarctica, with an ice volume equivalent to >3.5 m of global sea-level rise, is grounded below sea level and, therefore, vulnerable to ocean forcing. Here, we use bathymetric and oceanographic observations from previously unsampled parts of the Totten continental shelf to reveal on-shelf warm water pathways defined by deep topographic features. Access of warm water to the Totten Ice Shelf (TIS) cavity is facilitated by a deep shelf break, a broad and deep depression on the shelf, a cyclonic circulation that carries warm water to the inner shelf, and deep troughs that provide direct access to the TIS cavity. The temperature of the warmest water reaching the TIS cavity varies by ~0.8 °C on an interannual timescale. Numerical simulations constrained by the updated bathymetry demonstrate that the deep troughs play a critical role in regulating ocean heat transport to the TIS cavity and the subsequent basal melt of the ice shelf.
RESUMO
Antarctic Bottom Water (AABW) occupies the abyssal layer of the world ocean and contributes to the global overturning circulation. It originates from dense shelf water, which forms from brine rejection during sea ice production. An important region of AABW formation has been identified off the Cape Darnley polynya. However, it remains unclear why and how high ice production leads to AABW formation. Using moored acoustic measurements and a satellite microwave algorithm, we reveal that underwater frazil ice dominates in the polynya. This underwater ice formation prevents heat-insulating surface-cover ice forming, thereby enabling efficient ice production. The high ice production in the nearshore and longer residence times create high-salinity source water for the AABW. Underwater frazil ice occurs as long as strong winds continue and occasionally penetrates depths of at least 80 m. Deep-penetrating frazil ice is particularly prominent in this polynya, while it also occurs in other Antarctic coastal polynyas.
RESUMO
BACKGROUND: Sudden sensorineural hearing loss (SSHL) is a common condition in which patients lose the hearing in one ear within 3 days. Systemic glucocorticoid treatments have been used as standard therapy for SSHL; however, about 20% of patients do not respond. We tested the safety and efficacy of topical insulin-like growth factor 1 (IGF1) application using gelatin hydrogels as a treatment for SSHL. METHODS: Patients with SSHL that showed no recovery to systemic glucocorticoid administration were recruited. We applied gelatin hydrogels, impregnated with recombinant human IGF1, into the middle ear. The primary outcome measure was the proportion of patients showing hearing improvement 12 weeks after the test treatment. The secondary outcome measures were the proportion of patients showing improvement at 24 weeks and the incidence of adverse events. The null hypothesis was that 33% of patients would show hearing improvement, as was reported for a historical control after hyperbaric oxygen therapy. RESULTS: In total, 25 patients received the test treatment at a median of 23 days (range 15-32) after the onset of SSHL, between 2007 and 2009. At 12 weeks after the test treatment, 48% (95% CI 28% to 69%; P = 0.086) of patients showed hearing improvement, and the proportion increased to 56% (95% CI 35% to 76%; P = 0.015) at 24 weeks. No serious adverse events were observed. CONCLUSIONS: Topical IGF1 application using gelatin hydrogels is well tolerated and may be efficacious for hearing recovery in patients with SSHL that is resistant to systemic glucocorticoids.
Assuntos
Perda Auditiva Neurossensorial/tratamento farmacológico , Hidrogéis/administração & dosagem , Fator de Crescimento Insulin-Like I/administração & dosagem , Administração Tópica , Adulto , Idoso , Feminino , Glucocorticoides/uso terapêutico , Humanos , Hidrogéis/efeitos adversos , Fator de Crescimento Insulin-Like I/efeitos adversos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
The post-natal cochlear mammalian epithelium have no capacity to proliferate in tissue, however, dissociated supporting cells exhibit the ability to divide and trans-differentiate into new hair cells in vitro, with this process found to be correlated with the downregulation of the cyclin-dependent kinase inhibitor p27(kip1). Here we show that knockdown of p27(kip1) with short hairpin RNA-expressing vectors results in the cell-cycle reentry of post-mitotic supporting cells in the post-natal mouse cochleae ex vivo. The p27(kip1)-knockdown cells incorporated BrdU, and then divided into two daughter cells. However, there was also activation of the apoptotic pathway in some supporting cells. These results indicate that the use of RNA interference to target p27(kip1) is an effective strategy for inducing cell-cycle reentry in post-mitotic supporting cells in the post-natal mammalian cochleae, although additional manipulations of the supporting cells are required to achieve hair cell regeneration.
