Temporal Fidelity Research Articles

Effect of Different Gentamicin Dose on the Plasticity of the Ribbon Synapses in Cochlear Inner Hair Cells of C57BL/6J Mice

Faithful information transfer at the hair cell afferent synapse requires synaptic transmission to be both reliable and temporally precise. The release of neurotransmitter must exhibit both rapid on and off kinetics to accurately follow acoustic stimuli with a periodicity of 1 ms or less. To ensure such remarkable temporal fidelity, the cochlear hair cell afferent synapse undoubtedly relies on unique cellular and molecular specializations. To study effects of different doses of gentamicin on the changes of synaptic ribbons of cochlear inner hair cells (IHCs) in mice, the availability of genetic information, transgenic and knock-out animals make the C57BL/6J mouse a primary model in biomedical research. Aminoglycoside ototoxicity, however, has rarely been studied in mature mice because they are considered highly resistant to the drugs. This study presents models for gentamicin ototoxicity in adult C57BL/6J mouse strains. Five-week-old mice were injected intraperitoneally once daily with 50-300 mg gentamicin base/kg body weight for 7 days. Higher doses of gentamicin appear to be associated with earlier hearing damage in C57BL/6J mice, although not necessarily with more severe damage. At 200 mg/kg, gentamicin appears to induce significant hearing damage while not significantly affect the animal's general condition. Therefore, 200 mg/kg may be an ideal dose for ototoxicity modeling in C57BL/6J mice using gentamicin. In the early period of different dose of gentamicin effect, when the number of hair cells had not changed, the number changes of IHC ribbon synapses had taken place. Through the number of ribbon synapses changing, IHCs increased or decreased connections with spiral ganglion nerves (SGNs). The ribbon synapses played a compensatory role for gentamicin ototoxicity, while this effect was not sufficient to maintain the normal threshold of hearing.

A virtual time system for virtualization-based network emulations and simulations

Simulation and emulation are commonly used to study the behaviour of communication networks, owing to the cost and complexity of exploring new ideas on actual networks. Emulations executing real code have high functional fidelity, but may not have high temporal fidelity because virtual machines usually use their host's clock. To enhance temporal fidelity, we designed a virtual time system for virtualization-based network emulations and simulations, such that virtual machines perceive time as if they were running concurrently in physical world. Our time virtualization is not exact: there exist temporal errors primarily due to scheduler timeslice, which is tunable in our system. We then study the tradeoff between temporal fidelity and execution speed under different lengths of timeslices, both experimentally and analytically. We demonstrate that our virtual time system is flexible such that it can achieve different level of temporal accuracy at the cost of different execution speed.

Long‐term in vivo imaging of normal and pathological mouse spinal cord with subcellular resolution using implanted glass windows

Repeated in vivo two-photon imaging of adult mammalian spinal cords, with subcellular resolution, would be crucial for understanding cellular mechanisms under normal and pathological conditions. Current methods are limited because they require surgery for each imaging session. Here we report a simple glass window methodology avoiding repeated surgical procedures and subsequent inflammation. We applied this strategy to follow axon integrity and the inflammatory response over months by multicolour imaging of adult transgenic mice. We found that glass windows have no significant effect on axon number or structure, cause a transient inflammatory response, and dramatically increase the throughput of in vivo spinal imaging. Moreover, we used this technique to track retraction/degeneration and regeneration of cut axons after a ‘pin-prick' spinal cord injury with high temporal fidelity. We showed that regenerating axons can cross an injury site within 4 days and that their terminals undergo dramatic morphological changes for weeks after injury. Overall the technique can potentially be adapted to evaluate cellular functions and therapeutic strategies in the normal and diseased spinal cord.

