RESUMEN
Locomotion generates adventitious sounds which enable detection and localization of predators and prey. Such sounds contain brisk changes or transients in amplitude. We investigated the hypothesis that ill-understood temporal specializations in binaural circuits subserve lateralization of such sound transients, based on different time of arrival at the ears (interaural time differences, ITDs). We find that Lateral Superior Olive (LSO) neurons show exquisite ITD-sensitivity, reflecting extreme precision and reliability of excitatory and inhibitory postsynaptic potentials, in contrast to Medial Superior Olive neurons, traditionally viewed as the ultimate ITD-detectors. In vivo, inhibition blocks LSO excitation over an extremely short window, which, in vitro, required synaptically evoked inhibition. Light and electron microscopy revealed inhibitory synapses on the axon initial segment as the structural basis of this observation. These results reveal a neural vetoing mechanism with extreme temporal and spatial precision and establish the LSO as the primary nucleus for binaural processing of sound transients.
Asunto(s)
Neuronas/fisiología , Núcleo Olivar , Localización de Sonidos/fisiología , Animales , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Gerbillinae , Glicina/metabolismo , Potenciales Postsinápticos Inhibidores/fisiología , Masculino , Núcleo Olivar/citología , Núcleo Olivar/fisiologíaRESUMEN
The neurons of the medial superior olive (MSO) of mammals extract azimuthal information from the delays between sounds reaching the two ears (interaural time differences, or ITDs). Traditionally, all models of sound localization have assumed that MSO neurons represent a single population of cells with specialized and homogeneous intrinsic and synaptic properties that enable detection of synaptic coincidence on a time scale of tens to hundreds of microseconds. Here, using patch-clamp recordings from large populations of anatomically labeled neurons in brainstem slices from male and female Mongolian gerbils (Meriones unguiculatus), we show that MSO neurons are far more physiologically diverse than previously appreciated, with properties that depend regionally on cell position along the topographic map of frequency. Despite exhibiting a similar morphology, neurons in the MSO exhibit sub-threshold oscillations of differing magnitudes that drive action potentials at rates between 100-800 Hz. These oscillations are driven primarily by voltage-gated sodium channels and are distinct from resonant properties derived from other active membrane properties. We show that graded differences in these and other physiological properties across the MSO neuron population enable the MSO to duplex the encoding of ITD information in both fast, sub-millisecond time varying signals as well as slower envelopes.SIGNIFICANCE STATEMENTNeurons in the medial superior olive (MSO) encode sound localization cues by detecting microsecond differences in the arrival times of inputs from the left and right ears, and it has been assumed this computation is made possible by highly stereotyped structural and physiological specializations. Here we report using a large (>400) sample size that MSO neurons show a strikingly large continuum of functional properties despite exhibiting similar morphologies. We demonstrate that subthreshold oscillations mediated by voltage-gated Na+ channels play a key role in conferring graded differences in firing properties. This functional diversity likely confers capabilities of processing both fast, submillisecond-scale synaptic activity (acoustic "fine structure"), and slow-rising envelope information that is found in amplitude modulated sounds and speech patterns.
RESUMEN
The central nucleus of the inferior colliculus (ICC) integrates information about different features of sound and then distributes this information to thalamocortical circuits. However, the lack of clear definitions of circuit elements in the ICC has limited our understanding of the nature of these circuit transformations. Here, we combine virus-based genetic access with electrophysiological and optogenetic approaches to identify a large family of excitatory, cholecystokinin-expressing thalamic projection neurons in the ICC of the Mongolian gerbil. We show that these neurons form a distinct cell type, displaying uniform morphology and intrinsic firing features, and provide powerful, spatially restricted excitation exclusively to the ventral auditory thalamus. In vivo, these neurons consistently exhibit V-shaped receptive field properties but strikingly diverse temporal responses to sound. Our results indicate that temporal response diversity is maintained within this population of otherwise uniform cells in the ICC and then relayed to cortex through spatially restricted thalamic subdomains.