Assuntos
Ciclo Celular/fisiologia , Cóclea , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Inativação Gênica , Animais , Animais Recém-Nascidos , Antimetabólitos/metabolismo , Apoptose/fisiologia , Bromodesoxiuridina/metabolismo , Cóclea/citologia , Cóclea/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/genética , Eletroporação , Células Ciliadas Auditivas/citologia , Células Ciliadas Auditivas/fisiologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Interferência de RNA , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
Mass loss from the Antarctic ice sheet, Earth's largest freshwater reservoir, results directly in global sea-level rise and Southern Ocean freshening. Observational and modeling studies have demonstrated that ice shelf basal melting, resulting from the inflow of warm water onto the Antarctic continental shelf, plays a key role in the ice sheet's mass balance. In recent decades, warm ocean-cryosphere interaction in the Amundsen and Bellingshausen seas has received a great deal of attention. However, except for Totten Ice Shelf, East Antarctic ice shelves typically have cold ice cavities with low basal melt rates. Here we present direct observational evidence of high basal melt rates (7-16 m yr-1) beneath an East Antarctic ice shelf, Shirase Glacier Tongue, driven by southward-flowing warm water guided by a deep continuous trough extending to the continental slope. The strength of the alongshore wind controls the thickness of the inflowing warm water layer and the rate of basal melting.
RESUMO
Each vestibular sensory epithelium in the inner ear is divided morphologically and physiologically into two zones, called the striola and extrastriola in otolith organ maculae, and the central and peripheral zones in semicircular canal cristae. We found that formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)-mediated degradation of retinoic acid (RA). In Cyp26b1 conditional knockout mice, formation of striolar/central zones is compromised, such that they resemble extrastriolar/peripheral zones in multiple features. Mutants have deficient vestibular evoked potential (VsEP) responses to jerk stimuli, head tremor and deficits in balance beam tests that are consistent with abnormal vestibular input, but normal vestibulo-ocular reflexes and apparently normal motor performance during swimming. Thus, degradation of RA during embryogenesis is required for formation of highly specialized regions of the vestibular sensory epithelia with specific functions in detecting head motions.
Assuntos
Membrana dos Otólitos/embriologia , Ácido Retinoico 4 Hidroxilase/metabolismo , Tretinoína/metabolismo , Animais , Potenciais Evocados/genética , Potenciais Evocados/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Cabeça/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteopontina/metabolismo , Membrana dos Otólitos/citologia , Membrana dos Otólitos/metabolismo , Retinal Desidrogenase/genética , Retinal Desidrogenase/metabolismo , Ácido Retinoico 4 Hidroxilase/genética , Sáculo e Utrículo/citologia , Sáculo e Utrículo/embriologia , Tremor/genética , Tremor/fisiopatologia , Testes de Função Vestibular , Vestíbulo do Labirinto/embriologia , Vestíbulo do Labirinto/metabolismoRESUMO
TRIOBP remodels the cytoskeleton by forming unusually dense F-actin bundles and is implicated in human cancer, schizophrenia, and deafness. Mutations ablating human and mouse TRIOBP-4 and TRIOBP-5 isoforms are associated with profound deafness, as inner ear mechanosensory hair cells degenerate after stereocilia rootlets fail to develop. However, the mechanisms regulating formation of stereocilia rootlets by each TRIOBP isoform remain unknown. Using 3 new Triobp mouse models, we report that TRIOBP-5 is essential for thickening bundles of F-actin in rootlets, establishing their mature dimensions and for stiffening supporting cells of the auditory sensory epithelium. The coiled-coil domains of this isoform are required for reinforcement and maintenance of stereocilia rootlets. A loss of TRIOBP-5 in mouse results in dysmorphic rootlets that are abnormally thin in the cuticular plate but have increased widths and lengths within stereocilia cores, and causes progressive deafness recapitulating the human phenotype. Our study extends the current understanding of TRIOBP isoform-specific functions necessary for life-long hearing, with implications for insight into other TRIOBPopathies.