Modeling and prediction of conduction delay in an unmyelinated axon

Conduction delay in axons is a function of the axon morphology, passive membrane properties and voltage-gated ionic currents. Although conduction delay is usually assumed to be constant, indicating perfect temporal fidelity, recent work has shown that the delay of each action potential depends on the prior short- and long-term history of activity in the axon [1]. Violation of temporal fidelity leads to substantial variations in inter-spike intervals which has potential impact on temporal neural activity. In experiments using the motor axon of the pyloric dilator (PD) neuron of the lobster, H. americanus, we measured conduction delay using Poisson random stimuli applied at different mean rates [2]. These measurements showed that the mean value and the variance of conduction delay increases as a function of stimulus time until these values reach a steady state at about 5 minutes post-stimulation. Even at steady state, conduction delay showed a non-monotonic relationship with stimulus frequency (finst): it was higher at small or large values of finst but has a minimum at finst~45 Hz. Moreover, bath application of dopamine drastically improved the temporal fidelity of conduction delay. We have constructed a conductance-based model of the PD axon to examine the role of different ionic currents in shaping the history dependence of conduction delay. In addition to the standard Hodgkin-Huxley currents, this model includes a transient potassium current IA and a hyperpolarization activated inward current Ih, both of which have been characterized in this axon. The main effect of dopamine in the biological axon is an increase of Ih which counteracts the activity-dependent hyperpolarization [3], mimicked by adding a Na+/K+ pump in the model. We find that the Na+/K+ pump enables the model to reproduce the long-term history dependence observed in the biological PD axon. A pump current with a slow time constant (τ=90 sec) results in a slow increase of the mean and CV of conduction delay with stimulus time (Fig. ​(Fig.1A),1A), and a non-monotonic relationship between conduction delay and finst (Fig. ​(Fig.1B),1B), as observed experimentally [2]. Additionally, as in the experiments, temporal fidelity is improved as Ih is increased. Figure 1 Changes in action potential delay in the model axon in response to 5 mins of Poisson stimulation (mean rate 10 Hz). Compare with experimental data [2]. A. Both mean and CV of conduction delay increase slowly in response to activity. B. Delay (fifth minute) ... Action potential conduction velocity can be approximated by (d=axon diam, R*=total memb resistance/unit area at peak, Ra=axial resistivity, Cm=capacitance/unit area [4]. Although this equation accurately predicts the conduction velocity of a single action potential in our model, it fails to the variations in conduction velocity in the presence of the history-dependent effects. This discrepancy is partly due to non-uniform conduction velocity along the axon when active at high rates. We revise the formula to predict the relationship between the conduction delay and total membrane resistance at the action potential peak.

Fluorescence enhancement of N2O2-type dipyrrin ligand in two step responding to zinc(II) ion

Fluorescence imaging is well-suited for the live imaging of biological Zn(II), which has no facile spectroscopic or magnetic signature. The successful application of this methodology requires the development of robust Zn(II) imaging agents that display high sensitivity, selectivity and temporal fidelity. In this study, a N2O2-type dipyrrin based bimolecular zinc(II) complex was produced and shown to have sharper, blue-shifted and more enhanced fluorescence emission. An approximate three-fold fluorescence enhancement was achieved within the micromolar concentration range, which is an important parameter for Zn(II) detection in vivo. The increase in emission intensity was due to the dominant role of aryl-ring rotation in governing the excited state dynamics and fluorescence properties of the dipyrrin dye. Fluorescence titration showed that the ligand complex exhibited very strong zinc(II) binding affinity when compared to that in the binuclear chloro complex. The fluorescence emission changes in the dipyrrin dye to zinc(II) ion could be observed not only using instruments but also by the naked-eye (violet→sky blue).

