Auditory Neurons in the Dorsal Cortex of the Inferior Colliculus: Responses to Contralateral Tone Bursts and Modulations by the Auditory Cortex

The inferior colliculus plays a key role in auditory processing. In the current study I used the albino rat, Rattus norvegicus, as an animal model to investigate auditory responses in single neurons in the dorsomedial subdivision of the inferior colliculus (ICd). My results reveal that ICd neurons exhibit various temporal firing patterns and long and variable first spike latencies. These neurons displayed a variety of frequency-tuning curves. Both monotonic and non-monotonic rate-level functions were present in these neurons. ICd neurons displayed stimulus-specific adaptation by reducing the strength of firing during repetitive tone burst stimulation but restored their responses when the quality of sound was changed. Functional decortication changed the strength of firing in ICd neurons, suggesting these neurons were controlled by the auditory cortex. My results suggest that the ICd may provide a gating mechanism that helps the auditory system to selectively process novel sounds in the acoustic environment

The Inferior Colliculus: A Target for Deep Brain Stimulation for Tinnitus Suppression

University of Minnesota Ph.D. dissertation. August 2015. Major: Biomedical Engineering. Advisor: Hubert Lim. 1 computer file (PDF); xii, 173 pages.Tinnitus is a neurological condition that manifests as a phantom auditory perception in the absence of an external sound source. Tinnitus is often caused by hearing loss associated with noise exposure or aging and as such, the prevalence is only expected to rise in the coming years. Currently there is no cure for tinnitus and available treatment options have only shown limited success, thus there is an ever present need for continued research into new treatments. In this thesis we propose a new approach to treating tinnitus that uses deep brain stimulation to target the inferior colliculus (IC) with the goal of altering tinnitus-related neural activity, such as hyperactivity and increased neural synchrony, to suppress the tinnitus percept. We hypothesize that stimulation of the outer cortices of the inferior colliculus will modulate the tinnitus-affected neurons in the central region of the inferior colliculus (ICC) and in turn, these neural changes will be carried throughout the central auditory system by the extensive projection network originating in the IC, and will induce modulation in other tinnitus-affected auditory nuclei. The research of this thesis is aimed at determining the feasibility of this tinnitus treatment by assessing the IC as a potential neuromodulation target and identifying optimal stimulation locations and stimulation strategies for achieving maximal suppression. The first study was completed to better understand the auditory coding properties of the IC and to create a three dimensional reconstruction of these functional properties across the entire IC. These results narrowed down the stimulation target to the dorsal cortex of the inferior colliculus (ICD) and produced a tool that could be used to consistently place stimulating and recording electrodes in correct regions in the IC. The second and third studies focused on assessing the best stimulation locations and stimulation paradigms within the ICD, respectively, by stimulating throughout and measuring changes in neural activity in the ICC. These results show that maximal suppression is achieved by stimulation of the rostral-medial region of the ICD using either electrical stimulation only or electrical stimulation paired with acoustic stimulation with an 18 ms delay. These results will guide implementation in human patients. There are already deaf patients who suffer from tinnitus that are being implanted with a deep brain stimulator for hearing restoration called the auditory midbrain implant. Hardware modifications to the auditory midbrain implant have been completed that will allow us to stimulate the ICD and evaluate the effects on the tinnitus percept directly in patients

Convergence of Excitatory and Inhibitory Projections in the Mouse Medial Geniculate Body

The medial geniculate body (MGB) is the target of excitatory and inhibitory inputs from several neural sources. Among these, the inferior colliculus (IC) is an important nucleus in the midbrain that acts as a nexus for many auditory pathways and projections, ascending and descending, throughout the rest of the central auditory system and provides both excitatory and inhibitory projections to the MGB. In addition, the thalamic reticular nucleus (TRN) is a major source of inhibition to the MGB, particularly in rodents. Finally, the auditory cortex (AC) is a major source of descending input to the MGB, providing direct excitation and indirect inhibition via the TRN. In our study, we assessed the relative contribution from these excitatory and inhibitory projection sources to the MGB of the auditory system in mice. Using retrograde tract tracing with CTβ -Alexa Fluor 594 injected into the MGB of the mouse, we quantitatively mapped the projections from both the ipsilateral and contralateral IC, the TRN, and the AC to the ipsilateral MGB. Our results indicate significant GABAergic projections from the IC and TRN to the MGB and excitation from the AC that play an overlooked role in shaping auditory processing. These results complement prior studies in other species, which suggests that these pathways are important factors in the regulation of neuronal activity in the auditory forebrain

