Thesis (Ph. D.)--University of Missouri-Columbia, 1996. / Typescript. Vita. Includes bibliographical references (leaves 109-115). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 1996. / Typescript. Vita. Includes bibliographical references (leaves 109-115). Also available on the Internet.

An important question in sensory neuroscience is what coding strategies and mechanisms are used by the brain to detect and discriminate among behaviorally relevant stimuli. To address the noisy response properties of individual neurons, sensory systems often utilize broadly tuned neurons with overlapping receptive fields at the system's periphery, resulting in homogeneous responses among neighboring populations of neurons. It has been hypothesized that progressive response heterogeneity in ascending sensory pathways is evidence of an efficient encoding strategy that minimizes the redundancy of the peripheral neural code and maximizes information throughput for higher level processing. This hypothesis has been partly supported by the documentation of neural heterogeneity in various cortical structures. This dissertation examines whether selective and sensitive responses to behaviorally relevant stimuli contribute to a heterogeneous and efficient encoding in the auditory midbrain. Prior to this study, no compelling experimental framework existed to address this question. Stimulus design methodologies for neuroethological experiments were largely based on token vocalizations or simple approximations of vocalization components. This dissertation describes a novel state-space signal modeling methodology which makes possible the independent manipulation of the frequency, amplitude, duration, and harmonic structure of vocalization stimuli. This methodology was used to analyze four mouse vocalizations and create a suite of perturbed variants of each of these vocalizations. Responses of neurons in the mouse inferrior colliculus (IC) to the natural vocalizations and their perturbations were characterized using measures of both spike rate and spike timing. In order to compare these responses to those of peripheral auditory neurons, a data-driven model was developed and fit to each IC neuron based on the neuron's pure tone responses. These models were then used to approximate how peripheral auditory neurons would respond to our suite of vocalization stimuli. Using information theoretic measures, this dissertation argues that selectivity and sensitivity by individual neurons results in heterogeneous population responses in the IC and contributes to the efficient encoding of behaviorally relevant vocalizations.

Neural stem cells (NSCs) have been recently identified in the inferior colliculus (IC). These cells are of particular interest, as no casual therapeutic options for impaired neural structures exist. This research project aims to evaluate the neurogenic potential in the rat IC from early postnatal days until adulthood. The IC of rats from postnatal day 6 up to 48 was examined by neurosphere assays and histological sections. In free-floating IC cell cultures, neurospheres formed from animals from early postnatal to adulthood. The amount of generated neurospheres decreased in older ages and increased with the number of cell line passages. Cells in the neurospheres and the histological sections stained positively with NSC markers (Doublecortin, Sox-2, Musashi-1, Nestin, and Atoh1). Dissociated single cells from the neurospheres differentiated and were stained positively for the neural lineage markers β-III-tubulin, glial fibrillary acidic protein, and myelin basic protein. In addition, NSC markers (Doublecortin, Sox-2, CDK5R1, and Ascl-1) were investigated by qRT-PCR. In conclusion, a neurogenic potential in the rat IC was detected and evaluated from early postnatal days until adulthood. The identification of NSCs in the rat IC and their age-specific characteristics contribute to a better understanding of the development and the plasticity of the auditory pathway and might be activated for therapeutic use. / Neuronale Stammzellen wurden kürzlich im unteren Colliculus inferior (CI) identifiziert. Diese Zellen sind von besonderem Interesse, da es keine therapeutischen Optionen für geschädigte neuronale Strukturen gibt. Ziel dieses Forschungsprojekts ist es, das neurogene Potenzial im CI der Ratte von den ersten postnatalen Tagen bis zum Erwachsenenalter zu untersuchen. Der CI von Ratten vom 6. bis zum 48. postnatalen Tag wurde mit Neurosphären-Assays und histologischen Schnitten untersucht. In frei schwimmenden CI-Zellkulturen bildeten sich Neurosphären bei Tieren vom frühen postnatalen Alter bis zum Erwachsenenalter. Die Menge der gebildeten Neurosphären nahm im höheren Alter ab und stieg mit der Anzahl der Zelllinienpassagen. Die Zellen in den Neurosphären und die histologischen Schnitte zeigten eine positive Färbung mit neuronalen Stammzell-Markern (Doublecortin, Sox-2, Musashi-1, Nestin und Atoh1). Dissoziierte Einzelzellen aus den Neurosphären differenzierten und wurden positiv für die neuralen Abstammungsmarker β-III-Tubulin, GFAP und MBP angefärbt. Darüber hinaus wurden neuronalen Stammzell-Marker (Doublecortin, Sox-2, CDK5R1 und Ascl-1) mittels qRT-PCR untersucht. Zusammenfassend lässt sich sagen, dass ein neurogenes Potenzial im CI der Ratte von den frühen postnatalen Tagen bis zum Erwachsenenalter nachgewiesen und bewertet wurde. Die Identifizierung von neuronalen Stammzellen im CI der Ratte und ihre altersspezifischen Merkmale tragen zu einem besseren Verständnis der Entwicklung und der Plastizität der Hörbahn bei und könnten für eine therapeutische Nutzung aktiviert werden.

