A Model-based Study Of Cochlear Nucleus Neurons And Cochlear Amplification

Human hearing allows us to be conscious of what is going on around us. Auditory system is very complex; it is able to do wonderful things that powerful modern machines find extremely difficult, especially with respect to information processing, which has always been attracting great scientific interest. With the in-depth study of auditory mechanism, neurobiologists have realized that only by the neurophysiological and anatomical techniques will be difficult to understand the auditory system, Thus the model-based study has become an important means of exploring the auditory mechanism. Due to the complexity of biological systems, as well as the limitation of the experimental means and the experimental condition, the experimental data is always limited and incomplete. Therefore, it is necessary to combine the physiological experiments with model simulations, then we can deduce the unknown in auditory physiology and reveal the mechanism of auditory system by the limited experimental data. The research results can be applied to information processing, hearing rehabilitation and other application fields, which will contribute to human science and technology development. In this study, we aim to investigate the mechanism of the auditory system. Based on the the excitatory model derived from the integrate-and-fire model, we investigate the effects of excitatory intensity on the cochlear nucleus (CN) neuron response patterns. Meanwhile, we investigate the mechanism of outer hair cell and active amplification.Cochlear nucleus is the first relay station in the central auditory system. The cochlear nucleus neurons show3principal response patterns to short tone bursts, namely the primary-like, chopper and onset response patterns. We previously established an excitatory model to simulate the response patterns of cochlear nucleus neurons to stimuli. In this study, we aimed to investigate the effects of excitatory intensity on the cochlear nucleus neuron response patterns and explore the role of inhibitory inputs under normal physiological conditions. Based on the platform of Matlab and the excitatory model derived from the integrate-and-fire model, we altered the intensity of excitatory inputs in dB range and obtained the histograms to analyze the changes in the response patterns of the neurons using OriginPro7.5data analysis software. When the excitatory input increased, the chopping cycles became shorter, a result similar to that in animal experiments after blocking of the inhibitory input. The chopper response patterns became primary-like with increased discharge rate. The change of the input intensity, however, did not cause any significant changes of the original primary-like response pattern. This result was consistent with that from animal experiments in which the inhibitory input of a cochlear nucleus neuron was blocked by GABA and glycine antagonist. In the same way, we also observed changes in PSTHs of the onset response pattern, which eventually became primary-like when the input intensity increased, but this interconversion was rarely observed in animal experiments. These observations suggest that the excitatory input of a given cochlear nucleus neuron is limited within a small range possibly as a result of inhibition. The inhibitory input is thought to company the excitatory input to reduce the amplitude of the excitatory input and thus stabilize the neuronal membrane potential in a limited range. This balanced inhibitory input guarantees that the response pattern of a given neuron is not converted to another pattern in spite of a high excitatory input intensity and ensures accurate sound information encoding and sending.The study of cochlear auditory physiology has been one of the most active areas of auditory research. Scientists strive to explore the mechanism of cochlear physiology. In mammalian cochlea, the hair cells are the most important auditory receptors. Hair cells can convert hair bundle deflection to the change of cell membrane potential by mechano-electrical transduction. What kind of amplification mechanism that under normal cochlear to keep the amazing sensitivity and frequency selectivity become the research hot spot.Normal hearing depends on sound amplification within the mammalian cochlear. The exquisite frequency selectivity and amplification characteristics of mammalian hearing intimately depend on the fast electromechanical motion of the outer hair cells (OHCs) in the cochlea. The key feature of outer hair cells is their ability to undergo axial length changes in response to altered transmembrane potential, a process termed eletromotility. Outer hair cells electromotility occurs independent of ATP hydrolysis and in the absence of intracellular calcium. Prestin is the motor protein that provides the molecular basis for outer hair cells electromotility. At present there have been many biophysical, biochemical and molecular studies aim at the active amplification mechanism. While the mechanism of the cochlear amplifier remains unknown. Two mechanisms have been proposed for cochlear amplification in mammals:somatic eletromotility, whereby