Efecto de la ablación restringida de la corteza auditiva sobre el colículo inferior en la rata

[ES] En esta tesis se intenta llegar a un de un modelo, en el futuro, de plasticidad homeostática in toto o in vivo, útil para hallar soluciones terapéuticas, que busquen mejorar la capacidad de recuperación espontánea, hasta alcanzar los puntos de equilibrio homeostáticos, no solo de las células nerviosas a nivel individual, sino también de los circuitos y redes neuronales. En este estudio nos se plantea inducir un fuerte disbalance de señales, mediante la eliminación unilateral de la proyección descendente desde la corteza auditiva al colículo inferior.[EN] This thesis attempts to reach a model in the future, homeostatic plasticity in toto or in vivo, useful for therapeutic solutions, which seek to improve the ability of spontaneous recovery, reaching homeostatic equilibrium points, not only of nerve cells at the individual, but also the neural circuits and networks. In this study we raised induce a strong imbalance of signals, by unilateral removal of the downward projection from the auditory cortex to the inferior colliculus

Intercollicular modulation of auditory processing in the inferior colliculus

PhD ThesisThe inferior colliculi (ICs) are the principal nuclei of the auditory midbrain. Each IC processes converging inputs from numerous brainstem nuclei as well as from thalamus and cortex. The ICs are interconnected in mirror image by one of the largest afferent inputs to each IC, the commissure of the inferior colliculus. There is exiguous knowledge about how each IC influences the processing of auditory information in its contralateral counterpart. This thesis investigates how one IC modulates the neural representation of sounds in the contralateral IC. To this end, I established and validated an experimental model in anaesthetised guinea pig whereby neuronal activity in one IC was selectively and reversibly deactivated. Cryoloop cooling produced temperature changes sufficient to deactivate spiking activity in the dorsal half of one IC, whilst leaving other centres in the auditory pathway unaffected. Single units were recorded in one IC before, during and after deactivation of the other IC. The characteristic frequency (CF) of IC neurons was unaffected during cooling, but the threshold of the population was raised. The area of non-V-shaped frequency response areas (FRAs) changed more than V-shaped FRAs. Differential changes were also observed in the firing rate of units with different temporal response patterns. Onset responders increased their firing rate whilst the firing of Chopper units was reduced. The temporal firing patterns of all neurons were unchanged by cooling. Changes in first spike latency (FSL) were negatively correlated with changes in firing rate. These data indicate that each IC differentially modulates the frequency selectivity, sensitivity, firing rate and FSL, but not the temporal firing pattern or CF of neurons in the contralateral IC. These findings demonstrate that the analysis of auditory stimuli in each IC is dependent on intercollicular processing. The ICs should therefore be viewed as working cooperatively rather than independently