Transgenic APP expression during postnatal development causes persistent locomotor hyperactivity in the adult

BackgroundTransgenic mice expressing disease-associated proteins have become standard tools for studying human neurological disorders. Transgenes are often expressed using promoters chosen to drive continuous high-level expression throughout life rather than temporal and spatial fidelity to the endogenous gene. This approach has allowed us to recapitulate diseases of aging within the two-year lifespan of the laboratory mouse, but has the potential for creating aberrant phenotypes by mechanisms unrelated to the human disorder.ResultsWe show that overexpression of the Alzheimer’s-related amyloid precursor protein (APP) during early postnatal development leads to severe locomotor hyperactivity that can be significantly attenuated by delaying transgene onset until adulthood. Our data suggest that exposure to transgenic APP during maturation influences the development of neuronal circuits controlling motor activity. Both when matched for total duration of APP overexpression and when matched for cortical amyloid burden, animals exposed to transgenic APP as juveniles are more active in locomotor assays than animals in which APP overexpression was delayed until adulthood. In contrast to motor activity, the age of APP onset had no effect on thigmotaxis in the open field as a rough measure of anxiety, suggesting that the interaction between APP overexpression and brain development is not unilateral.ConclusionsOur findings indicate that locomotor hyperactivity displayed by the tet-off APP transgenic mice and several other transgenic models of Alzheimer’s disease may result from overexpression of mutant APP during postnatal brain development. Our results serve as a reminder of the potential for unexpected interactions between foreign transgenes and brain development to cause long-lasting effects on neuronal function in the adult. The tet-off APP model provides an easy means of avoiding developmental confounds by allowing transgene expression to be delayed until the mice reach adulthood.

Dopamine Modulation ofIhImproves Temporal Fidelity of Spike Propagation in an Unmyelinated Axon

We studied how conduction delays of action potentials in an unmyelinated axon depended on the history of activity and how this dependence was changed by the neuromodulator dopamine (DA). The pyloric dilator axons of the stomatogastric nervous system in the lobster, Homarus americanus, exhibited substantial activity-dependent hyperpolarization and changes in spike shape during repetitive activation. The conduction delays varied by several milliseconds per centimeter, and, during activation with realistic burst patterns or Poisson-like patterns, changes in delay occurred over multiple timescales. The mean delay increased, whereas the resting membrane potential hyperpolarized with a time constant of several minutes. Concomitantly with the mean delay, the variability of delay also increased. The variability of delay was not a linear or monotonic function of instantaneous spike frequency or spike shape parameters, and the relationship between these parameters changed with the increase in mean delay. Hyperpolarization was counteracted by a hyperpolarization-activated inward current (I(h)), and the magnitude of I(h) critically determined the temporal fidelity of spike propagation. Pharmacological block of I(h) increased the change in delay and the variability of delay, and increasing I(h) by application of DA diminished both. Consequently, the temporal fidelity of pattern propagation was substantially improved in DA. Standard measurements of changes in excitability or delay with paired stimuli or tonic stimulation failed to capture the dynamics of spike conduction. These results indicate that spike conduction can be extremely sensitive to the history of axonal activity and to the presence of neuromodulators, with potentially important consequences for temporal coding.

Neural correlates of auditory distraction revealed in theta-band EEG

Selective attention involves the exclusion of irrelevant information in order to optimize perception of a single source of sensory input; failure to do so often results in the familiar phenomenon of distraction. The term 'distraction' broadly refers to a perceptual phenomenon. In the present study we attempted to find the electrophysiological correlates of distraction using an auditory discrimination task. EEG and event-related potential responses to identical stimuli were compared under two levels of distraction (continuous broad-band noise or continuous speech). Relative to broad-band noise, the presence of a continuous speech signal in the unattended ear impaired task performance and also attenuated the N1 peak evoked by nontarget stimuli in the attended ear. As the magnitude of a peak in the event-related potential waveform can be modulated by differences in intertrial power but also by differences in the stability of EEG phase across trials, we sought to characterize the effect of distraction on intertrial power and intertrial phase locking around the latency of the N1. The presence of continuous speech resulted in a prominent reduction of theta EEG band intertrial phase locking around the latency of the N1. This suggests that distraction may act not only to disrupt a sensory gain mechanism but also to disrupt the temporal fidelity with which the brain responds to stimulus events.

