RESUMO
Usher syndrome (USH) is the most common form of monogenic deaf-blindness. Loss of vision is untreatable and there are no suitable animal models for testing therapeutic strategies of the ocular constituent of USH, so far. By introducing a human mutation into the harmonin-encoding USH1C gene in pigs, we generated the first translational animal model for USH type 1 with characteristic hearing defect, vestibular dysfunction, and visual impairment. Changes in photoreceptor architecture, quantitative motion analysis, and electroretinography were characteristics of the reduced retinal virtue in USH1C pigs. Fibroblasts from USH1C pigs or USH1C patients showed significantly elongated primary cilia, confirming USH as a true and general ciliopathy. Primary cells also proved their capacity for assessing the therapeutic potential of CRISPR/Cas-mediated gene repair or gene therapy in vitro. AAV-based delivery of harmonin into the eye of USH1C pigs indicated therapeutic efficacy in vivo.
Assuntos
Síndromes de Usher , Animais , Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto , Humanos , Células Fotorreceptoras , Suínos , Síndromes de Usher/genética , Síndromes de Usher/metabolismo , Síndromes de Usher/terapiaRESUMO
The LIM homeodomain transcription factor ISL1 is essential for the different aspects of neuronal development and maintenance. In order to study the role of ISL1 in the auditory system, we generated a transgenic mouse (Tg) expressing Isl1 under the Pax2 promoter control. We previously reported a progressive age-related decline in hearing and abnormalities in the inner ear, medial olivocochlear system, and auditory midbrain of these Tg mice. In this study, we investigated how Isl1 overexpression affects sound processing by the neurons of the inferior colliculus (IC). We recorded extracellular neuronal activity and analyzed the responses of IC neurons to broadband noise, clicks, pure tones, two-tone stimulation and frequency-modulated sounds. We found that Tg animals showed a higher inhibition as displayed by two-tone stimulation; they exhibited a wider dynamic range, lower spontaneous firing rate, longer first spike latency and, in the processing of frequency modulated sounds, showed a prevalence of high-frequency inhibition. Functional changes were accompanied by a decreased number of calretinin and parvalbumin positive neurons, and an increased expression of vesicular GABA/glycine transporter and calbindin in the IC of Tg mice, compared to wild type animals. The results further characterize abnormal sound processing in the IC of Tg mice and demonstrate that major changes occur on the side of inhibition.
Assuntos
Percepção Auditiva/genética , Colículos Inferiores/fisiologia , Proteínas com Homeodomínio LIM/genética , Fatores de Transcrição/genética , Animais , Percepção Auditiva/fisiologia , Limiar Auditivo/fisiologia , Encéfalo/fisiologia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Feminino , Expressão Gênica/genética , Audição , Humanos , Colículos Inferiores/metabolismo , Proteínas com Homeodomínio LIM/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/fisiologia , Fator de Transcrição PAX2/genética , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/metabolismoRESUMO
AUT00063 and AUT00202 are novel pharmaceutical modulators of the Kv3 subfamily of voltage-gated K+ channels. Kv3.1 channels, which control fast firing of many central auditory neurons, have been shown to decline with age and this may contribute to age-related deficits in central auditory processing. In the present study, the effects of the two novel compounds that specifically modulate Kv3 channels on auditory temporal processing were examined in aged (19-25-month-old) and young-adult (3-5 month-old) Fischer 344 rats (F344) using a behavioral gap-prepulse inhibition (gap-PPI) paradigm. The acoustic startle response (ASR) and its inhibition induced by a gap in noise were measured before and after drug administration. Hearing thresholds in tested rats were evaluated by the auditory brainstem response (ABR). Aged F344 rats had significantly higher ABR thresholds, lower amplitudes of ASR, and weaker gap-PPI compared with young-adult rats. No influence of AUT00063 and AUT00202 administration was observed on ABR hearing thresholds in rats of both age groups. AUT00063 and AUT00202 had suppressive effect on ASR of F344 rats that was more pronounced with AUT00063. The degree of suppression depended on the dose and age of the rats. Both compounds significantly improved the gap-PPI performance in gap detection tests in aged rats. These results indicate that AUT00063 and AUT00202 may influence intrinsic firing properties of neurons in the central auditory system of aged animals and have the potential to treat aged-related hearing disorders.
