Achim Klug

Dissecting the circuitry of the auditory system

Abstract The brainstem auditory system is a complex system composed of numerous parallel and serial pathways that converge on a common destination in the inferior colliculus (IC). The exact nature of the response transformations that occur in the IC have, however, been elusive – even though the IC has been the subject of numerous studies for more than 30 years. Recent studies have addressed this issue by recording from IC neurons before and during micro-iontophoresis of drugs that selectively block GABA A or glycine receptors (the dominant inhibitory receptors in the IC) or by reversibly inactivating a lower nucleus that provides inhibitory innervation to the IC. These studies have revealed some of the ways that signals, relayed via many different parallel routes, interact in the IC, and suggest some functional advantages that these interactions might have.

Roles of inhibition for transforming binaural properties in the brainstem auditory system

This review is concerned with the operation of circuits in the central auditory system, how they transform response features and what functional significance may be attributed to those transformations. We focus on the role that GABAergic inhibition plays in processing interaural intensity disparities (IIDs), the principal cues for localizing high frequencies, and the transformations of IID coding that occur between the superior olivary complex and the inferior colliculus (IC). IIDs are coded by excitatory-inhibitory (EI) cells, so called because they are excited by one ear and inhibited by the other. EI neurons are first created in the lateral superior olive (LSO), but they also dominate the dorsal nucleus of the lateral lemniscus (DNLL) and regions of the IC. The three nuclei are intimately linked through a complex arrangement of excitatory and inhibitory connections. One of these is a crossed excitatory projection from the LSO to both the DNLL and IC. The binaural properties of EI neurons in LSO, DNLL and IC appear strikingly similar, suggesting that the EI properties created in the LSO are simply imposed on the DNLL and IC through the crossed excitatory projections. Recent studies support the idea that EI properties created in lower centers are imposed on some IC cells. However, other studies show that the circuitry linking LSO, DNLL and IC generates a number of response transformations in many IC cells. These transformations include marked changes in EI properties with stimulus duration, the generation of highly focused spatial receptive fields, shifts in sensitivity to IIDs, and the de novo creation of the EI response property. All of these transformations are produced by inhibitory innervation of the IC. An additional emergent property is also imposed on IC cells that receive GABAergic innervation from the DNLL. That property is a change in the binaural features of the IC cell, a change produced by the reception of an earlier sound whose IID is strongly excitatory to the IC cell. We illustrate each of these transformations, propose circuitry that could account for the observed properties and suggest some functional relevance for each. In the final section, we discuss some of the inherent uncertainties associated with attributing functional consequences to response features and then consider whether the transformations found in some mammals are species-specific or are universal features of all mammals.

Latency as a function of intensity in auditory neurons: influences of central processing.

The response latencies of sensory neurons typically shorten with increases in stimulus intensity. In the central auditory system this phenomenon should have a significant impact on a number of auditory functions that depend critically on an integration of precisely timed neural inputs. Evidence from previous studies suggests that the auditory system not only copes with the potential problems associated with intensity-dependent latency change, but that it also modifies latency change to shape the response properties of many cells for specific functions. This observation suggests that intensity-dependent latency change may undergo functional transformations along the auditory neuraxis. The goal of our study was to explore these transformations by making a direct, quantitative comparison of intensity-dependent latency change among a number of auditory centers from the lower brainstem to the thalamus. We found two main ways in which intensity-dependent latency change transformed along the neuraxis: (1) the range of latency change increased substantially and (2) one particular type of latency change, which has been suggested to be associated with sensitivity to temporally segregated stimulus components, occurred only at the highest centers tested, the midbrain and thalamus. Additional testing in the midbrain (inferior colliculus) indicated that inhibitory inputs are involved in shaping latency change. Our findings demonstrate that the central auditory system modifies intensity-dependent latency changes. We suggest that these changes may be functionally incorporated, actively enhanced, or modified to suit specific functions of the auditory system.