ACTIVITY-DEPENDENT CHANGES IN A NEURONAL CIRCUIT IMPORTANT FOR SOUND LOCALIZATION

Aside from recognizing and distinguishing sound patterns, the ability to localize sounds in the horizontal plane is an essential component of the mammalian auditory system. It facilitates approaching potential mating partners and allows avoiding predators. The superior olivary complex (SOC) within the auditory brainstem is the first site of binaural interaction and its major projections and inputs are well investigated. The adult input pattern, however, is not set from the beginning but changes over the period of development. Mammals including humans experience different stages and conditions of hearing during auditory development. The human brain for instance has to perform a transition after birth from the perception of sound waves transmitted in amniotic fluid to the perception of airborne sounds. Furthermore, small mammals like rodents, which are common model organisms for auditory research, perceive airborne sounds for the first time some days after birth, when their ear canals open. The basic neuronal projections and the intrinsic properties of neurons, such as the expression of specific ion channels, are already established and adjusted in the SOC during the perinatal period of partial deafness. An additional refinement of inputs and further adaptations of intrinsic characteristics occur with the onset of hearing in response to the new acoustic environment. It is likely that with ongoing maturation well-established inputs within the sound localization network need these adaptations to balance anatomical changes such as an increasing head size. In addition, short-term adjustments of synaptic inputs in the adult auditory system are equally necessary for a faithful representation of auditory space. A recent study suggests that these short-term adaptations are partially represented at the auditory brainstem level. The question of how intrinsic properties change during auditory development, to what extent auditory experience is involved in these changes and the functional implications of these changes on the sound localization circuitry is only partially answered. I used the hyperpolarization-activated and cyclic nucleotide-gated cation channels (HCN channels), which are a key determinant of the intrinsic properties of auditory brainstem neurons, as a target to study the influence of auditory experience on the intrinsic properties of neurons in the auditory brainstem. Another important question still under discussion is how neurons in the auditory brainstem might fine-tune their firing behavior to cope optimally with an altered acoustic environment. Recent data suggest that auditory processing is also affected by modulatory mechanisms at the brainstem level, which for instance change the input strength and thus alter the spike output of these neurons. One possible candidate is the metabotropic GABAB receptor (GABABR) which has been shown to be abundant in the adult auditory brainstem, although GABAergic projections are scarce in the mature auditory brainstem. These questions were investigated by performing whole-cell patch-clamp recordings of SOC neurons from Mongolian gerbils at different developmental stages in the acute brain slice preparation. Specific currents and receptors were isolated using pharmacological means. Immmunohistochemical results additionally supported physiological findings. In the first study, I investigated the developmental regulation of HCN channels in the SOC and their underlying depolarizing current Ih, which has been shown to regulate the excitability of neurons and to enhance the temporally precise analysis of binaural acoustic cues. I characterized the developmental changes of Ih in neurons of the lateral superior olive (LSO) and the medial nucleus of the trapezoid body (MNTB), which in the adult animals show different HCN subunit composition. I showed that right after hearing onset there was a strong increase of Ih in the LSO and just a minor increase in the MNTB. In addition, the open probability of HCN channels was shifted towards more positive voltages in both nuclei and the activation time constants accelerated during the first days of auditory experience. These results implicate that Ih is actively regulated by sensory input activity. I tested this hypothesis by inducing auditory deprivation which was achieved by surgically removing the cochlea in gerbils before hearing onset. The effect was opposite in neurons of the MNTB and the LSO. Whereas in LSO neurons auditory deprivation resulted in increased Ih amplitude, MNTB neurons displayed a moderate decrease in Ih. These results suggest that auditory experience differentially changes the amount of HCN channels dependent on the subunit composition or possibly alters intracellular cAMP levels, thereby shifting the voltage dependence of Ih. This regulatory mechanism might thus maintain adequate excitability levels within the SOC. A second study was carried out to investigate the role of GABABRs in the medial superior olive (MSO). Upon activation, these metabotropic receptors are known to decrease the release probability of neurotransmitters at the presynapse thereby altering excitatory and inhibitory currents at the postsynaptic site. Neurons in the MSO analyze interaural time differences (ITDs) by comparing the relative timing of the excitatory inputs from the two ears using a coincidence mechanism. In addition, these neurons receive a precisely timed inhibitory input from each ear which shifts ITDs in the physiological relevant range. Since the major inhibitory input changes its transmitter type from mixed GABA/glycinergic to only glycinergic after hearing onset it was now interesting to examine the mediated effects of GABABRs, which have been shown to be abundant in the prehearing and adult MSO of gerbils. Furthermore, revealing the precise expression pattern of GABABRs and their influence on excitatory and inhibitory currents in the MSO during auditory development should provide further evidence of their functional relevance. Performing pharmacological experiments I could now demonstrate that the activation of GABABRs before hearing onset decreases the current of excitatory inputs stronger than that of inhibitory inputs whereas a switch is performed after hearing onset and inhibitory currents are stronger decreasedcompared to excitatory currents. In a similar way, also the expression pattern of GABABRs changes before and after hearing onset as revealed by immunohistochemistry. Since the main inhibitory inputs to the adult MSO are purely glycinergic, it was commonly assumed that GABABRs occupy only a minor role in the mature auditory brainstem. Contradictory to this, it was possible to activate presynaptic GABABRs by synaptic stimulation even in adult animals and to observe a profound decrease of inhibitory current in MSO neurons. These results suggest GABAergic projections of yet unknown origin targeting the MSO. It is therefore quite likely that GABABRs modulate and possibly improve the localization of low frequency sounds even in adult mammals. Summarized, the outcome of this thesis contributes to a better understanding of the developmental adaptation in the auditory system and demonstrates that the orderly specification of intrinsic properties within the SOC is dependent on auditory experience. Moreover, I show that even in mature animals the synaptic strength of MSO inputs can be modulated by synaptic GABA release. This should emphasize the importance of modulatory mechanisms and could be the basis for future studies concerning the field of sound localization