Assuntos
Percepção Auditiva , Potenciais Evocados Auditivos do Tronco Encefálico , Estimulação Acústica , Animais , Limiar Auditivo , Inibição Pré-Pulso , Ratos , Ratos Endogâmicos F344 , Reflexo de Sobressalto , Canais de Potássio ShawRESUMO
Noise-exposed rat pups provide a model of early deprivation of sensory input to the central auditory system, allowing the study of developmental neuroplasticity. Our previous results have demonstrated that a brief exposure of rats to broadband noise (125â¯dB SPL 8â¯min, 14th postnatal day) at the onset of hearing resulted in an altered intensity perception and frequency discrimination in adulthood despite normal hearing thresholds. In this study, we assessed the gap-detection ability and possible presence of tinnitus- and hyperacusis-like behavior in adult rats after the same neonatal acoustic trauma, using measurements of the acoustic startle response (ASR) in quiet and noisy environments and its prepulse inhibition by gaps in noise (gap-PPI). A significant deficit in the ability to detect gap was observed in the exposed rats when 55â¯dB SPL broadband noise was used as background. An increase of noise intensity to 65-75â¯dB SPL led to strengthening of the gap-PPI in exposed animals, which approached the gap-PPI values of control animals at these levels. Behavioral signs of tinnitus (gap detection deficits in 10â¯kHz narrow band noise) were found in 25% of exposed rats. An increased sensitivity to continuous noise was manifested in all exposed rats by suppression of the ASR at significantly lower background noise levels than in the controls. This effect was particularly pronounced in rats with tinnitus-like behavior. Our results indicate that neonatal acoustic trauma, producing only a transient threshold shift, may produce permanent abnormalities in suprathreshold auditory functions and the development of tinnitus and hyperacusis-like behavior.
Assuntos
Limiar Auditivo , Comportamento Animal , Transtornos da Audição/etiologia , Transtornos da Audição/psicologia , Perda Auditiva Provocada por Ruído/psicologia , Ruído/efeitos adversos , Animais , Feminino , Hiperacusia/etiologia , Hiperacusia/psicologia , Masculino , Plasticidade Neuronal , Gravidez , Ratos , Ratos Long-Evans , Reflexo de Sobressalto , Zumbido/etiologia , Zumbido/psicologiaRESUMO
Inhibitory circuits in the auditory brainstem undergo multiple postnatal changes that are both activity-dependent and activity-independent. We tested to see if the shift from GABA- to glycinergic transmission, which occurs in the rat medial nucleus of the trapezoid body (MNTB) around the onset of hearing, depends on sound-evoked neuronal activity. We prevented the activity by bilateral cochlear ablations in early postnatal rats and studied ionotropic GABA and glycine receptors in MNTB neurons after hearing onset. The removal of the cochlea decreased responses of GABAA and glycine receptors to exogenous agonists as well as the amplitudes of inhibitory postsynaptic currents. The reduction was accompanied by a decrease in the number of glycine receptor- or vesicular GABA transporter-immunopositive puncta. Furthermore, the ablations markedly affected the switch in presynaptic GABAA to glycine receptors. The increase in the expression of postsynaptic glycine receptors and the shift in inhibitory transmitters were not prevented. The results suggest that inhibitory transmission in the MNTB is subject to multiple developmental signals and support the idea that auditory experience plays a role in the maturation of the brainstem glycinergic circuits.