Inhibiting the Inhibition: A Neuronal Network for Sound Localization in Reverberant Environments

The precedence effect describes the phenomenon whereby echoes are spatially fused to the location of an initial sound by selectively suppressing the directional information of lagging sounds (echo suppression). Echo suppression is a prerequisite for faithful sound localization in natural environments but can break down depending on the behavioral context. To date, the neural mechanisms that suppress echo directional information without suppressing the perception of echoes themselves are not understood. We performed in vivo recordings in Mongolian gerbils of neurons of the dorsal nucleus of the lateral lemniscus (DNLL), a GABAergic brainstem nucleus that targets the auditory midbrain, and show that these DNLL neurons exhibit inhibition that persists tens of milliseconds beyond the stimulus offset, so-called persistent inhibition (PI). Using in vitro recordings, we demonstrate that PI stems from GABAergic projections from the opposite DNLL. Furthermore, these recordings show that PI is attributable to intrinsic features of this GABAergic innervation. Implementation of these physiological findings into a neuronal model of the auditory brainstem demonstrates that, on a circuit level, PI creates an enhancement of responsiveness to lagging sounds in auditory midbrain cells. Moreover, the model revealed that such response enhancement is a sufficient cue for an ideal observer to identify echoes and to exhibit echo suppression, which agrees closely with the percepts of human subjects.

Electrical Activity Suppresses Axon Growth through Cav1.2 Channels in Adult Primary Sensory Neurons

BACKGROUND Primary sensory neurons of the dorsal root ganglia (DRG) regenerate their spinal cord axon if the peripheral nerve axon has previously been cut. This conditioning lesion confers axon growth competence to the neurons. However, the signal that is sensed by the cell upon peripheral lesion to initiate the regenerative response remains elusive. RESULTS We show here that loss of electrical activity following peripheral deafferentiation is an important signal to trigger axon regrowth. We first verified that firing in sensory fibers, as recorded from dorsal roots in vivo, declined after peripheral lesioning but was not altered after central lesioning. We found that electrical activity strongly inhibited axon outgrowth in cultured adult sensory neurons. The inhibitory effect depended on the L-type voltage-gated Ca(2+) channel current and involved transcriptional changes. After a peripheral lesion, the L-type current was consistently diminished and the L-type pore-forming subunit, Ca(v)1.2, was downregulated. Genetic ablation of Ca(v)1.2 in the nervous system caused an increase in axon outgrowth from dissociated DRG neurons and enhanced peripheral nerve regeneration in vivo. CONCLUSIONS Our data indicate that cessation of electrical activity after peripheral lesion contributes to the regenerative response observed upon conditioning and might be necessary to promote regeneration after central nervous system injury.

Fenestration of the calyx of Held occurs sequentially along the tonotopic axis, is influenced by afferent activity, and facilitates glutamate clearance.

The calyx of Held is a type of giant glutamatergic presynaptic terminal in the mammalian auditory brainstem that transmits afferent information from the cochlear nucleus to the medial nucleus of the trapezoid body (MNTB). It participates in sound localization, a process that requires very high temporal precision. Consistent with its functional role, the calyx shows a number of specializations for temporal fidelity, one of them being the giant terminal itself with its many release sites. During the first 3 weeks of postnatal development, the calyx transforms from a spoon‐shaped, closed morphology to a highly fenestrated open structure. Calyces in Mongolian gerbils (Meriones unguiculatus) were labeled via injection of fluorescent tracers and their morphology was reconstructed at various timepoints during early postnatal development. We show that the fenestration process does not occur simultaneously in all calyces. Calyces transmitting high‐frequency sound information fenestrate significantly earlier than those transmitting low‐frequency information, such that a temporary developmental gradient along the tonotopic axis is established around the time of hearing onset. Animals that were deprived of afferent activity before hearing onset, either via cochlear removal or administration of ototoxic drugs, do not show this developmental gradient. Glial processes containing glutamate transporters occupy the newly created windows in the calyx and thus could augment the fast clearance of neurotransmitter. The physiological consequences of this faster clearance include a faster decay time course of synaptic currents as well as a lower amount of residual current accumulating during the processing of repeated activity such as stimulus trains. J. Comp. Neurol. 514:92–106, 2009.

