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1.
J Neurophysiol ; 126(5): 1660-1669, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34644166

RESUMEN

Studies of in vivo neuronal responses to auditory inputs in the superior olive complex (SOC) are usually done under anesthesia. However, little attention has been paid to the effect of anesthesia itself on response properties. Here, we assessed the effect of anesthesia depth under ketamine-xylazine anesthetics on auditory evoked response properties of lateral SOC neurons. Anesthesia depth was tracked by monitoring EEG spectral peak frequencies. An increase in anesthesia depth led to a decrease of spontaneous discharge activities and an elevated response threshold. The temporal responses to suprathreshold tones were also affected, with adapted responses reduced but peak responses unaffected. Deepening the anesthesia depth also increased first spike latency. However, spike jitter was not affected. Auditory brainstem responses to clicks confirmed that ketamine-xylazine anesthesia depth affects auditory neuronal activities and the effect on spike rate and spike timing persists through the auditory pathway. We concluded from those observations that ketamine-xylazine affects lateral SOC response properties depending on the anesthesia depth.NEW & NOTEWORTHY We studied how the depth of ketamine-xylazine anesthesia altered response properties of lateral superior olive complex neurons, and auditory brainstem evoked responses. Our results provide direct evidence that anesthesia depth affects auditory neuronal responses and reinforce the notion that both the anesthetics and the anesthesia depth should be considered when interpreting/comparing in vivo neuronal recordings.


Asunto(s)
Anestesia , Anestésicos Generales/farmacología , Percepción Auditiva/efectos de los fármacos , Ketamina/farmacología , Complejo Olivar Superior/efectos de los fármacos , Xilazina/farmacología , Animales , Electroencefalografía/efectos de los fármacos , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Femenino , Gerbillinae , Masculino
2.
PLoS Biol ; 16(7): e2005114, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-30048446

RESUMEN

Detecting regular patterns in the environment, a process known as statistical learning, is essential for survival. Neuronal adaptation is a key mechanism in the detection of patterns that are continuously repeated across short (seconds to minutes) temporal windows. Here, we found in mice that a subcortical structure in the auditory midbrain was sensitive to patterns that were repeated discontinuously, in a temporally sparse manner, across windows of minutes to hours. Using a combination of behavioral, electrophysiological, and molecular approaches, we found changes in neuronal response gain that varied in mechanism with the degree of sound predictability and resulted in changes in frequency coding. Analysis of population activity (structural tuning) revealed an increase in frequency classification accuracy in the context of increased overlap in responses across frequencies. The increase in accuracy and overlap was paralleled at the behavioral level in an increase in generalization in the absence of diminished discrimination. Gain modulation was accompanied by changes in gene and protein expression, indicative of long-term plasticity. Physiological changes were largely independent of corticofugal feedback, and no changes were seen in upstream cochlear nucleus responses, suggesting a key role of the auditory midbrain in sensory gating. Subsequent behavior demonstrated learning of predictable and random patterns and their importance in auditory conditioning. Using longer timescales than previously explored, the combined data show that the auditory midbrain codes statistical learning of temporally sparse patterns, a process that is critical for the detection of relevant stimuli in the constant soundscape that the animal navigates through.


Asunto(s)
Estimulación Acústica , Vías Auditivas/fisiología , Mesencéfalo/fisiología , Patrones de Reconocimiento Fisiológico , Animales , Corteza Auditiva/fisiología , Conducta Animal , Cóclea/fisiología , Potenciales Evocados/fisiología , Femenino , Colículos Inferiores/fisiología , Ratones Endogámicos C57BL , Plasticidad Neuronal , Sonido , Sinapsis/fisiología
3.
Proc Natl Acad Sci U S A ; 113(32): E4716-25, 2016 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-27462107

