108 research outputs found

    Optimization of Functional MRI methods for olfactory interventional studies at 3T

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    Functional MRI technique is vital in investigating the effect of an intervention on cortical activation in normal and patient population. In many such investigations, block stimulation paradigms are still the preferred method of inducing brain activation during functional imaging sessions because of the high BOLD response, ease in implementation and subject compliance especially in patient population. However, effect of an intervention can be validly interpreted only after reproducibility of a detectable BOLD response evoked by the stimulation paradigm is first verified in the absence of the intervention. Detecting a large BOLD response that is also reproducible is a difficult task particularly in olfactory Functional MRI studies due to the factors such as (a) susceptibility-induced signal loss in olfactory related brain areas and (b) desensitization to odors due to prolonged odor stimulation, which is typical when block paradigms are used. Therefore, when block paradigms are used in olfactory interventional Functional MRI studies, the effect of the intervention may not be easily interpretable due to the factors mentioned above. The first task of this thesis was to select a block stimulation paradigm that would produce a large and reproducible BOLD response. It was hypothesized that a BOLD response of this nature could be produced if within-block and across-session desensitization could be minimized and further, that desensitization could be minimized by reducing the amount of odor by pulsing the odor stimulus within a block instead of providing a continuous odor throughout the block duration. Once the best paradigm was selected, the second task of the thesis was to select the best model for use in general linear model (GLM) analysis of the functional data, so that robust activation is detected in olfactory related brain areas. Finally, the third task was to apply the paradigm and model that were selected as the best among the ones tested in this thesis, to an olfactory interventional Functional MRI study investigating the effect of food (bananas) eaten to satiety on the brain activation to the odor related to that food. The methods used in this thesis to ensure valid interpretation of an interventional effect, can serve as a template for the experimental design of future interventional Functional MRI studies

    Mechanisms and Function of Neural Synchronization in an Insect Olfactory System

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    One of the fundamental questions in modem integrative neurobiology relates to the encoding of sensory information by populations of neurons, and to the significance of this activity for perception, learning, memory and behavior. Synchronization of activity across a population of neurons has been observed many times over, but has never been demonstrated to be a necessary component of this coding process. Neural synchronization has been found in many brain areas in animals across several phyla, from molluscs to mammals. Studies in mammals have correlated the degree of neural synchronization with specific behavioral or cognitive states, such as sensorimotor tasks, segmentation and binocular rivalry suggesting a functional link. In the locust olfactory system, oscillatory synchronization is a prominent feature of the odor-evoked neural activity. Stimulation of the antenna by odors evokes synchronized firing in dynamic and odor-specific ensembles of the projection neurons of the antennal lobe, the principal neurons of the first-order olfactory relay in insects. The coherent activity of these projection neurons underlies an odor-evoked oscillatory field potential which can be recorded in the mushroom body, the second-order olfactory relay to which they project. In this dissertation, we investigated two important questions raised by these findings: how are such stimulus-evoked synchronous ensembles generated, and what is their functional significance? To address these questions, we performed electrophysiological experiments and recorded odor responses from neurons of the antennal lobes and mushroom bodies of locusts, in vivo and using natural odor stimulation in an unanesthetized, semi-intact preparation. We demonstrated the critical mechanism involved in neural synchronization of the antennal lobe neurons. The synchronization of the projection neurons relies critically on fast GABA (γ-aminobutyric acid) -mediated inhibition from the local interneurons. Projection neuron synchronization could be selectively blocked by local injection of the GABA receptor antagonist, picrotoxin. Picrotoxin spared the odor-specific, slow modulation of individual projection neuron responses, but desynchronized the firing of the odor-activated projection neuron assemblies. The oscillatory activity of the local intemeurons was also blocked by picrotoxin, which indicates that such activity depends on network synaptic dynamics. We also showed that the mushroom body networks are capable of generating oscillatory behavior of a similar frequency as that of its projection neuron inputs, and that they may thus be "tuned" to accept synchronized, oscillatory inputs of that frequency range. Our understanding of this mechanism, in tum, made possible the functional investigation of neural synchronization by selective disruption of projection neuron synchronization. We studied a population of neurons downstream from the antennal lobe projection neurons, the extrinsic neurons of the β-lobe of the mushroom body (βLNs). These βLNs were chosen for investigation because they were found to be odor-responsive and because their position in the olfactory pathway makes them a suitable "read-out" of population activity in the antennal lobe. We characterized βLN odor responses before and after selective disruption of the synchronization of the projection neuron ensembles with local picrotoxin injection into the antennal lobe. We showed that the tuning of these βLN responses was altered by PN desynchronization by changing existing responses and inducing new responses. This alteration in tuning resulted in a significant loss of odor specificity in individual βLN responses, an effect that never occurred in the responses of individual, desynchronized projection neurons. We thus propose that neural synchronization is indeed important for information processing in the brain: it serves, at least in part, as a temporal substrate for the transmission of information that is contained across co-activated neurons (relational code) early in the pathway.</p