Intrinsic response properties of auditory thalamic neurons in the Gerbil (Meriones unguiculatus)

Neurons in the medial geniculate body (MGB) have the complex task of processing the auditory ascending information from the periphery and a more extensive descending input from the cortex. Differences in the pattern of afferent and efferent neuronal connections suggest that neurons in the ventral and dorsal divisions of the MGB take different roles in this complex task. The ventral MGB (vMGB) is the primary, tonotopic, division and the dorsal MGB (dMGB) is one of the higher order, nontonotopic divisions. The vMGB neurons are arranged tonotopically, have sharp tuning properties, and a short response delay to acoustic stimuli. The dMGB neurons are not tonotopically arranged, have broad tuning properties, and a long response delay to acoustical stimuli. These two populations of neurons, with inherently different tasks, may display differences in intrinsic physiological properties, e.g. the capacity to integrate information on a single cell level. Neurons of the ventral and dorsal divisions of the MGB offer an ideal system to explore and compare the intrinsic neuronal properties related to auditory processing. Coronal slices of 200 &#956;m thicknesses were prepared from the thalamus of 4 - 5 week old gerbils. The current-clamp configuration of the patch-clamp technique was used to do experiments on the dorsal and ventral divisions of the medial geniculate body. Slices were subsequently Nissl stained to verify the location of recording. Recordings from the dorsal and ventral divisions exhibited differences in response to depolarizing current injections. The ventral division responded with significantly shorter first spike latency (vMGB = 41.50 ± 7.7, dMGB = 128.43 ± 16.28; (p < 0.01)) and rise time constant (vMGB = 6.95 ± 0.90, dMGB = 116.67 ± 0.13; (p < 0.01)) than the dMGB. Neurons in the dorsal division possessed a larger proportion of slowly accommodating neurons (rapidly accommodating: vMGB: 89%, dMGB: 64%), including a subpopulation of neurons that fired at resting membrane potential. Neurons in the vMGB are primarily responsible for relaying primary auditory input. Dorsal MGB neurons relay converging multimodal input. A comparative analysis with the primary auditory neurons, the Type I and Type II spiral ganglion neurons, reveals a similar pattern. Type I neurons relay primary auditory input and exhibit short first spike latencies and rise time constants. The Type II neurons relay converging input from many sources, while possessing significantly slower response properties and a greater subpopulation of slowly accommodating neurons. Hence, accommodation, first spike latency, and rise time constant are suggested to be a reflection of the amount of input that must be integrated before an action potential can be fired. More converging input correlates to slower accommodation, a longer first spike latency and rise time. Conversely, a greater capacity to derive discrete input is associated with rapid accommodation, along with a short first spike latency and rise time.Der Nucleus geniculatum mediale (MGB, medial geniculate body) ist in der aufsteigenden Hörbahn der Säuger die Umschaltstation auf der Ebene des Diencephalon (Zwischenhirn), nach den Kerngebieten Ganglion ciliare (dessen Fasern den Hörnerven bilden), dem Nucleus cochlearis, dem oberen Olivenkomplexes, dem Colliculus inferior und dem Lemniscus laterale. Vom MGB aus wird die Erregung zu den auditorischen Arealen des Cortex cerebri (Hörkortex) weitergeleitet. Der MGB ist aber Teil der absteigenden Hörbahn. Er erhält direkte Eingänge vom Hörkortex und hat selbst Afferenzen zum Colliculus inferior. Diese absteigende Hörbahn reicht über den Olivenkomplex bis einer Innervation des Innenohrs, wo die Erregung der (äußeren Haarsinneszellen) beeinflusst werden kann. Der MGB ist damit sehr wahrscheinlich in unterschiedliche funktionelle Verarbeitungsschritte eingebunden. Die Einbindung in mehrere Funktionen deutet sich auch in der internen Struktur des MGB an. Der ventrale Bereich des MGB (vMGB) ist tonotop organisiert, d.h. enthält eine systematische Frequenzanordnung, und ist ein Teil der primären Hörbahn. Neurone im vMGB sind damit Teil einer systematischen Frequenzrepräsentation, haben meist eine schmale Frequenzabstimmung und zeigen eine kurze Antwortlatenz bei akustischer Reizung. Der dorsale