scholarly journals Modelling firing regularity in the ventral cochlear nucleus: mechanisms, and effects of stimulus level and synaptopathy

2017 ◽  
Author(s):  
Dan F. M. Goodman ◽  
Ian M. Winter ◽  
Agnès C. Léger ◽  
Alain de Cheveigné ◽  
Christian Lorenzi
Keyword(s):  
Auditory System ◽  
Cochlear Nucleus ◽  
Time Course ◽  
Multiple Scales ◽  
Stimulus Level ◽  
Model Parameters ◽  
List Type ◽  
Ventral Cochlear Nucleus ◽  
Wide Range ◽  
Interactive Version

AbstractThe auditory system processes temporal information at multiple scales, and disruptions to this temporal processing may lead to deficits in auditory tasks such as detecting and discriminating sounds in a noisy environment. Here, a modelling approach is used to study the temporal regularity of firing by chopper cells in the ventral cochlear nucleus, in both the normal and impaired auditory system. Chopper cells, which have a strikingly regular firing response, divide into two classes, sustained and transient, based on the time course of this regularity. Several hypotheses have been proposed to explain the behaviour of chopper cells, and the difference between sustained and transient cells in particular. However, there is no conclusive evidence so far. Here, a reduced mathematical model is developed and used to compare and test a wide range of hypotheses with a limited number of parameters. Simulation results show a continuum of cell types and behaviours: chopper-like behaviour arises for a wide range of parameters, suggesting that multiple mechanisms may underlie this behaviour. The model accounts for systematic trends in regularity as a function of stimulus level that have previously only been reported anecdotally. Finally, the model is used to predict the effects of a reduction in the number of auditory nerve fibres (deafferentation due to, for example, cochlear synaptopathy). An interactive version of this paper in which all the model parameters can be changed is available online.HighlightsA low parameter model reproduces chopper cell firing regularityMultiple factors can account for sustained vs transient chopper cell responseThe model explains stimulus level dependence of firing regularityThe model predicts chopper cells fire more irregularly after deafferentationAn interactive version of the paper allows readers to change parameters

Differential Expression of Three Distinct Potassium Currents in the Ventral Cochlear Nucleus

2003 ◽  
Vol 89 (6) ◽  
pp. 3070-3082 ◽  
Author(s):  
Jason S. Rothman ◽  
Paul B. Manis
Keyword(s):  
Differential Expression ◽  
Cochlear Nucleus ◽  
Nerve Fibers ◽  
Delayed Rectifier ◽  
High Threshold ◽  
Type I ◽  
Acoustic Environment ◽  
Ventral Cochlear Nucleus ◽  
Wide Range ◽  
Slope Factor

In the ventral cochlear nucleus (VCN), neurons transform information from auditory nerve fibers into a set of parallel ascending pathways, each emphasizing different aspects of the acoustic environment. Previous studies have shown that VCN neurons differ in their intrinsic electrical properties, including the K+ currents they express. In this study, we examine these K+ currents in more detail using whole cell voltage-clamp techniques on isolated VCN cells from adult guinea pigs at 22°C. Our results show a differential expression of three distinct K+ currents. Whereas some VCN cells express only a high-threshold delayed-rectifier-like current ( IHT), others express IHT in combination with a fast inactivating current ( IA) and/or a slow-inactivating low-threshold current ( ILT). IHT, ILT, and IA, were partially blocked by 1 mM 4-aminopyridine. In contrast, only ILT was blocked by 10–100 nM dendrotoxin-I. A surprising finding was the wide range of levels of ILT, suggesting ILT is expressed as a continuum across cell types rather than modally in a particular cell type. IA, on the other hand, appears to be expressed only in cells that show little or no ILT, the Type I cells. Boltzmann analysis shows IHT activates with 164 ± 12 (SE) nS peak conductance, -14.3 ± 0.7 mV half-activation, and 7.0 ± 0.5 mV slope factor. Similar analysis shows ILT activates with 171 ± 22 nS peak conductance, -47.4 ± 1.0 mV half-activation, and 5.8 ± 0.3 mV slope factor.

