The cochlea presumably possesses a number of regulatory mechanisms to maintain cochlear sensitivity in the face of disturbances to its function. Evidence for such mechanisms can be found in the time-course of the recovery of CAP thresholds during experimental manipulations, and in observations of slow oscillations in cochlear micromechanics following exposure to low-frequency tones (the “bounce phenomenon”) and other perturbations. To increase our understanding of the these oscillatory processes within the cochlea, and OHCs in particular, investigations into cochlear regulation were carried out using a combination of mathematical modelling of the ionic and mechanical interactions likely to exist within the OHCs, and electrophysiological experiments conducted in guinea pigs. The electrophysiological experiments consisted of electrocochleographic recordings and, in some cases, measurement of otoacoustic emissions, during a variety of experimental perturbations, including the application of force to the cochlear wall, exposure to very-low-frequency tones, injection of direct current into scala tympani, and intracochlear perfusions of artificial perilymph containing altered concentrations of potassium, sodium, and sucrose. To obtain a panoramic view of cochlear regulation under these conditions, software was written to enable the interleaved and near-simultaneous measurement of multiple indicators of cochlear function, including the compound action potential (CAP) threshold, amplitude and waveshape at multiple frequencies, the OHC transfer curves derived from low-frequency cochlear microphonic (CM) waveforms, distortion-product otoacoustic emissions (DPOAEs), the spectrum of the round-window neural noise (SNN), and the endocochlear potential (EP). The mathematical model takes into account the known electrical properties of OHC, and includes the effect of fast and slow-motility of the cell body on transducer operating point and apical conductance. Central to the operation of the model is a putative intracellular 2nd-messenger system based on cytosolic calcium, which is involved in regulation of i) the operating point of OHC MET channels via slow motility and axial stiffness; ii) the permeability of the basolateral wall to potassium (via calcium-sensitive potassium channels); and iii) the cytosolic concentration of calcium itself, via modulation of its own sequestration into (and release from) intracellular storage organelles, and extrusion from the cell. The model was constructed in a manner which allowed simulation of different cochlear perturbations, and the comparison of results from these simulations to experimental data. The mathematical model we have developed provided a physiologically-plausible and internally-consistent explanation for the time-courses of the cochlear changes observed during a number of different perturbations. We show that much of the oscillatory behaviour within the cochlea is consistent with underlying oscillations in cytosolic calcium concentration. We conclude that a number of the discrepancies between the simulation results and the experimental data can be resolved if the cytosolic calcium functions as two distinct pools: one which controls basolateral permeability and one which controls slow motility. This two-calcium-pool model is discussed. / Thesis presented in partial fulfilment of the requirements of the degree of Master of Clinical Audiology / Doctor of Philosophy of The University of Western Australia

<p>This thesis aims to elucidate the mechanisms and response characteristics of neural circuits in the vertebrate brain capable of responding selectively to stimulus duration. The research within focused on, but is not limited to, auditory neurons; however, most of the results extend to other sensory modalities. These neurons are known, appropriately, as duration-tuned neurons (DTNs). Duration-tuned neurons tend to prefer stimulus durations similar to the duration of species-specific vocalizations and have preferred durations ranging from 1 ms up to over 100 ms across species.</p> <p>To study the mechanisms underlying DTNs, biologically inspired computational models were produced to explore previously hypothesized mechanisms of duration tuning. These models support the mechanisms by reproducing the responses of <em>in vivo</em> DTNs and predicting additional <em>in vivo</em> response characteristics. The models demonstrate an inherent flexibility in the mechanisms to extend across a wide range of durations and also reveal subtleties in response profiles that arise from particular model parameters.</p> <p>To quantify the encoding efficiency of <em>in vivo</em> DTNs, information theoretic measures were applied to the responses of 97 DTNs recorded from the auditory midbrain (inferior colliculus) of the big brown bat. Stimulus duration encoding robustness, as measured by stimulus-specific information, tended to align with the stimulus durations that produce the largest responses. In contrast, stimulus durations with the most sensitivity to changes in stimulus duration, as measured with an approximation of the observed Fisher information, tended to be stimulus durations shorter or longer than the duration evoking the largest response. Remarkably, both optimal and non-optional Bayesian decoding methods were able to accurately recover stimulus duration from population responses, including durations that lacked neurons dedicated to best representing that duration. These results suggest that DTNs are excellent at encoding stimulus duration, a feature that has been generally assumed but not previously quantified.</p> / Doctor of Philosophy (PhD)

