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<p>Based on the concept that the tactile hypersensitivity and the central sensitization observed in animal models of peripheral neuropathy are maintained by peripheral drive from primary sensory neurons, the present project measured the changes in electrophysiological, immunohistochemical, and pharmacological properties of the dorsal root ganglia (DRG) neurons induced by a peripheral neuropathy. The aim of this study was to make a systematic survey and a unique understanding of changes that occur in primary sensory neurons that can sustain peripheral drive in this model. The data of this study indicate a prominent role of large diameter Aβ-fibers, including low threshold mechanoreceptors in peripheral neuropathy.</p> / Doctor of Philosophy (Medical Science)

<p>The small intestine holds an intrinsic ability to digest and absorb nutrients from the food we intake without intervention from the central nervous system. This ability is made possible by the population of cells that inhabit the gut, particularly interstitial cells of Cajal of the myenteric plexus and sensory primary intrinsic neurons (AH cells), which ultimately influence muscle function and motility. The AH cells are the first neurons in the hierarchy of sensory neurons in the gut and are therefore a perfect candidate to test the effects of <em>Bifidobacterium longum</em> NCC3001 supernatant since in a physiological setting the metabolites secreted by this bacterium can interact with the AH cells directly or indirectly through absorption by the mucosa.</p> <p>The probiotic <em>Bifidobacterium</em> <em>longum</em> NCC3001 has been shown to normalize anxiety-like behaviour and hippocampal brain derived neurotropic factor (BDNF) levels in mice infected with <em>Trichuris</em> <em>muris </em>in a model of infectious colitis. Utilizing a chronic model of colitis, a study was conducted to decipher whether or not the anxiolytic effects of <em>Bifidobacterium longum</em> NCC3001 involved the vagus. My specific objective in this study was to find evidence for interaction between <em>B.longum</em> NCC3001 and myenteric neurons as a potential route for <em>B.longum</em> NCC3001 to influence CNS function. We assessed a cell’s electro-responsiveness through spike discharge, which is the number of action potentials elicited in response to a supra-threshold depolarizing current injection.</p> <p>The electro-responsiveness of neurons perfused with <em>B. longum</em> NCC3001 supernatant (conditioned medium; n = 4) was significantly reduced compared to the control group (those perfused with Krebs solution; n = 5; <em>P</em> = 0.016). The electro-responsiveness of neurons perfused with the conditioned medium was also significantly lower than that of neurons perfused with unconditioned group (MRS growth medium alone) group (n = 4; <em>P</em> = 0.029). In comparing the excitabilities of the neurons in the control group with that of the control media group, there was no statistical difference (<em>P</em> = 0.29).</p> <p>In subsequent studies, the objective was to identify the AH cells and to determine the effect of <em>B. longum</em> NCC3001 conditioned medium on this population of cells. The electro-responsiveness as measured through spike discharge of AH cells perfused with the conditioned medium (n = 5) was significantly reduced compared to neurons perfused with the unconditioned medium (n = 5; <em>P</em> = 0.02). Sensory neurons perfused with the conditioned medium (n = 9) exhibited a significant reduction in their instantaneous input resistances compared to neurons perfused with the unconditioned medium (n = 8; <em>P </em>= 0.01). There was also a significant reduction in the time-dependent input resistance of neurons perfused with the conditioned medium (n = 9) compared to neurons perfused with the unconditioned medium (n = 8; <em>P </em>= 0.02). In addition, perfusion of the conditioned medium over sensory neurons (n = 9) significantly reduced the magnitude of the hyperpolarization-activated cationic current (<em>I</em>_h) compared to neurons perfused with the unconditioned medium (n = 8; <em>P</em> = 0.0003). Furthermore, there was also a significant reduction in the action potential half width duration of myenteric sensory neurons perfused with conditioned medium (n = 5) compared to that exhibited by neurons perfused with the unconditioned medium (n = 5; <em>P</em> = 0.008).</p> <p>In later experiments, we wanted to gain a more comprehensive understanding of the effect of this bacterium on the gut so we evaluated its effects on the gut musculature. Upon full immersion, the supernatant of <em>Bifidobacterium longum</em> NCC3001 (conditioned medium) caused an initial depolarization of the circular smooth muscle cell. This depolarization continued until the slow wave oscillations in these cells ceased and membrane potential would plateau. Several minutes after this plateau, the slow wave oscillations reappeared and the cell was significantly hyperpolarized relative to the conditions before conditioned medium was added. The resting membrane potential of circular smooth muscle cells in Krebs solution was -54.3 mV and -70.3 mV approximately two minutes after full immersion by the supernatant when the cell was hyperpolarized and a stable recorded was achieved (n = 7; <em>P</em> = 0.02). The average time of onset of depolarization was 18.6 s and the average change in membrane potential (depolarization) from onset of effect to its plateau was 14.0 mV (n = 7). Occasionally, the addition of the conditioned medium only caused an immediate but slight depolarization (n = 3) and in other cases caused only a hyperpolarization of the cell (n = 3) with no significant changes in any slow wave characteristics in either case. Furthermore, any cells that exhibited the waxing and waning of the slow wave lost this pattern upon the addition of the conditioned medium (n = 10).