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Description
Learning by trial-and-error requires retrospective information that whether a past action resulted in a rewarded outcome. Previous outcome in turn may provide information to guide future behavioral adjustment. But the specific contribution of this information to learning a task and the neural representations during the trial-and-error learning process is not well understood. In this dissertation, such learning is analyzed by means of single unit neural recordings in the rats' motor agranular medial (AGm) and agranular lateral (AGl) while the rats learned to perform a directional choice task. Multichannel chronic recordings using implanted microelectrodes in the rat's brain were essential to this study. Also for fundamental scientific investigations in general and for some applications such as brain machine interface, the recorded neural waveforms need to be analyzed first to identify neural action potentials as basic computing units. Prior to analyzing and modeling the recorded neural signals, this dissertation proposes an advanced spike sorting system, the M-Sorter, to extract the action potentials from raw neural waveforms. The M-Sorter shows better or comparable performance compared with two other popular spike sorters under automatic mode. With the sorted action potentials in place, neuronal activity in the AGm and AGl areas in rats during learning of a directional choice task is examined. Systematic analyses suggest that rat's neural activity in AGm and AGl was modulated by previous trial outcomes during learning. Single unit based neural dynamics during task learning are described in detail in the dissertation. Furthermore, the differences in neural modulation between fast and slow learning rats were compared. The results show that the level of neural modulation of previous trial outcome is different in fast and slow learning rats which may in turn suggest an important role of previous trial outcome encoding in learning.
ContributorsYuan, Yu'an (Author) / Si, Jennie (Thesis advisor) / Buneo, Christopher (Committee member) / Santello, Marco (Committee member) / Chae, Junseok (Committee member) / Arizona State University (Publisher)
Created2014
Description
To uncover the neural correlates to go-directed behavior, single unit action potentials are considered fundamental computing units and have been examined by different analytical methodologies under a broad set of hypotheses. Using a behaving rat performing a directional choice learning task, we aim to study changes in rat's cortical neural patterns while he improved his task performance accuracy from chance to 80% or higher. Specifically, simultaneous multi-channel single unit neural recordings from the rat's agranular medial (AGm) and Agranular lateral (AGl) cortices were analyzed using joint peristimulus time histogram (JPSTHs), which effectively unveils firing coincidences in neural action potentials. My results based on data from six rats revealed that coincidences of pair-wise neural action potentials are higher when rats were performing the task than they were not at the learning stage, and this trend abated after the rats learned the task. Another finding is that the coincidences at the learning stage are stronger than that when the rats learned the task especially when they were performing the task. Therefore, this coincidence measure is the highest when the rats were performing the task at the learning stage. This may suggest that neural coincidences play a role in the coordination and communication among populations of neurons engaged in a purposeful act. Additionally, attention and working memory may have contributed to the modulation of neural coincidences during the designed task.
ContributorsCheng, Bing (Author) / Si, Jennie (Thesis advisor) / Chae, Junseok (Committee member) / Seo, Jae-Sun (Committee member) / Arizona State University (Publisher)
Created2014
Description
The ability to monitor electrophysiological signals from the sentient brain is requisite to decipher its enormously complex workings and initiate remedial solutions for the vast amount of neurologically-based disorders. Despite immense advancements in creating a variety of instruments to record signals from the brain, the translation of such neurorecording instrumentation to real clinical domains places heavy demands on their safety and reliability, both of which are not entirely portrayed by presently existing implantable recording solutions. In an attempt to lower these barriers, alternative wireless radar backscattering techniques are proposed to render the technical burdens of the implant chip to entirely passive neurorecording processes that transpire in the absence of formal integrated power sources or powering schemes along with any active circuitry. These radar-like wireless backscattering mechanisms are used to conceive of fully passive neurorecording operations of an implantable microsystem. The fully passive device potentially manifests inherent advantages over current wireless implantable and wired recording systems: negligible heat dissipation to reduce risks of brain tissue damage and minimal circuitry for long term reliability as a chronic implant. Fully passive neurorecording operations are realized via intrinsic nonlinear mixing properties of the varactor diode. These mixing and recording operations are directly activated by wirelessly interrogating the fully passive device with a microwave carrier signal. This fundamental carrier signal, acquired by the implant antenna, mixes through the varactor diode along with the internal targeted neuropotential brain signals to produce higher frequency harmonics containing the targeted neuropotential signals. These harmonics are backscattered wirelessly to the external interrogator that retrieves and recovers the original neuropotential brain signal. The passive approach removes the need for internal power sources and may alleviate heat trauma and reliability issues that limit practical implementation of existing implantable neurorecorders.