Asunto(s)
Vías Auditivas/metabolismo , Colecistoquinina/metabolismo , Potenciales Evocados Auditivos , Mesencéfalo/metabolismo , Neuronas/metabolismo , Tálamo/metabolismo , Animales , Femenino , Gerbillinae , MasculinoRESUMEN
The Mongolian gerbil (Meriones unguiculatus) is a member of the rodent family that displays several features not found in mice or rats, including sensory specializations and social patterns more similar to those in humans. These features have made gerbils a valuable animal for research studies of auditory and visual processing, brain development, learning and memory, and neurological disorders. Here, we report the whole gerbil annotated genome sequence, and identify important similarities and differences to the human and mouse genomes. We further analyze the chromosomal structure of eight genes with high relevance for controlling neural signaling and demonstrate a high degree of homology between these genes in mouse and gerbil. This homology increases the likelihood that individual genes can be rapidly identified in gerbil and used for genetic manipulations. The availability of the gerbil genome provides a foundation for advancing our knowledge towards understanding evolution, behavior and neural function in mammals. ACCESSION NUMBER: The Whole Genome Shotgun sequence data from this project has been deposited at DDBJ/ENA/GenBank under the accession NHTI00000000. The version described in this paper is version NHTI01000000. The fragment reads, and mate pair reads have been deposited in the Sequence Read Archive under BioSample accession SAMN06897401.
Asunto(s)
Genoma , Gerbillinae/genética , Análisis de Secuencia de ADN , Animales , Secuencia de Bases , Masculino , Anotación de Secuencia MolecularRESUMEN
Utilization of timing-based sound localization cues by neurons in the medial superior olive (MSO) depends critically on glycinergic inhibitory inputs. After hearing onset, the strength and subcellular location of these inhibitory inputs are dramatically altered, but the cellular processes underlying this experience-dependent refinement are unknown. Here we reveal a form of inhibitory long-term potentiation (iLTP) in MSO neurons that is dependent on spiking and synaptic activation but is not affected by their fine-scale relative timing at higher frequencies prevalent in auditory circuits. We find that iLTP reinforces inhibitory inputs coactive with binaural excitation in a cumulative manner, likely well suited for networks featuring persistent high-frequency activity. We also show that a steep drop in action potential size and backpropagation limits induction of iLTP to the first 2 weeks of hearing. These intrinsic changes would deprive more distal inhibitory synapses of reinforcement, conceivably establishing the mature, soma-biased pattern of inhibition.
Asunto(s)
Potenciales de Acción/fisiología , Potenciales Postsinápticos Inhibidores/fisiología , Inhibición Neural/fisiología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Receptores de Glicina/fisiología , Animales , Femenino , Gerbillinae , Masculino , Núcleo Olivar/fisiologíaRESUMEN
The principal neurons of the medial superior olive (MSO) encode cues for horizontal sound localization through comparisons of the relative timing of EPSPs. To understand how the timing and amplitude of EPSPs are maintained during propagation in the dendrites, we made dendritic and somatic whole-cell recordings from MSO principal neurons in brain slices from Mongolian gerbils. In somatic recordings, EPSP amplitudes were largely uniform following minimal stimulation of excitatory synapses at visualized locations along the dendrites. Similar results were obtained when excitatory synaptic transmission was eliminated in a low calcium solution and then restored at specific dendritic sites by pairing input stimulation and focal application of a higher calcium solution. We performed dual dendritic and somatic whole-cell recordings to measure spontaneous EPSPs using a dual-channel template-matching algorithm to separate out those events initiated at or distal to the dendritic recording location. Local dendritic spontaneous EPSP amplitudes increased sharply in the dendrite with distance from the soma (length constant, 53.6 µm), but their attenuation during propagation resulted in a uniform amplitude of â¼0.2 mV at the soma. The amplitude gradient of dendritic EPSPs was also apparent in responses to injections of identical simulated excitatory synaptic currents in the dendrites. Compartmental models support the view that these results extensively reflect the influence of dendritic cable properties. With relatively few excitatory axons innervating MSO neurons, the normalization of dendritic EPSPs at the soma would increase the importance of input timing versus location during the processing of interaural time difference cues in vivoSIGNIFICANCE STATEMENT The neurons of the medial superior olive analyze cues for sound localization by detecting the coincidence of binaural excitatory synaptic inputs distributed along the dendrites. Previous studies have shown that dendritic voltages undergo severe attenuation as they propagate to the soma, potentially reducing the influence of distal inputs. However, using dendritic and somatic patch recordings, we found that dendritic EPSP amplitude increased with distance from the soma, compensating for dendritic attenuation and normalizing EPSP amplitude at the soma. Much of this normalization reflected the influence of dendritic morphology. As different combinations of presynaptic axons may be active during consecutive cycles of sound stimuli, somatic EPSP normalization renders spike initiation more sensitive to synapse timing than dendritic location.