Assuntos
Técnicas de Ablação , Cóclea/fisiopatologia , Cóclea/cirurgia , Inibição Neural/fisiologia , Transmissão Sináptica , Corpo Trapezoide/fisiologia , Animais , Animais Recém-Nascidos , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Agonistas de Receptores de GABA-A/farmacologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Inibição Neural/efeitos dos fármacos , Ratos , Receptores de GABA-A/fisiologia , Receptores de Glicina/agonistas , Receptores de Glicina/metabolismo , Receptores de Glicina/fisiologia , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismoRESUMO
Temporal bone reconstruction is a persisting problem following middle ear cholesteatoma surgery. Seeking to advance the clinical transfer of stem cell therapy we attempted the reconstruction of temporal bone using a composite bioartificial graft based on a hydroxyapatite bone scaffold combined with human bone marrow-derived mesenchymal stromal cells (hBM-MSCs). The aim of this study was to evaluate the effect of the combined biomaterial on the healing of postoperative temporal bone defects and the preservation of physiological hearing functions in a guinea pig model. The treatment's effect could be observed at 1 and 2 months after implantation of the biomaterial, as opposed to the control group. The clinical evaluation of our results included animal survival, clinical signs of an inflammatory response, and exploration of the tympanic bulla. Osteogenesis, angiogenesis, and inflammation were evaluated by histopathological analyses, whereas hBM-MSCs survival was evaluated by immunofluorescence assays. Hearing capacity was evaluated by objective audiometric methods, i.e. auditory brainstem responses and otoacoustic emission. Our study shows that hBM-MSCs, in combination with hydroxyapatite scaffolds, improves the repair of bone defects providing a safe and effective alternative in their treatment following middle ear surgery due to cholesteatoma.
Assuntos
Colesteatoma da Orelha Média , Audição , Mastoidectomia/efeitos adversos , Transplante de Células-Tronco Mesenquimais , Osteogênese , Complicações Pós-Operatórias , Recuperação de Função Fisiológica , Osso Temporal , Animais , Colesteatoma da Orelha Média/metabolismo , Colesteatoma da Orelha Média/patologia , Colesteatoma da Orelha Média/cirurgia , Modelos Animais de Doenças , Cobaias , Xenoenxertos , Humanos , Masculino , Complicações Pós-Operatórias/metabolismo , Complicações Pós-Operatórias/patologia , Complicações Pós-Operatórias/terapia , Osso Temporal/lesões , Osso Temporal/metabolismo , Osso Temporal/patologiaRESUMO
Recently, there has been growing evidence that development and maturation of the auditory system depends substantially on the afferent activity supplying inputs to the developing centers. In cases when this activity is altered during early ontogeny as a consequence of, e.g., an unnatural acoustic environment or acoustic trauma, the structure and function of the auditory system may be severely affected. Pathological alterations may be found in populations of ribbon synapses of the inner hair cells, in the structure and function of neuronal circuits, or in auditory driven behavioral and psychophysical performance. Three characteristics of the developmental impairment are of key importance: first, they often persist to adulthood, permanently influencing the quality of life of the subject; second, their manifestations are different and sometimes even contradictory to the impairments induced by noise trauma in adulthood; third, they may be 'hidden' and difficult to diagnose by standard audiometric procedures used in clinical practice. This paper reviews the effects of early interventions to the auditory system, in particular, of sound exposure during ontogeny. We summarize the results of recent morphological, electrophysiological, and behavioral experiments, discuss the putative mechanisms and hypotheses, and draw possible consequences for human neonatal medicine and noise health.
