RESUMO
In sensory systems, the neuronal representation of external stimuli is enhanced along the sensory pathway. In the auditory system, strong enhancement of binaural information takes place between the brainstem and the midbrain; however, the underlying cellular mechanisms are unknown. Here we investigated the transformation of binaural information in the dorsal nucleus of the lateral lemniscus (DNLL), a nucleus that connects the binaural nuclei in the brainstem and the inferior colliculus in the midbrain. We used in vitro and in vivo electrophysiology in adult Mongolian gerbils to show that N-methyl-D-aspartate receptor (NMDARs) play a critical role in neuronal encoding of stimulus properties in the DNLL. While NMDARs increase firing rates, the timing and the accuracy of the neuronal responses remain unchanged. NMDAR-mediated excitation increases the information about the acoustic stimulus. Taken together, our results show that NMDARs in the DNLL enhance the auditory information content in adult mammal brainstem.
Assuntos
Tronco Encefálico/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Estimulação Acústica , Potenciais de Ação/fisiologia , Animais , Vias Auditivas/fisiologia , Feminino , Gerbillinae , Masculino , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
Interaural differences in stimulus intensity and timing are major cues for sound localization. In mammals, these cues are first processed in the lateral and medial superior olive by interaction of excitatory and inhibitory synaptic inputs from ipsi- and contralateral cochlear nucleus neurons. To preserve sound localization acuity following changes in the acoustic environment, the processing of these binaural cues needs neuronal adaptation. Recent studies have shown that binaural sensitivity adapts to stimulation history within milliseconds, but the actual extent of binaural adaptation is unknown. In the current study, we investigated long-term effects on binaural sensitivity using extracellular in vivo recordings from single neurons in the dorsal nucleus of the lateral lemniscus that inherit their binaural properties directly from the lateral and medial superior olives. In contrast to most previous studies, we used a noninvasive approach to influence this processing. Adult gerbils were exposed for 2 weeks to moderate noise with no stable binaural cue. We found monaural response properties to be unaffected by this measure. However, neuronal sensitivity to binaural cues was reversibly altered for a few days. Computational models of sensitivity to interaural time and level differences suggest that upregulation of inhibition in the superior olivary complex can explain the electrophysiological data.
Assuntos
Adaptação Fisiológica/fisiologia , Vias Auditivas/fisiologia , Tronco Encefálico/fisiologia , Neurônios/fisiologia , Localização de Som/fisiologia , Estimulação Acústica/métodos , Fatores Etários , Animais , Vias Auditivas/anatomia & histologia , Tronco Encefálico/anatomia & histologia , Feminino , Gerbillinae , Masculino , Modelos Neurológicos , Ruído/efeitos adversosRESUMO
Neuronal plasticity underlying cerebellar learning behavior is strongly associated with type 1 metabotropic glutamate receptor (mGluR1) signaling. Activation of mGluR1 leads to activation of the Gq/11 pathway, which is involved in inducing synaptic plasticity at the parallel fiber-Purkinje cell synapse (PF-PC) in form of long-term depression (LTD). To optogenetically modulate mGluR1 signaling we fused mouse melanopsin (OPN4) that activates the Gq/11 pathway to the C-termini of mGluR1 splice variants (OPN4-mGluR1a and OPN4-mGluR1b). Activation of both OPN4-mGluR1 variants showed robust Ca2+ increase in HEK cells and PCs of cerebellar slices. We provide the prove-of-concept approach to modulate synaptic plasticity via optogenetic activation of OPN4-mGluR1a inducing LTD at the PF-PC synapse in vitro. Moreover, we demonstrate that light activation of mGluR1a signaling pathway by OPN4-mGluR1a in PCs leads to an increase in intrinsic activity of PCs in vivo and improved cerebellum driven learning behavior.
RESUMO
Interaural time differences (ITDs) are the major cue for localizing low-frequency sounds. The activity of neuronal populations in the brainstem encodes ITDs with an exquisite temporal acuity of about 10 µs. The response of single neurons, however, also changes with other stimulus properties like the spectral composition of sound. The influence of stimulus frequency is very different across neurons and thus it is unclear how ITDs are encoded independently of stimulus frequency by populations of neurons. Here we fitted a statistical model to single-cell rate responses of the dorsal nucleus of the lateral lemniscus. The model was used to evaluate the impact of single-cell response characteristics on the frequency-invariant mutual information between rate response and ITD. We found a rough correspondence between the measured cell characteristics and those predicted by computing mutual information. Furthermore, we studied two readout mechanisms, a linear classifier and a two-channel rate difference decoder. The latter turned out to be better suited to decode the population patterns obtained from the fitted model.
