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Functional roles of synaptic inhibition in auditory temporal processing [Elektronische Ressource] / vorgelegt von Michael Pecka

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Functional roles of synaptic inhibition in auditory temporal processing Dissertation zur Erlangung des Grades eines Doktors der Naturwissenschaften an der Fakultät für Biologie der Ludwig-Maximilians-Universität München vorgelegt von Michael Pecka München, Juli 2008 Erstgutachter: Prof. Dr. Benedikt Grothe Zweitgutachter: Prof. Dr. Mark Hübener Tag der mündlichen Prüfung: 27.10.

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Published 01 January 2008
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Functional roles of synaptic inhibition
in auditory temporal processing







Dissertation
zur Erlangung des Grades eines Doktors der Naturwissenschaften
an der Fakultät für Biologie
der Ludwig-Maximilians-Universität München




vorgelegt von
Michael Pecka
München, Juli 2008































Erstgutachter: Prof. Dr. Benedikt Grothe
Zweitgutachter: Prof. Dr. Mark Hübener
Tag der mündlichen Prüfung: 27.10.2008

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Für Oldřich Pecka

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Table of Contents
SUMMARY 7
ZUSAMMENFASSUNG 11
INTRODUCTION 15
General motivation 15
The encoding of auditory stimuli in the mammalian brain 16
The mammalian ascending auditory pathway 17
Sound localization cues in the horizontal plane 19
ITD processing in the MSO 20
ITD coding in the Nucleus Laminaris in Birds 24
IID processing in the LSO 25
The medial nucleus of the trapezoid body 26
The dorsal nucleus of the lateral lemniscus 27
Persistent Inhibition in the DNLL and the Precedence Effect 28
Synaptic inhibition in neuronal processing 30
Goals of this study and contributions of the author to the individual chapters 32
RESULTS 35
CHAPTER 1 37
CHAPTER 2 51
CHAPTER 3 69
CHAPTER 4 85
GENERAL DISCUSSION 97
Functional roles of inhibition in coincidence detection 97
Sustained inhibition as a functional role for GABAergic transmission 100
Gain of information by disinhibition: Implications on coding strategies 101
Future perspectives 102
REFERENCES 105
List of abbreviations 115
Curriculum Vitae 117
List of publications 118
Acknowledgments 119
Ehrenwörtliche Erklärung 121

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SUMMARY

Hearing and vision are important senses that mammals – including humans – use to
orientate in their environment. The accurate localization of a sound source represents a
particular challenge to the central nervous system, because unlike for vision, a particular
location in auditory space is not mapped onto a specific location in the brain. Instead,
locations in space are neuronally computed by the evaluation of physical parameters of the
sound. The detection and processing of some of these physical parameters requires extreme
temporal precision. Specifically, low frequency sound sources along the azimuth are
localized by utilizing differences in the arrival time of the sound at the two ears (interaural
time differences, ITDs) in the range of microseconds. In contrast, the duration of action
potentials – the electrical signals by which neurons transmit information – is in the range of a
millisecond. To overcome this discrepancy, specialized neurons of the auditory brainstem
evolved to function as coincidence detectors between the inputs they receive from the left
and right ear. These neurons modulate their response rate as a function of ITD with
microsecond precision. Recent findings revealed that synaptic inhibition tunes these
coincidence detector neurons to achieve optimal ITD sensitivity. However, the functional
mechanism by which inhibition enhances ITD processing is unclear. In particular, it is
unknown whether the timing of the inhibitory inputs relative to the excitatory inputs is crucial
for the enhancement.
In addition to the extreme temporal sensitivity required for faithful sound source localization,
the auditory system is additionally confronted with spurious spatial cues stemming from
reflections and echoes. The system copes with this challenge by suppressing the directional
information of these secondary sounds without eliminating their overall perception. Hence,
identification and facultative evaluation of echoes is another fundamental requirement for
accurate orientation in space. However, the neuronal mechanisms underlying the exquisite
ability of the brain to cope with this challenge are not yet understood.
To gain insight into the functional roles of synaptic inhibition for sound localization and to
identify relevant neuronal circuits, we made in vivo extracellular single cell recordings in
anesthetized gerbils, at times combined with pharmacological manipulations. Additionally, we
obtained human behavioral and modeling data, confirming our physiological results in a
general framework. In the following, the result section of this thesis is divided into four
chapters, reflecting the different studies that were conducted:




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Chapter 1
In this study, we investigated the mechanisms of ITD processing at the initial binaural stage
within the ascending auditory pathway, the medial superior olive (MSO), where ITD
sensitivity is first created. The data acquired by in vivo single cell recordings in the MSO
strongly corroborated a recently formulated hypothesis about the ITD-coding strategy in
mammals. This hypothesis was predominately based on data from recordings of the auditory
midbrain and stated that low frequency sound localization is accomplished by rate-coding of
the entire population of ITD sensitive neurons. Moreover, to probe the role of the prominent
inhibitory inputs to the MSO, we performed pharmacological experiments. Tonic application
of the inhibitory transmitter glycine affected the ITD tuning of MSO neurons in an analogous
way to pharmacological blockade of the endogenous glycinergic inhibition. Specifically, both
drugs degraded the ITD sensitivity in the MSO cells. Thus, these experiments suggest that
endogenous inhibition at the MSO is not acting tonically, but rather that precise timing of the
glycinergic inputs in relation to the excitatory inputs on a cycle-by-cycle basis is essential for
the ITD detection mechanism.

Chapter 2
As mentioned before, the MSO is the initial stage at which ITD sensitivity is created.
Unfortunately, in vivo recordings from the MSO are notoriously difficult because of its
relatively small size and distant location in the brainstem, surrounded by auditory fiber
bundles which further hinder the isolation of single neuronal responses. MSO neurons
project directly to the dorsal nucleus of the lateral lemniscus (DNLL), a nucleus that is readily
accessible in in vivo preparations. Performing in vivo extracellular recordings, we determined
that the ITD sensitivity of DNLL neurons is similar to the ITD sensitivity of MSO neurons,
hence that no major transformations are present at the level of the DNLL. Hence, we showed
that the DNLL is a surrogate model nucleus to investigate ITD processing. Subsequently, we
investigated the relative timing of inhibition and excitation for ITD processing in DNLL
neurons and found indirect evidence for contralateral inhibition preceding the net
contralateral excitation on the level of the MSO.
Chapter 3
The findings described in chapters 1 and 2 demonstrated that inhibition is an integral part of
the ITD processing mechanism. The majority of the inhibitory inputs to the MSO originate
from the neurons of the medial nucleus of the trapezoid body (MNTB). MNTB neurons
receive excitatory input from the contralateral cochlear nucleus via a giant calyx-shaped
synapse showing remarkable specializations for both high temporal precision and reliable
transmission. However, in vitro studies using brain-slice preparations have reported very high
depression in the output strength and unexpectedly long recovery times from this depression.

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To investigate the response characteristics of MNTB neurons in the intact brain, we
performed in vivo extra-cellular single cell recordings and found that the recovery time
constants of MNTB neurons to sustained sound stimulation in vivo were much shorter than
those derived from in vitro measurements. Furthermore, MNTB neurons exhibited a wide
spectrum of spontaneous activity, i.e. activity that was not driven by sound stimulation.
Simulation of this spontaneous activity in in vitro experiments caused a pre-adaptation in the
response strength in the MNTB neurons. Consequently, full in vitro recovery from depression
during sustained activity was shorter in these experiments than in previous studies in which
spontaneous activity was missing. Moreover, the in vitro recovery time courses obtained with
simulated spontaneous activity matched the in vivo recovery time courses that we obtained.

Chapter 4
The ability to identify echoes and the context-dependent suppression of directional
information in echoes is a prerequisite for faithful sound localization. However, so far the
neuronal mechanisms that underlie this ability are unknown. To investigate a circuit
potentially dedicated to context-dependent suppression of echo directional information, we
performed in vivo extracellular single cell recordings in the DNLL. DNLL neurons that were
sensitive to differences in the intensity of sounds at the two ears were excited by
contralateral stimuli and inhibited by ipsilateral stimuli. Remarkably, in many neurons this
inhibition persisted for tens of milliseconds beyond stimulus offset and suppressed
responses to trailing stimuli that were excitatory if presented alone. Employing a
computational model as well as human psychophysics, we showed that this persistent
inhibition created sufficient information at higher auditory stages to generate context
dependent echo suppression that agreed closely with the percepts of human subjects.

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