Assuntos
Vias Auditivas/fisiopatologia , Percepção Auditiva , Perda Auditiva Provocada por Ruído/etiologia , Audição , Ruído/efeitos adversos , Estimulação Acústica , Animais , Vias Auditivas/embriologia , Vias Auditivas/patologia , Limiar Auditivo , Perda Auditiva Provocada por Ruído/patologia , Perda Auditiva Provocada por Ruído/fisiopatologia , Humanos , Prognóstico , Fatores de RiscoRESUMO
Fischer 344 (F344) rats represent a strain that is frequently used as a model for fast aging. In this study, we systematically compare the hearing function during aging in male and female F344 rats, by recording auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). In addition to this, the functional parameters are correlated with the cochlear histology. The parameters of the hearing function were not different in the young (3-month-old) male and female F344 rats; the gender differences occurred only in adult and aged animals. In 8-24-month-old males, the ABR thresholds were higher and the ABR amplitudes were smaller than those measured in females of the same age. There were no gender differences in the neural adaptation tested by recording ABRs, elicited by a series of clicks with varying inter-click interval (ICI). Amplitudes of DPOAEs in both the males and females decreased with age, but in the males, the decrease of DPOAE amplitudes was faster. In males older than 20 months, the DPOAEs were practically absent, whereas in 20-24-month-old females, the DPOAEs were still measurable. There were no gender differences in the number of surviving outer hair cells (OHC) and the number of inner hair cell ribbon synapses in aged animals. The main difference was found in the stria vascularis (SV). Whereas the SV was well preserved in females up to the age of 24 months, in most of the age-matched males the SV was evidently deteriorated. The results demonstrate more pronounced age-related changes in the cochlear morphology, hearing thresholds, ABR amplitudes and DPOAE amplitudes in F344 males compared with females.
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 RiscoRESUMO
Canal wall down mastoidectomy is one of the most effective treatments for cholesteatoma. However, it results in anatomical changes in the external and middle ear with a negative impact on the patient's quality of life. To provide complete closure of the mastoid cavity and normalize the anatomy of the middle and external ear, we used human multipotent mesenchymal stromal cells (hMSCs), GMP grade, in a guinea pig model. A method for preparing a biomaterial composed of hMSCs, hydroxyapatite, and tissue glue was developed. Animals from the treated group were implanted with biomaterial composed of hydroxyapatite and hMSCs, while animals in the control group received hydroxyapatite alone. When compared to controls, the group implanted with hMSCs showed a significantly higher ratio of new bone formation (p = 0.00174), as well as a significantly higher volume percentage of new immature bone (p = 0.00166). Our results proved a beneficial effect of hMSCs on temporal bone formation and provided a promising tool to improve the quality of life of patients after canal wall down mastoidectomy by hMSC implantation.
Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Células-Tronco Multipotentes/citologia , Cuidados Pós-Operatórios , Osso Temporal/patologia , Osso Temporal/cirurgia , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Orelha Interna/patologia , Cobaias , Humanos , Inflamação/patologia , Masculino , Osso Temporal/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
There are powerful pathways descending from the auditory cortex (AC) to the inferior colliculus (IC), yet their function is not fully understood. The aim of this study is to examine the effects of a reversible cortical inactivation, achieved by cooling of the AC, on the responses of neurons in the rat IC. Extracellular single-unit or multi-unit activity was recorded in the IC of anaesthetized rats with a 16-channel multielectrode probe introduced along the IC dorso-ventral axis through the dorsal cortex (DCIC) to the central nucleus of the IC (CIC). Cooling of the AC produced an increase in spontaneous activity and magnitude of the sound-evoked response in 47% of the IC neurons. Maximal changes in the neuronal activity were observed in the DCIC and the central part of the CIC. The final segments of the sustained responses to 60 ms stimuli and the off responses were more affected than the onset segments. Inactivation of the AC resulted in a suppression of the post-excitatory inhibition and neuronal adaptation, which was reflected in a pronounced enhancement of synchronized responses to a series of fast repeated clicks. The response parameters recovered, at least partly, to the pre-cooling levels 1 h after the cooling cessation. The frequency tuning properties of the IC neurons did not show any significant changes during the cooling period. The results demonstrate that AC cooling inactivates excitatory corticofugal pathways and results in a less activated intrinsic inhibitory network in the IC.