ContributorsSchwerdt, Helen N (Author) / Chae, Junseok (Thesis advisor) / Miranda, Félix A. (Committee member) / Phillips, Stephen (Committee member) / Towe, Bruce C (Committee member) / Balanis, Constantine A (Committee member) / Frakes, David (Committee member) / Arizona State University (Publisher)
Created2014
Description
In this thesis, I present a lab-on-a-chip (LOC) that can separate and detect Escherichia Coli (E. coli) in simulated urine samples for Urinary Tract Infection (UTI) diagnosis. The LOC consists of two (concentration and sensing) chambers connected in series and an integrated impedance detector. The two-chamber approach is designed to reduce the non-specific absorption of proteins, e.g. albumin, that potentially co-exist with E. coli in urine. I directly separate E. coli K-12 from a urine cocktail in a concentration chamber containing micro-sized magnetic beads (5 µm in diameter) conjugated with anti-E. coli antibodies. The immobilized E. coli are transferred to a sensing chamber for the impedance measurement. The measurement at the concentration chamber suffers from non-specific absorption of albumin on the gold electrode, which may lead to a false positive response. By contrast, the measured impedance at the sensing chamber shows ~60 kÙ impedance change between 6.4x104 and 6.4x105 CFU/mL, covering the threshold of UTI (105 CFU/mL). The sensitivity of the LOC for detecting E. coli is characterized to be at least 3.4x104 CFU/mL. I also characterized the LOC for different age groups and white blood cell spiked samples. These preliminary data show promising potential for application in portable LOC devices for UTI detection.
ContributorsKim, Sangpyeong (Author) / Chae, Junseok (Thesis advisor) / Phillips, Stephen M. (Committee member) / Blain Christen, Jennifer M. (Committee member) / Arizona State University (Publisher)
Created2011
Description
A dual-channel directional digital hearing aid (DHA) front-end using a fully differential difference amplifier (FDDA) based Microphone interface circuit (MIC) for a capacitive Micro Electro Mechanical Systems (MEMS) microphones and an adaptive-power analog font end (AFE) is presented. The Microphone interface circuit based on FDDA converts the capacitance variations into voltage signal, achieves a noise of 32 dB SPL (sound pressure level) and an SNR of 72 dB, additionally it also performs single to differential conversion allowing for fully differential analog signal chain. The analog front-end consists of 40dB VGA and a power scalable continuous time sigma delta ADC, with 68dB SNR dissipating 67u¬W from a 1.2V supply. The ADC implements a self calibrating feedback DAC, for calibrating the 2nd order non-linearity. The VGA and power scalable ADC is fabricated on 0.25 um CMOS TSMC process. The dual channels of the DHA are precisely matched and achieve about 0.5dB gain mismatch, resulting in greater than 5dB directivity index. This will enable a highly integrated and low power DHA
ContributorsNaqvi, Syed Roomi (Author) / Kiaei, Sayfe (Thesis advisor) / Bakkaloglu, Bertan (Committee member) / Chae, Junseok (Committee member) / Barnby, Hugh (Committee member) / Aberle, James T., 1961- (Committee member) / Arizona State University (Publisher)
Created2011
Description
Demand for biosensor research applications is growing steadily. According to a new report by Frost & Sullivan, the biosensor market is expected to reach $14.42 billion by 2016. Clinical diagnostic applications continue to be the largest market for biosensors, and this demand is likely to continue through 2016 and beyond. Biosensor technology for use in clinical diagnostics, however, requires translational research that moves bench science and theoretical knowledge toward marketable products. Despite the high volume of academic research to date, only a handful of biomedical devices have become viable commercial applications. Academic research must increase its focus on practical uses for biosensors. This dissertation is an example of this increased focus, and discusses work to advance microfluidic-based protein biosensor technologies for practical use in clinical diagnostics. Four areas of work are discussed: The first involved work to develop reusable/reconfigurable biosensors that are useful in applications like biochemical science and analytical chemistry that require detailed sensor calibration. This work resulted in a prototype sensor and an in-situ electrochemical surface regeneration technique that can be used to produce microfluidic-based reusable biosensors. The second area of work looked at non-specific adsorption (NSA) of biomolecules, which is a persistent challenge in conventional microfluidic biosensors. The results of this work produced design methods that reduce the NSA. The third area of work involved a novel microfluidic sensing platform that was designed to detect target biomarkers using competitive protein adsorption. This technique uses physical adsorption of proteins to a surface rather than complex and time-consuming immobilization procedures. This method enabled us to selectively detect a thyroid cancer biomarker, thyroglobulin, in a controlled-proteins cocktail and a cardiovascular biomarker, fibrinogen, in undiluted human serum. The fourth area of work involved expanding the technique to produce a unique protein identification method; Pattern-recognition. A sample mixture of proteins generates a distinctive composite pattern upon interaction with a sensing platform consisting of multiple surfaces whereby each surface consists of a distinct type of protein pre-adsorbed on the surface. The utility of the "pattern-recognition" sensing mechanism was then verified via recognition of a particular biomarker, C-reactive protein, in the cocktail sample mixture.