Asunto(s)
Dendritas/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Células Receptoras Sensoriales/fisiología , Localización de Sonidos/fisiología , Complejo Olivar Superior/fisiología , Sinapsis/fisiología , Animales , Células Cultivadas , Femenino , Gerbillinae , MasculinoRESUMEN
The axon initial segment (AIS) serves as the site of action potential initiation in most neurons, but difficulties in isolating the effects of voltage-gated ion channels in the AIS from those of the soma and dendrites have hampered understanding how AIS properties influence neural coding. Here we have combined confocal microscopy, patch-clamp recordings and light-sensitive channel blockers ('photoswitches') in binaural auditory gerbil neurons to show that hyperpolarization and cyclic-nucleotide-gated (HCN) channels are expressed in the AIS and decrease spike probability, in a manner distinct from that of HCN channels in the soma and dendrites. Furthermore, the control of spike threshold by HCN channels in the AIS can be altered through serotonergic modulation of 5-hydroxytryptamine 1A (5-HT1A) receptors, which hyperpolarizes the activation range of HCN channels. As release of serotonin signals changes in motivation and attention states, axonal HCN channels provide a mechanism to translate these signals into changes in the threshold for sensory stimuli.
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Potenciales de Acción/fisiología , Segmento Inicial del Axón/metabolismo , Canales Catiónicos Regulados por Nucleótidos Cíclicos/metabolismo , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Serotonina/metabolismo , Animales , Axones/fisiología , Dendritas/fisiología , Gerbillinae , Técnicas de Placa-Clamp/métodosRESUMEN
Sound localization critically depends on detection of differences in arrival time of sounds at the two ears (acoustic delay). The fundamental mechanisms are debated, but all proposals include a process of coincidence detection and a separate source of internal delay that offsets the acoustic delay and determines neural tuning. We used in vivo patch-clamp recordings of binaural neurons in the Mongolian gerbil and pharmacological manipulations to directly compare neuronal input to output and to separate excitation from inhibition. Our results cannot be accounted for by existing models and reveal that coincidence detection is not an instantaneous process, but is instead shaped by the interaction of intrinsic conductances with preceding synaptic activity. This interaction generates an internal delay as an intrinsic part of the process of coincidence detection. The multiplication and time-shifting stages thought to extract synchronous activity in many brain areas can therefore be combined in a single operation.
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Vías Auditivas/citología , Encéfalo/citología , Neuronas/fisiología , Detección de Señal Psicológica/fisiología , Localización de Sonidos , Estimulación Acústica , Animales , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Gerbillinae , Glicinérgicos/farmacología , Técnicas In Vitro , Masculino , Técnicas de Placa-Clamp , Psicoacústica , Quinoxalinas/farmacología , Tiempo de Reacción/fisiología , Detección de Señal Psicológica/efectos de los fármacos , Estricnina/farmacologíaRESUMEN
The medial superior olive (MSO) senses microsecond differences in the coincidence of binaural signals, a critical cue for detecting sound location along the azimuth. An important component of this circuit is provided by inhibitory neurons of the medial and lateral nuclei of the trapezoid body (MNTB and LNTB, respectively). While MNTB neurons are fairly well described, little is known about the physiology of LNTB neurons. Using whole cell recordings from gerbil brainstem slices, we found that LNTB and MNTB neurons have similar membrane time constants and input resistances and fire brief action potentials, but only LNTB neurons fire repetitively in response to current steps. We observed that LNTB neurons receive graded excitatory and inhibitory synaptic inputs, with at least some of the latter arriving from other LNTB neurons. To address the relative timing of inhibition to the MSO from the LNTB versus the MNTB, we examined inhibitory responses to auditory nerve stimulation using a slice preparation that retains the circuitry from the auditory nerve to the MSO intact. Despite the longer physical path length of excitatory inputs driving contralateral inhibition, inhibition from both pathways arrived with similar latency and jitter. An analysis of paired whole cell recordings between MSO and MNTB neurons revealed a short and reliable delay between the action potential peak in MNTB neurons and the onset of the resulting IPSP (0.55 ± 0.01 ms, n = 4, mean ± SEM). Reconstructions of biocytin-labeled neurons showed that MNTB axons ranged from 580 to 858 µm in length (n = 4). We conclude that while both LNTB and MNTB neurons provide similarly timed inhibition to MSO neurons, the reliability of inhibition from the LNTB at higher frequencies is more constrained relative to that from the MNTB due to differences in intrinsic properties, the strength of excitatory inputs, and the presence of feedforward inhibition.