Assuntos
Tronco Encefálico/fisiologia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Modelos Neurológicos , Localização de Som/fisiologia , Algoritmos , Animais , Feminino , Gerbillinae , Modelos Lineares , Masculino , Modelos Estatísticos , Neurônios/fisiologia , Distribuição Normal , Distribuição de Poisson , Fatores de TempoRESUMO
To counterbalance long-term environmental changes, neuronal circuits adapt the processing of sensory information. In the auditory system, ongoing background noise drives long-lasting adaptive mechanism in binaural coincidence detector neurons in the superior olive. However, the compensatory cellular mechanisms of the binaural neurons in the medial superior olive (MSO) to long-term background changes are unexplored. Here we investigated the cellular properties of MSO neurons during long-lasting adaptations induced by moderate omnidirectional noise exposure. After noise exposure, the input resistance of MSO neurons of mature Mongolian gerbils was reduced, likely due to an upregulation of hyperpolarisation-activated cation and low voltage-activated potassium currents. Functionally, the long-lasting adaptations increased the action potential current threshold and facilitated high frequency output generation. Noise exposure accelerated the occurrence of spontaneous postsynaptic currents. Together, our data suggest that cellular adaptations in coincidence detector neurons of the MSO to continuous noise exposure likely increase the sensitivity to differences in sound pressure levels.
Assuntos
Adaptação Fisiológica/fisiologia , Vias Auditivas/fisiologia , Tronco Encefálico/fisiologia , Neurônios/fisiologia , Estimulação Acústica , Potenciais de Ação/fisiologia , Animais , Gerbillinae/fisiologia , Ruído/efeitos adversos , Complexo Olivar Superior/fisiologiaRESUMO
Opn7b is a non-visual G protein-coupled receptor expressed in zebrafish. Here we find that Opn7b expressed in HEK cells constitutively activates the Gi/o pathway and illumination with blue/green light inactivates G protein-coupled inwardly rectifying potassium channels. This suggests that light acts as an inverse agonist for Opn7b and can be used as an optogenetic tool to inhibit neuronal networks in the dark and interrupt constitutive inhibition in the light. Consistent with this prediction, illumination of recombinant expressed Opn7b in cortical pyramidal cells results in increased neuronal activity. In awake mice, light stimulation of Opn7b expressed in pyramidal cells of somatosensory cortex reliably induces generalized epileptiform activity within a short (<10 s) delay after onset of stimulation. Our study demonstrates a reversed mechanism for G protein-coupled receptor control and Opn7b as a tool for controlling neural circuit properties.
Assuntos
Proteínas de Ligação ao GTP/metabolismo , Neurônios/metabolismo , Opsinas/metabolismo , Optogenética/métodos , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Proteínas de Ligação ao GTP/genética , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Opsinas/genética , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/genética , Córtex Somatossensorial/citologia , Córtex Somatossensorial/metabolismo , Sinapses/genética , Sinapses/fisiologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
The mammalian binaural system compares the timing of monaural inputs with microsecond precision. This temporal precision is required for localizing sounds in azimuth. However, temporal features of the monaural inputs, in particular their latencies, highly depend on the overall sound level. In a combined psychophysical, electrophysiological, and modeling approach, we investigate how level-dependent latency shifts of the monaural responses are reflected in the perception and neural representation of interaural time differences. We exploit the sensitivity of the binaural system to the timing of high-frequency stimuli with binaurally incongruent envelopes. Using these novel stimuli, both the perceptually adjusted interaural time differences and the time differences extracted from electrophysiological recordings systematically depend on overall sound pressure level. The perceptual and electrophysiological time differences of the envelopes can be explained in an existing model of temporal integration only if a level-dependent firing threshold is added. Such an adjustment of firing threshold provides a temporally accurate neural code of the temporal structure of a stimulus and its binaural disparities independent of overall sound level.