Assuntos
Audição/fisiologia , Proteínas dos Microfilamentos/fisiologia , Estereocílios/fisiologia , Actinas/fisiologia , Animais , Surdez/etiologia , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/deficiência , Isoformas de Proteínas/fisiologia , Estereocílios/ultraestruturaRESUMO
HYPOTHESIS: Local application of recombinant human insulin-like growth factor 1 (rhIGF-1) via a biodegradable hydrogel after onset of noise-induced hearing loss (NIHL) can attenuate functional and histologic damage. BACKGROUND: The biodegradable gelatin hydrogel makes a complex with drugs by static electric charges and releases drugs by degradation of gelatin polymers. We previously demonstrated the efficacy of local rhIGF-1 application via hydrogels before noise exposure for prevention of NIHL. METHODS: First, we used an enzyme-linked immunosorbent assay to measure human IGF-1 concentrations in the cochlear fluid after placing a hydrogel containing rhIGF-1 onto the round window membrane of guinea pigs. Second, the functionality and the histology of guinea pig cochleae treated with local rhIGF-1 application at different concentrations after noise exposure were examined. Control animals were treated with a hydrogel immersed in physiologic saline alone. RESULTS: The results revealed sustained delivery of rhIGF-1 into the cochlear fluid via the hydrogel. The measurement of auditory brainstem responses demonstrated that local rhIGF-1 treatment significantly reduced the threshold elevation from noise. Histologic analysis exhibited increased survival of outer hair cells by local rhIGF-1 application through the hydrogel. CONCLUSION: These findings indicate that local rhIGF-1 treatment via gelatin hydrogels is effective for treatment of NIHL.
Assuntos
Cóclea , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Fator de Crescimento Insulin-Like I/administração & dosagem , Fator de Crescimento Insulin-Like I/uso terapêutico , Animais , Limiar Auditivo/fisiologia , Química Farmacêutica , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Feminino , Gelatina , Cobaias , Perda Auditiva Provocada por Ruído/patologia , Hidrogéis , Imuno-Histoquímica , Injeções , Fator de Crescimento Insulin-Like I/efeitos adversos , Ruído/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêuticoRESUMO
Social isolation of rodents (SI) elicits a variety of stress responses such as increased aggressiveness, hyper-locomotion, and reduced susceptibility to pentobarbital. To obtain a better understanding of the relevance of SI-induced behavioral abnormalities to psychiatric disorders, we examined the effect of SI on latent learning as an index of spatial attention, and discussed the availability of SI as an epigenetic model of attention deficit hyperactivity disorder (ADHD). Except in specially stated cases, 4-week-old male mice were housed in a group or socially isolated for 3-70 days before experiments. The animals socially isolated for 1 week or more exhibited spatial attention deficit in the water-finding test. Re-socialized rearing for 5 weeks after 1-week SI failed to attenuate the spatial attention deficit. The effect of SI on spatial attention showed no gender difference or correlation with increased aggressive behavior. Moreover, SI had no effect on cognitive performance elucidated in a modified Y-maze or an object recognition test, but it significantly impaired contextual and conditional fear memory elucidated in the fear-conditioning test. Drugs used for ADHD therapy, methylphenidate (1-10 mg/kg, i.p.) and caffeine (0.5-1 mg/kg, i.p.), improved SI-induced latent learning deficit in a manner reversible with cholinergic but not dopaminergic antagonists. Considering the behavioral features of SI mice together with their susceptibility to ADHD drugs, the present findings suggest that SI provides an epigenetic animal model of ADHD and that central cholinergic systems play a role in the effect of methylphenidate on SI-induced spatial attention deficit.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Atenção/fisiologia , Aprendizagem/fisiologia , Isolamento Social , Comportamento Espacial/fisiologia , Agressão/efeitos dos fármacos , Animais , Atenção/efeitos dos fármacos , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Modelos Animais de Doenças , Medo/efeitos dos fármacos , Medo/fisiologia , Feminino , Aprendizagem/efeitos dos fármacos , Masculino , Metilfenidato/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Comportamento Espacial/efeitos dos fármacosRESUMO
BACKGROUND: In this cohort study, we investigated the background factors promoting and inhibiting a return to work after long-term absence from work due to sickness among psychiatric outpatients. METHODS: We surveyed 73 psychiatric outpatients who were absent from work for a long time (POAWs), and 42 POAWs who were followed up until the 2-year time point. GHQ-30, NEO-FFI, MPS, RSS and questionnaires in-quiring about background factors, including relationships with others, were used, and the data were compared those who had returned to the work by the 2-year time point with those who had not. RESULTS: Factors promoting a return to work were "extroversion (NEO-FFI)", "organization (MPS)", and "neuroticism (NEO-FFI)", whereas "concern over mistakes (MPS)" was an inhibitory factor. Period of absence from work was markedly associated with psychological stress outside the workplace, while depression, anxiety, and even psychological stress inside the workplace were not. CONCLUSIONS: POAWs left from work by the result of psychiatric problems like depression, anxiety and so on. These were the result of their background factors, their characteristics, and psychological stress in/outside the workplace. After two-year psychiatric treatment, their psychological stress outside the workplace remained as an essential matter. These were inescapable because they were set in private place, while stress at the workplace could be left at the workplace.