RESUMEN

For sounds of a given frequency, spiral ganglion neurons (SGNs) with different thresholds and dynamic ranges collectively encode the wide range of audible sound pressures. Heterogeneity of synapses between inner hair cells (IHCs) and SGNs is an attractive candidate mechanism for generating complementary neural codes covering the entire dynamic range. Here, we quantified active zone (AZ) properties as a function of AZ position within mouse IHCs by combining patch clamp and imaging of presynaptic Ca(2+) influx and by immunohistochemistry. We report substantial AZ heterogeneity whereby the voltage of half-maximal activation of Ca(2+) influx ranged over ∼20 mV. Ca(2+) influx at AZs facing away from the ganglion activated at weaker depolarizations. Estimates of AZ size and Ca(2+) channel number were correlated and larger when AZs faced the ganglion. Disruption of the deafness gene GIPC3 in mice shifted the activation of presynaptic Ca(2+) influx to more hyperpolarized potentials and increased the spontaneous SGN discharge. Moreover, Gipc3 disruption enhanced Ca(2+) influx and exocytosis in IHCs, reversed the spatial gradient of maximal Ca(2+) influx in IHCs, and increased the maximal firing rate of SGNs at sound onset. We propose that IHCs diversify Ca(2+) channel properties among AZs and thereby contribute to decomposing auditory information into complementary representations in SGNs.


Asunto(s)
Calcio/metabolismo , Células Ciliadas Auditivas Internas/fisiología , Proteínas Adaptadoras Transductoras de Señales/fisiología , Animales , Canales de Calcio/fisiología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Sonido , Ganglio Espiral de la Cóclea/fisiología , Sinapsis/metabolismo
4.
EMBO J ; 34(21): 2686-702, 2015 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-26446278

RESUMEN

Active zones (AZs) of inner hair cells (IHCs) indefatigably release hundreds of vesicles per second, requiring each release site to reload vesicles at tens per second. Here, we report that the endocytic adaptor protein 2µ (AP-2µ) is required for release site replenishment and hearing. We show that hair cell-specific disruption of AP-2µ slows IHC exocytosis immediately after fusion of the readily releasable pool of vesicles, despite normal abundance of membrane-proximal vesicles and intact endocytic membrane retrieval. Sound-driven postsynaptic spiking was reduced in a use-dependent manner, and the altered interspike interval statistics suggested a slowed reloading of release sites. Sustained strong stimulation led to accumulation of endosome-like vacuoles, fewer clathrin-coated endocytic intermediates, and vesicle depletion of the membrane-distal synaptic ribbon in AP-2µ-deficient IHCs, indicating a further role of AP-2µ in clathrin-dependent vesicle reformation on a timescale of many seconds. Finally, we show that AP-2 sorts its IHC-cargo otoferlin. We propose that binding of AP-2 to otoferlin facilitates replenishment of release sites, for example, via speeding AZ clearance of exocytosed material, in addition to a role of AP-2 in synaptic vesicle reformation.


Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/fisiología , Células Ciliadas Auditivas/fisiología , Vesículas Sinápticas/metabolismo , Potenciales de Acción , Animales , Potenciales Evocados Auditivos del Tronco Encefálico , Audición , Ratones Endogámicos C57BL , Ratones Transgénicos , Sinapsis/fisiología , Transmisión Sináptica
5.
Proc Natl Acad Sci U S A ; 112(24): E3141-9, 2015 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-26034270