Assuntos
Córtex Auditivo/fisiopatologia , Regulação da Temperatura Corporal , Hipotermia Induzida , Colículos Inferiores/fisiopatologia , Estimulação Acústica , Adaptação Fisiológica , Animais , Córtex Auditivo/metabolismo , Córtex Auditivo/patologia , Vias Auditivas/fisiopatologia , Potenciais Evocados Auditivos , Feminino , Neurônios GABAérgicos/metabolismo , Colículos Inferiores/metabolismo , Colículos Inferiores/patologia , Inibição Neural , Ratos Long-Evans , Fatores de TempoRESUMO
Sound exposure during the early postnatal period can significantly influence the function of the auditory system in rats during adulthood. In the present study, rat pups (strain Long-Evans) were exposed to broad-band noise at 125dB SPL for 8, 12 or 25min on postnatal day 14 and then at the age of 3-5months their frequency discrimination at 4 and 16kHz was assessed using a modified method of the prepulse inhibition of the acoustic startle reflex. In all groups of exposed rats, an altered frequency discrimination of the tonal stimuli was observed, in comparison with controls, at 70dB SPL. A worsening of frequency discrimination was observed even in animals exposed for 8min, the auditory thresholds of which were almost identical to that of control animals. The individual auditory thresholds did not correlate with frequency discrimination. The difference in frequency discrimination between the exposed and control animals disappeared at 85-90dB SPL. Our data suggests that brief noise exposure during the critical period of development results in the altered frequency discrimination at moderate sound intensities in adult rats, which may appear even in individuals with normal hearing thresholds.
Assuntos
Limiar Auditivo/fisiologia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Ruído , Inibição Pré-Pulso/fisiologia , Reflexo de Sobressalto/fisiologia , Estimulação Acústica , Análise de Variância , Animais , Animais Recém-Nascidos , Eletroencefalografia , Feminino , Masculino , Psicoacústica , Ratos , Ratos Long-Evans , Fatores de TempoRESUMO
Even brief acoustic trauma during the critical period of development that results in no permanent hearing threshold shift may lead to altered auditory processing in adulthood. By monitoring the acoustic startle response (ASR), we examined the development of auditory function in control rats and in rats exposed to intense noise at the 14th postnatal day (P14). First ASRs appeared on P10-P11 to intense low-frequency tones. By P14, the range of sound intensities and frequencies eliciting ASRs extended considerably, the ASR reactivity being similar at all frequencies (4-32 kHz). During the subsequent two weeks, ASR amplitudes to low-frequency stimuli (4-8 kHz) increased, whereas the ASRs to high-frequency tones were maintained (16 kHz) or even decreased (32 kHz). Compared to controls, noise exposure on P14 (125 dB SPL for 8, 12, or 25 min) produced transient hyper-reactivity to startle stimuli, manifested by a decrease of ASR thresholds and an increase of ASR amplitudes. ASR enhancement occurred regardless of permanent hearing loss and was more pronounced at high frequencies. The hyper-reactivity of ASRs declined by P30; the ASR amplitudes in adult exposed rats were lower than in controls. The histological control did not reveal loss of hair cells in adult exposed rats, however, the number of inner hair cell ribbon synapses was significantly decreased, especially in the high-frequency part of the cochlea. The results indicate that early acoustic trauma may result in complex changes of ASRs during development.