Intercepter une cible en mouvement est un défi spatiotemporel relevé par de nombreuses espèces animales. Ici, nous nous sommes intéressés à la capture fovéale lors de l’orientation saccadique du regard vers une cible visuelle mobile chez le singe vigile. La théorie actuelle propose que l’interception saccadique fasse intervenir deux voies neuronales. Une première voie acheminerait, via le colliculus supérieur profond (CSp), un signal de position échantillonnée au générateur saccadique. La seconde, via le cervelet, fournirait une commande supplémentaire sur la base des signaux de mouvement visuel. Une étude comportementale a été réalisée afin d’analyser la dynamique de l’influence de ces signaux sur la trajectoire saccadique et a permis de mettre en évidence une influence continue. Dans une seconde étude, nous avons testé la robustesse du système oculomoteur à une perturbation spatiotemporelle inattendue (par microstimulation électrique du CSp) et montré la présence de saccades de correction précises. L’ensemble de nos résultats plaide pour une représentation continue du but des saccades d’interception. / Intercepting a visual moving target is a spatiotemporal challenge for the brain achieved by various species. Here, we investigated the foveal capture of a moving target by saccadic gaze shifts in the awake monkey. The current theory proposes that the saccadic interception involves two neural pathways. A first pathway would convey to the saccade burst generator a sampled target position signal through the superior colliculus (SC). The second one, through the cerebellum, would convey an additional command on the basis of motion-related signals. A behavioral experiment was performed to analyze the influence of motion-related signals on the saccade dynamics and allowed showing a continuous influence. In a second study, we tested the robustness of the oculomotor system to an unexpected spatiotemporal perturbation (by electrical microstimulation in the deep SC) and showed the presence of accurate correction saccades. Our results argue for a continuous representation of the saccade goal.