RESUMEN

Ca(2+) influx triggers the fusion of synaptic vesicles at the presynaptic active zone (AZ). Here we demonstrate a role of Ras-related in brain 3 (Rab3)-interacting molecules 2α and ß (RIM2α and RIM2ß) in clustering voltage-gated CaV1.3 Ca(2+) channels at the AZs of sensory inner hair cells (IHCs). We show that IHCs of hearing mice express mainly RIM2α, but also RIM2ß and RIM3γ, which all localize to the AZs, as shown by immunofluorescence microscopy. Immunohistochemistry, patch-clamp, fluctuation analysis, and confocal Ca(2+) imaging demonstrate that AZs of RIM2α-deficient IHCs cluster fewer synaptic CaV1.3 Ca(2+) channels, resulting in reduced synaptic Ca(2+) influx. Using superresolution microscopy, we found that Ca(2+) channels remained clustered in stripes underneath anchored ribbons. Electron tomography of high-pressure frozen synapses revealed a reduced fraction of membrane-tethered vesicles, whereas the total number of membrane-proximal vesicles was unaltered. Membrane capacitance measurements revealed a reduction of exocytosis largely in proportion with the Ca(2+) current, whereas the apparent Ca(2+) dependence of exocytosis was unchanged. Hair cell-specific deletion of all RIM2 isoforms caused a stronger reduction of Ca(2+) influx and exocytosis and significantly impaired the encoding of sound onset in the postsynaptic spiral ganglion neurons. Auditory brainstem responses indicated a mild hearing impairment on hair cell-specific deletion of all RIM2 isoforms or global inactivation of RIM2α. We conclude that RIM2α and RIM2ß promote a large complement of synaptic Ca(2+) channels at IHC AZs and are required for normal hearing.


Asunto(s)
Canales de Calcio Tipo L/metabolismo , Células Ciliadas Auditivas Internas/metabolismo , Proteínas de Unión al GTP rab3/metabolismo , Animales , Señalización del Calcio , Tomografía con Microscopio Electrónico , Potenciales Evocados Auditivos del Tronco Encefálico , Exocitosis , Células Ciliadas Auditivas Internas/ultraestructura , Audición/fisiología , Activación del Canal Iónico , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Emisiones Otoacústicas Espontáneas , Técnicas de Placa-Clamp , Ganglio Espiral de la Cóclea/metabolismo , Sinapsis/metabolismo , Sinapsis/ultraestructura , Vesículas Sinápticas/metabolismo , Proteínas de Unión al GTP rab3/deficiencia , Proteínas de Unión al GTP rab3/genética
6.
J Vis Exp ; (92): e52069, 2014 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-25350571

RESUMEN

Direct electrical stimulation of spiral ganglion neurons (SGNs) by cochlear implants (CIs) enables open speech comprehension in the majority of implanted deaf subjects(1-) (6). Nonetheless, sound coding with current CIs has poor frequency and intensity resolution due to broad current spread from each electrode contact activating a large number of SGNs along the tonotopic axis of the cochlea(7-) (9). Optical stimulation is proposed as an alternative to electrical stimulation that promises spatially more confined activation of SGNs and, hence, higher frequency resolution of coding. In recent years, direct infrared illumination of the cochlea has been used to evoke responses in the auditory nerve(10). Nevertheless it requires higher energies than electrical stimulation(10,11) and uncertainty remains as to the underlying mechanism(12). Here we describe a method based on optogenetics to stimulate SGNs with low intensity blue light, using transgenic mice with neuronal expression of channelrhodopsin 2 (ChR2)(13) or virus-mediated expression of the ChR2-variant CatCh(14). We used micro-light emitting diodes (µLEDs) and fiber-coupled lasers to stimulate ChR2-expressing SGNs through a small artificial opening (cochleostomy) or the round window. We assayed the responses by scalp recordings of light-evoked potentials (optogenetic auditory brainstem response: oABR) or by microelectrode recordings from the auditory pathway and compared them with acoustic and electrical stimulation.


Asunto(s)
Nervio Coclear/fisiología , Optogenética/métodos , Animales , Channelrhodopsins , Ganglios Espinales/citología , Ganglios Espinales/metabolismo , Ganglios Espinales/fisiología , Ratones , Ratones Transgénicos , Microelectrodos , Neuronas/metabolismo , Neuronas/fisiología
7.
J Clin Invest ; 124(3): 1114-29, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24509078