Light scattering properties vary across different regions of the adult mouse brain.

Recently developed optogenetic tools provide powerful approaches to optically excite or inhibit neural activity. In a typical in-vivo experiment, light is delivered to deep nuclei via an implanted optical fiber. Light intensity attenuates with increasing distance from the fiber tip, determining the volume of tissue in which optogenetic proteins can successfully be activated. However, whether and how this volume of effective light intensity varies as a function of brain region or wavelength has not been systematically studied. The goal of this study was to measure and compare how light scatters in different areas of the mouse brain. We delivered different wavelengths of light via optical fibers to acute slices of mouse brainstem, midbrain and forebrain tissue. We measured light intensity as a function of distance from the fiber tip, and used the data to model the spread of light in specific regions of the mouse brain. We found substantial differences in effective attenuation coefficients among different brain areas, which lead to substantial differences in light intensity demands for optogenetic experiments. The use of light of different wavelengths additionally changes how light illuminates a given brain area. We created a brain atlas of effective attenuation coefficients of the adult mouse brain, and integrated our data into an application that can be used to estimate light scattering as well as required light intensity for optogenetic manipulation within a given volume of tissue.

Features of contralaterally evoked inhibition in the inferior colliculus

Cells in the central nucleus of the inferior colliculus (ICc) receive a large number of convergent inputs that are not only excitatory but inhibitory as well. While the excitatory responses of ICc cells have been studied extensively, less attention has been paid to the effects that inhibitory inputs have on auditory processing in the ICc. The purpose of this study was to examine the role of contralaterally evoked inhibition in single ICc cells in awake Mexican free-tailed bats. To study the contralaterally evoked inhibition, we created background activity by the iontophoretic application of the excitatory neurotransmitters glutamate and aspartate and visualized the inhibition as a gap in the carpet of background activity. We found that 85% of ICc cells exhibit a contralaterally evoked excitation followed by a period of inhibition. The inhibition acts primarily through GABA(A)20 ms) tones in generating persistent inhibition. While the early inhibition has clear roles in the shaping of excitatory response properties to a stimulus, the later persistent component of the inhibition is more enigmatic. The fact that the persistent inhibition lasts well beyond the duration of excitatory inputs to the ICc cell implies that the persistent inhibition may be important for the temporal segregation of the responses to multiple sound sources.

How Do Short-Term Changes at Synapses Fine-Tune Information Processing?

Synaptic transmission is highly dependent on recent activity and can lead to depression or facilitation of synaptic strength. This phenomenon is called “short-term synaptic plasticity” and is shown at all synapses. While much work has been done to understand the mechanisms of short-term changes in the state of synapses, short-term plasticity is often thought of as a mechanistic consequence of the design of a synapse. This review will attempt to go beyond this view and discuss how, on one hand, complex neuronal activity affects the short-term state of synapses, but also how these dynamic changes in synaptic strength affect information processing in return.

Modulation of synaptic input by GABAB receptors improves coincidence detection for computation of sound location

•  Organisms localise low frequencies using interaural time disparities (ITDs) in which specialized neurones in the medial superior olive (MSO) compute submillisecond differences in arrival time of sounds to each ear, a value that varies systematically with sound location. •  These neurones compute sound location over a 1012 fold range in sound intensities, despite large intensity‐dependent changes in input strength. Modulation of synaptic gain has been suggested as a mechanism to maintain accurate ITD processing. •  Here we show that activation of GABAB receptors suppresses both the excitatory and inhibitory inputs to the MSO and alters the kinetics of inhibitory synaptic currents. •  Using in vitro physiological methods and computational modelling, we show that the modulation by GABAB receptor activation contributes to spatial tuning of MSO neurones. •  These results contribute to the understanding of how neurones maintain computational stability under widely varying input conditions.