Assuntos
Estimulação Acústica/métodos , Vias Auditivas/fisiologia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Tempo de Reação/fisiologia , Adulto , Animais , Feminino , Lateralidade Funcional/fisiologia , Gerbillinae , Humanos , Masculino , Adulto JovemRESUMO
Sensory systems use a variety of strategies to increase the signal-to-noise ratio in their inputs at the receptor level. However, important cues for sound localization are not present at the individual ears but are computed after inputs from the two ears converge within the brain, and we hypothesized that additional strategies to enhance the representation of these cues might be employed in the initial stages after binaural convergence. Specifically, we investigated the transformation that takes place between the first two stages of the gerbil auditory pathway that are sensitive to differences in the arrival time of a sound at the two ears (interaural time differences; ITDs): the medial superior olive (MSO), where ITD tuning originates, and the dorsal nucleus of the lateral lemniscus (DNLL), to which the MSO sends direct projections. We use a combined experimental and computational approach to demonstrate that the coding of ITDs is dramatically enhanced between these two stages, with the mutual information in the responses of single neurons increasing by a factor of 2. We also show that this enhancement is related to an increase in dynamic range for neurons with high preferred frequencies and a decrease in variability for neurons with low preferred frequencies. These results suggest that a major role of the initial stages of the ITD pathway may be to enhance the representation created at the site of coincidence detection and illustrate the potential of this pathway as a model system for the study of strategies for enhancing sensory representations in the mammalian brain.
Assuntos
Vias Auditivas/fisiologia , Percepção Auditiva/fisiologia , Tronco Encefálico/fisiologia , Neurônios/fisiologia , Núcleo Olivar/fisiologia , Estimulação Acústica , Potenciais de Ação , Animais , Orelha , Gerbillinae , Teoria da Informação , Fatores de TempoRESUMO
The mammalian auditory system is the temporally most precise sensory modality: To localize low-frequency sounds in space, the binaural system can resolve time differences between the ears with microsecond precision. In contrast, the binaural system appears sluggish in tracking changing interaural time differences as they arise from a low-frequency sound source moving along the horizontal plane. For a combined psychophysical and electrophysiological approach, we created a binaural stimulus, called "Phasewarp," that can transmit rapid changes in interaural timing. Using this stimulus, the binaural performance in humans is significantly better than reported previously and comparable with the monaural performance revealed with amplitude-modulated stimuli. Parallel, electrophysiological recordings of binaural brainstem neurons in the gerbil show fast temporal processing of monaural and different types of binaural modulations. In a refined electrophysiological approach that was matched to the psychophysics, the seemingly faster binaural processing of the Phasewarp was confirmed. The current data provide both psychophysical and physiological evidence against a general, hard-wired binaural sluggishness and reconcile previous contradictions of electrophysiological and psychophysical estimates of temporal binaural performance.
Assuntos
Potenciais de Ação/fisiologia , Vias Auditivas/fisiologia , Lateralidade Funcional/fisiologia , Psicofísica , Tempo de Reação/fisiologia , Localização de Som/fisiologia , Estimulação Acústica/métodos , Animais , Limiar Auditivo/fisiologia , Tronco Encefálico/citologia , Relação Dose-Resposta à Radiação , Gerbillinae , Humanos , Neurônios Aferentes/fisiologia , Curva ROC , Fatores de TempoRESUMO
In natural environments our auditory system is exposed to multiple and diverse signals of fluctuating amplitudes. Therefore, to detect, localize, and single out individual sounds the auditory system has to process and filter spectral and temporal information from both ears. It is known that the overall sound pressure level affects sensory signal transduction and therefore the temporal response pattern of auditory neurons. We hypothesize that the mammalian binaural system utilizes a dynamic mechanism to adjust the temporal filters in neuronal circuits to different overall sound pressure levels. Previous studies proposed an inhibitory mechanism generated by the reciprocally coupled dorsal nuclei of the lateral lemniscus (DNLL) as a temporal neuronal-network filter that suppresses rapid binaural fluctuations. Here we investigated the consequence of different sound levels on this filter during binaural processing. Our in vivo and in vitro electrophysiology in Mongolian gerbils shows that the integration of ascending excitation and contralateral inhibition defines the temporal properties of this inhibitory filter. The time course of this filter depends on the synaptic drive, which is modulated by the overall sound pressure level and N-methyl-D-aspartate receptor (NMDAR) signaling. In psychophysical experiments we tested the temporal perception of humans and show that detection and localization of two subsequent tones changes with the sound pressure level consistent with our physiological results. Together our data support the hypothesis that mammals dynamically adjust their time window for sound detection and localization within the binaural system in a sound level dependent manner.