Assuntos
Estimulação Acústica/efeitos adversos , Percepção Auditiva/fisiologia , Cóclea/crescimento & desenvolvimento , Reflexo de Sobressalto/fisiologia , Animais , Cóclea/citologia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Feminino , Testes Auditivos , Ratos Long-Evans , Limiar Sensorial/fisiologia , Sinapses/fisiologiaRESUMO
The structure and function of the auditory system may be influenced by acoustic stimulation, especially during the early postnatal period. This study explores the effects of an acoustically enriched environment applied during the third and fourth week of life on the responsiveness of inferior colliculus neurons in rats. The enrichment comprised a spectrally and temporally modulated complex sound reinforced with several target acoustic stimuli, one of which triggered a reward release. The exposure permanently influenced neuronal representation of the sound frequency and intensity, resulting in lower excitatory thresholds at neuronal characteristic frequency, an increased frequency selectivity, larger response magnitudes, steeper rate-intensity functions and an increased spontaneous activity. The effect was general and non-specific, spanning the entire hearing range - no changes specific to the frequency band of the target stimuli were found. The alterations depended on the activity of animals during the enrichment - a higher activity of rats in the stimulus-reward paradigm led to more profound changes compared with the treatment when the stimulus-reward paradigm was not used. Furthermore, the exposure in early life led to permanent changes in response parameters, whereas the application of the same environment in adulthood influenced only a subset of the examined parameters and had only a temporary effect. These findings indicate that a rich and stimulating acoustic environment during early development, particularly when reinforced by positive feedback, may permanently affect signal processing in the subcortical auditory nuclei, including the excitatory thresholds of neurons and their frequency and intensity resolution.
Assuntos
Percepção Auditiva/fisiologia , Colículos Inferiores/crescimento & desenvolvimento , Colículos Inferiores/fisiologia , Neurônios/fisiologia , Recompensa , Estimulação Acústica/métodos , Potenciais de Ação , Animais , Meio Ambiente , Feminino , Microeletrodos , Ratos Long-EvansRESUMO
The strength of the acoustic startle response (ASR) to short bursts of broadband noise or tone pips (4, 8 and 16 kHz) and the prepulse inhibition (PPI) of the ASR elicited by prepulse tones (4, 8 and 16 kHz) were measured in parvalbumin-deficient (PV-/-) mice and in age-matched PV+/+ mice as controls. Hearing thresholds as determined from recordings of auditory brainstem responses were found to be similar in both genotypes. The ASRs to broadband noise and tones of low and middle frequencies were stronger than the ASRs in response to high-frequency tones in both groups. In PV-/- mice, we observed smaller ASR amplitudes in response to relatively weak startling stimuli (80-90 dB sound pressure level (SPL)) of either broadband noise or 8-kHz tones compared to those recorded in PV+/+ mice. For these startling stimuli, PV-/- mice had higher ASR thresholds and longer ASR latencies. PPI of the ASR in PV-/- mice was less effective than in PV+/+ mice, for all tested prepulse frequencies (4, 8 or 16 kHz) at 70 dB SPL. Our findings demonstrate no effect of PV deficiency on hearing thresholds in PV-/- mice. However, the frequency-specific differences in the ASR and the significant reduction of PPI of ASR likely reflect specific changes of neuronal circuits, mainly inhibitory, in the auditory centers in PV-deficient mice.
Assuntos
Audição/fisiologia , Parvalbuminas/metabolismo , Reflexo de Sobressalto , Estimulação Acústica , Animais , Potenciais Evocados Auditivos do Tronco Encefálico , Camundongos Endogâmicos C57BL , Camundongos Knockout , Parvalbuminas/genética , Limiar SensorialRESUMO
We investigated the representation of four typical guinea pig vocalizations in the auditory cortex (AI) in anesthetized guinea pigs with the aim to compare cortical data to the data already published for identical calls in subcortical structures - the inferior colliculus (IC) and medial geniculate body (MGB). Like the subcortical neurons also cortical neurons typically responded to many calls with a time-locked response to one or more temporal elements of the calls. The neuronal response patterns in the AI correlated well with the sound temporal envelope of chirp (an isolated short phrase), but correlated less well in the case of chutter and whistle (longer calls) or purr (a call with a fast repetition rate of phrases). Neuronal rate vs. characteristic frequency profiles provided only a coarse representation of the calls' frequency spectra. A comparison between the activity in the AI and those of subcortical structures showed a different transformation of the neuronal response patterns from the IC to the AI for individual calls: i) while the temporal representation of chirp remained unchanged, the representations of whistle and chutter were transformed at the thalamic level and the response to purr at the cortical level; ii) for the wideband calls (whistle, chirp) the rate representation of the call spectra was preserved in the AI and MGB at the level present in the IC, while in the case of low-frequency calls (chutter, purr), the representation was less precise in the AI and MGB than in the IC; iii) the difference in the response strength to natural and time-reversed whistle was found to be smaller in the AI than in the IC or MGB.
