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Title: DEORPHANIZATION AND CHARACTERIZATION OF SEA LAMPREY OLFACTORY TRACE AMINE-ASSOCIATED RECEPTORS
Creator: JIA, LIANG
Date: 2022
Collection: Electronic Theses & Dissertations
Description: The sense of smell plays an important role in mediating diverse behaviors in the animal kingdom. Odor detection in the sea lamprey is mediated by a limited number of odorant receptors (ORs) and trace amine-associated receptors (TAARs). Upon binding with odorants, the receptors are activated and subsequently activate the downstream neuronal signaling cascade that transforms the chemical information into electrophysiological signals. Odorous biogenic amines, when enriched in biological...
Show moreThe sense of smell plays an important role in mediating diverse behaviors in the animal kingdom. Odor detection in the sea lamprey is mediated by a limited number of odorant receptors (ORs) and trace amine-associated receptors (TAARs). Upon binding with odorants, the receptors are activated and subsequently activate the downstream neuronal signaling cascade that transforms the chemical information into electrophysiological signals. Odorous biogenic amines, when enriched in biological excretions, stimulate TAARs of the main olfactory epithelium and evoke innate behaviors in animals. I hypothesized that these biogenic amines are potent ligands for lamprey TAARs, and characterized the structural basis for amine recognition in these receptors. Chapter 1 describes discovery that spermine, an odorous polyamine in semen, serves as a sex pheromone in sea lamprey. Spermine potently stimulates the lamprey olfactory system, activates TAAR348 receptor, and attracts ovulated females. A novel antagonist to this receptor inhibits olfactory and female behavioral responses to spermine. This discovery elucidates a mechanism that male animals recruit mates through the release of chemical cues in ejaculates. In chapter 2, I demonstrated that two clades of independently evolved TAARs, represented by sea lamprey TAAR365 (sTAAR365) and mouse TAAR9 (mTAAR9), share a similar response profile. The results suggest a conserved mechanism whereby independently evolved TAAR receptors utilize convergent structural bases to detect various biogenic polyamines. In chapter 3, I found that a cadaverine-responsive sea lamprey TAAR receptor, TAAR346a, exhibits high basal activity when heterologously expressed in HEK293T cells. Triethylamine serves as an inverse agonist for TAAR346a that can specifically attenuate its high basal activity. These data support a model in which the inverse agonist recognizes only one of the two orthosteric sites used by the agonist as it elicits its inhibitory effect on the basal activity of the receptor. Further evidence was provided to highlight the importance of interhelical interactions in modulating ligand-independent activation of TAAR346a. Thus, this thesis contributes to a better understanding of sea lamprey olfaction and the structural basis of TAARs for amine recognition in vertebrate animals.
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Title: Circuit-Specific Inhibition of Dopaminergic Signaling Associated with Phantom Gustatory Sensations in Disrupted-in-Schizophrenia-1 Mice
Creator: Fry, Benjamin R.
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Schizophrenia is a severe neuropsychiatric disorder characterized by a suite of symptoms occurring across cognitive (delayed processing, paraphasia, attentional deficits), negative (anhedonia, blunted affect, catatonia), and positive (hallucinations, delusions) domains. Antipsychotics are the most commonly prescribed medication to treat positive symptoms, however their use is complicated by substantial side-effects and inadequate efficacy. This reflects a lack of progress in understanding the...
Show moreSchizophrenia is a severe neuropsychiatric disorder characterized by a suite of symptoms occurring across cognitive (delayed processing, paraphasia, attentional deficits), negative (anhedonia, blunted affect, catatonia), and positive (hallucinations, delusions) domains. Antipsychotics are the most commonly prescribed medication to treat positive symptoms, however their use is complicated by substantial side-effects and inadequate efficacy. This reflects a lack of progress in understanding the precise neurobiological mechanisms underlying these symptoms, due in part to a lack of appropriate preclinical animal models. Here, I used an animal model of genetic vulnerability for neuropsychiatric illness known as Disrupted-in-schizophrenia-1 (DISC-1) to examine impaired reality testing, which reflects an aberrant internal representation of an absent event. In mice, this can be observed by an associatively evoked perception of an absent sweet taste. This effect is dopaminergically-dependent and associated with elevated activity in the insular cortex (IC). By combining sophisticated Pavlovian behavioral procedures with chemogenetic inhibition of dopamine neurons projecting from the ventral tegmental area (VTA) to the IC, I show that inactivation of the VTA --> IC dopaminergic circuitry leads to impaired reality testing in wild-type mice, and that DISC-1 mice have significantly less dopamine neurons which send projections to the IC, specifically. These data yield new insights with regard to the neurobiology underlying reality testing and the functional anatomical outcomes following perturbations of the DISC-1 genetic locus. My studies also suggest potential targets for the development of novel pharmacological treatments in humans with schizophrenia.
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Title: MAPPING THE TAU PROTEIN INTERACTOME USING THE BIOID2 IN SITU LABELLING APPROACH
Creator: Atwa, Ahmed
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Pathological inclusions composed of tau protein are hallmarks of neurodegenerative diseases collectively known as tauopathies, of which the most common is Alzheimer’s Disease (AD). Tau is most well-known as a microtubule-associated protein involved in regulating microtubule dynamics, but accumulating evidence suggests tau is involved in many biological functions. Deciphering the tau protein interactome is critical for better understating the physiological and pathological roles of tau. This...