    Perception and representation of temporally patterned odour stimuli in the mammalian olfactory bulb

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    Sensory stimuli in natural environments are dynamic and complex. The neural circuits of sensory systems in the brain are therefore adapted to extract meaningful information from this dynamic input. An attractive model system for understanding how such sensory input is processed in neural circuits is the mammalian olfactory bulb (OB). The OB has a convenient dorsal anatomical location for e.g. probe implantation, viral delivery and a well-defined circuit architecture. Furthermore, olfaction in rodent models is extremely behaviourally salient and OB circuit function can therefore be efficiently investigated in the context of behavioural response. Historically, investigation of OB function has focused on encoding of odour quality, utilising static, square pulse stimuli to explore this problem. This is in stark contrast to odour transmission in natural environments, which is governed by the chaotic structure of air turbulence, creating odour plumes. There are a number of lines of evidence suggesting that temporal information in odour plumes – the fluctuations in odour concentration within this structure – can be behaviourally relevant for olfactory based navigation and odour scene segmentation. I here posit that temporal correlations in concentration for mixtures of odours transmitted in plumes are a potential mechanism by which animals identify odour objects: mixtures of odours emanating from a common source. Using neuronal imaging, high-throughput behavioural methods, high-speed odour delivery and physical recording of odour plume dynamics, I show that temporal correlations exist between pairs of odours emanating from the same source; that mice can perceive this correlation structure and that temporal correlation is represented in the output cells of the olfactory bulb. These results indicate that mammalian olfaction operates at a higher temporal bandwidth than previously thought, and that detection of temporal features in odour signals may represent a potential mechanism for olfactory scene segmenetation