<p>Neurons throughout the auditory pathway respond selectively to the frequency and amplitude of sound. In the auditory midbrain there exists a class of neurons that are also selective to the duration of sound. These duration-tuned neurons (DTNs) provide a potential neural mechanism underlying temporal processing in the central nervous system. Temporal processing is necessary for human speech, discriminating species-specific acoustic signals as well as echolocation. This dissertation aims to explore the role and underlying mechanisms of DTNs through single-unit in vivo electrophysiological recordings in the auditory midbrain of the big brown bat. The durations that DTNs are selective to in echolocating and non-echolocating species are first compared to the durations of each species vocalizations. This comparison reveals that the durations DTNs respond best to correlates to the durations of echolocation calls in echolocating species and to species-specific communication calls in non-echolocating species. The ability of DTNs in the bat to respond to stimulus parameters thought to be important for echolocation processing, such as pairs of pulses and binaural sound localization cues, are subsequently tested. The responses of DTNs to a paired tone spike suppressing paradigm presented monaurally and binaurally are also compared to characterize the role each ear plays in recruiting inhibition known to be involved in duration tuning. The results show that DTNs are able to respond to pairs of pulses at a timescale relevant to bat echolocation, and a majority also responded selectively to binaural sound localizing cues. Nearly half (48%) of DTNs did not show spike suppression to an ipsilaterally presented suppressing tone. When ipsilaterally evoked spike suppression occurred, the effect was significantly smaller than the suppression evoked by a contralateral suppressing tone. These findings provide evidence that DTNs may play a role in echolocation in bats as DTNs are able to respond to the outgoing pulse and returning echoes and localize the echo source and that the neural mechanism underlying duration tuning is monaural in nature.</p> / Doctor of Philosophy (PhD)

Duration tuning in the mammalian inferior colliculus (IC) is created by the interaction of excitatory and inhibitory synaptic inputs. We used extracellular recording and paired-tone stimulation to measure the strength and time-course of the contralateral inhibition and offset-evoked excitation underlying duration-tuned neurons (DTNs) in the IC of the awake bat. The onset time of a short, best duration (BD), excitatory probe tone was varied relative to the onset of a longer-duration, non-excitatory (NE) suppressor tone. Spikes evoked by the roving BD tone were suppressed or facilitated when the stationary NE tone was varied in frequency or amplitude. When the NE tone frequency was presented away from the cell’s best excitatory frequency (BEF) or at lower SPLs, the onset of inhibition was relatively constant whereas the offset and duration of inhibition decreased. Excitatory and inhibitory frequency response areas were measured and best inhibitory frequencies matched best excitatory frequencies; however, inhibitory bandwidths were broader than excitatory bandwidths. Excitatory rate-level and inhibitory suppression-level functions were also measured and the dynamic ranges and inflection points were similar, which is hypothesized to play a role in the level tolerance of responses measured from DTNs. We compared the latency of offset-locked facilitation to the onset or offset of inhibition as a function of frequency and amplitude; we found that the facilitation was more related to the onset of inhibition. Moreover, facilitation typically preceded the offset of inhibition – suggesting that it is a separate excitatory input to DTNs and not a rebound from inhibition. We conclude that DTNs receive inputs that generate and preserve temporal selectivity. / Dissertation / Doctor of Philosophy (PhD)