RESUMO
Social isolation stress induces behavioral disturbances such as aggression, cognitive impairments, and deficits in prepulse inhibition in mice. Social isolation mice have, therefore, been studied as an animal model of neuropsychiatric disorders such as schizophrenia. Recently, the decrease in early growth response (Egr) gene expression levels were reported in the post-mortem brains of schizophrenia patients. In this study, we investigate the effects of social isolation stress on the expression levels of Egr mRNA and protein in the frontal cortex. Social isolation stress exposure significantly down-regulated the expression of Egr-1 protein and Egr-1 gene transcript in nucleus of cortical neurons in a manner dependent on a social isolation period. This stress had no effect on the expression level of Egr-1 in the striatum or the expression levels of other Egr family members (Egr-2, -3, and -4) in the frontal cortex. These results suggest that the decrease in Egr-1 expression in the frontal cortex may be involved in social isolation stress-induced behavioral abnormalities.
Assuntos
Comportamento Animal/fisiologia , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Transtornos Neurocognitivos/genética , Isolamento Social , Estresse Psicológico/genética , Animais , Modelos Animais de Doenças , Regulação para Baixo/genética , Proteína 1 de Resposta de Crescimento Precoce/antagonistas & inibidores , Proteína 1 de Resposta de Crescimento Precoce/genética , Lobo Frontal/metabolismo , Lobo Frontal/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/fisiopatologia , Isolamento Social/psicologia , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologiaRESUMO
OBJECT: Hearing levels following microsurgical treatment gradually deteriorate in a number of patients treated for vestibular schwannoma (VS), especially in the subacute postoperative stage. The cause of this late-onset deterioration of hearing is not completely understood. The aim of this study was to investigate the possibility that reactive gliosis is a contributory factor. METHODS: Mechanical damage to nerve tissue is a feature of complex surgical procedures. To explore this aspect of VS treatment, the authors compressed rat auditory nerves with 2 different degrees of injury while monitoring the compound action potentials of the auditory nerve and the auditory brainstem responses. In this experimental model, the axons of the auditory nerve were quantitatively and highly selectively damaged in the cerebellopontine angle without permanent compromise of the blood supply to the cochlea. The temporal bones were processed for immunohistochemical analysis at 1 week and at 8 weeks after compression. RESULTS: Reactive gliosis was induced not only in the auditory nerve but also in the cochlear nucleus following mechanical trauma in which the general shape of the auditory brainstem response was maintained. There was a substantial outgrowth of astrocytic processes from the transitional zone into the peripheral portion of the auditory nerve, leading to an invasion of dense gliotic tissue in the auditory nerve. The elongated astrocytic processes ran in parallel with the residual auditory neurons and entered much further into the cochlea. Confocal images disclosed fragments of neurons scattered in the gliotic tissue. In the cochlear nucleus, hypertrophic astrocytic processes were abundant around the soma of the neurons. The transverse diameter of the auditory nerve at and proximal to the compression site was considerably reduced, indicating atrophy, especially in rats in which the auditory nerve was profoundly compressed. CONCLUSIONS: The authors found for the first time that mechanical stress to the auditory nerve causes substantial reactive gliosis in both the peripheral and central auditory pathways within 1-8 weeks. Progressive reactive gliosis following surgical stress may cause dysfunction in the auditory pathways and may be a primary cause of progressive hearing loss following microsurgical treatment for VS.