Computation of Interaural Time Difference in the Owl's Coincidence Detector Neurons

Both the mammalian and avian auditory systems localize sound sources by computing the interaural time difference (ITD) with submillisecond accuracy. The neural circuits for this computation in birds consist of axonal delay lines and coincidence detector neurons. Here, we report the first in vivo intracellular recordings from coincidence detectors in the nucleus laminaris of barn owls. Binaural tonal stimuli induced sustained depolarizations (DC) and oscillating potentials whose waveforms reflected the stimulus. The amplitude of this sound analog potential (SAP) varied with ITD, whereas DC potentials did not. The amplitude of the SAP was correlated with firing rate in a linear fashion. Spike shape, synaptic noise, the amplitude of SAP, and responsiveness to current pulses differed between cells at different frequencies, suggesting an optimization strategy for sensing sound signals in neurons tuned to different frequencies

Developmental alterations and electrophysiological properties

The medial superior olive (MSO) is an auditory brainstem nucleus within the superior olivary complex. Its functional role for sound source localization has been thoroughly investigated (for review see Grothe et al., 2010). However, few quantita tive data about the morphology of these neuronal coincidence detectors are available and computational models incorporating detailed reconstructions do not exist. This leaves open questions about metric characteristics of the morphology of MSO neurons as well as about electrophysiological properties that can be discovered using detailed multicompartmental models: what are the passive parameters of the membrane? What is the axial resistivity? How do dendrites integrate synaptic events? Is the medial dendrite symmetric to the lateral dendrite with respect to integration of synaptic events? This thesis has two main aspects: on the one hand, I examined the shape of a MSO neuron by developing and applying various morphological quantifications. On the other hand, I looked at the impact of morphology on basic electrophysiological properties and on characteristics of coincidence detection. As animal model I used Mongolian gerbils (Meriones unguiculatus) during the late phase of development between postnatal day 9 (P9) and 37 (P37). This period of time is of special interest, as it spans from just before hearing onset at P12 – P13 (Finck et al., 1972; Ryan et al., 1982; Smith and Kraus, 1987) to adulthood. I used single cell electroporation, microscopic reconstruction, and compartmentalization to extract anatomical parameters of MSO neurons, to quantitatively describe their morphology and development, and to establish multi-compartmental models. I found that maturation of the morphology is completed around P27, when the MSO neurons are morphologically compact and cylinder-like. Dendritic arbors become less complex between P9 and P21 as the number of branch points, the total cell length, and the amount of cell membrane decrease. Dendritic radius increases until P27 and is likely to be the main source of the increase in cell volume. In addition, I showed that in more than 85% of all MSO neurons, the axonal origin is located at the soma. I estimated the axial resistivity (80 Ω·cm) and the development of the resting conductance (total conductance during the state of resting potential) which reaches 3 mS/cm2 in adult gerbils. Applying these parameters, multi-compartmental models showed that medial versus lateral dendritic trees do not equally integrate comparable synaptic inputs. On average, latencies to peak and rise times of lateral stimulation are longer (12 μs and 5 μs, respectively) compared to medial stimulation. This is reflected in the fact that volume, surface area, and total cell length of the lateral dendritic trees are significantly more larger in comparison to the medial ones. Simplified models of MSO neurons showed that dendrites improve coincidence detection (Agmon-Snir et al., 1998; Grau-Serrat et al., 2003; Dasika et al., 2007). Here, I confirmed these findings also for multi-compartmental models with biological realistic morphologies. However, the improvement of coincidence detection by dendrites decreases during early postnatal development

Coding of auditory space

Behavioral, anatomical, and physiological approaches can be integrated in the study of sound localization in barn owls. Space representation in owls provides a useful example for discussion of place and ensemble coding. Selectivity for space is broad and ambiguous in low-order neurons. Parallel pathways for binaural cues and for different frequency bands converge on high-order space-specific neurons, which encode space more precisely. An ensemble of broadly tuned place-coding neurons may converge on a single high-order neuron to create an improved labeled line. Thus, the two coding schemes are not alternate methods. Owls can localize sounds by using either the isomorphic map of auditory space in the midbrain or forebrain neural networks in which space is not mapped

The role of short term synamptic plasticity in temporal coding of neuronal networks

Short term synaptic plasticity is a phenomenon which is commonly found in the central nervous system. It could contribute to functions of signal processing namely, temporal integration and coincidence detection by modulating the input synaptic strength. This dissertation has two parts. First we study the effects of short term synaptic plasticity in enhancing coincidence detecting ability of neurons in the avian auditory brainstem. Coincidence detection means a target neuron has a higher firing rate when it receives simultaneous inputs from different neurons as opposed to inputs with large phase delays. This property is used by birds in sound localization. When there is no plasticity from the inputs, the firing rate of the neuron, depends more on input frequencies and less on phase delays between inputs. This leads to ambiguity in localizing the sound source. We derive a mathematical model of a reduced avian brainstem network and show that inputs with synaptic plasticity, to the coincidence detector neuron, play a vital role in enhancing coincidence detecting ability of the bird. We present comparisons to experiments. In the second part of the thesis, we prove the existence and stability of a ncluster solution in a m-cell network, in the presence of synaptic depression. The model used to represent a single neuron is based on the Hodgkin-Huxley model for the spiking neurons and we use techniques from geometric singular perturbation theory to show that any n-cluster solution must satisfy a set of consistency conditions that can be geometrically derived. The results of both problems are validated using numerical simulations