Kcna1Gene Deletion Lowers the Behavioral Sensitivity of Mice to Small Changes in Sound Location and Increases Asynchronous Brainstem Auditory Evoked Potentials But Does Not Affect Hearing Thresholds

Sound localization along the azimuth depends on the sensitivity of binaural nuclei in the auditory brainstem to small differences in interaural level and timing occurring within a submillisecond epoch and on monaural pathways that transmit level and timing cues with high temporal fidelity to insure their coincident arrival at the binaural targets. The soma and axons of these brainstem neurons are heavily invested with ion channels containing the low-threshold potassium channel subunit Kv1.1, which previous in vitro and in vivo studies suggest are important for regulating their high input-output correspondence and temporal synchrony. We compared awake Kcna1-null mutant (Kcna1-/-) mice lacking Kv1.1 with Kcna1+/+ mice to determine whether Kv1.1 activity contributes to sound localization and examined anesthetized mice for absolute hearing thresholds for suprathreshold differences that may be revealed in the waveforms of auditory brainstem response potentials. The awake -/- mice tested with reflex modification audiometry had reduced sensitivity to an abrupt change in the location of a broad band noise compared to +/+ mice, while anesthetized -/- mice had normal absolute thresholds for tone pips but a high level of stimulus-evoked but asynchronous background activity. Evoked potential waveforms had progressively earlier peaks and troughs in -/- mice, but the amplitude excursions between adjacent features were identical in the two groups. Their greater excitability and asynchrony in suprathreshold evoked potentials coupled with their normal thresholds suggests that a disruption in central neural processing in -/- mice and not peripheral hearing loss is responsible for their poor sound localization.

Application of QuikSCAT Backscatter to SMAP Validation Planning: Freeze/Thaw State Over ALECTRA Sites in Alaska From 2000 to 2007

The mapping of the predominant freeze/thaw state of the landscape is one of the main objectives of the National Aeronautics and Space Administration's proposed Soil Moisture Active Passive (SMAP) mission. This study applies Alaska Ecological Transect (ALECTRA) biophysical network temperature measurements and satellite radar scatterometer data from the Quick Scatterometer (QuikSCAT) to evaluate some of the validation issues regarding the planned SMAP freeze/thaw measurements. Although the QuikSCAT data are acquired at Ku-band frequency, rather than at the L-band frequency of the proposed SMAP instrument, QuikSCAT data do provide a high temporal fidelity over the ALECTRA sites, similar to SMAP. The results of this study show that multiple temperature measurements representative of individual landscape components (soil, snow cover, vegetation, and atmosphere) covering different types of terrain within the satellite field of view are important for understanding the freeze/thaw process and the aggregate radar backscatter response to that process. The backscatter temporal dynamics and relative contribution of the freeze/thaw state of these landscape elements to radar signal vary with land cover, seasonal weather, and climate conditions.

Synaptic profile of nucleus tractus solitarius neurons involved with the peripheral chemoreflex pathways

The glomus cells in the carotid bodies (CB) detect alterations in pH and pCO₂ and low pO₂ level in arterial blood. The carotid sinus nerve conveys the information related to the oxygen level to 2nd-order neurons in the nucleus tractus solitarius (NTS) via tractus solitarius (TS), which is part of the chemoreflex pathways. It has been demonstrated that in 2nd-order NTS neurons receiving inputs from the aortic depressor nerve (ADN), the TS stimulation presents high temporal fidelity. However, the temporal properties of synaptic activity in NTS neurons receiving inputs from CB were not yet fully investigated. Herein using patch-clamp recordings in NTS brainstem slices, we studied TS-evoked excitatory postsynaptic currents (TS-eEPSCs) on morphologically identified 2nd-order NTS neurons that receive afferent inputs from the CB and compared with 2nd-order ADN-NTS neurons recorded in the same experimental conditions. The amplitudes of TS-eEPSCs were similar in both groups, but the latencies and standard deviation (SD) of latency were significantly higher in the CB-NTS neurons (latency: 4±0.2 ms, SD: 0.49±0.03 ms) than in ADN-NTS neurons (latency: 3.3±0.3 ms, SD: 0.19±0.02 ms; P=0.049 for latency and P<0.001 for SD of latency). In a series of double-labeling experiments, we confirmed that some CB-NTS 2nd-order neurons send direct projections to the rostral ventrolateral medulla (RVLM). We conclude that: (a) CB-NTS 2nd-order neurons present temporally distinct postsynaptic currents when compared with ADN-NTS 2nd-order neurons; (b) low SD of latency of TS-eEPSCs is not necessarily a characteristic of all 2nd-order neurons in the NTS; and (c) the presence of direct connections between these 2nd-order neurons in the NTS and RVLM is indicative that these synaptic properties of CB-NTS neurons are relevant for the processing of respiratory and autonomic responses to chemoreflex activation.