RESUMEN

Auditory prostheses can partially restore speech comprehension when hearing fails. Sound coding with current prostheses is based on electrical stimulation of auditory neurons and has limited frequency resolution due to broad current spread within the cochlea. In contrast, optical stimulation can be spatially confined, which may improve frequency resolution. Here, we used animal models to characterize optogenetic stimulation, which is the optical stimulation of neurons genetically engineered to express the light-gated ion channel channelrhodopsin-2 (ChR2). Optogenetic stimulation of spiral ganglion neurons (SGNs) activated the auditory pathway, as demonstrated by recordings of single neuron and neuronal population responses. Furthermore, optogenetic stimulation of SGNs restored auditory activity in deaf mice. Approximation of the spatial spread of cochlear excitation by recording local field potentials (LFPs) in the inferior colliculus in response to suprathreshold optical, acoustic, and electrical stimuli indicated that optogenetic stimulation achieves better frequency resolution than monopolar electrical stimulation. Virus-mediated expression of a ChR2 variant with greater light sensitivity in SGNs reduced the amount of light required for responses and allowed neuronal spiking following stimulation up to 60 Hz. Our study demonstrates a strategy for optogenetic stimulation of the auditory pathway in rodents and lays the groundwork for future applications of cochlear optogenetics in auditory research and prosthetics.


Asunto(s)
Estimulación Acústica , Sordera/cirugía , Optogenética , Animales , Channelrhodopsins , Cóclea/fisiopatología , Cóclea/cirugía , Implantación Coclear , Estimulación Eléctrica , Potenciales Evocados Auditivos , Luz , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Estimulación Luminosa , Ratas , Ratas Transgénicas , Ratas Wistar , Ganglio Espiral de la Cóclea/patología , Ganglio Espiral de la Cóclea/fisiopatología
8.
EMBO J ; 33(5): 512-27, 2014 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-24442636

RESUMEN

Endbulb of Held terminals of auditory nerve fibers (ANF) transmit auditory information at hundreds per second to bushy cells (BCs) in the anteroventral cochlear nucleus (AVCN). Here, we studied the structure and function of endbulb synapses in mice that lack the presynaptic scaffold bassoon and exhibit reduced ANF input into the AVCN. Endbulb terminals and active zones were normal in number and vesicle complement. Postsynaptic densities, quantal size and vesicular release probability were increased while vesicle replenishment and the standing pool of readily releasable vesicles were reduced. These opposing effects canceled each other out for the first evoked EPSC, which showed unaltered amplitude. We propose that ANF activity deprivation drives homeostatic plasticity in the AVCN involving synaptic upscaling and increased intrinsic BC excitability. In vivo recordings from individual mutant BCs demonstrated a slightly improved response at sound onset compared to ANF, likely reflecting the combined effects of ANF convergence and homeostatic plasticity. Further, we conclude that bassoon promotes vesicular replenishment and, consequently, a large standing pool of readily releasable synaptic vesicles at the endbulb synapse.


Asunto(s)
Núcleos Talámicos Anteriores/fisiología , Núcleos Talámicos Anteriores/ultraestructura , Proteínas del Tejido Nervioso/deficiencia , Neuronas/fisiología , Neuronas/ultraestructura , Sinapsis/fisiología , Sinapsis/ultraestructura , Animales , Ratones , Ratones Noqueados , Vesículas Sinápticas/metabolismo
9.
J Neurosci ; 33(26): 10661-6, 2013 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-23804089

RESUMEN

Hearing over a wide range of sound intensities is thought to require complementary coding by functionally diverse spiral ganglion neurons (SGNs), each changing activity only over a subrange. The foundations of SGN diversity are not well understood but likely include differences among their inputs: the presynaptic active zones (AZs) of inner hair cells (IHCs). Here we studied one candidate mechanism for causing SGN diversity-heterogeneity of Ca(2+) influx among the AZs of IHCs-during postnatal development of the mouse cochlea. Ca(2+) imaging revealed a change from regenerative to graded synaptic Ca(2+) signaling after the onset of hearing, when in vivo SGN spike timing changed from patterned to Poissonian. Furthermore, we detected the concurrent emergence of stronger synaptic Ca(2+) signals in IHCs and higher spontaneous spike rates in SGNs. The strengthening of Ca(2+) signaling at a subset of AZs primarily reflected a gain of Ca(2+) channels. We hypothesize that the number of Ca(2+) channels at each IHC AZ critically determines the firing properties of its corresponding SGN and propose that AZ heterogeneity enables IHCs to decompose auditory information into functionally diverse SGNs.