Bereich des MGB (vMGB) ist eine dagegen nicht tonotop organisierte Struktur, die sehr wahrscheinlich abgeleitete Funktionen bei der Hörverarbeitung hat, wie zum Beispiel die Integration der Hörinformation mit anderen Sinnessystemen. Neurone im dMGB sind nicht Teil einer systematischen Frequenzabbildung, haben meist eine breite Frequenzabstimmung und zeigen lange Antwortlatenzen bei der Reizung mit Reintönen (Calford & Webster 1981, Webster 1983). Neuronen aus dem dMGB und dem vMGB, die jeweils an unterschiedlichen Verarbeitungsschritten im neuronalen Verbund beteiligt sind, zeigen möglicherweise auch Unterschiede in ihren elektrophysiologischen Eigenschaften als Einzelneurone. Dies könnte wesentlich zu Unterschieden in der Verarbeitung beitragen. Solche Unterschiede können bei grundlegenden neuronalen Eigenschaften wie Ruhemembranpotenzial, Erregungsschwelle oder Antwortlatenz vorhanden sein. Solche Unterschiede sind zum Beispiel zwischen den Typ I- und Typ II- Neuronen des Ganglion ciliare zu finden (Reid et al. 2004). Es können aber auch abgeleitete Eigenschaften sein, wie z.B. den Fähigkeiten Erregung räumlich oder zeitlich zu integrieren. Der Vergleich der Neurone aus vMGB und dMGB eignet sich gut um mögliche Unterschiede in den intrinsischen elektrophysiologischen Eigenschaften der Nervenzellen mit unterschiedlichen Aufgaben bei der Hörverarbeitung zu korrelieren. Deshalb wurde dieser Vergleich zum zentralen Thema der vorliegenden Arbeit gemacht. Für die Untersuchungen wurden lebende, frontal orientierte Hirnschnitte (200 &#956;m Dicke) des Thalamus von 4 bis 5 Wochen alten Wüstenrennmäusen präpariert. Mit der patch clamp-Technik wurde elektrophysiologisch Potenziale von Neuronen des dorsalen und ventralen Bereichs des MGB abgeleitet. Es wurden sowohl die Reaktionen der Zellen auf hyper- als auch depolarisierende Strominjektion untersucht. Die dabei notwendigen Parameter für einen gute physiologischen Zustand der Hirnschnitte und eine stabile patchclamp-Ableitung wurden in umfangreichen Vorversuchen ermittelt. Bereits in der Ableitapparatur war eine genaue Positionierung der Elektrode im dMGB oder vMGB unter optischer Kontrolle möglich. Zusätzlich wurden nach erfolgreicher Ableitung die Hirnschnitte fixiert, gegen Nissl gefärbt und zur Bestätigung der Ableitposition lichtmikroskopisch untersucht. Insgesamt wurden 73 Neurone (vMGB: 34 Neurone, dMGB: 39 Neurone) vollständig untersucht. Deren Ruhepotenzial lag zwischen -79 mV und -45 mV. Dabei gab es keine Unterschiede zwischen vMGB-Neuronen und dMGB-Neuronen (vMGB: 62.9 mV; dMGB: 60.1 mV; Abb. 3.2). Wurden die Neurone vom Ruhepotenzial aus durch zunehmende Strominjektion überschwellig depolarisiert, dann antworteten sie mit einer zunehmenden Anzahl von Aktionspotenzialen (Abb. 3.1). Diese wurden bei zunehmender Reizstärke in immer schnellerer Folge und mit immer kürzerer Latenz ausgelöst wurden. Allerdings gab es ein Potenzialniveau (zwischen -35 mV und -25 mV) bei dem eine maximale Feuerrate erreicht wurde. Bei noch höherer Depolarisation blieb diese maximale Feuerrate gleich oder nahm wieder ab. Bei Stimulation von einem hyperpolarisierten Haltepotenzial aus (z.B. -90 mV) kam es zusätzlich zu Beginn der Antwort zu einem kleinen initialen Gipfel, dem eine schnelle Repolarisation (durch offensichtlichen Einstrom) folgte (Abb. 3.0). Nach deren Abklingen kam es zum Potenzialanstieg mit einer schnellen Folge von Aktionspotenzialen. Die Feuerschwellen zum Auslösen von Aktionspotenzialen im MGB lagen zwischen -54 mV und -32 mV. Die mittleren Schwellenwerte im vMGB (42.9 mV) und dMGB (44.3 mV) waren nicht signifikant verschieden. Die Dauer der an der Schwelle ausgelösten Aktionspotenziale wurde bei halber Höhe gemessen und vergleichen. Auch dieser Wert war im Mittel zwischen vMGB (2.04 ms) und dMGB (1.95 ms) nicht verschieden. Diese Werte änderten sich bei höherer Stimulation kaum. Außerdem wurden der Membranwiderstand (d.h. der "Eingangswiderstand") der Neurone bei Potenzialen um das Ruhepotenzial ("niedriges Potenzial") und bei Potenzialen oberhalb der Feuerschwelle ("hohes Potenzial") gemessen. Die Membranwiderstände in beiden Bereichen des MGB waren im Mittel bei niedrigem Potenzial deutliche höher (vMGB: 307.0 M&#937;; dMGB: 237.5 M&#937;) als bei hohem Potenzial (vMGB: 61.0 M&#937;; dMGB: 64.2 M&#937;) und in beiden Zuständen zwischen vMGB und dMGB nicht signifikant unterschiedlich....