Assuntos
Córtex Auditivo/fisiologia , Vocalização Animal/fisiologia , Estimulação Acústica , Animais , Potenciais Evocados Auditivos , Feminino , Cobaias , Neurônios/fisiologia , Especificidade da EspécieRESUMO
The behavioral consequences of age-related changes in the auditory system were studied in Fischer 344 (F344) rats as a model of fast aging and in Long Evans (LE) rats as a model of normal aging. Hearing thresholds, the strength of the acoustic startle responses (ASRs) to noise and tonal stimuli, and the efficiency of the prepulse inhibition (PPI) of ASR were assessed in young-adult, middle-aged, and aged rats of both strains. Compared with LE rats, F344 rats showed larger age-related hearing threshold shifts, and the amplitudes of their startle responses were mostly lower. Both rat strains demonstrated a significant decrease of startle reactivity during aging. For tonal stimuli, this decrease occurred at an earlier age in the F344 rats: middle-aged F344 animals expressed similar startle reactivity as aged F344 animals, whereas middle-aged LE animals had similar startle reactivity as young-adult LE animals. For noise stimuli, on the other hand, a similar progression of age-related ASR changes was found in both strains. No significant relationship between the hearing thresholds and the ASR amplitudes was found within any age group. Auditory PPI was less efficient in F344 rats than in LE rats. An age-related reduction of the PPI of ASR was observed in rats of both strains; however, a significant reduction of PPI occurred only in aged rats. The results indicate that the ASR may serve as an indicator of central presbycusis.
Assuntos
Envelhecimento/psicologia , Reflexo Acústico/fisiologia , Reflexo de Sobressalto/fisiologia , Estimulação Acústica/métodos , Senilidade Prematura/fisiopatologia , Senilidade Prematura/psicologia , Animais , Limiar Auditivo/fisiologia , Feminino , Presbiacusia/fisiopatologia , Presbiacusia/psicologia , Ratos , Ratos Endogâmicos F344 , Ratos Long-Evans , Especificidade da EspécieRESUMO
Direct drug delivery to the cochlea is associated with the risk of irreversible damage to the ear. In this study, liposome and polymersome nanoparticles (NPs), both formed from amphiphilic molecules (lipids in liposomes and block copolymers in polymersomes), were tested as potential tools for drug delivery to the cochlea via application onto the round window membrane in adult mice (strain C3H). One day after round window membrane application, both types of NPs labeled with fluorescent markers were identified in the spiral ganglion in all cochlear turns without producing any distinct morphological or functional damage to the inner ear. NPs were detected, although to a lesser extent, in the organ of Corti and the lateral wall. The potential of liposome and polymersome NPs as therapeutic delivery systems into the cochlea via the round window membrane was evaluated using disulfiram, a neurotoxic agent, as a model payload. Disulfiram-loaded NP delivery resulted in a significant decrease in the number of spiral ganglion cells starting 2 days postapplication, with associated pronounced hearing loss reaching 20-35 dB 2 weeks postapplication as assessed through auditory brainstem responses. No changes in hair cell morphology and function (as assessed by recording otoacoustic emissions) were detected after disulfiram-loaded NP application. No effects were observed in controls where solution of free disulfiram was similarly administered. The results demonstrate that liposome and polymersome NPs are capable of carrying a payload into the inner ear that elicits a biological effect, with consequences measurable by a functional readout.