Asunto(s)
Señalización del Calcio/fisiología , Calcio/metabolismo , Nervio Coclear/fisiología , Células Ciliadas Auditivas Internas/fisiología , Audición/fisiología , Animales , Canales de Calcio/fisiología , Cóclea/crecimiento & desarrollo , Cóclea/inervación , Nervio Coclear/crecimiento & desarrollo , Núcleo Coclear/citología , Núcleo Coclear/fisiología , Simulación por Computador , Fenómenos Electrofisiológicos , Femenino , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal , Modelos Neurológicos , Mutación/fisiología , Proteínas del Tejido Nervioso/genética , Técnicas de Placa-Clamp , Receptores Presinapticos/fisiología , Ganglio Espiral de la Cóclea/citología , Ganglio Espiral de la Cóclea/crecimiento & desarrollo , Ganglio Espiral de la Cóclea/fisiología , Fracciones Subcelulares/fisiología
10.
J Neurosci ; 33(10): 4456-67, 2013 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-23467361

RESUMEN

Inner hair cells (IHCs) of the cochlea use ribbon synapses to transmit auditory information faithfully to spiral ganglion neurons (SGNs). In the present study, we used genetic disruption of the presynaptic scaffold protein bassoon in mice to manipulate the morphology and function of the IHC synapse. Although partial-deletion mutants lacking functional bassoon (Bsn(ΔEx4/5)) had a near-complete loss of ribbons from the synapses (up to 88% ribbonless synapses), gene-trap mutants (Bsn(gt)) showed weak residual expression of bassoon and 56% ribbonless synapses, whereas the remaining 44% had a loosely anchored ribbon. Patch-clamp recordings and synaptic CaV1.3 immunolabeling indicated a larger number of Ca(2+) channels for Bsn(gt) IHCs compared with Bsn(ΔEx4/5) IHCs and for Bsn(gt) ribbon-occupied versus Bsn(gt) ribbonless synapses. An intermediate phenotype of Bsn(gt) IHCs was also found by membrane capacitance measurements for sustained exocytosis, but not for the size of the readily releasable vesicle pool. The frequency and amplitude of EPSCs were reduced in Bsn(ΔEx4/5) mouse SGNs, whereas their postsynaptic AMPA receptor clusters were largely unaltered. Sound coding in SGN, assessed by recordings of single auditory nerve fibers and their population responses in vivo, was similarly affected in Bsn(gt) and Bsn(ΔEx4/5) mice. Both genotypes showed impaired sound onset coding and reduced evoked and spontaneous spike rates. In summary, reduced bassoon expression or complete lack of full-length bassoon impaired sound encoding to a similar extent, which is consistent with the comparable reduction of the readily releasable vesicle pool. This suggests that the remaining loosely anchored ribbons in Bsn(gt) IHCs were functionally inadequate or that ribbon independent mechanisms dominated the coding deficit.


Asunto(s)
Cóclea/citología , Células Ciliadas Auditivas Internas/metabolismo , Mutación/genética , Proteínas del Tejido Nervioso/metabolismo , Sinapsis/fisiología , Estimulación Acústica , Acústica , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Oxidorreductasas de Alcohol , Animales , Umbral Auditivo/fisiología , Biofisica , Calcio/metabolismo , Canales de Calcio Tipo L/genética , Canales de Calcio Tipo L/metabolismo , Proteínas Co-Represoras , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Ácido Egtácico/farmacología , Estimulación Eléctrica , Potenciales Evocados Auditivos del Tronco Encefálico/genética , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/genética , Femenino , Regulación de la Expresión Génica/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Emisiones Otoacústicas Espontáneas/efectos de los fármacos , Emisiones Otoacústicas Espontáneas/genética , Técnicas de Placa-Clamp , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores AMPA/genética , Receptores AMPA/metabolismo
11.
J Immunol ; 185(11): 6719-27, 2010 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-21048106