    Biomimetic set up for chemosensor-based machine olfaction

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    The thesis falls into the field of machine olfaction and accompanying experimental set up for chemical gas sensing. Perhaps more than any other sensory modality, chemical sensing faces with major technical and conceptual challenges: low specificity, slow response time, long term instability, power consumption, portability, coding capacity and robustness. There is an important trend of the last decade pushing artificial olfaction to mimic the biological olfaction system of insects and mammalians. The designers of machine olfaction devices take inspiration from the biological olfactory system, because animals effortlessly accomplish some of the unsolved problems in machine olfaction. In a remarkable example of an olfactory guided behavior, male moths navigate over large distances in order to locate calling females by detecting pheromone signals both rapidly and robustly. The biomimetic chemical sensing aims to identify the key blocks in the olfactory pathways at all levels from the olfactory receptors to the central nervous system, and simulate to some extent the operation of these blocks, that would allow to approach the sensing performance known in biological olfactory system of animals. New technical requirements arise to the hardware and software equipment used in such machine olfaction experiments. This work explores the bioinspired approach to machine olfaction in depth on the technological side. At the hardware level, the embedded computer is assembled, being the core part of the experimental set up. The embedded computer is interfaced with two main biomimetic modules designed by the collaborators: a large-scale sensor array for emulation of the population of the olfactory receptors, and a mobile robotic platform for autonomous experiments for guiding olfactory behaviour. At the software level, the software development kit is designed to host the neuromorphic models of the collaborators for processing the sensory inputs as in the olfactory pathway. Virtualization of the set up was one of the key engineering solutions in the development. Being a device, the set up is transformed to a virtual system for running data simulations, where the software environment is essentially the same, and the real sensors are replaced by the virtual sensors coming from especially designed data simulation tool. The proposed abstraction of the set up results in an ecosystem containing both the models of the olfactory system and the virtual array. This ecosystem can loaded from the developed system image on any personal computer. In addition to the engineering products released in the course of thesis, the scientific results have been published in three journal articles, two book chapters and conference proceedings. The main results on validation of the set up under the scenario of robotic odour localization are reported in the book chapters. The series of three journal articles covers the work on the data simulation tool for machine olfaction: the novel model of drift, the models to simulate the sensor array data based on the reference data set, and the parametrized simulated data and benchmarks proposed for the first time in machine olfaction. This thesis ends up with a solid foundation for the research in biomimetic simulations and algorithms on machine olfaction. The results achieved in the thesis are expected to give rise to new bioinspired applications in machine olfaction, which could have a significant impact in the biomedical engineering research area.Esta tesis se enmarca en el campo de bioingeneria, mas particularmente en la configuración de un sistema experimental de sensores de gases químicos. Quizás más que en cualquier otra modalidad de sensores, los sensores químicos representan un conjunto de retos técnicos y conceptuales ya que deben lidiar con problemas como su baja especificidad, su respuesta temporal lenta, su inestabilidad a largo plazo, su alto consumo enérgético, su portabilidad, así como la necesidad de un sistema de datos y código robusto. En la última década, se ha observado una clara tendencia por parte de los sistemas de machine olfaction hacia la imitación del sistema de olfato biológico de insectos y mamíferos. Los diseñadores de estos sistemas se inspiran del sistema olfativo biológico, ya que los animales cumplen, sin apenas esfuerzo, algunos de los escenarios no resueltos en machine olfaction. Por ejemplo, las polillas machos recorren largas distancias para localizar las polillas hembra, detectando sus feromonas de forma rápida y robusta. La detección biomimética de gases químicos tiene como objetivo identificar los elementos fundamentales de la vía olfativa a todos los niveles, desde los receptores olfativos hasta el sistema nervioso central, y simular, en cierta medida, el funcionamiento de estos bloques, lo que permitiría acercar el rendimiento de la detección al rendimiento de los sistemas olfativos conociodos de los animales. Esto conlleva nuevos requisitos técnicos a nivel de equipamiento tanto hardware como software utilizado en este tipo de experimentos de machine olfaction. Este trabajo propone un enfoque bioinspirado para la ¿machine olfaction¿, explorando a fondo la parte tecnológica. A nivel hardware, un ordenador embedido se ha ensamblado, siendo ésta la parte más importante de la configuración experimental. Este ordenador integrado está interconectado con dos módulos principales biomiméticos diseñados por los colaboradores: una matriz de sensores a gran escala y una plataforma móvil robotizada para experimentos autónomos. A nivel software, el kit de desarrollo software se ha diseñado para recoger los modelos neuromórficos de los colaboradores para el procesamiento de las entradas sensoriales como en la vía olfativa biológica. La virtualización del sistema fue una de las soluciones ingenieriles clave de su desarrollo. Al ser un dispositivo, el sistema se ha transformado en un sistema virtual para la realización de simulaciones de datos, donde el entorno de software es esencialmente el mismo, y donde los sensores reales se sustituyen por sensores virtuales procedentes de una herramienta de simulación de datos especialmente diseñada. La propuesta de abstracción del sistema resulta en un ecosistema que contiene tanto los modelos del sistema olfativo como la matriz virtual . Este ecosistema se puede cargar en cualquier ordenador personal como una imagen del sistema desarrollado. Además de los productos de ingeniería entregados en esta tesis, los resultados científicos se han publicado en tres artículos en revistas, dos capítulos de libros y los proceedings de dos conferencias internacionales. Los principales resultados en la validación del sistema en el escenario de la localización robótica de olores se presentan en los capítulos del libro. Los tres artículos de revistas abarcan el trabajo en la herramienta de simulación de datos para machine olfaction: el novedoso modelo de drift, los modelos para simular la matriz de sensores basado en el conjunto de datos de referencia, y la parametrización de los datos simulados y los benchmarks propuestos por primera vez en machine olfaction. Esta tesis ofrece una base sólida para la investigación en simulaciones biomiméticas y en algoritmos en machine olfaction. Los resultados obtenidos en la tesis pretenden dar lugar a nuevas aplicaciones bioinspiradas en machine olfaction, lo que podría tener un significativo impacto en el área de investigación en ingeniería biomédic

    The contribution of glomerular activity maps to olfactory perceptual judgements in mice