Le Colliculus Supérieur (SC) est bien connu pour son rôle dans la génération des saccades oculaires. Sa connectivité réciproque avec les Ganglions de la Base (BG) a récemment été mise en évidence, ainsi que son implication active dans les processus de sélection saccadique. Indépendamment du rôle des BG dans la sélection en général, les hypothèses traditionnelles suggèrent que la sélection au sein du SC résulte d'inhibitions latérales réciproques. Notre modèle propose de développer une autre hypothèse, dans laquelle les BG jouent un rôle important pour la sélection des cibles des saccades par un circuit purement sous-cortical SC-BG. En partant du constat que les profils d'activités des populations neuronales du SC peuvent être assimilés à ceux des neurones accumulateurs stochastiques des modèles phénoménologiques de sélection par course, ce nouveau modèle propose que la sélection observée dans le SC résulte non pas d'interactions latérales dans le SC, mais d'un processus de course vers un seuil de sélection dans les couches colliculaires intermédiaires, seuil dynamiquement déterminé par une désinhibition sélective opérée par les BG dans le cadre d'une boucle de rétrocontrôle double des BG vers le SC. Ce modèle reproduit divers profils d'activité neuronaux observés in-vivo, ainsi que les profils de sélection de plusieurs tâches expérimentales relatives à la discrimination entre de nombreux stimuli similaires. Son neuromimétisme lui permet de proposer diverses prédictions sur les substrats neurologiques de ses composants, et les substrats neurologiques de divers phénomènes particuliers de sélection comme les saccades moyennes ou le remote distractor effect. / The Superior Colliculus (SC) is well-known for its role in the generation of ocular saccades. Its reciprocal connectivity with the Basal Ganglia (BG) has recently been highligted, as well as its active involvement in the saccadic selection processes. Yet, the most common hypothesis explaining its role in saccade target selection neglect the potential implication of the BG and focus on unproven networks of lateral reciprocal inhibitions within the SC. We propose a model based on a the SC-BG loop hypothesis, in the framework of a purely subcortical saccade selection process Since the activity profiles of specific SC neurons populations can be seen as equivalent to the stochastic accumulators of the phenomelogical race models, we propose that the selection operated bythe SC is based not on lateral inhibitions within its maps, but on a race to a selection threshold in the intermediate layers of the SC, the threshold being dynamically set by the selective disinhibition of the SC maps by a double closed loops with the BG. Our model is able to reproduce various in-vivo neuronal activity profiles, as well as the selection distributions observed in various experimental setups involving the discrimination between numerous identical stimuli. Our model's neuromimetism level allows us to propose predictions about the neuronal substrates of the model's components, as well as the substrates for various selection phenomenons such as average saccades and the remote distractor effect.

Das Ziel dieser Arbeit war es, die Modulation der GABAergen synaptischen Transmission in den visuellen Schichten des Colliculus superior der Maus durch das Neurotrophin BDNF zu charakterisieren. Hierzu wurden bdnf+/+ und -/- Mäuse kurz vor und nach der Augenöffnung in einer die Morphologie erhaltenden Schnittpräparation elektrophysiologisch und molekularbiologisch untersucht. Das Fehlen von BDNF veränderte das Präparat hinsichtlich Neurondichte und -größe nicht. Ebenso blieben der Membranwiderstand und die Ganzzellkapazität unbeeinflusst von der chronischen Abwesenheit von BDNF. Im Gegensatz dazu zeigten sich deutliche funktionelle Defizite im Entladungsverhalten und in der GABAergen Hemmung. Durch Registrierung von Aktionspotentialen wurde demonstriert, dass BDNF für die Aufrechterhaltung der Netzwerkaktivität erforderlich ist. Durch Applikation eines GABAA-Rezeptor-Inhibitors konnte die Suppression der GABAergen Hemmung durch BDNF als zugrunde liegender Mechanismus aufgedeckt werden. Daraufhin durchgeführte Ganzzellableitungen bestätigten dies und legten einen postsynaptischen, TrkB-vermittelten Mechanismus der BDNF-Wirkung nahe. Es war möglich, den Einfluss der chronischen Abwesenheit von BDNF durch akute lokale Superfusion von BDNF vollständig aufzuheben. Die ausschließlich postsynaptische Blockade der PKC reichte aus, dies zu verhindern. Hierdurch wird unterstrichen, dass in diesem Präparat der Angriffspunkt von BDNF an der GABAergen Synapse auf der postsynaptischen Seite liegt. Um den genauen Wirkungsmechanismus von BDNF an der GABAergen Synapse zu beleuchten, wurde die mRNA-Expression der GABAA-Rezeptor-Untereinheiten alpha 1-3 untersucht. Diese ist in Anwesenheit von BDNF höher. Demzufolge sollte eine reduzierte Expression dieser Untereinheiten in bdnf-/- Tieren zu einer verringerten Rezeptoranzahl und