ContributorsChoi, Seokheun (Author) / Chae, Junseok (Thesis advisor) / Tao, Nongjian (Committee member) / Yu, Hongyu (Committee member) / Forzani, Erica (Committee member) / Arizona State University (Publisher)
Created2011
Description
Measuring molecular interaction with membrane proteins is critical for understanding cellular functions, validating biomarkers and screening drugs. Despite the importance, developing such a capability has been a difficult challenge, especially for small molecules binding to membrane proteins in their native cellular environment. The current mainstream practice is to isolate membrane proteins from the cell membranes, which is difficult and often lead to the loss of their native structures and functions. In this thesis, novel detection methods for in situ quantification of molecular interactions with membrane proteins are described.
First, a label-free surface plasmon resonance imaging (SPRi) platform is developed for the in situ detection of the molecular interactions between membrane protein drug target and its specific antibody drug molecule on cell surface. With this method, the binding kinetics of the drug-target interaction is quantified for drug evaluation and the receptor density on the cell surface is also determined.
Second, a label-free mechanically amplification detection method coupled with a microfluidic device is developed for the detection of both large and small molecules on single cells. Using this method, four major types of transmembrane proteins, including glycoproteins, ion channels, G-protein coupled receptors (GPCRs) and tyrosine kinase receptors on single whole cells are studied with their specific drug molecules. The basic principle of this method is established by developing a thermodynamic model to express the binding-induced nanometer-scale cellular deformation in terms of membrane protein density and cellular mechanical properties. Experiments are carried out to validate the model.
Last, by tracking the cell membrane edge deformation, molecular binding induced downstream event – granule exocytosis is measured with a dual-optical imaging system. Using this method, the single granule exocytosis events in single cells are monitored and the temporal-spatial distribution of the granule fusion-induced cell membrane deformation are mapped. Different patterns of granule release are resolved, including multiple release events occurring close in time and position. The label-free cell membrane deformation tracking method was validated with the simultaneous fluorescence recording. And the simultaneous cell membrane deformation detection and fluorescence recording allow the study of the propagation of the granule release-induced membrane deformation along cell surfaces.
First, a label-free surface plasmon resonance imaging (SPRi) platform is developed for the in situ detection of the molecular interactions between membrane protein drug target and its specific antibody drug molecule on cell surface. With this method, the binding kinetics of the drug-target interaction is quantified for drug evaluation and the receptor density on the cell surface is also determined.
Second, a label-free mechanically amplification detection method coupled with a microfluidic device is developed for the detection of both large and small molecules on single cells. Using this method, four major types of transmembrane proteins, including glycoproteins, ion channels, G-protein coupled receptors (GPCRs) and tyrosine kinase receptors on single whole cells are studied with their specific drug molecules. The basic principle of this method is established by developing a thermodynamic model to express the binding-induced nanometer-scale cellular deformation in terms of membrane protein density and cellular mechanical properties. Experiments are carried out to validate the model.
Last, by tracking the cell membrane edge deformation, molecular binding induced downstream event – granule exocytosis is measured with a dual-optical imaging system. Using this method, the single granule exocytosis events in single cells are monitored and the temporal-spatial distribution of the granule fusion-induced cell membrane deformation are mapped. Different patterns of granule release are resolved, including multiple release events occurring close in time and position. The label-free cell membrane deformation tracking method was validated with the simultaneous fluorescence recording. And the simultaneous cell membrane deformation detection and fluorescence recording allow the study of the propagation of the granule release-induced membrane deformation along cell surfaces.
