This research provides a proof of concept and background theory for the physics behind the state-of-the-art ultra-fast plasmonic spiking neurons (PSN), which can serve as a primary synaptic device for developing a platform for fast neural computing. Such a plasmonic-powered computing system allows localized AI with ultra-fast operation speed. The designed architecture for a plasmonic spiking neuron (PSN) presented in this thesis is a photonic integrated nanodevice consisting of two electro-optic and optoelectronic active components and works based on their coupling. The electro-optic active structure incorporated a periodic array of seeded quantum nanorods sandwiched between two electrodes and positioned at a near-field distance from the topmost metal layer of a sub-wavelength metal-oxide multilayer metamaterial. Three of the metal layers of the metamaterials form the active optoelectronic component. The device operates based on the coupling of the two active components through optical complex modes supported by the multilayer and switching between two of them. Both action and resting potentials occur through subsequent quantum and extraordinary photonics phenomena. These phenomena include the generation of plasmonic high-k complex modes, switching between the modes by enhanced quantum-confined stark effect, decay of the plasmonic excitations in each metal layer into hot-electrons, and collecting hot-electrons by the optoelectronic component. The underlying principles and functionality of the plasmonic spiking neuron are illustrated using computer simulation.

The central nervous system (CNS) is protected by a vascular blood-brain barrier that prevents many types of pathogens from entering the brain. Still, some pathogens have evolved mechanisms to traverse this barrier and establish a long-term infection. The apicomplexan parasite, Toxoplasma gondii, is one such pathogen with the ability to infect the CNS in virtually all warm-blooded animals, including humans. Across the globe, an estimated 30% of the human population is infected with Toxoplasma, an infection for which mounting evidence suggests increases the risk for developing neurological and neuropsychiatric disorders, like seizures and schizophrenia. In my dissertation, I investigate the telencephalic neural circuit changes induced by long-term Toxoplasma infection in the mouse brain and the neuroimmune signaling role of the complement system in mediating microglial remodeling of neural circuits following parasitic infection. While there has been keen interest in investigating neural circuit changes in the amygdala – a region of the brain involved in fear response and which Toxoplasma infection alters in many species of infected hosts – the hippocampus and cortex have been less explored. These are brain regions for which Toxoplasma also has tropism, and moreover, are rich with fast-spiking parvalbumin perisomatic synapses, a type of GABAergic synapse whose dysfunction has been implicated in epilepsy and schizophrenia. By employing a range of visualization techniques to assess cell-to-cell connectivity and neuron-glia interactions (including immunohistochemistry, ultrastructural microscopy, and microglia-specific reporter mouse lines), I discovered that longterm Toxoplasma infection causes microglia to target and ensheath neuronal somata in these regions and subsequently phagocytose their perisomatic inhibitory synapses. These findings provide a novel model by which Toxoplasma infection within the brain can lead to seizure susceptibility and a wider range of behavioral and cognitive changes unrelated to fear response. In the Toxoplasma infected brain, microglia, along with monocytes recruited to the brain from the periphery, coordinate a neuroinflammatory response against pathogenic invasion. This is characterized by a widespread activation of these cells and their increased interaction with neurons and their synaptic inputs. Yet, whether T. gondii infection triggers microglia and monocytes (i.e. phagocytes) to target, ensheath, and remove perisomatic inhibitory synapses on neuronal somata indiscriminately, or whether specificity exists in this type of circuit remodeling, remained unclear. Through a comprehensive assessment of phagocyte interactions with cortical neuron subtypes, I demonstrate that phagocytes selectively target and ensheath excitatory pyramidal cells in long-term infection. Moreover, coupling of in situ hybridization with transgenic reporter lines and immunolabeling revealed that