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    Odours are first represented in the brain as spatiotemporal maps of activity in the olfactory bulb (OB). Imaging and electrophysiological studies have shown that these maps are both temporally and spatially complex and unique to each odour. Behavioural tasks that probe perceptual differences between odours suggest that odours that evoke similar spatial activity maps in the OB are perceived as similar. However, combination of lesion and behavioural experiments of either the olfactory epithelium or bulb has suggested that rodents can detect and discriminate between odours using minimal stimulus-related input. This has led to a consensus in the field that sensory inputs to the olfactory system contain significant redundant signal and that spatial activity maps are unnecessary for odour coding. The work presented here used a go/no-go behavioural paradigm to investigate the ability of mice not just to detect or discriminate odours after nasal epithelial lesion but also to recognise odours – which enables odour quality perception to be probed. Intrinsic optical imaging was used in the same animals, to observe changes in odour-evoked signals in the OB before and after lesion. The results revealed that even moderatechanges to intrinsic activity maps caused deficits in both odour discrimination and recognition, suggesting that perception of odour quality was significantly altered. Reduction in odour inputs could be equivalent to reducing the intensity of inputs, so alterations to odour quality perception after changes in odour concentration were also examined. Recognition scores were reduced when mice were presented with a familiar odour at an unfamiliar concentration, suggesting odour perception was also significantly altered by reduction of stimulus intensity. In order to determine whether reductions in recognition score caused by lesioning and change in odour concentration had different perceptual origins, mice were trained to generalise across odour concentrations and tested for recognition after lesion. This revealed that impaired recognition after lesion resulted, not from experiencing an altered odour concentration, but from perception of apparent novel odour qualities. Consistent with this, intrinsic imaging data revealed that relative intensity of glomerular activity following lesions was altered compared with maps recorded in shams or by varying odour concentration. Long-standing theories of sensory coding suggest that sensory systems actively match odours in the environment with stored stimulus templates. Odours familiar before lesioning were re-learnt more rapidly after lesioning than novel odours were learnt either before or after lesioning. This suggests that stored templates of familiar odours were compared to moderately altered incoming inputs and, with reinforcement, were rapidly incorporated into those templates. In all, this work suggests that odour quality perception requires comprehensive matching of input patterns to stored representations, suggesting that spatial activity maps are a crucial component of odour coding

    NMDAR plasticity and metaplasticity in early odor preference learning in rats

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    Early odor preference learning is a classical conditioning behavioral model which can be used to understand the molecular mechanism of learning and memory, and synaptic plasticity. In this thesis the research is focused on the role of N-methyl D-aspartate receptor (NMADR) plasticity and metaplasticity in early odor preference learning. In Chapter 2, we investigated the differential roles of L-type calcium channel (LTCC) and NMDAR in early odor preference learning. The results suggest that the NMDAR is crucial for creating stimulus-specific memory and LTCC is required for maintenance of the memory. Activation of LTCC without NMDAR can cause loss of input specificity and as a result, generalization of the memory. Chapter 3 depicts that, the effect of altered number of NMDARs in the anterior piriform cortex (aPC) can significantly modifies future learning and synaptic plasticity. Here we show that NMDARs are down regulated at 3hr following the early odor preference learning. Repeated training at 3hr leads to unlearning and this unlearning is mediated by NMDAR itself. Inhibition of the NMDAR prior to retraining at 3hr, blocks unlearning. In continuation of Chapter 3, we have characterized the molecular mechanism underlying the NMDAR mediated unlearning in Chapter 4. Calcineurine and metabotropic glutamate receptor (mGluR) plays a vital role in NMDAR downregulation at 3hr following early odor preference training. In Chapter 5, we have investigated whether NMDAR plasticity and its mediated metaplasiticity observed in the early odor preference learning can be induced by stronger trainings that produce prolonged memories. Previous research has shown that infusing trichostatin A (TSA), a histone deacetylation inhibitor, in the olfactory bulb (OB) extends odor preference memory up to 5 days. Our data suggests that OB TSA infusion prevents NMDAR down-regulation and unlearning. These outcomes argue that it is critical to understand the metaplastic effects of training which have implications for learning optimization