Assuntos
Audição/fisiologia , Localização de Som/fisiologia , Som , 2-Amino-5-fosfonovalerato/farmacologia , Estimulação Acústica , Potenciais de Ação/efeitos dos fármacos , Animais , Vias Auditivas/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Gerbillinae , Colículos Inferiores/fisiologia , Masculino , Inibição Neural , Neurônios/efeitos dos fármacos , Psicofísica , Quinoxalinas/farmacologia , Fatores de TempoRESUMO
The precedence effect describes the phenomenon whereby echoes are spatially fused to the location of an initial sound by selectively suppressing the directional information of lagging sounds (echo suppression). Echo suppression is a prerequisite for faithful sound localization in natural environments but can break down depending on the behavioral context. To date, the neural mechanisms that suppress echo directional information without suppressing the perception of echoes themselves are not understood. We performed in vivo recordings in Mongolian gerbils of neurons of the dorsal nucleus of the lateral lemniscus (DNLL), a GABAergic brainstem nucleus that targets the auditory midbrain, and show that these DNLL neurons exhibit inhibition that persists tens of milliseconds beyond the stimulus offset, so-called persistent inhibition (PI). Using in vitro recordings, we demonstrate that PI stems from GABAergic projections from the opposite DNLL. Furthermore, these recordings show that PI is attributable to intrinsic features of this GABAergic innervation. Implementation of these physiological findings into a neuronal model of the auditory brainstem demonstrates that, on a circuit level, PI creates an enhancement of responsiveness to lagging sounds in auditory midbrain cells. Moreover, the model revealed that such response enhancement is a sufficient cue for an ideal observer to identify echoes and to exhibit echo suppression, which agrees closely with the percepts of human subjects.
Assuntos
Vias Auditivas/fisiologia , Meio Ambiente , Inibição Neural/fisiologia , Neurônios/fisiologia , Localização de Som , Estimulação Acústica/métodos , Animais , Animais Recém-Nascidos , Relação Dose-Resposta à Radiação , Estimulação Elétrica/métodos , Lateralidade Funcional , Antagonistas GABAérgicos/farmacologia , Gerbillinae , Técnicas In Vitro , Colículos Inferiores/citologia , Potenciais da Membrana/fisiologia , Modelos Biológicos , Técnicas de Patch-Clamp/métodos , Piridazinas/farmacologiaRESUMO
To capture the context of sensory information, neural networks must process input signals across multiple timescales. In the auditory system, a prominent change in temporal processing takes place at an inhibitory GABAergic synapse in the dorsal nucleus of the lateral lemniscus (DNLL). At this synapse, inhibition outlasts the stimulus by tens of milliseconds, such that it suppresses responses to lagging sounds, and is therefore implicated in echo suppression. Here, we untangle the cellular basis of this inhibition. We demonstrate with in vivo whole-cell patch-clamp recordings in Mongolian gerbils that the duration of inhibition increases with sound intensity. Activity-dependent spillover and asynchronous release translate the high presynaptic firing rates found in vivo into a prolonged synaptic output in acute slice recordings. A key mechanism controlling the inhibitory time course is the passive integration of the hyperpolarizing inhibitory conductance. This prolongation depends on the synaptic conductance amplitude. Computational modeling shows that this prolongation is a general mechanism and relies on a non-linear effect caused by synaptic conductance saturation when approaching the GABA reversal potential. The resulting hyperpolarization generates an efficient activity-dependent suppression of action potentials without affecting the threshold or gain of the input-output function. Taken together, the GABAergic inhibition in the DNLL is adjusted to the physiologically relevant duration by passive integration of inhibition with activity-dependent synaptic kinetics. This change in processing timescale combined with the reciprocal connectivity between the DNLLs implements a mechanism to suppress the distracting localization cues of echoes and helps to localize the initial sound source reliably.