in addition to phagocytes, excitatory neurons also express complement component C3 following infection (while inhibitory interneurons do not). Lastly, by employing targeted deletion of complement components, C1q and C3, I show that complement is required for phagocyte ensheathment of excitatory cells and the subsequent removal of perisomatic inhibitory synapses on these cells (albeit not through the classical pathway). Together, these studies highlight a novel role for complement in mediating synapse-type and cell-type specific circuit remodeling in the Toxoplasma infected brain. / Doctor of Philosophy / Parasites are microorganisms that rely on other living organisms (called hosts) for their survival. Although some parasites only live on their hosts, others have developed ways to establish infections and obtain the nutrients that keep them alive from host cells. My Ph.D. research has focused on studying one of these parasites, Toxoplasma gondii (commonly referred to as Toxo), that has evolved the unique ability to establish brain infections in almost all animals around the world, from rodents to humans. Recent discoveries show that brain infection with this parasite can cause seizures, an imbalance in the way that specialized cells of the brain (called neurons) communicate with each other, causing harmful hyperactivity within the brain. Toxo infection can also cause behavioral and cognitive changes in infected animals, making them more susceptible to predation. In humans, infection with Toxo increases their risk for developing different types of mental illness, such as schizophrenia. The focus of my Ph.D. research has been in trying to understand, at the cellular and molecular level, how infection with this parasite can lead to seizures and behavioral changes, by using mice as a model. Mice have a similar brain structure to humans, and over the years, scientists have developed many tools that allow us to visualize and study the connections between neurons (called synapses). I'm interested in understanding how changes in these connections affect how neurons communicate with each other, and ultimately, how we behave and think. I have been studying a type of connection that, if lost or damaged, can lead to seizures and some types of mental illness. These connections are called 'perisomatic inhibitory synapses', and they form on many distinct types of neurons, but specifically on the cell bodies of these neurons. They act as a traffic light, informing neurons when and for how long to 'slow down' their activity. I discovered that after the parasite enters the brain, it causes another type of cell in the brain, called microglia, to extensively interact with neurons in the cortex and hippocampus (areas of your brain important for thinking, executing behavior, and learning). Microglia are immune cells of the brain that inspect the brain for anything damaged or that doesn't belong (like parasites) and removes them from the brain. By performing experiments where I delete individual immune molecules from mice, I found that one immune molecule, called 'complement component C3' acts as cue for microglia to find these cells, wrap around them, and permanently remove these important connections. Surprisingly, however, microglia don't remove these connections from all neurons, indiscriminately, they do so only on one specific cell type called 'excitatory pyramidal neurons,' and as the name implies, they're the ones who drive activity in the brain. My half-a-decade's worth of research helps us understand parasitic infections in the brain in a couple of ways: First, I have discovered one of the mechanisms by which neuronal connections are lost in the Toxo-infected brain (which is a mechanism that leads to loss of neuronal connections in the injured and aging brain as well). This is significant because it might provide insight into why some people who are infected with Toxo develop seizures or mental illness, while others don't. More importantly, Toxo-infection causes changes in the brain that are very specific, in terms of both the type of neuronal connection that is affected and the type of cell that is affected. Why these changes are so specific remain to be uncovered, but it suggests that Toxo can either a) trigger a unique immune response in the brain that leads to very precise changes in neuron-toneuron connections and signaling or b) the parasite, while hiding inside of neurons, may hijack the machinery of certain cell types in a way that helps them survive longer.