somit zur Sättigung postsynaptischer Rezeptoren führen. Durch die Analyse von Amplitude und Kinetik GABAerger IPSC und die Applikation von Zolpidem wurde dies bestätigt. Demnach führt die Abwesenheit von BDNF zur Aufregulation der GABAergen Inhibition, obwohl die Rezeptorzahl in der Postsynapse wahrscheinlich niedriger ist. Als zentraler Mechanismus der akuten BDNF-Wirkung kommt deshalb am ehesten eine PKC-vermittelte Phosphorylierung und nachfolgende Veränderung des Desensitisierungsverhaltens in Betracht. Außerdem muss an eine Reduktion der Öffnungswahrscheinlichkeit oder der Leitfähigkeit des Rezeptors gedacht werden. Unmittelbar vor der Augenöffnung hatte die BDNF-Defizienz keinerlei Einfluss auf die GABAerge Hemmung. Es ist also davon auszugehen, dass BDNF im CS erst nach der Augenöffnung eine wesentliche Rolle in der Modulation der GABAergen Synapsen und damit in der Kontrolle der Netzwerkaktivität spielt. Dies steht in Einklang mit der Vorstellung, dass sowohl Translation und Freisetzung als auch Transport von BDNF durch neuronale Aktivität reguliert werden. Der Ablauf der neurotrophinergen Regulation im Colliculus superior stellt sich wie folgt dar: Durch Aktivation colliculärer Afferenzen wird BDNF vermehrt freigesetzt. BDNF reduziert nun zunächst über die Modulation von Rezeptoreigenschaften die GABAerge Hemmung und disinhibiert die Netzwerkaktivität. Längerfristig kommt es über eine vermehrte Expression von GABAA-Rezeptor-Untereinheiten zum Anstieg der Rezeptorzahl, damit zur Wiederherstellung der GABAergen Hemmung und letztlich zu einer Reduktion der Netzwerkaktivität. BDNF ist also in der kritischen Zeitperiode der Augenöffnung, wenn das Mustersehen einsetzt, ein wichtiger Faktor in der Regulation neuronaler Aktivität. / The aim of the study was to characterise the influence of the neurotrophin BDNF on the GABAergic synaptic transmission in the visual layers of the mouse superior colliculus. Acute slices prepared from bdnf+/+ and -/- mice shortly before and after eye opening were employed in the experiments. The absence of BDNF altered neither the density or size of neurons nor their membrane resistance or whole cell capacity. However, registration of action potentials revealed a decreased firing rate in the absence of BDNF. Stronger disinhibition induced by application of a GABAA receptor blocker suggested an enhanced GABAergic inhibition as an underlying mechanism. This assumption was confirmed by performing whole cell experiments. Further analysis indicated a postsynaptic enhancement of GABAergic synaptic transmission in the absence of BDNF. In bdnf+/+ slices, blockade of BDNF signalling through the TrkB receptor strengthened GABAergic synaptic transmission. Contrariwise, superfusion of exogenous BDNF in bdnf-/- suppressed GABAergic synaptic transmission. An exclusively postsynaptic block of the PKC abolished the effect of BDNF application. Therefore, a BDNF induced, TrkB mediated, PKC dependent suppression of the GABAergic synaptic transmission at the postsynaptic site can be assumed. To further elucidate the mechanism of BDNF action the expression of the GABAA receptor subunits alpha 1-3 mRNA was studied. In the presence of BDNF an elevated expression was observed. A lower expression of these subunits in bdnf-/- slices could result in a reduced number of GABAA receptors. During synaptic transmission they may become saturated. Two observations support this idea: In bdnf-/- slices application of Zolpidem does not induce an increase of GABAergic IPSC amplitude as present in bdnf+/+ slices. Amplitude and decay kinetics of GABAergic IPSCs correlate in bdnf-/- but not +/+ slices. Therefore, absence of BDNF may strengthen GABAergic synaptic transmission although mediated by a reduced number of postsynaptic receptors. A BDNF induced PKC dependent receptor phosphorylation followed by a change in receptor desensitisation is most likely the underlying mechanism. Nevertheless, a reduction of the receptor opening probability or a reduced receptor conductance have to be considered as well. Shortly before eye opening BDNF deficiency had no impact on GABAergic inhibition. In accordance with the general idea that expression and release of BDNF is activity dependent, this finding suggests that BDNF controls network activity by modulating GABAergic synaptic transmission only after eye opening. Taken together, the following sequence of BDNF action in the superior colliculus during eye opening can be proposed: Activation of collicular inputs triggers an increased BDNF release. BDNF suppresses GABAergic synaptic transmission leading to a disinhibition of network activity. Later, the increased expression of GABAA receptor subunits by prolonged BDNF release results in an increased GABAA receptor number, the recovery of the GABAergic inhibition and finally a gently tuned network activity. In summary, BDNF constitutes a major regulator of neuronal activity in the critical period of eye opening marking the transition to pattern vision.