Time-processing and postnatal development in the auditory cortex of the bat Carollia perspicillata

Echoortende Fledermäuse verfügen über ein hochauflösendes Gehör. Sie können anhand einer geringen Zeitverzögerung zwischen ausgesendetem Echoortungsruf und dem Echo die Entfernung von Objekten bestimmen. Je nach Spezies und deren spezifischer Ortungsstrategie gibt es unterschiedliche Typen von Ortungslauten. Die meisten Fledermäuse verwenden frequenzmodulierte (FM) Ortungssignale und zählen zu den FM-Fledermäusen. CF-FM-Fledermäuse verwenden dagegen zusätzlich zu FM-Komponenten konstantfrequente Signalelemente (CF-FM). Diese sind besonders zur Detektion flügelschlagender Beuteinsekten in dichter Vegetation von Vorteil. Im auditorischen Kortex (AC) von Fledermäusen existieren so genannte FM-FM-Neurone, die auf die Auswertung der Verzögerungszeiten zwischen Rufaussendung (FM-Ruf) und Echo (FM-Echo) spezialisiert sind. Eine Besonderheit von FM-FM-Neuronen ist, dass sie bei CF-FM-Fledermäusen systematisch, entsprechend ihrer bevorzugten Echoverzögerungen, im AC angeordnet sind. Somit sind die FM-FM-Neurone chronotop entlang einer rostro-kaudalen Achse organisiert. Solche FM-FM-Neurone wurden bislang auch in FM-Fledermäusen nachgewiesen, jedoch waren sie nicht chronotop organisiert. Ein Ziel dieser Promotionsarbeit war es, FM-FM-Neurone bei der FM-Fledermaus Carollia perspicillata hinsichtlich ihrer Eigenschaften und ihrer räumlichen Anordnung im AC zu untersuchen. Die Befunde der vorliegenden Studie an C. perspicillata zeigen, dass alle untersuchten Neurone im dorsalen AC sowohl auf hochfrequente Reintöne als auch auf FM-FM-Stimulation reagierten. Die Echoverzögerungen, auf welche die Neurone im Areal reagierten, lagen zwischen 1 und 32 ms, was einer Distanz zwischen Fledermaus und Objekt von 16 cm bis 5,3 m entspricht. Überraschenderweise waren die kortikalen FM-FM-Neurone bei C. perspicillata chronotop organisiert, ähnlich wie bei insektenfressenden CF-FM-Fledermäusen. Warum eine chronotope Anordnung von FM-FM-Neuronen im AC bei CF-FM-Fledermäusen von Nutzen sein kann, ist nicht geklärt. Bislang wurde vermutet, dass eine systematische Anordnung die Zeitverarbeitungsprozesse optimiert und vor allem beim Insektenjagen in dichter Vegetation vorteilhaft sein könnte. Der vorliegende Befund ist außergewöhnlich, da er zeigt, dass auch bei der überwiegend frugivoren Fledermaus C. perspicillata FM-FM-Neurone chronotop angeordnet sind, und damit verdeutlicht, dass der funktionelle Rückschluss hinsichtlich des Beutefangs neu diskutiert werden muss. Neben der Charakterisierung von FM-FM-Neuronen bei adulten C. perspicillata war Ziel der vorliegenden Arbeit, die postnatale Entwicklung des AC im Hinblick auf die Frequenzrepräsentation zu untersuchen. Während der Entwicklung von C. perspicillata wurden drei wichtige Veränderungen festgestellt: (1) Das Audiogramm zeigt, dass der Hörbereich von Neugeborenen charakteristische Frequenzen (CF) zwischen 15 und 80 kHz aufweist. Dieser Frequenzbereich entspricht etwa 72% des Hörbereichs von Adulten. Während der ersten vier postnatalen Entwicklungswochen findet eine Frequenzverschiebung um etwa 0,4 Oktaven hin zu höheren Frequenzen statt. Insgesamt erhöhen sich die CF der Neurone im dorsalen AC von Neugeborenen bis hin zu Adulten um 30 kHz. (2) Die Sensitivität der