    INTEGRATION OF CMOS TECHNOLOGY INTO LAB-ON-CHIP SYSTEMS APPLIED TO THE DEVELOPMENT OF A BIOELECTRONIC NOSE

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    This work addresses the development of a lab-on-a-chip (LOC) system for olfactory sensing. The method of sensing employed is cell-based, utilizing living cells to sense stimuli that are otherwise not easily sensed using conventional transduction techniques. Cells have evolved over millions of years to be exquisitely sensitive to their environment, with certain types of cells producing electrical signals in response to stimuli. The core device that is introduced here is comprised of living olfactory sensory neurons (OSNs) on top of a complementary metal-oxide-semiconductor (CMOS) integrated circuit (IC). This hybrid bioelectronic approach to sensing leverages the sensitivity of OSNs with the electronic signal processing capability of modern ICs. Intimately combining electronics with biology presents a number of unique challenges to integration that arise from the disparate requirements of the two separate domains. Fundamentally the obstacles arise from the facts that electronic devices are designed to work in dry environments while biology requires not only a wet environment, but also one that is precisely controlled and non-toxic. Design and modeling of such heterogeneously integrated systems is complicated by the lack of tools that can address the multiple domains and techniques required for integration, namely IC design, fluidics, packaging, and microfabrication, and cell culture. There also arises the issue of how to handle the vast amount of data that can be generated by such systems, and specifically how to efficiently identify signals of interest and communicate them off-chip. The primary contributions of this work are the development of a new packaging scheme for integration of CMOS ICs into fluidic LOC systems, a methodology for cross-coupled multi-domain iterative modeling of heterogeneously integrated systems, demonstration of a proof-of-concept bioelectronic olfactory sensor, and a novel event-based technique to minimize the bandwidth required to communicate the information contained in bio-potential signals produced by dense arrays of electrically active cells

    "Neural Networks linking crypt neurons to innate attractive behaviour in zebrafish"

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    Kryptneuronen sind eine der Typen von Sinnesneuronen im Riechepithel des Zebrafisches. Es wurde festgestellt, dass ein einzelnes Mitglied der ORA-Genfamilie, ORA 4, in allen Kryptneuronen exprimiert wird. Alle Kryptneuronen projizieren auf einen einzigen Glomerulus des medio-dorsalen Clusters im Riechkolben, dem Bulbus olfactorius. Die Funktion der Kryptneuronen muss jedoch noch aufgeklärt werden. Einige Studien haben die Rolle von Kryptneuronen bei der Verwandtschafts-erkennung von Zebrafischlarven impliziert, jedoch wurden die entsprechenden Liganden in diesen Studien nicht identifiziert. Um die Funktion von Kryptneuronen zu verstehen, haben wir in unserem Labor einen ORA4-knockout erzeugt. Zuerst prüfte ich, ob Kryptneuronen ohne einen ORA4-Rezeptor lebensfähig sind. Ich fand heraus, dass Kryptneuronen den ORA4-Rezeptor nicht zum Überleben benötigen und dass sie ihren Ziel-Glomerulus auch in Abwesen-heit eines funktionierenden ORA4 beibehalten. Interessanterweise ist die Anzahl der Kryptneuronen im knockout signifikant erhöht, was einen Kompensations-mechanismus implizieren könnte. Ich habe dann neurale Aktivitäts¬marker, wie p-Erk bei Wildtyp- und knockout-Fischen zusammen mit der Kalzium-Live-Bildgebung bei Wildtyp-Fischen verwendet, um zu untersuchen, ob die im heterologen Expressions-system beobachtete Aktivierung des ORA4-Rezeptors auch in vivo vorhanden ist. p-Erk-Ergebnisse waren variabel, aber die Kalzium-Live-Bildgebung zeigte reprodu-zierbar aktivierte Neuronen sowohl im Riechkolben. In einem ersten Schritt zur Analy-se der Funktion des ORA4-Rezeptor-Signalweges stellte ich fest, dass Zebrafischlar-ven unabhängig von ihrem Stoffwechselzustand den aktivierenden Reiz bevorzugen. Die in der Calcium-Bildgebung beobachtete räumliche Verteilung der aktivierten Neu-ronen unterstützt jedoch nicht die Vermittlung dieser angeborenen Anziehung durch Kryptneuronen. Aus Zeitgründen konnte das Verhalten bei den knockout-Fischen nicht untersucht werde
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