A teoria neuronal prerroga a existência da unidade básica do sistema nervoso, o neurônio. A teoria neuronal foi proposta e formulada nas últimas décadas do século XIX. Ela é comumente associada ao nome de Santiago Ramón y Cajal (1852-1934), que a formulou em oposição à proposta de que o tecido nervoso é constituído por redes contínuas formadas por células nervosas. Os trabalhos de Ramón y Cajal são, portanto, considerados ponto de inflexão nas pesquisas em Neurociência. Este trabalho objetiva investigar a constituição da teoria neuronal de acordo com a formação do conceito de neurônio. A formação do conceito de neurônio está diretamente ligada ao conceito de plasticidade. Como parte da pesquisa, serão investigados os principais trabalhos de um dos mais fervorosos defensores do reticularismo, o italiano Camillo Golgi (1843-1926). Em linhas gerais, o trabalho pretende um exame da constituição da teoria neuronal a partir da formação do conceito de neurônio e do papel que o conceito de plasticidade teve na formulação do conceito de neurônio / The neuron theory prerogatives the existence of the basic unit of the nervous system, the neuron. The neuron theory was proposed and formulated in the last decades of the nineteenth century. It is commonly associated with the name of Santiago Ramón y Cajal (1852-1934), who formulated it in contradiction to the proposal that nervous tissue consists of seamless networks formed by nerve cells. Ramón y Cajals works are, therefore, considered the turning point in neuroscience research. This work aims to investigate the formation of neuronal theory according to the neurons concept. The formation of the neuron concept is directly linked to the plasticity concept. As part of the research, it will be studied the major works of one of the most fervent advocates of reticular theory, the Italian scientist, Camillo Golgi (1843-1926). In general, this study aims to examine the formation of neuronal theory from the formation of the neuron concept and the role that the plasticity concept had in formulating the neuron concept

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by reduced levels of the survival motor neuron (SMN) protein. SMA results in degeneration of motor neurons, progressive muscle atrophy, and death in severe forms of the disease. Currently, there is a lack of inexpensive, readily accessible, accurate biomarkers to study the disease. Furthermore, the current FDA approved therapeutic is neither 100 % effective nor accessible for all patients, thus more research is required. Tiny cell derived vesicles known as exosomes have been evaluated in an attempt to identify novel biomarkers for many disease states and have also shown therapeutic promise through their ability to deliver protein and nucleic acid to recipient cells. The research presented herein investigates whether (1) the level of SMN protein in exosomes isolated from the medium of cells, and serum from animal models and patients of SMA is indicative of disease, to serve as a biomarker for monitoring disease progression and therapeutic efficacy; (2) SMN-protein loaded exosomes can be utilized to deliver SMN protein to SMN-deficient cells; (3) adenoviral vectors are effective at creating SMN protein-loaded exosomes in situ for body wide distribution of SMN protein. This research has shown SMN protein is naturally released in extracellular vesicles, and the level of exosomal SMN protein is reflective of the disease state. Exosomes can also be modified to hold enhanced levels of SMN protein and deliver them to both the cytoplasm and nucleus of SMN-deficient cells. Furthermore, adenoviral vectors expressing luciferase-tagged SMN1 cDNA, targeted to the liver, results in SMN protein-loaded exosomes and detectable luciferase activity, body-wide. Thus, exosomes present as an effective biomarker and potentially a novel approach to treat SMA.

Over time astrocytes have been thought to function in an auxiliary manner, providing neurons with metabolic and structural support. However, recent research suggests they may play a fundamental role in the generation and propagation of focal epileptic seizures by causing synchronized electrical bursts in neurons. It would be helpful to have a simple mathematical model that represents this dynamic and incorporates these updated experimental results. We have created a two-compartment model of a typical neuron found in the hippocampal CA1 region, an area often thought to be the origin of these seizures. The focus is on properly modeling the astrocytic input to examine the pathological excitation of these neurons and subsequent transmission of the signals. In particular, we consider the intracellular astrocytic calcium fluctuations which are associated with slow inward currents in neighbouring neurons. Using our model, a variety of experimental results are reproduced, and comments are made about the potential differences between graded and “all-or-none” astrocytes.

Over time astrocytes have been thought to function in an auxiliary manner, providing neurons with metabolic and structural support. However, recent research suggests they may play a fundamental role in the generation and propagation of focal epileptic seizures by causing synchronized electrical bursts in neurons. It would be helpful to have a simple mathematical model that represents this dynamic and incorporates these updated experimental results. We have created a two-compartment model of a typical neuron found in the hippocampal CA1 region, an area often thought to be the origin of these seizures. The focus is on properly modeling the astrocytic input to examine the pathological excitation of these neurons and subsequent transmission of the signals. In particular, we consider the intracellular astrocytic calcium fluctuations which are associated with slow inward currents in neighbouring neurons. Using our model, a variety of experimental results are reproduced, and comments are made about the potential differences between graded and “all-or-none” astrocytes.