the soma of an outer hair cell changes length in response to membrane potential, and active hair-bundle movement, in which bundles produce force driven by calcium current when respond to a stimulus.Prestin belongs to a solute cattier (SLC26) family of anion transporters and is densely packed in the lateral membrane of outer hair cells. Prestin molecular shape changes were dependent on intracellular anions, especially chloride. Because Prestin is unique to mammals, it may provide the main motor power for mammalian cochlear amplification. Outer hair cells undergo length changes of up to5%in response to altered transmembrane potential, elongating under hyperpolarization and contracting under depolarization. The capacitance properties of outer hair cell are related to eletromotility. Outer hair cells membrane capacitance has two components, a linear one, which derived from the dielectric properties of the membrane and is proportional to cell size, and a nonlinear one caused by prestin-related charge movement. This charge movement, analogous to the gating current in ion channels, is commonly described as nonlinear capacitance (NLC) and thought to result from prestin conformational change. The total membrane capacitance is the sum of the linear and nonlinear capacitance. The ratio relationship of charge to voltage and the ratio relationship of outer hair cell-length to voltage are well fit by a sigmoidal two-state Boltzmann function. As a result, the measured nonlinear capacitance in outer hair cells is a bell shaped curve since it is the derivative of the sigmoidal ratio relationship of charge to voltage. The tight coupling between outer hair cell motility and nonlinear capacitance has established this measure as a reliable "electrical signature" of eletromotility, and therefore a surrogate measure of outer hair cell function. Nonlinear capacitance measurements are obtained using patch clamp technique.The excitatory or inhibitory of hair cells dependent on the deflection direction of hair bundle. Deflection of hair bundle toward the tallest stereocilium increases the tension in the tip link and consequently opens the mechanosensitive ion channel. This greatly increases the inward flux of cations from the endolymph and depolarizes the hair cell. A negative deflection of the hair bundle causes hyperpolarization and generates inhibition. Mechano-electrical transduction channels are gated by tip links. However, there is not a fixed tension at which the channel opens. Instead the channel opening is probabilistic with open probability increasing when the tension becomes greater. Mechano-electrical transduction channel is a nonselective cation channel with a high calcium ions permeability and unusually large single-channel conductance of100pS or more. It also displays ultrafast kinetics to hair bundle deformation. The most rigorous determination of channel number found～1.5channels per stereocilum. Mechano-electrical transduction channels show both fast and slow adaptation. Adaptation behaves as a restoration of sensitivity by decreasing the response to a maintained stimulus. Mechano-electrical transduction channels are thus able to adjust their sensitivity according to stimulate condition, and only respond to changing stimulus. Calcium is an important signal of mechano-electrical transduction channel performance. Stereocilia calcium ions change can affect the fast and slow adaptation and the activation of transduction channel. Reducing external calcium ions or increasing intracellular calcium ions will slow down the channel activation and fast adaptation.In this study, we investigate the effects of excitatory intensity on the cochlear nucleus neurons response patterns and review research progress on cochlear amplification mechanism as preparatory work. This thesis reviews the research history of cochlear amplification, describes the basilar membrane vibration characteristics, as a literature review study for follow-up research of inner and outer hair cell sound transformation. Then we introduce the outer hair cell eletromotility and nonlinear capacitance, and simulate prestin with sine wave to analyze how the molecular clusters to realize amplitude amplification. Simulate results show that only when each prestin change in a synchronous manner, can the largest amplitude value be achieved, which can make good use of energy. This thesis has also established a model to simulate the hair bundle deflection. We try to explore the effect of distance and height difference between the stereocilia and the deflection angle on the tension of tip link respectively. The results show that the distance and height difference between the stereocilia will have the same effect, and in response to a positive deflection, tension in the tip link increases. The significance of this study is to lay the foundation for research the loop relationship between eletromotility and mechano-electrical transduction current, and then we will explore the mechanism of inner ear sensitivity and frequency selectivity.At the end of this thesis, we discuss some problems which have not yet completed. In addition, some works which will be done in the future are prospected.