Assuntos
Vias Auditivas , Sinapses/fisiologia , Potenciais de Ação , Animais , Polaridade Celular , Gerbillinae , Fatores de Tempo , Ácido gama-Aminobutírico/metabolismoRESUMO
Across all sensory modalities, the effect of context-dependent neural adaptation can be observed at every level, from receptors to perception. Nonetheless, it has long been assumed that the processing of interaural time differences, which is the primary cue for sound localization, is nonadaptive, as its outputs are mapped directly onto a hard-wired representation of space. Here we present evidence derived from in vitro and in vivo experiments in gerbils indicating that the coincidence-detector neurons in the medial superior olive modulate their sensitivity to interaural time differences through a rapid, GABA(B) receptor-mediated feedback mechanism. We show that this mechanism provides a gain control in the form of output normalization, which influences the neuronal population code of auditory space. Furthermore, psychophysical tests showed that the paradigm used to evoke neuronal GABA(B) receptor-mediated adaptation causes the perceptual shift in sound localization in humans that was expected on the basis of our physiological results in gerbils.
Assuntos
Adaptação Fisiológica/fisiologia , Núcleo Olivar/citologia , Receptores de GABA-B/metabolismo , Localização de Som/fisiologia , Sinapses/fisiologia , Estimulação Acústica , Adaptação Fisiológica/efeitos dos fármacos , Adulto , Animais , Animais Recém-Nascidos , Feminino , GABAérgicos/farmacologia , Gerbillinae , Glutamato Descarboxilase/metabolismo , Humanos , Técnicas In Vitro , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Localização de Som/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Fatores de Tempo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Adulto Jovem , Ácido gama-Aminobutírico/farmacologiaRESUMO
We are regularly exposed to several concurrent sounds, producing a mixture of binaural cues. The neuronal mechanisms underlying the localization of concurrent sounds are not well understood. The major binaural cues for localizing low-frequency sounds in the horizontal plane are interaural time differences (ITDs). Auditory brain stem neurons encode ITDs by firing maximally in response to "favorable" ITDs and weakly or not at all in response to "unfavorable" ITDs. We recorded from ITD-sensitive neurons in the dorsal nucleus of the lateral lemniscus (DNLL) while presenting pure tones at different ITDs embedded in noise. We found that increasing levels of concurrent white noise suppressed the maximal response rate to tones with favorable ITDs and slightly enhanced the response rate to tones with unfavorable ITDs. Nevertheless, most of the neurons maintained ITD sensitivity to tones even for noise intensities equal to that of the tone. Using concurrent noise with a spectral composition in which the neuron's excitatory frequencies are omitted reduced the maximal response similar to that obtained with concurrent white noise. This finding indicates that the decrease of the maximal rate is mediated by suppressive cross-frequency interactions, which we also observed during monaural stimulation with additional white noise. In contrast, the enhancement of the firing rate to tones at unfavorable ITD might be due to early binaural interactions (e.g., at the level of the superior olive). A simple simulation corroborates this interpretation. Taken together, these findings suggest that the spectral composition of a concurrent sound strongly influences the spatial processing of ITD-sensitive DNLL neurons.
Assuntos
Percepção Auditiva/fisiologia , Tronco Encefálico/citologia , Neurônios Aferentes/fisiologia , Ruído , Tempo de Reação/fisiologia , Análise Espectral , Estimulação Acústica/métodos , Animais , Vias Auditivas/fisiologia , Sinais (Psicologia) , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Feminino , Gerbillinae , MasculinoRESUMO
Differences in intensity and arrival time of sounds at the two ears, interaural intensity and time differences (IID, ITD), are the chief cues for sound localization. Both cues are initially processed in the superior olivary complex (SOC), which projects to the dorsal nucleus of the lateral lemniscus (DNLL) and the auditory midbrain. Here we present basic response properties of low-frequency (< 2 kHz) DNLL neurons and their binaural sensitivity to ITDs and IIDs in the anesthetized gerbil. We found many neurons showing binaural properties similar to those reported for SOC neurons. IID-properties were similar to that of the contralateral lateral superior olive (LSO). A majority of cells had an ITD sensitivity resembling that of either the ipsilateral medial superior olive (MSO) or the contralateral LSO. A smaller number of cells displayed intermediate types of ITD sensitivity. In neurons with MSO-like response ITDs that evoked maximal discharges were mostly outside of the range of ITDs the gerbil naturally experiences. The maxima of the first derivative of their ITD-functions (steepest slope), however, were well within the physiological range of ITDs. This finding is consistent with the concept of a population rather than a place code for ITDs. Moreover, we describe several other binaural properties as well as physiological and anatomical evidence for a small but significant input from the contralateral MSO. The large number of ITD-sensitive low-frequency neurons implicates a substantial role for the DNLL in ITD processing and promotes this nucleus as a suitable model for further studies on ITD-coding.