RESUMEN

Tumor-associated dendritic cells (DCs) often induce T cell anergy or deletion and regulatory T cells instead of antitumor immunity. Although many tumor-associated Ags have been found, there is still no effective vaccine for cancer. Thus, novel rational strategies to enhance the immunogenicity of cancer-specific Ags are needed. Chromosome 1 open reading frame 190 (c1orf190), a gene that encodes a 239-aa hypothetical protein and contains multiple kinase phosphorylation sites, has a wide relationship with multiple signaling pathway molecules and can be regulated by multiple factors, such as TLR ligands. In this study, we demonstrate that c1orf190 can activate NF-κB, drive the production of cytokines, and promote the Ag-presenting function and the priming ability of DCs. Furthermore, c1orf190 can promote resistance of DCs to tumor-associated inhibition not only in the Ag-presenting function but also in the priming ability to induce Ag-specific T lymphocytes. Thus, c1orf190, an NF-κB activator, may be a candidate gene for regulating the function of DCs to resist tumor-associated factor-mediated dysfunction. We also found that c1orf190-mediated cytokine release is achieved by activating the canonical but not the noncanonical NF-κB pathway.


Asunto(s)
Cromosomas Humanos Par 1/fisiología , Células Dendríticas/inmunología , Inmunidad Innata , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Neoplasias Ováricas/inmunología , Transducción de Señal/inmunología , Proteínas Supresoras de Tumor/fisiología , Proteínas Adaptadoras Transductoras de Señales , Secuencia de Aminoácidos , Presentación de Antígeno/inmunología , Línea Celular , Células Cultivadas , Técnicas de Cocultivo , Citocinas/biosíntesis , Células Dendríticas/metabolismo , Células Dendríticas/patología , Dimerización , Femenino , Células HeLa , Humanos , Mediadores de Inflamación/fisiología , Datos de Secuencia Molecular , FN-kappa B/fisiología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Fosforilación/inmunología , Transactivadores/metabolismo
12.
Cancer Res ; 69(4): 1578-86, 2009 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-19190337

RESUMEN

Suppressor of cytokine signaling 3 (SOCS3) expression in bone marrow cells (BMC) was up-regulated upon exposure to interleukin 6, lipopolysaccharide, or tumor-associated factors. But, how the up-regulated SOCS3 affects differentiation of BMCs is incompletely characterized. Here, we showed that SOCS3 promoted BMCs to intently differentiate into CD8 T cells. Importantly, lung can be as one athymus tissue for the BMCs to differentiate into CD8(+) T cells. Notch1 plays a critical role in the differentiation from SOCS3-transfected BMCs to CD8(+) T cells. We conclude that the up-regulated SOCS3 in some pathologic conditions, such as tumor and inflammation, might promote BMCs to differentiate into CD8(+) T lymphocytes in lung tissue via up-regulating Notch1 expression. This may represent a new mechanism against diseases such as tumor.


Asunto(s)
Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Pulmón/inmunología , Receptor Notch1/genética , Proteínas Supresoras de la Señalización de Citocinas/fisiología , Animales , Células de la Médula Ósea/efectos de los fármacos , Linfocitos T CD8-positivos/efectos de los fármacos , Línea Celular , Técnicas de Cocultivo , Femenino , Expresión Génica , Humanos , Inflamación/inmunología , Interleucina-6/farmacología , Neoplasias Pulmonares/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Ovario , Células del Estroma/inmunología , Proteína 3 Supresora de la Señalización de Citocinas
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