hochfrequenten Neurone nimmt während der ersten postnatalen Woche um 15 dB zu und bleibt ab dieser Entwicklungsphase relativ konstant. (3) Die Sensitivität der tieffrequenten Neurone im ventralen AC nimmt im Laufe der Entwicklung um etwa 30 dB zu. Die CF der tieffrequenten Neurone sinken unerwartet während der postnatalen Entwicklung von Juvenilen zu Adulten um etwa 10 kHz. Diese Ergebnisse könnten auf eine bidirektionale Ausreifung der Cochlea hinweisen. Eine dritte ontogenetische Teilstudie der vorliegenden Arbeit befasste sich erstmalig mit den FM-FM-Neuronen und deren Organisation während der postnatalen Entwicklung. Die Befunde zeigen, dass während der Ontogenese drei wichtige Modifikationen auftreten: (1) Bereits bei Neugeborenen liegt der Anteil an FM-FM-Neuronen bei 21% im Vergleich zur Aktivität auf Reintöne. Dieser Anteil nimmt in der ersten Entwicklungswoche auf 56% zu und steigt einhergehend mit der beginnenden Flugtüchtigkeit der Tiere in der dritten Entwicklungswoche abrupt auf 84%. (2) Bei Neugeborenen werden im Vergleich zu älteren Entwicklungsphasen ausschließlich Entfernungen zwischen Fledermaus und Objekt von 50 cm bis 2,5 m auf neuronaler Ebene mittels FM-FM-Neurone codiert. Bereits nach der ersten postnatalen Woche sind die CD ähnlich verteilt wie bei adulten Tieren. Die Sensitivität an den CD nimmt während der Entwicklung vom Neugeborenen zum Adulten um etwa 20 dB zu. (3) Bereits bei Neugeborenen sind die FM-FM-Neurone im dorsalen AC chronotop angeordnet und über alle Altersgruppen hinweg bleibt die Chronotopie bestehen. Die Befunde der vorliegenden Studie zeigen erstmalig, dass die kortikalen Zeitverarbeitungsareale und die Chronotopie pränatal angelegt werden.Echolocating bats are sophisticated hearing specialists. They can precisely determine the distance of objects based on a short time-delay between their echolocation call and the echo. Depending on the species, their diet and specific hunting strategies, different echolocation types can be classified. Most bats use short frequency-modulated (FM) sweep signals for echolocation and are, therefore, called FM bats. In contrast, CF-FM bats use constant-frequent components (CF-FM) in addition to the FM signals for echolocation. This echolocation call is particularly advantageous for detecting small insects in highly cluttered habitats. There exist specialized FM-FM neurons in the auditory cortex (AC) of bats, which analyze the temporal time difference between a bat’s call (FM call) and the returning echo (FM echo). A particular feature of FM-FM neurons in CF-FM bats is their systematic topographic arrangement in the AC according to their preferential echo delays. Thus, the FM-FM neurons are chronotopically organized along a rostro-caudal echo-delay axis representing object distance. Such FM-FM neurons have also been detected in FM bats but a chronotopical organization has not been observed. The present study focuses on the FM-FM neurons in the FM bat Carollia perspicillata to assess, if different requirements for echolocation in the context of either insect detection or general orientation are reflected in response properties and the topographic arrangement of such neurons. The results demonstrate that neurons which are located in a large dorsal cortical area are responsive to high-frequency pure-tones, and are also