Brain development and function depend on intrinsic and extrinsic factors. In particular, the proper functioning of sensory systems can be altered according to the quality of extrinsic sensory information received during life. In this context, questions concerning neuroplasticity take on special relevance when considering that sensory experience has a big impact on the degree of plasticity of the brain. In this thesis, we have sought to understand how visual deprivation affects the development and maintenance of visual centers in the brain and the role of visual deprivation on plasticity throughout life. We have addressed this question by studying the retinocollicular projection, which is the neuronal pathway that connects the retina with a visual input processing center, the superior colliculus (SC). Unexpectedly, we found that in Syrian hamsters (Mesocricetus auratus) the size of receptive fields (RFs) of neurons in the SC is plastic in adult animals if they have been deprived of a minimum of visual experience when juveniles. Specifically, dark-reared (DR) hamsters refine SC RFs as do their normally-reared counterparts, but they lose RF refinement if they remain in the dark after their RFs get refined. We found that a well defined period and duration of visual experience can stabilize RF size in adulthood. Furthermore, we sought to investigate the mechanisms by which RF size is increased in adult DR hamsters. By testing the strength of intracollicular inhibition using electrophysiological and molecular techniques, we have found that visually-deprived animals have weaker inhibitory circuitry in their SC than normal animals. The quantity of GABA receptors and GABA containing neurons is decreased in the SC of adult DR animals. We propose that these results explain at least in part the RF enlargement we find in visually-deprived animals. Knowledge from this study provides general insight into sensory system plasticity in adulthood and new information about visual system development that is relevant for treatments of diseases.

No description available.

The superior colliculus (SC) is a laminated oculomotor structure in the midbrain. In non-human primates SC has long been known to contain a retinotopically-organized map of visual stimulation in its superficial layers, which is aligned to a map of saccadic eye movements in the deeper layers. Microstimulation and electrophysiology experiments have shown that SC also plays a key role in covert visuospatial attention and suggest that attentional modulation also occurs in a retinotopic manner. Retinotopic organization of the visual field can be non-invasively mapped in humans using functional MRI with a technique called phase-encoded retinotopy. In this technique, rotating wedges and expanding rings of visual stimuli are used to map the polar angle and eccentricity dimensions of a polar coordinates system, respectively. A similar technique can also be used to map spatial attention by keeping the visual stimulus constant and cueing subjects to attend to apertures of rotating wedges and expanding rings within the stimulus. A previous study using fMRI has shown the polar angle representation of visual stimulation in human SC but was unable to find a representation of eccentricity. This work uses high-resolution fMRI along with special surface analysis techniques developed in our lab to demonstrate maps of both polar angle and eccentricity for visual stimulation. Moreover, visual attention is also shown to be topographically organized within SC and in registration with visual stimulation. Finally, in human visual cortex, fMRI is known to show activity for sustained spatial attention even in the absence of a significant visual stimulus, an attentional "base response". In this work, SC is shown to exhibit a similar sustained attention base response using a threshold-contrast detection paradigm. This base response was compared with a response for attention with visual stimulation. The peak amplitude of the base response occurred more deeply within SC tissue than the peak for attention with stimulation. It is proposed that this reflects the specific attentional enhancement of the deeper visuomotor neurons, which are hypothesized to be a direct neuronal correlate of the oculomotor theory of attention. / text