Frequency extent of two-tone facilitation in onset units in the ventral cochlear nucleus

1996 ◽  
Vol 75 (1) ◽  
pp. 380-395 ◽  
Author(s):  
D. Jiang ◽  
A. R. Palmer ◽  
I. M. Winter
Keyword(s):  
Cochlear Nucleus ◽  
Auditory Nerve ◽  
Low Frequency ◽  
Nerve Fibers ◽  
Inhibitory Input ◽  
Ventral Cochlear Nucleus ◽  
Narrow Region ◽  
Morphological Studies ◽  
Wide Range ◽  
Auditory Nerve Fibers

1. The frequency threshold curves (FTCs) of 91 single units in the cochlear nucleus of the anesthetized guinea pig were measured using a conventional single-tone paradigm and a two-tone paradigm designed to elucidate the frequency extent of two-tone facilitation in onset units (On). Units were classified according to existing classification schemes into primary-like (n = 3), chopper (n = 23), and three onset groups: OnI (n = 12), OnC (n = 29), and OnL (n = 24). Histological reconstructions show onset units to be widely distributed within the ventral cochlear nucleus in a manner generally consistent with its tonotopic organization. 2. The FTCs of onset units differed in their minimum thresholds, the steepness of their high- and low-frequency cutoffs, and their sharpness of tuning as quantified by the quality factor at 10 dB (Q10dB) above best frequency (BF) threshold values. There was considerable overlap in the sharpness of tuning between onset units and auditory nerve fibers, as indicated by the distribution of Q10dB values in the octave around 10 kHz: onset units had Q10dB values of 3.56 +/- 1.38 (SD), compared with 6.3 +/- 2.48 for auditory nerve fibers. The tuning of chopper units was similar to that of auditory nerve fibers (5.52 +/- 1.46). 3. Seventy-five percent of onset units showed some degree of facilitation (a threshold reduction) when their FTCs were measured in the presence of BF tones 4 dB below BF threshold. The frequency extent of such facilitation was variable, with a maximum of 6 octaves around the BF. In extreme cases facilitation could be measured when the BF tone was as low as 30 dB below BF threshold. 4. In 17% of onset units, suppressive effects were evident, as shown by noncontiguous frequency regions of facilitation. These suppressive effects might be a reflection either of suppression in the auditory nerve input or of a direct inhibitory input to the onset units. The strength of this effect suggests that inhibition is a likely explanation, consistent with the finding in previous morphological studies of profuse synapses with pleomorphic vesicles on multipolar cells. 5. FTCs of chopper and primary-like units measured in the presence of BF tones showed little facilitation. The facilitation that was observed in chopper units was confined to a narrow region around BF and disappeared when the facilitatory tone was lowered to 4 dB below BF threshold. 6. These data support the hypothesis that onset units, but not chopper or primary-like units, receive excitatory inputs from auditory nerve fibers with a wide range of BFs. However, the frequency range of facilitation and the magnitude of the threshold facilitation varied from unit to unit, suggesting that the off-BF inputs from auditory nerve fibers are not evenly distributed or equally effective in all units.

The electrotonic structure of regular-spiking neurons in the ventral cochlear nucleus may determine their response properties

1994 ◽  
Vol 71 (5) ◽  
pp. 1774-1786 ◽  
Author(s):  
J. A. White ◽  
E. D. Young ◽  
P. B. Manis
Keyword(s):  
Cochlear Nucleus ◽  
Transfer Functions ◽  
Brain Slices ◽  
Auditory Brainstem ◽  
Spiking Neurons ◽  
Membrane Properties ◽  
Physiological Data ◽  
Model Parameters ◽  
Type I ◽  
Ventral Cochlear Nucleus

1. Intracellular recordings were obtained from neurons in parasagittal brain slices of the guinea pig ventral cochlear nucleus (VCN). The principal neurons of the VCN can be parceled into two categories. Regular-spiking (Type I) neurons have a linear current-voltage (I–V) relationship over a large range of intracellularly injected currents and fire tonically in response to suprathreshold depolarizing currents. Phasically spiking (Type II) neurons have a nonlinear I–V relationship and fire only phasically at the onset of a depolarizing current or offset of a hyperpolarizing current. Regular-spiking neurons have been shown to be of the stellate morphological type, whereas phasically spiking neurons have been shown to be bushy cells. 2. The electrotonic structure of regular-spiking neurons was studied by applying previously developed modeling techniques based on the somatic shunt model. In these techniques, physiological data are used to determine the set of parameters best describing the neuron. As predicted from previous theoretical investigations, the use of an anatomic constraint (somatic surface area) reduces the variance in estimates of model parameters, especially for the dendritic membrane time constant tau D. 3. Model representations of regular-spiking cells fall into two categories: those with (passive) somatic membrane properties that are nearly identical to those of the dendrite (8/15 cases), and those with a significant amount of somatic shunt (7/15). Estimates of tau D (mean = 7.7 ms) are lower than those often described in the literature. We argue that this low value of tau D may be related to the need of neurons in the auditory brainstem to operate at high firing rates and/or to encode audio-frequency temporal fluctuations. 4. Dendritic transfer functions were calculated as functions of synaptic location using somatic shunt representations of regular-spiking neurons. These transfer functions allow us to predict that mid-range auditory frequencies (approximately 1 kHz) are greatly attenuated, even for synapses near the soma. Thus it is suggested that the electrotonic architecture of regular-spiking cells creates sufficient low-pass filtering of synaptic inputs to reduce the synchronization of firing of these neurons to mid-frequency auditory stimuli.