A teoria neuronal prerroga a existência da unidade básica do sistema nervoso, o neurônio. A teoria neuronal foi proposta e formulada nas últimas décadas do século XIX. Ela é comumente associada ao nome de Santiago Ramón y Cajal (1852-1934), que a formulou em oposição à proposta de que o tecido nervoso é constituído por redes contínuas formadas por células nervosas. Os trabalhos de Ramón y Cajal são, portanto, considerados ponto de inflexão nas pesquisas em Neurociência. Este trabalho objetiva investigar a constituição da teoria neuronal de acordo com a formação do conceito de neurônio. A formação do conceito de neurônio está diretamente ligada ao conceito de plasticidade. Como parte da pesquisa, serão investigados os principais trabalhos de um dos mais fervorosos defensores do reticularismo, o italiano Camillo Golgi (1843-1926). Em linhas gerais, o trabalho pretende um exame da constituição da teoria neuronal a partir da formação do conceito de neurônio e do papel que o conceito de plasticidade teve na formulação do conceito de neurônio / The neuron theory prerogatives the existence of the basic unit of the nervous system, the neuron. The neuron theory was proposed and formulated in the last decades of the nineteenth century. It is commonly associated with the name of Santiago Ramón y Cajal (1852-1934), who formulated it in contradiction to the proposal that nervous tissue consists of seamless networks formed by nerve cells. Ramón y Cajals works are, therefore, considered the turning point in neuroscience research. This work aims to investigate the formation of neuronal theory according to the neurons concept. The formation of the neuron concept is directly linked to the plasticity concept. As part of the research, it will be studied the major works of one of the most fervent advocates of reticular theory, the Italian scientist, Camillo Golgi (1843-1926). In general, this study aims to examine the formation of neuronal theory from the formation of the neuron concept and the role that the plasticity concept had in formulating the neuron concept

This thesis proposes a novel set of generic and compact biologically plausible VLSI (Very Large Scale Integration) neural circuits, suitable for implementing a parallel VLSI network that closely resembles the function of a small-scale neocortical network. The proposed circuits include a cortical neuron, two different long-term plastic synapses and four different short-term plastic synapses. These circuits operate in accelerated-time, where the time scale of neural responses is approximately three to four orders of magnitude faster than the biological-time scale of the neuronal activities, providing higher computational throughput in computing neural dynamics. Further, a novel biological-time cortical neuron circuit with similar dynamics as of the accelerated-time neuron is proposed to demonstrate the feasibility of migrating accelerated-time circuits into biological-time circuits. The fabricated accelerated-time VLSI neuron circuit is capable of replicating distinct firing patterns such as regular spiking, fast spiking, chattering and intrinsic bursting, by tuning two external voltages. It reproduces biologically plausible action potentials. This neuron circuit is compact and enables implementation of many neurons in a single silicon chip. The circuit consumes extremely low energy per spike (8pJ). Incorporating this neuron circuit in a neural network facilitates diverse non-linear neuron responses, which is an important aspect in neural processing. Two of the proposed long term plastic synapse circuits include spike-time dependent plasticity (STDP) synapse, and dopamine modulated STDP synapse. The short-term plastic synapses include excitatory depressing, inhibitory facilitating, inhibitory depressing, and excitatory facilitating synapses. Many neural parameters of short- and long- term synapses can be modified independently using externally controlled tuning voltages to obtain distinct synaptic properties. Having diverse synaptic dynamics in a network facilitates richer network behaviours such as learning, memory, stability and dynamic gain control, inherent in a biological neural network. To prove the concept in VLSI, different combinations of these accelerated-time neural circuits are fabricated in three integrated circuits (ICs) using a standard 0.35 µm CMOS technology. Using first two ICs, functions of cortical neuron and STDP synapses have been experimentally verified. The third IC, the Cortical Neural Layer (CNL) Chip is designed and fabricated to facilitate cortical network emulations. This IC implements neural circuits with a similar composition to the cortical layer of the neocortex. The CNL chip comprises 120 cortical neurons and 7 560 synapses. Many of these CNL chips can be combined together to form a six-layered VLSI neocortical network to validate the network dynamics and to perform neural processing of small-scale cortical networks. The proposed neuromorphic systems can be used as a simulation acceleration platform to explore the processing principles of biological brains and also move towards realising low power, real-time intelligent computing devices and control systems.

