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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 ( gKL) 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. [ABSTRACT FROM AUTHOR]

We performed simultaneous patch-electrode recordings from the soma and apical dendrite of CA1 pyramidal neurons in hippocampal slices, in order to determine the degree of voltage attenuation along CA1 dendrites. Fifty per cent attenuation of steady-state somatic voltage changes occurred at a distance of 238 μm from the soma in control and 409 μm after blocking the hyperpolarization-activated (H) conductance. The morphology of three neurons was reconstructed and used to generate computer models, which were adjusted to fit the somatic and dendritic voltage responses. These models identify several factors contributing to the voltage attenuation along CA1 dendrites, including high axial cytoplasmic resistivity, low membrane resistivity, and large H conductance. In most cells the resting membrane conductances, including the H conductances, were larger in the dendrites than the soma. Simulations suggest that synaptic potentials attenuate enormously as they propagate from the dendrite to the soma, with greater than 100-fold attenuation for synapses on many small, distal dendrites. A prediction of this powerful EPSP attenuation is that distal synaptic inputs are likely only to be effective in the presence of conductance scaling, dendritic excitability, or both. [ABSTRACT FROM AUTHOR]

Presents a study which examined the significance of dendritic spikes to the cooperative long-term potentiation (LTP) of synapses. Assessment of the role of back propagation in LTP; Evidence of the hypothesis that the somatic regenerative events reflected dendritically generated spikes; Implication of the persistence of dendritic spikes and LTP during partial block of voltage-gated calcium channels.

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 (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 the detection of synaptic coincidence on a timescale 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 subthreshold oscillations of differing magnitudes that drive action potentials at rates between 100 and 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, submillisecond time-varying signals as well as in slower envelopes. [ABSTRACT FROM AUTHOR]

Summary 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. [ABSTRACT FROM AUTHOR]

The authors comment on a study which examined the functional implication of gamma-aminobutyric acid (GABA) B receptor modulation in the medial superior olive (MSO). They state that the study provides compelling evidence that pre-synaptic GABAB receptors modulate neurotransmitter release at synapses onto MSO neurons. They believe that such modulation improves the resolution of binaural coincidence detection.

Summary: 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. [ABSTRACT FROM AUTHOR]

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 (V1/2=-30 mV), they exhibited an unusually negative range of steady-state inactivation (V1/2=-77 mV), leaving ~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. [ABSTRACT FROM AUTHOR]

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 μm), 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 μm 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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

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; τ = 5.2d). 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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. [ABSTRACT FROM AUTHOR]

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 ~0.2 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 vivo. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

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 hyperpolarizationactivated current (Ih ) 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, andHCN4in the MSO, but onlyHCN1and HCN4 were expressed strongly in principal neurons. Ih recorded in nucleated patches from electrophysiologically mature MSO neurons (>P18) exhibited kinetics and an activation range nearly identical to the Ih found in whole-cell recordings before hearing onset. These results indicate that the developmental changes in Ih 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 Ih , 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. [ABSTRACT FROM AUTHOR]

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 (IK-LVA ) and a hyperpolarization-activated cation current (Ih ). Both Ih and IK-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 Ih and IK-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 Ih and IK-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. [ABSTRACT FROM AUTHOR]

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 Kv1 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 Kv1 channels underlies the degree of compensation for passive cable filtering during propagation of EPSPs in dendrites. Thus, both the spatial distribution and properties of Kv1 channels are important for preserving binaural synaptic timing. [ABSTRACT FROM AUTHOR]