Asunto(s)
Vías Auditivas/fisiología , Inhibición Neural/fisiología , Neuronas/fisiología , Núcleo Olivar/fisiología , Puente/fisiología , Potenciales de Acción/fisiología , Animales , Nervio Coclear/fisiología , Gerbillinae , Sinapsis/fisiologíaRESUMEN
Feedforward inhibition sharpens the precision of neurons throughout ascending auditory pathways, including the binaural neurons of the medial superior olive (MSO). However, the biophysical influence of inhibition is poorly understood, particularly at higher frequencies at which the relative phase of inhibition and excitation becomes ambiguous. Here, we show in gerbil MSO principal cells in vitro that feedforward inhibition precedes direct excitation, providing a concurrent hyperpolarization and conductance shunt during EPSP summation. We show with dual-patch recordings and dynamic clamp that both the linearity and temporal fidelity of synaptic integration is improved by reducing Kv1 potassium channel conductance during inhibition, which counters membrane shunting even at high frequencies at which IPSPs sum. The reduction of peak excitation by preceding inhibition lowers spike probability, narrowing but not shifting the window for detecting binaural coincidence. The interplay between inhibition and potassium conductances thus improves the consistency and resolution of ITD coding across different frequencies.
Asunto(s)
Red Nerviosa/fisiología , Inhibición Neural/fisiología , Neuronas/fisiología , Núcleo Olivar/citología , Localización de Sonidos/fisiología , 4-Aminopiridina/farmacología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Animales Recién Nacidos , Vías Auditivas/fisiología , Fenómenos Biofísicos/efectos de los fármacos , Fenómenos Biofísicos/fisiología , Biofisica , Venenos Elapídicos/farmacología , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/fisiología , Lateralidad Funcional , Gerbillinae , Técnicas In Vitro , Red Nerviosa/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Neuronas/efectos de los fármacos , Neurotoxinas/farmacología , Bloqueadores de los Canales de Potasio/farmacologíaRESUMEN
Neurons in the medial superior olive (MSO) enable sound localization by their remarkable sensitivity to submillisecond interaural time differences (ITDs). Each MSO neuron has its own "best ITD" to which it responds optimally. A difference in physical path length of the excitatory inputs from both ears cannot fully account for the ITD tuning of MSO neurons. As a result, it is still debated how these inputs interact and whether the segregation of inputs to opposite dendrites, well-timed synaptic inhibition, or asymmetries in synaptic potentials or cellular morphology further optimize coincidence detection or ITD tuning. Using in vivo whole-cell and juxtacellular recordings, we show here that ITD tuning of MSO neurons is determined by the timing of their excitatory inputs. The inputs from both ears sum linearly, whereas spike probability depends nonlinearly on the size of synaptic inputs. This simple coincidence detection scheme thus makes accurate sound localization possible.
Asunto(s)
Lateralidad Funcional/fisiología , Audición , Modelos Lineales , Neuronas/fisiología , Núcleo Olivar/fisiología , Localización de Sonidos/fisiología , Estimulación Acústica , Potenciales de Acción , Animales , Animales Recién Nacidos , Vías Auditivas/fisiología , Fenómenos Biofísicos , Mapeo Encefálico , Estimulación Eléctrica , Gerbillinae , Técnicas In Vitro , Potenciales Postsinápticos Inhibidores/fisiología , Modelos Neurológicos , Inhibición Neural/fisiología , Núcleo Olivar/citología , Técnicas de Placa-Clamp , Tiempo de ReacciónRESUMEN
Some neurons in the mammalian auditory system are able to detect and report the coincident firing of inputs with remarkable temporal precision. A strong, low-voltage-activated potassium conductance (g(KL)) at the cell body and dendrites gives these neurons sensitivity to the rate of depolarization by EPSPs, allowing neurons to assess the coincidence of the rising slopes of unitary EPSPs. Two groups of neurons in the brain stem, octopus cells in the posteroventral cochlear nucleus and principal cells of the medial superior olive (MSO), extract acoustic information by assessing coincident firing of their inputs over a submillisecond timescale and convey that information at rates of up to 1000 spikes s(-1). Octopus cells detect the coincident activation of groups of auditory nerve fibres by broadband transient sounds, compensating for the travelling wave delay by dendritic filtering, while MSO neurons detect coincident activation of similarly tuned neurons from each of the two ears through separate dendritic tufts. Each makes use of filtering that is introduced by the spatial distribution of inputs on dendrites.