Soma-Axon Coupling Configurations That Enhance Neuronal Coincidence Detection

Coincidence detector neurons transmit timing information by responding preferentially to concurrent synaptic inputs. Principal cells of the medial superior olive (MSO) in the mammalian auditory brainstem are superb coincidence detectors. They encode sound source location with high temporal precision, distinguishing submillisecond timing differences among inputs. We investigate computationally how dynamic coupling between the input region (soma and dendrite) and the spike-generating output region (axon and axon initial segment) can enhance coincidence detection in MSO neurons. To do this, we formulate a two-compartment neuron model and characterize extensively coincidence detection sensitivity throughout a parameter space of coupling configurations. We focus on the interaction between coupling configuration and two currents that provide dynamic, voltage-gated, negative feedback in subthreshold voltage range: sodium current with rapid inactivation and low-threshold potassium current, IKLT. These currents reduce synaptic summation and can prevent spike generation unless inputs arrive with near simultaneity. We show that strong soma-to-axon coupling promotes the negative feedback effects of sodium inactivation and is, therefore, advantageous for coincidence detection. Furthermore, the feedforward combination of strong soma-to-axon coupling and weak axon-to-soma coupling enables spikes to be generated efficiently (few sodium channels needed) and with rapid recovery that enhances high-frequency coincidence detection. These observations detail the functional benefit of the strongly feedforward configuration that has been observed in physiological studies of MSO neurons. We find that IKLT further enhances coincidence detection sensitivity, but with effects that depend on coupling configuration. For instance, in models with weak soma-to-axon and weak axon-to-soma coupling, IKLT in the axon enhances coincidence detection more effectively than IKLT in the soma. By using a minimal model of soma-to-axon coupling, we connect structure, dynamics, and computation. Although we consider the particular case of MSO coincidence detectors, our method for creating and exploring a parameter space of two-compartment models can be applied to other neurons

A Comparative Study on the Modulatory Effects of Inhibition in the Mammalian and Avian Sound Localization Circuits

Sound localization is a critically important task for many animals including humans. Due to physical constraints acting on the circuits that process sound localization cues, many neural specializations have evolved. One of the key features and the focus of this dissertation is inhibitory input. To assess the impact of inhibition, I employ in vitro patch clamp techniques to observe cellular and synaptic physiology in brainstem circuits dedicated to sound localization processing. Using a mammalian model, I test the impact that GABAB receptor (GABABR) activation has on the inputs to the medial superior olive (MSO), the first area where sound localization computations take place. Activation of GABABRs modulates both excitatory and inhibitory inputs such that the magnitude of these inputs is decreased and the time course of inhibitory inputs is slowed. The functional significance of this modulation was tested using a bilateral stimulation protocol, which simulates the coincidence of in vivo excitatory inputs. Here, activation of GABABRs increased the sensitivity of MSO neurons to simulated interaural time disparity (ITD), the main cue for low frequency sound localization. To expand on these results, a computational model was used to show that each GABABR dependent modulation had a beneficial impact on ITD sensitivity in the MSO. In an avian system, I described the synaptic activity involving the superior olivary nucleus (SON), which provides the main inhibitory input in the avian sound localization circuit. At the SON itself, synaptic transmission consists of both GABA- and glycinergic components where glycine release is the result of co-release with GABA. I also show that functional glycine receptors localize at brainstem nuclei and that high frequency stimulation results in the release glycine onto nucleus magnocellularis neurons, a feature of the avian brainstem that has not been observed previously. In related experiments, I evaluate possible interactions that may occur when both GABA and glycine receptor systems are activated simultaneously. Here, a pre-activation of GlyRs leads the a decrease in conductance through the GABAAR likely due to changes in Cl- ion concentrations which manipulate the driving force of the ion

Multiplicative Auditory Spatial Receptive Fields Created by a Hierarchy of Population Codes

A multiplicative combination of tuning to interaural time difference (ITD) and interaural level difference (ILD) contributes to the generation of spatially selective auditory neurons in the owl's midbrain. Previous analyses of multiplicative responses in the owl have not taken into consideration the frequency-dependence of ITD and ILD cues that occur under natural listening conditions. Here, we present a model for the responses of ITD- and ILD-sensitive neurons in the barn owl's inferior colliculus which satisfies constraints raised by experimental data on frequency convergence, multiplicative interaction of ITD and ILD, and response properties of afferent neurons. We propose that multiplication between ITD- and ILD-dependent signals occurs only within frequency channels and that frequency integration occurs using a linear-threshold mechanism. The model reproduces the experimentally observed nonlinear responses to ITD and ILD in the inferior colliculus, with greater accuracy than previous models. We show that linear-threshold frequency integration allows the system to represent multiple sound sources with natural sound localization cues, whereas multiplicative frequency integration does not. Nonlinear responses in the owl's inferior colliculus can thus be generated using a combination of cellular and network mechanisms, showing that multiple elements of previous theories can be combined in a single system