Evaluation of MERRA Land Surface Estimates in Preparation for the Soil Moisture Active Passive Mission

Abstract The authors evaluated several land surface variables from the Modern-Era Retrospective Analysis for Research and Applications (MERRA) product that are important for global ecological and hydrological studies, including daily maximum (Tmax) and minimum (Tmin) surface air temperatures, atmosphere vapor pressure deficit (VPD), incident solar radiation (SWrad), and surface soil moisture. The MERRA results were evaluated against in situ measurements, similar global products derived from satellite microwave [the Advanced Microwave Scanning Radiometer for Earth Observing System (EOS) (AMSR-E)] remote sensing and earlier generation atmospheric analysis [Goddard Earth Observing System version 4 (GEOS-4)] products. Relative to GEOS-4, MERRA is generally warmer (~0.5°C for Tmin and Tmax) and drier (~50 Pa for VPD) for low- and middle-latitude regions (&amp;lt;50°N) associated with reduced cloudiness and increased SWrad. MERRA and AMSR-E temperatures show relatively large differences (&amp;gt;3°C) in mountainous areas, tropical forest, and desert regions. Surface soil moisture estimates from MERRA (0–2-cm depth) and two AMSR-E products (~0–1-cm depth) are moderately correlated (R ~ 0.4) for middle-latitude regions with low to moderate vegetation biomass. The MERRA derived surface soil moisture also corresponds favorably with in situ observations (R = 0.53 ± 0.01, p &amp;lt; 0.001) in the midlatitudes, where its accuracy is directly proportional to the quality of MERRA precipitation. In the high latitudes, MERRA shows inconsistent soil moisture seasonal dynamics relative to in situ observations. The study’s results suggest that satellite microwave remote sensing may contribute to improved reanalysis accuracy where surface meteorological observations are sparse and in cold land regions subject to seasonal freeze–thaw transitions. The upcoming NASA Soil Moisture Active Passive (SMAP) mission is expected to improve MERRA-type reanalysis accuracy by providing accurate global mapping of freeze–thaw state and surface soil moisture with 2–3-day temporal fidelity and enhanced (≤9 km) spatial resolution.

The role of hyperpolarization‐activated cationic current in spike‐time precision and intrinsic resonance in cortical neurons in vitro

Hyperpolarization-activated cyclic nucleotide modulated current (I(h)) sets resonance frequency within the θ-range (5–12 Hz) in pyramidal neurons. However, its precise contribution to the temporal fidelity of spike generation in response to stimulation of excitatory or inhibitory synapses remains unclear. In conditions where pharmacological blockade of I(h) does not affect synaptic transmission, we show that postsynaptic h-channels improve spike time precision in CA1 pyramidal neurons through two main mechanisms. I(h) enhances precision of excitatory postsynaptic potential (EPSP)--spike coupling because I(h) reduces peak EPSP duration. I(h) improves the precision of rebound spiking following inhibitory postsynaptic potentials (IPSPs) in CA1 pyramidal neurons and sets pacemaker activity in stratum oriens interneurons because I(h) accelerates the decay of both IPSPs and after-hyperpolarizing potentials (AHPs). The contribution of h-channels to intrinsic resonance and EPSP waveform was comparatively much smaller in CA3 pyramidal neurons. Our results indicate that the elementary mechanisms by which postsynaptic h-channels control fidelity of spike timing at the scale of individual neurons may account for the decreased theta-activity observed in hippocampal and neocortical networks when h-channel activity is pharmacologically reduced.

Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1

Ionotropic glutamate receptors principally mediate fast excitatory transmission in the brain. Among the three classes of ionotropic glutamate receptors, kainate receptors (KARs) display a categorical brain distribution, which has been historically defined by 3H-radiolabeled kainate binding. Compared with recombinant KARs expressed in heterologous cells, synaptic KARs exhibit characteristically slow rise-time and decay kinetics. However, the mechanisms responsible for these unique KAR properties remain unclear. Here we found that both the distinct high affinity biding pattern in the mouse brain and the channel properties of native KARs are determined by the KAR auxiliary subunit Neto1. Through modulation of agonist binding affinity and off-kinetics of KARs, but not trafficking of KARs, Neto1 determines both KAR high affinity binding pattern and the distinctively slow kinetics of postsynaptic KARs. By regulating KAR-EPSC kinetics, Neto1 can control synaptic temporal summation, spike generation and fidelity.

On the undersampling strategies to accelerate time‐resolved 3D imaging using k‐t‐GRAPPA

The purpose of this study was to explore how to optimally undersample and reconstruct time-resolved 3D data using a k-t-space-based GRAPPA technique. The performance of different reconstruction strategies was evaluated using data sets with different ratios of phase (N(y)) and partition (N(z)) encoding lines (N(y) × N(z) = 64-128 × 40-64) acquired in a moving phantom. Image reconstruction was performed for different kernel configurations and different reduction factors (R = 5, 6, 8, and 10) and was evaluated using regional error quantification and SNR analysis. To analyze the temporal fidelity of the different kernel configurations in vivo, time-resolved 3D phase contrast data were acquired in the thoracic aorta of two healthy volunteers. Results demonstrated that kernel configurations with a small kernel extension yielded superior results especially for more asymmetric data matrices as typically used in clinical applications. The application of k-t-GRAPPA to in vivo data demonstrated the feasibility of undersampling of time-resolved 3D phase contrast data set with a nominal reduction factors of up to R(net) = 8, while maintaining the temporal fidelity of the measured velocity field. Extended GRAPPA-based parallel imaging with optimized multidimensional reconstruction kernels has the potential to substantially accelerate data acquisitions in time-resolved 3D MRI.

K‐t group sparse: A method for accelerating dynamic MRI

Compressed sensing (CS) is a data-reduction technique that has been applied to speed up the acquisition in MRI. However, the use of this technique in dynamic MR applications has been limited in terms of the maximum achievable reduction factor. In general, noise-like artefacts and bad temporal fidelity are visible in standard CS MRI reconstructions when high reduction factors are used. To increase the maximum achievable reduction factor, additional or prior information can be incorporated in the CS reconstruction. Here, a novel CS reconstruction method is proposed that exploits the structure within the sparse representation of a signal by enforcing the support components to be in the form of groups. These groups act like a constraint in the reconstruction. The information about the support region can be easily obtained from training data in dynamic MRI acquisitions. The proposed approach was tested in two-dimensional cardiac cine MRI with both downsampled and undersampled data. Results show that higher acceleration factors (up to 9-fold), with improved spatial and temporal quality, can be obtained with the proposed approach in comparison to the standard CS reconstructions.

Interleaved variable density sampling with a constrained parallel imaging reconstruction for dynamic contrast-enhanced MR angiography

For MR applications such as contrast-enhanced MR angiography, it is desirable to achieve simultaneously high spatial and temporal resolution. The current clinical standard uses view-sharing methods combined with parallel imaging; however, this approach still provides limited spatial and temporal resolution. To improve on the clinical standard, we present an interleaved variable density (IVD) sampling method that pseudorandomly undersamples each individual frame of a 3D Cartesian ky-kz plane combined with parallel imaging acceleration. From this dataset, time-resolved images are reconstructed with a method that combines parallel imaging with a multiplicative constraint. Total acceleration factors on the order of 20 are achieved for contrast-enhanced MR angiography of the lower extremities, and improvements in temporal fidelity of the depiction of the contrast bolus passage are demonstrated relative to the clinical standard.