Asunto(s)
Dendritas/fisiología , Sinapsis/fisiología , Animales , Vías Auditivas/fisiología , Potenciales Postsinápticos Excitadores , Octopodiformes , Tiempo de ReacciónRESUMEN
In sensory circuits of the brain, developmental changes in the expression and modulation of voltage-gated ion channels are a common occurrence, but such changes are often difficult to assign to clear functional roles. We have explored this issue in the binaural neurons of the medial superior olive (MSO), whose temporal precision in detecting the coincidence of binaural inputs dictates the resolution of azimuthal sound localization. We show that in MSO principal neurons of gerbils during the first week of hearing, a hyperpolarization-activated current (I(h)) progressively undergoes a 13-fold increase in maximal conductance, a >10-fold acceleration of kinetics, and, most surprisingly, a 30 mV depolarizing shift in the voltage dependence of activation. This period is associated with an upregulation of the hyperpolarization-activated and cyclic nucleotide-gated (HCN) channel subunits HCN1, HCN2, and HCN4 in the MSO, but only HCN1 and HCN4 were expressed strongly in principal neurons. I(h) recorded in nucleated patches from electrophysiologically mature MSO neurons (>P18) exhibited kinetics and an activation range nearly identical to the I(h) found in whole-cell recordings before hearing onset. These results indicate that the developmental changes in I(h) in MSO neurons can be explained predominantly by modulation from diffusible intracellular factors, and not changes in channel subunit composition. The exceptionally large modulatory changes in I(h), together with refinements in synaptic properties transform the coding strategy from one of summation and integration to the submillisecond coincidence detection known to be required for transmission of sound localization cues.
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Fenómenos Biofísicos/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Activación del Canal Iónico/fisiología , Neuronas/fisiología , Factores de Edad , Análisis de Varianza , Androstadienos/farmacología , Animales , Fenómenos Biofísicos/efectos de los fármacos , Bucladesina/farmacología , Colforsina/farmacología , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Canales Catiónicos Regulados por Nucleótidos Cíclicos/metabolismo , Estimulación Eléctrica , Inhibidores Enzimáticos/farmacología , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Gerbillinae , Imidazoles/farmacología , Técnicas In Vitro , Activación del Canal Iónico/efectos de los fármacos , Masculino , Neuronas/efectos de los fármacos , Núcleo Olivar/citología , Núcleo Olivar/crecimiento & desarrollo , Técnicas de Placa-Clamp , Piridinas/farmacología , Pirimidinas/farmacología , WortmaninaRESUMEN
In neurons of the medial superior olive (MSO), voltage-gated ion channels control the submillisecond time resolution of binaural coincidence detection, but little is known about their interplay during trains of synaptic activity that would be experienced during auditory stimuli. Here, using modeling and patch-clamp recordings from MSO principal neurons in gerbil brainstem slices, we examined interactions between two major currents controlling subthreshold synaptic integration: a low-voltage-activated potassium current (I(K-LVA)) and a hyperpolarization-activated cation current (I(h)). Both I(h) and I(K-LVA) contributed strongly to the resting membrane conductance and, during trains of simulated EPSPs, exhibited cumulative deactivation and inactivation, respectively. In current-clamp recordings, regular and irregular trains of simulated EPSCs increased input resistance up to 60%, effects that accumulated and decayed (after train) over hundreds of milliseconds. Surprisingly, the mean voltage and peaks of EPSPs increased by only a few millivolts during trains. Using a model of an MSO cell, we demonstrated that the nearly uniform response during modest depolarizing stimuli relied on changes in I(h) and I(K-LVA), such that their sum remained nearly constant over time. Experiments and modeling showed that, for simplified binaural stimuli (EPSC pairs in a noisy background), spike probability gradually increased in parallel with the increasing input resistance. Nevertheless, the interplay between I(h) and I(K-LVA) helps to maintain a nearly uniform shape of individual synaptic responses, and we show that the time resolution of synaptic coincidence detection can be maintained during trains if EPSC size gradually decreases (as in synaptic depression), counteracting slow increases in excitability.