Der Cortex von Säugetieren ist der Hirnbereich, der fundamental für höhere kognitive Funktionen wie Lernen, Gedächtnis, Aufmerksamkeit und komplexes Denken ist. Die Entwicklung des Cortex wird von neuralen Vorläuferzellen gesteuert, die schnell proliferieren, um ihren Pool zu expandieren, bevor sie zu differenzierenden Zellteilungen wechseln, um alle Neuronen zu generieren, aus denen der reife sechs schichtige Neokortex besteht. Der schrittweise Wechsel von Selbsterneuerung zu Neurogenese ist ein zeitlich regulierter Prozess, dessen Fehler schwere lebenslange kognitive Erkrankungen verursachen können. Aus diesem Grund ist es enorm wichtig zu verstehen, welche Faktoren die Schicksalsentscheidung der neuralen Vorläuferzellen regulieren. In den letzten zwei Jahrzehnten haben mehrere Studien die Wichtigkeit von nicht-kodierenden RNAs, wie lange nicht-kodierende und micro RNAs, für diese zeitliche Regulierung hervorgehoben. Mithilfe der Generierung einer kombinatorischen RFP/GFP Reporter Mauslinie, die die Isolierung von proliferierenden und differenzierenden Vorläuferzellen und neugeborenen Neuronen erlaubt, wurde berichtet, dass die lange nicht-kodierende RNA Miat als ein Regulator des neuralen Vorläuferzellen-Schicksals mittels Spleißen fungiert. Die Arbeit dieser Thesis zeigt, dass die Überexpression von Miat den Wechsel der neuralen Vorläuferzellen von proliferierenden zu neurogenen Zellteilungen verzögert und etabliert eine Strategie, um Miat-gespleißte Ziele auf Einzelpopulationslevel während der Corticogenese zu entdecken. Außerdem wurde die doppelte Reporter Mauslinie genutzt, um einen umfassenden und kompletten Katalog von micro RNAs, die in neuralen Vorläuferzellen und Neuronen exprimiert sind, zu erstellen. Dies führte zur Identifizierung von miR-486-5p als ein neuer Regulator der neuralen Vorläuferzellen-Schicksalsentscheidung.

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder, which causes dysfunction/loss of lower motor neurons and muscle weakness as well as atrophy. While SMA is primarily considered as a motor neuron disease, recent data suggests that survival motor neuron (SMN) deficiency in muscle causes intrinsic defects. We systematically profiled secreted proteins from control and SMN deficient muscle cells with two combined metabolic labeling methods and mass spectrometry. From the screening, we found lower levels of C1q/TNF-related protein 3 (CTRP3) in the SMA muscle secretome and confirmed that CTRP3 levels are indeed reduced in muscle tissues and serum of an SMA mouse model. We identified that CTRP3 regulates neuronal protein synthesis including SMN via mTOR pathway. Furthermore, CTRP3 enhances axonal outgrowth and protein synthesis rate, which are well-known impaired processes in SMA motor neurons. Our data revealed a new molecular mechanism by which muscles regulate the physiology of motor neurons via secreted molecules. Dysregulation of this mechanism contributes to the pathophysiology of SMA.