</p> <p>In attempts to understand the role of neurotransmission in this system, we conducted several experiments whereby carbachol (acetylcholine agonist) and L-NNA (nitric oxide synthase inhibitor) were administered to the muscle. Prior to the addition of 1μM carbachol or 2e^-4M L-NNA, we would only observe the pacemaker slow wave associated with the interstitial cells of Cajal of the myenteric plexus during the perfusion of Krebs solution. Upon the addition of carbachol (n = 3) or L-NNA (n = 4), we would observe a second slower frequency pattern appear, referred to as a waxing and waning pattern.</p> / Master of Science (MSc)

Artificial intelligence is a new paradigm of information processing where machines emulate human intelligence and perform tasks that cannot be done with standard computers. Neuromorphic computing is in particular inspired by how the brain computes. Large network of interconnected neurons whose synapses are varied during a learning phase, and where the information flows in parallel throughout different connections. Photonics platforms represent an interesting possibility where to implement neuromorphic processing schemes, exploiting light and its advantages in terms of speed, low energy consumption and inherent parallelism via wavelength division multiplexing. In particular, a candidate playing a diversity of key roles in integrated networks is the microring resonator. In silicon photonics, the microring resonator can implement the strength of a synapse, the spiking emission of a biological neuron, and it can exhibit a fading memory based on its multiple linear and nonlinear dynamical timescales. This manuscript presents an overview of the main applications of silicon microring resonators in neuromorphic silicon photonics, and then focuses on its implementation in a processing scheme, named time delay reservoir computing (RC). Time delay RC is a hardwarefriendly approach by which implement a large neural network, where this is folded in the nonlinear dynamical response of only one physical node, such as a dynamical system with delay feedback. The manuscript illustrates, both numerically and experimentally, how to make time delay RC exploiting the linear and nonlinear dynamical response of a silicon microring resonator. The microring is coupled to an external optical feedback and the results on a diversity of time series prediction tasks and delayed-boolean tasks are presented. Numerically, it is shown that the microring nonlinearities can be exploited to improve the performance on prediction tasks, such as the Santa Fe and Mackey Glass ones. Experimentally, it is shown how the network can be set to solve delayed boolean tasks with error-free operation, at 12 MHz operational speed, together with possible upgrades and alternative implementations that can boost its performances. / La inteligencia artificial es un nuevo paradigma de procesamiento de información en el que las máquinas emulan la inteligencia humana y realizan tareas que no pueden ser realizadas con ordenadores estándar. La computación neuromórfica está particularmente inspirada en cómo el cerebro realiza cálculos. Consiste en una gran red de neuronas interconectadas cuyas sinapsis varían durante una fase de aprendizaje, y donde la información fluye en paralelo a través de diferentes conexiones. Las plataformas fotónicas representan una interesante posibilidad para implementar esquemas de procesamiento neuromórfico, aprovechando las ventajas de la luz en términos de velocidad, bajo consumo de energía e inherente paralelismo a través de la multiplexación por división de longitud de onda. En particular, un candidato que desempeña una diversidad de roles clave en redes integradas es el micro-anillo resonador. En la fotónica de silicio, el micro-anillo resonador puede implementar la intensidad sináptica, la emisión de pulsos de una neurona biológica, y puede exhibir una memoria que decae con el tiempo basada en sus múltiples escalas temporales dinámicas lineales y no lineales. Esta tesis presenta una visión general de las principales aplicaciones de los resonadores de anillo microscópicos de silicio en la fotónica neuromórfica de silicio y se centra en su implementación en un esquema de procesamiento llamado time delay reservoir computing (RC). Time delay RC es un enfoque favorable para el hardware mediante el cual se implementa una gran red neural, a través de la respuesta dinámica no lineal de solo un nodo físico, como un sistema dinámico sujeto a retroalimentación. Este trabajo ilustra, tanto numérica como experimentalmente, cómo realizar la computación en time delay RC utilizando la respuesta dinámica lineal y no lineal de un resonador de anillo microscópico de silicio. El microanillo resonador está acoplado a una retroalimentación óptica externa y se presentan los resultados de una diversidad de tareas de predicción de series temporales y tareas booleanas retrasadas. Numéricamente, se muestra que las no-linealidades del micro-anillo resonador se pueden aprovechar para mejorar el rendimiento en tareas de predicción, como las de Santa Fe y Mackey Glass. Experimentalmente, se muestra cómo la red se puede configurar para resolver tareas booleanas retrasadas sin errores, a una velocidad operativa de 12 MHz, junto con posibles mejoras e implementaciones alternativas que pueden aumentar su rendimiento.