scholarly journals Modelling firing regularity in the ventral cochlear nucleus: Mechanisms, and effects of stimulus level and synaptopathy

2018 ◽  
Vol 358 ◽  
pp. 98-110 ◽  
Author(s):  
Dan F.M. Goodman ◽  
Ian M. Winter ◽  
Agnès C. Léger ◽  
Alain de Cheveigné ◽  
Christian Lorenzi
Keyword(s):  
Cochlear Nucleus ◽  
Stimulus Level ◽  
Ventral Cochlear Nucleus

Neurophysiological Correlates of Auditory Maturation

1980 ◽  
Vol 89 (5_suppl) ◽  
pp. 103-113 ◽  
Author(s):  
Eric Javel
Keyword(s):  
Auditory System ◽  
Cochlear Nucleus ◽  
Physiological Response ◽  
Time Course ◽  
Low Frequency ◽  
Developmental Time ◽  
Response Property ◽  
Central System ◽  
Response Properties ◽  
Peripheral Auditory System

At the time of its birth, the auditory system of the cat is not completely developed. Anatomic maturity of the peripheral auditory system, ie, the cochlea, auditory nerve and cochlear nucleus, is attained at about two or three weeks of age. Physiological response properties of neural elements of the peripheral auditory system change radically during the first few weeks of life, with most measures of responsiveness to acoustic stimuli reaching adult status by the end of the third or fourth postnatal week. The physiological maturation of neural responses correlates well with the anatomic maturation of the auditory structures. At least one physiological response property, namely the ability of cochlear nucleus neurons to time their discharges in response to low-frequency tones, is not fully achieved until the sixth postnatal week or later. Although considerably less is known about the development of the central auditory system, it appears that it is in part dependent upon the maturation of more peripheral elements. Auditory evoked responses, for example, follow roughly the same developmental time course as do the majority of response properties of peripheral neurons. This implies that the central system is ready to function at birth, but that it must await the maturation of more peripheral elements before it can function properly. In contrast to that of the cat and other mammals, the auditory system of the human is relatively well advanced at birth. Certain aspects of brain development, such as dendritic aborization and axonal myelination, undergo considerable change postnatally. How these factors influence hearing is not known.

scholarly journals A kinetic operational model of agonism incorporating receptor desensitization for G-protein-coupled receptors

2019 ◽  
Author(s):  
Sam R.J. Hoare ◽  
David A. Hall ◽  
Lloyd J. Bridge
Keyword(s):  
Drug Discovery ◽  
Time Course ◽  
Drug Effect ◽  
Model Parameters ◽  
List Type ◽  
Receptor Desensitization ◽  
Short Term ◽  
In Vivo Efficacy ◽  
Regulation Mechanisms

AbstractPharmacological responses are modulated over time by regulation of signaling mechanisms. The canonical short-term regulation mechanisms are receptor desensitization and degradation of the response. Here for the first time a pharmacological model for measuring drug parameters is developed that incorporates short-term mechanisms of regulation of signaling. The model is formulated in a manner that enables measurement of drug parameters using familiar curve fitting methods. The efficacy parameter is kτ, which is simply the initial rate of signaling before it becomes limited by regulation mechanisms. The regulation parameters are rate constants, kDES for receptor desensitization and kD for response degradation. Efficacy and regulation are separate parameters, meaning these properties can be optimized independently of one another in drug discovery. The parameters can be applied to translate in vitro findings to in vivo efficacy in terms of the magnitude and duration of drug effect. When the time course data conform to certain shapes, for example the association exponential curve, a mechanism-agnostic approach can be applied to estimate agonist efficacy, without the need to know the underlying regulatory mechanisms. The model was verified by comparison with historical data and by fitting these data to estimate the model parameters. This new model for quantifying drug activity can be broadly applied to the short-term cell signaling assays used routinely in drug discovery and to aid their translation to in vivo efficacy, facilitating the development of new therapeutics.HighlightsRegulation of signaling impacts measurement of drug effectReceptor desensitization is incorporated here into a kinetic model of signalingDrug effect and signaling regulation can now be measured independentlyThe analysis framework is designed for signaling assays used in drug discoveryThese new analysis capabilities will aid development of new therapeutics

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