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Activación del Canal Iónico/fisiología , Neuronas/fisiología , Dinámicas no Lineales , Núcleo Olivar/citología , Canales de Potasio con Entrada de Voltaje/fisiología , Potenciales Sinápticos/fisiología , Animales , Animales Recién Nacidos , Biofisica , Cardiotónicos/farmacología , Simulación por Computador , Estimulación Eléctrica/métodos , Femenino , Gerbillinae , Técnicas In Vitro , Activación del Canal Iónico/efectos de los fármacos , Masculino , Modelos Neurológicos , Neuronas/efectos de los fármacos , Distribución Normal , Técnicas de Placa-Clamp , Péptidos/farmacología , Canales de Potasio con Entrada de Voltaje/efectos de los fármacos , Pirimidinas/farmacología , Potenciales Sinápticos/efectos de los fármacos , Factores de TiempoRESUMEN
Neurons in the medial superior olive process sound-localization cues via binaural coincidence detection, in which excitatory synaptic inputs from each ear are segregated onto different branches of a bipolar dendritic structure and summed at the soma and axon with submillisecond time resolution. Although synaptic timing and dynamics critically shape this computation, synaptic interactions with intrinsic ion channels have received less attention. Using paired somatic and dendritic patch-clamp recordings in gerbil brainstem slices together with compartmental modeling, we found that activation of K(v)1 channels by dendritic excitatory postsynaptic potentials (EPSPs) accelerated membrane repolarization in a voltage-dependent manner and actively improved the time resolution of synaptic integration. We found that a somatically biased gradient of K(v)1 channels underlies the degree of compensation for passive cable filtering during propagation of EPSPs in dendrites. Thus, both the spatial distribution and properties of K(v)1 channels are important for preserving binaural synaptic timing.
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Neuronas/fisiología , Tiempo de Reacción/fisiología , Canales de Potasio de la Superfamilia Shaker/metabolismo , Sinapsis/fisiología , Factores de Edad , Animales , Animales Recién Nacidos , Biofisica , Tronco Encefálico/citología , Dendritas/fisiología , Venenos Elapídicos/farmacología , Estimulación Eléctrica/métodos , Potenciales Postsinápticos Excitadores/fisiología , Gerbillinae , Técnicas In Vitro , Modelos Neurológicos , Neuronas/citología , Técnicas de Placa-Clamp/métodos , Tiempo de Reacción/efectos de los fármacos , Factores de TiempoRESUMEN
Principal neurons of the medial superior olive (MSO) compute azimuthal sound location by integrating phase-locked inputs from each ear. While previous experimental and modeling studies have proposed that voltage-gated sodium channels (VGSCs) play an important role in synaptic integration in the MSO, these studies appear at odds with the unusually weak active backpropagation of action potentials into the soma and dendrites. To understand the spatial localization and biophysical properties of VGSCs, we isolated sodium currents in MSO principal neurons in gerbil brainstem slices. Nucleated and cell-attached patches revealed that VGSC density at the soma is comparable to that of many other neuron types, but channel expression is largely absent from the dendrites. Further, while somatic VGSCs activated with conventional voltage dependence (V(1/2) = -30 mV), they exhibited an unusually negative range of steady-state inactivation (V(1/2) = -77 mV), leaving approximately 92% of VGSCs inactivated at the resting potential (approximately -58 mV). In current-clamp experiments, non-inactivated VGSCs were sufficient to amplify subthreshold EPSPs near action potential threshold, counterbalancing the suppression of EPSP peaks by low voltage-activated potassium channels. EPSP amplification was restricted to the perisomatic region of the neuron, and relatively insensitive to preceding inhibition. Finally, computational modeling showed that the exclusion of VGSCs from the dendrites equalizes somatic EPSP amplification across synaptic locations and lowered the threshold for bilateral versus unilateral excitatory synaptic inputs. Together, these findings suggest that the pattern of sodium channel expression in MSO neurons contributes to these neurons' selectivity for coincident binaural inputs.