delay-tuned and chronotopically organized comparable to that of CF-FM insectivorous bat species. Their characteristic delays (CD) range between 1 and 32 ms, which corresponds to a distance between bat and object of 16 cm to 5.3 m. The computational advantage of chronotopic echo-delay maps can be interpreted to be providing the substrate for integration of different echo parameters as they are important, for instance, in tracking an object and in enhancing acuity of target range calculation, in particular for small targets in highly cluttered habitats. The present findings are extraordinary, as they show that in the predominantly frugivorous FM bat C. perspicillata the FM-FM neurons are arranged chronotopically in the AC. These findings show that the functional conclusion regarding correlation between chronotopy and active insect-hunting has to be reconsidered. In the second part of the present study, the postnatal development of hearing range, auditory sensitivity, frequency representation and organisation in the dorsal AC was examined in C. perspicillata. During ongoing postnatal maturation, three developmental changes can be observed: (1) The audiogram of newborn C. perspicillata includes characteristic frequencies (CF) between 15 and 80 kHz, which represents about 72% of the adult hearing range. During the first postnatal week, an upward frequency shift to CF between 25 and 90 kHz takes place. The increase of the CF during development from newborn to adults amounts to about 30 kHz. (2) The sensitivity of high-frequency neurons in the dorsal AC increases by about 15 dB during the first postnatal week and remains constant from this stage onward. (3) The sensitivity of low-frequency neurons in the ventral part of the AC increases during development by about 30 dB. Unexpectedly, the CF of these neurons decreased during ontogenesis by about 10 kHz, in contrast to the development of the high-frequency neurons in the dorsal part. These results could indicate a bidirectional maturation of the cochlea and modification of cortical processing, as already assumed for the inferior colliculus in C. perspicillata. In the third part of the present study, the properties of FM-FM neurons were examined during ontogenesis. During ongoing postnatal maturation, three key developmental changes of the FM-FM neurons and their cortical organization can be observed. (1) In newborn bats 21% of auditory neurons in the dorsal auditory cortex are already delay-tuned. During ontogenesis the percentage of FM-FM neurons rises in general and increases abruptly to 84% in the third postnatal week, which reflects the developing flight capability of the animals. As opposed to older stages of postnatal maturation, only distances between 50 cm and 2.5 m are encoded on the cortical level in newborn bats. After the first postnatal week, the CD are distributed in the same way as in adult animals. (2) During the development from newborn to adults, the sensitivity at the CD increases by approximately 20 dB. (3) In newborn bats, the FM-FM neurons were chronotopically arranged in the dorsal AC. A consistent correlation between CD and rostro-caudal position is present across all estimated age groups. This study demonstrates for the first time that cortical time processing areas and the chronotopic organization are established prenatally