ContributorsZhang, Fenni (Author) / Tao, Nongjian (Thesis advisor) / Chae, Junseok (Committee member) / Borges, Chad (Committee member) / Jing, Tianwei (Committee member) / Wang, Shaopeng (Committee member) / Arizona State University (Publisher)
Created2018
Description
Rasopathies are a family of developmental syndromes that exhibit craniofacial abnormalities, cognitive disabilities, developmental delay and increased risk of cancer. However, little is known about the pathogenesis of developmental defects in the nervous system. Frequently, gain-of-function mutations in the Ras/Raf/MEK/ERK cascade (aka ERK/MAPK) are associated with the observed pathogenesis. My research focuses on defining the relationship between increased ERK/MAPK signaling and its effects on the nervous system, specifically in the context of motor learning. Motor function depends on several neuroanatomically distinct regions, especially the spinal cord, cerebellum, striatum, and cerebral cortex. We tested whether hyperactivation of ERK/MAPK specifically in the cortex was sufficient to drive changes in motor function. We used a series of genetically modified mouse models and cre-lox technology to hyperactivate ERK/MAPK in the cerebral cortex. Nex:Cre/NeuroD6:Cre was employed to express a constitutively active MEK mutation throughout all layers of the cerebral cortex from an early stage of development. RBP4:Cre, caMEK only exhibited hyper activation in cortical glutamatergic neurons responsible for cortical output (neurons in layer V of the cerebral cortex). First, the two mouse strains were tested in an open field paradigm to assess global locomotor abilities and overall fitness for fine motor tasks. Next, a skilled motor reaching task was used to evaluate motor learning capabilities. The results show that Nex:Cre/NeuroD6:Cre, caMEK mutants do not learn the motor reaching task, although they performed normally on the open field task. Preliminary results suggest RBP4:Cre, caMEK mutants exhibit normal locomotor capabilities and a partial lack of learning. The difference in motor learning capabilities might be explained by the extent of altered connectivity in different regions of the corticospinal tract. Once we have identified the neuropathological effects of various layers in the cortex we will be able to determine whether therapeutic interventions are sufficient to reverse these learning defects.
ContributorsRoose, Cassandra Ann (Author) / Newbern, Jason M. (Thesis director) / Olive, Foster (Committee member) / Bjorklund, Reed (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
The RAS/MAPK (RAS/Mitogen Activated Protein Kinase) pathway is a highly conserved, canonical signaling cascade that is highly involved in cellular growth and proliferation as well as cell migration. As such, it plays an important role in development, specifically in development of the nervous system. Activation of ERK is indispensable for the differentiation of Embryonic Stem Cells (ESC) into neuronal precursors (Li z et al, 2006). ERK signaling has also shown to mediate Schwann cell myelination of the peripheral nervous system (PNS) as well as oligodendrocyte proliferation (Newbern et al, 2011). The class of developmental disorders that result in the dysregulation of RAS signaling are known as RASopathies. The molecular and cell-specific consequences of these various pathway mutations remain to be elucidated. While there is evidence for altered DNA transcription in RASopathies, there is little work examining the effects of the RASopathy-linked mutations on protein translation and post-translational modifications in vivo. RASopathies have phenotypic and molecular similarities to other disorders such as Fragile X Syndrome (FXS) and Tuberous Sclerosis (TSC) that show evidence of aberrant protein synthesis and affect related pathways. There are also well-defined downstream RAS pathway elements involved in translation. Additionally, aberrant corticospinal axon outgrowth has been observed in disease models of RASopathies (Xing et al, 2016). For these reasons, this present study examines a subset of proteins involved in translation and translational regulation in the context of RASopathy disease states. Results indicate that in both of the tested RASopathy model systems, there is altered mTOR expression. Additionally the loss of function model showed a decrease in rps6 activation. This data supports a role for the selective dysregulation of translational control elements in RASopathy models. This data also indicates that the primary candidate mechanism for control of altered translation in these modes is through the altered expression of mTOR.
ContributorsHilbert, Alexander Robert (Author) / Newbern, Jason (Thesis director) / Olive, M. Foster (Committee member) / Bjorklund, Reed (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05