Low‐voltage activated Kv1.1 subunits are crucial for the processing of sound source location in the lateral superior olive in mice

Voltage-gated potassium (Kv) channels containing Kv1.1 subunits are strongly expressed in neurons that fire temporally precise action potentials (APs). In the auditory system, AP timing is used to localize sound sources by integrating interaural differences in time (ITD) and intensity (IID) using sound arriving at both cochleae. In mammals, the first nucleus to encode IIDs is the lateral superior olive (LSO), which integrates excitation from the ipsilateral ventral cochlear nucleus and contralateral inhibition mediated via the medial nucleus of the trapezoid body. Previously we reported that neurons in this pathway show reduced firing rates, longer latencies and increased jitter in Kv1.1 knockout (Kcna1−/−) mice. Here, we investigate whether these differences have direct impact on IID processing by LSO neurons. Single-unit recordings were made from LSO neurons of wild-type (Kcna1+/+) and from Kcna1−/− mice. IID functions were measured to evaluate genotype-specific changes in integrating excitatory and inhibitory inputs. In Kcna1+/+ mice, IID sensitivity ranged from +27 dB (excitatory ear more intense) to −20 dB (inhibitory ear more intense), thus covering the physiologically relevant range of IIDs. However, the distribution of IID functions in Kcna1−/− mice was skewed towards positive IIDs, favouring ipsilateral sound positions. Our computational model revealed that the reduced performance of IID encoding in the LSO of Kcna1−/− mice is mainly caused by a decrease in temporal fidelity along the inhibitory pathway. These results imply a fundamental role for Kv1.1 in temporal integration of excitation and inhibition during sound source localization.

Ih-mediated depolarization enhances the temporal precision of neuronal integration

Feed-forward inhibition mediated by ionotropic GABAA receptors contributes to the temporal precision of neuronal signal integration. These receptors exert their inhibitory effect by shunting excitatory currents and by hyperpolarizing neurons. The relative roles of these mechanisms in neuronal computations are, however, incompletely understood. In this study, we show that by depolarizing the resting membrane potential relative to the reversal potential for GABAA receptors, the hyperpolarization-activated mixed cation current (Ih) maintains a voltage gradient for fast synaptic inhibition in hippocampal pyramidal cells. Pharmacological or genetic ablation of Ih broadens the depolarizing phase of afferent synaptic waveforms by hyperpolarizing the resting membrane potential. This increases the integration time window for action potential generation. These results indicate that the hyperpolarizing component of GABAA receptor-mediated inhibition has an important role in maintaining the temporal fidelity of coincidence detection and suggest a previously unrecognized mechanism by which Ih modulates information processing in the hippocampus.

Medial Superior Olivary Neurons Receive Surprisingly Few Excitatory and Inhibitory Inputs with Balanced Strength and Short-Term Dynamics

Neurons in the medial superior olive (MSO) process microsecond interaural time differences, the major cue for localizing low-frequency sounds, by comparing the relative arrival time of binaural, glutamatergic excitatory inputs. This coincidence detection mechanism is additionally shaped by highly specialized glycinergic inhibition. Traditionally, it is assumed that the binaural inputs are conveyed by many independent fibers, but such an anatomical arrangement may decrease temporal precision. Short-term depression on the other hand might enhance temporal fidelity during ongoing activity. For the first time we show that binaural coincidence detection in MSO neurons may require surprisingly few but strong inputs, challenging long-held assumptions about mammalian coincidence detection. This study exclusively uses adult gerbils for in vitro electrophysiology, single-cell electroporation and immunohistochemistry to characterize the size and short-term plasticity of inputs to the MSO. We find that the excitatory and inhibitory inputs to the MSO are well balanced both in strength and short-term dynamics, redefining this fastest of all mammalian coincidence detector circuits.