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Neuronas/fisiología , Núcleo Olivar/fisiología , Canales de Sodio/fisiología , Sinapsis/fisiología , Potenciales de Acción , Animales , Dendritas/fisiología , Gerbillinae , Técnicas In Vitro , Activación del Canal Iónico , Técnicas de Placa-Clamp , Potenciales SinápticosRESUMEN
Principal neurons of the medial superior olive (MSO) convey azimuthal sound localization cues through modulation of their rate of action potential firing. Previous intracellular studies in vitro have shown that action potentials appear highly attenuated at the soma of MSO neurons, potentially reflecting specialized action potential initiation and/or a physically distant site of generation. To examine this more directly, we made dual patch-clamp recordings from MSO principal neurons in gerbil brainstem slices. Using somatic and dendritic whole-cell recordings, we show that graded action potentials at the soma are highly sensitive to the rate of rise of excitation and undergo strong attenuation in their backpropagation into the dendrites (length constant, 76 microm), particularly during strong dendritic excitation. Using paired somatic whole-cell and axonal loose-patch recordings, we show that action potentials recorded in the axon at distances > 25 microm are all-or-none, and uniform in amplitude even when action potentials appear graded at the soma. This proximal zone corresponded to the start of myelination in the axon, as assessed with immunocytochemical staining for myelin basic protein in single-labelled neurons. Finally, the axon was capable of sustaining remarkably high firing rates, with perfect entrainment occurring at frequencies of up to 1 kHz. Together, our findings show that action potential signalling in MSO principal neurons is highly secure, but shows a restricted invasion of the somatodendritic compartment of the cell. This restriction may be important for minimizing distortions in synaptic integration during the high frequencies of synaptic input encountered in the MSO.
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Vías Auditivas/fisiología , Axones/fisiología , Conducción Nerviosa , Neuronas/fisiología , Núcleo Olivar/fisiología , Localización de Sonidos , Potenciales de Acción , Animales , Vías Auditivas/química , Vías Auditivas/citología , Axones/química , Dendritas/fisiología , Gerbillinae , Técnicas In Vitro , Proteína Básica de Mielina/análisis , Fibras Nerviosas Mielínicas/química , Fibras Nerviosas Mielínicas/fisiología , Neuronas/química , Núcleo Olivar/química , Núcleo Olivar/citología , Técnicas de Placa-Clamp , Transmisión Sináptica , Factores de TiempoRESUMEN
Care and therapy of patients experiencing an anaphylactic reaction should be known by the physicians working in the emergency medical unit or in pre-hospital care. The epidemiology of these reactions varies according to the countries. The main aetiologies are due to food, hymenoptera or drugs. The clinical scale proposed by Ring and Messmer aims to classify the reactions in 4 grades according to their severity and is useful to stratify therapy. According to the grade of the reaction, the drug of choice for the treatment of anaphylaxis is epinephrine associated to vascular expansion. Anaphylaxis during pregnancy is described. Patients who experienced an immediate hypersensitivity reaction should undergo an allergological investigation to prove the immune mechanism and to identify the culprit allergen. Reporting to the Drug Safety Monitoring Authorities when a drug is implicated should not be forgotten.
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Anafilaxia/tratamiento farmacológico , Servicio de Urgencia en Hospital , Agonistas Adrenérgicos/uso terapéutico , Alérgenos/efectos adversos , Anafilaxia/diagnóstico , Anafilaxia/epidemiología , Anafilaxia/inmunología , Diagnóstico Diferencial , Epinefrina/uso terapéutico , Humanos , Índice de Severidad de la EnfermedadRESUMEN
In mammals, principal neurons of the medial superior olive (MSO) exhibit biophysical specializations that enable them to detect sound localization cues with microsecond precision. In the present study, we used whole-cell patch recordings to examine the development of the intrinsic electrical properties of these neurons in brainstem slices from postnatal day 14 (P14) to P38 gerbils. In the week after hearing onset (P14-P21), we observed dramatic reductions in somatic EPSP duration, input resistance, and membrane time constant. Surprisingly, somatically recorded action potentials also dramatically declined in amplitude over a similar period (38 +/- 3 to 17 +/- 2 mV; tau = 5.2 d). Simultaneous somatic and dendritic patch recordings revealed that these action potentials were initiated in the axon, which primarily emerged from the soma. In older gerbils, the rapid speed of membrane voltage changes and the attenuation of action potential amplitudes were mediated extensively by low voltage-activated potassium channels containing the Kv1.1 subunit. In addition, whole-cell voltage-clamp recordings revealed that these potassium channels increase nearly fourfold from P14 to P23 and are thus a major component of developmental changes in excitability. Finally, the electrophysiological features of principal neurons of the medial nucleus of the trapezoid body did not change after P14, indicating that posthearing regulation of intrinsic membrane properties is not a general feature of all time-coding auditory neurons. We suggest that the striking electrical segregation of the axon from the soma and dendrites of MSO principal neurons minimizes spike-induced distortion of synaptic potentials and thus preserves the accuracy of binaural comparisons.