Assuntos
Cóclea/metabolismo , Citotoxinas/administração & dosagem , Dissulfiram/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/análise , Janela da Cóclea/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Cóclea/efeitos dos fármacos , Cóclea/ultraestrutura , Citotoxinas/farmacologia , Dissulfiram/farmacologia , Feminino , Lipossomos/análise , Masculino , Camundongos , Órgão Espiral/efeitos dos fármacos , Órgão Espiral/ultraestrutura , Janela da Cóclea/efeitos dos fármacos , Janela da Cóclea/ultraestrutura , Gânglio Espiral da Cóclea/citologia , Gânglio Espiral da Cóclea/efeitos dos fármacos , Tensoativos/químicaRESUMO
Presbycusis, as the deterioration of hearing ability occurring with aging, can be manifested not only in a shift of hearing thresholds, but also in a deterioration of the temporal processing of acoustical signals, which may in elderly people result in degraded speech comprehension. In this study we assessed the age-related changes in the temporal processing of acoustical signals in the auditory system of pigmented rats (Long Evans strain). The temporal resolution was investigated in young adult (3-4 months) and old (30-34 months) rats by behavioral and electrophysiological methods: the rats' ability to detect and discriminate gaps in a continuous noise was examined behaviorally, and the amplitude-rate function was assessed for the middle latency response (MLR) to clicks. A worsening of the temporal resolution with aging was observed in the results of all tests. The values of the gap detection threshold (GDT) and the gap duration difference limen (GDDL) in old rats increased about two-fold in comparison with young adult rats. The MLR to a click train in old rats exhibited a significantly faster reduction in amplitude with an increasing stimulation rate in comparison with young adult rats. None of the age-related changes in the parameters characterizing temporal resolution (GDT, GDDL and MLR to a click train) correlated with the degree of the age-related hearing loss. However, the age-related changes in MLR amplitude-rate function correlated with the age-related changes in GDDL, but not with the changes in GDT. The behavioral and electrophysiological data clearly show that aging in rats is accompanied with a pronounced deficit in the temporal processing of acoustical signals that is associated with the deteriorated function of the central auditory system.
Assuntos
Envelhecimento , Limiar Auditivo , Presbiacusia/fisiopatologia , Estimulação Acústica , Envelhecimento/fisiologia , Animais , Limiar Auditivo/fisiologia , Aprendizagem por Discriminação , Potenciais Evocados Auditivos , Feminino , Ratos , Ratos Long-EvansRESUMO
Noise exposure during the critical period of postnatal development in rats results in anomalous processing of acoustic stimuli in the adult auditory system. In the present study, the behavioral consequences of an acute acoustic trauma in the critical period are assessed in adult rats using the acoustic startle reflex (ASR) and prepulse inhibition (PPI) of ASR. Rat pups (strain Long-Evans) were exposed to broad-band noise of 125 dB SPL for 8 min on postnatal day 14; at the age of 3-5 months, ASR and PPI of ASR were examined and compared with those obtained in age-matched controls. In addition, hearing thresholds were measured in all animals by means of auditory brainstem responses. The results show that although the hearing thresholds in both groups of animals were not different, a reduced strength of the startle reflex was observed in exposed rats compared with controls. The efficacy of PPI in exposed and control rats was also markedly different. In contrast to control rats, in which an increase in prepulse intensity was accompanied by a consistent increase in the efficacy of PPI, the PPI function in the exposed animals was characterized by a steep increase in inhibitory efficacy at low prepulse intensities of 20-30 dB SPL. A further increase of prepulse intensity up to 60-70 dB SPL caused only a small and insignificant change of PPI. Our findings demonstrate that brief noise exposure in rat pups results in altered behavioral responses to sounds in adulthood, indicating anomalies in intensity coding and loudness perception.