Show morePathological inclusions composed of tau protein are hallmarks of neurodegenerative diseases collectively known as tauopathies, of which the most common is Alzheimer’s Disease (AD). Tau is most well-known as a microtubule-associated protein involved in regulating microtubule dynamics, but accumulating evidence suggests tau is involved in many biological functions. Deciphering the tau protein interactome is critical for better understating the physiological and pathological roles of tau. This work aimed to identify tau interacting partners using the in situ protein labelling BioID2 method by creating fusion proteins between full-length human tau and either BioID2 on the N-terminus (BioID2-Tau) or C-terminus (Tau-BioID2). A total of 372 proteins were identified, of which 269 interacted with Tau-BioID2, 169 with BioID2-Tau, and 66 proteins overlapped between both tau proteins. Gene Ontology (GO) cellular component analysis mapped protein interactions in the mitochondria, cytoskeleton, dendrites, nucleus, synaptic vesicles, and the ribonucleoprotein complex. While GO molecular function pathways identified proteins involved in RNA binding, translation regulation, ubiquitin ligase activity, kinase binding, mitochondrial oxidoreductase, and peroxidase activity. KEGG pathway analysis identified proteins associated with neurodegenerative diseases, including AD, Parkinson’s disease, Huntington’s disease, and Amyotrophic lateral sclerosis. Thus, this approach can identify members of the tau interactome via in situ labeling, that may help shed light on tau’s functional roles and provide novel therapeutic strategies for neurodegenerative diseases.
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Title: ENABLING REAL-TIME COMMUNICATION FOR HUMAN AUGMENTATION SYSTEMS VIA UNOBTRUSIVE HIGH BANDWIDTH MACHINE TO HUMAN ELECTROTACTILE PERIPHERAL NERVE STIMULATION
Creator: Parsnejad, Sina
Date: 2022
Collection: Electronic Theses & Dissertations
Description: The advent of sensor technologies and the resulting abundance of information together with modern advanced processing capabilities makes improving human lives via human augmentation technologies ever more appealing. To establish a new effective form of human-machine-communication (M2HC) for augmentation, this dissertation explores non-invasive peripheral nerve stimulation via electrotactile waveforms. This dissertation conducts extensive convergence research between the fields of psychology,...
Show moreThe advent of sensor technologies and the resulting abundance of information together with modern advanced processing capabilities makes improving human lives via human augmentation technologies ever more appealing. To establish a new effective form of human-machine-communication (M2HC) for augmentation, this dissertation explores non-invasive peripheral nerve stimulation via electrotactile waveforms. This dissertation conducts extensive convergence research between the fields of psychology, electrical engineering, neuroscience and human augmentation and established innovations to create distinct sensations that can be utilized as iconic electrotactile M2HC. Existing electrotactile stimulation models deliver a limited range of distinct sensations, making iconic communication challenging. To address this issue, we created a software/hardware infrastructure, including novel electrotactile electrode arrays and improved stimulation circuitry, that allows for rapid prototyping and testing various electrotactile innovations. We created a model for electrotactile waveform generation (MEWS) wherein a train of high-frequency electrotactile pulses is shaped into electrotactile waveforms through a multi-layer on-off-keying modulation forgoing the need for constant frequency recalibration and making painful sensations less likely to happen. Using MEWS, we conducted multiple human trials on 15 volunteering participants stimulating a total of ~6000 electrotactile sensations which led us to create 13 distinct electrotactile waveform with an accuracy of 85.4%. To increase the number of messages that can be delivered by electrotactile stimulation, a model for creating varying electrotactile waveforms (MOVES) was created based on linguistic concept of phonemes and taking a semi-heuristic approach to creating electrotactile waveforms. Using MOVES we conducted multiple human trials on 21 volunteering participants stimulating a total of ~5000 electrotactile sensations. Our human trials proved that MOVES was able to create 24 distinct sensations with an accuracy of 89% that can be used to convey messages through iconic communication and has the potential to expand further beyond the 24 messages. The number of messages delivered by MOVES pentuples the best recorded number of distinct electrotactile sensations in literature.
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Title: THE PERSISTENT AND MULTIDIMENSIONAL MICROGLIAL RESPONSE TO PATHOLOGICAL ALPHA-SYNUCLEIN AGGREGATION
Creator: Stoll, Anna C.
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Parkinson’s Disease, the second most common neurodegenerative disease, affects approximately 1 million people in the USA with 60,000 newly diagnosed people each year. Pathologically, PD is characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies) and the progressive loss of the nigrostriatal dopamine (DA) neurons. While the exact cause of PD remains unknown, mounting evidence has suggested that neuroinflammation may play a significant role in PD...
Show moreParkinson’s Disease, the second most common neurodegenerative disease, affects approximately 1 million people in the USA with 60,000 newly diagnosed people each year. Pathologically, PD is characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies) and the progressive loss of the nigrostriatal dopamine (DA) neurons. While the exact cause of PD remains unknown, mounting evidence has suggested that neuroinflammation may play a significant role in PD progression. The pathological features of PD can be recapitulated in vivo using the α-syn preformed fibril (PFF) model of synucleinopathy in rats. Specifically, in association with accumulation of phosphorylated α-syn (pSyn) inclusions in the SNpc, microglia increase soma size and MHC-II expression. This microglial response parallels pSyn inclusion formation, peaking at 2 months following intrastriatal PFF injection, months prior to the SNpc degeneration observed in the model. The overarching question of this dissertation is: does the microglial response to pathological α-syn accumulation contribute to degeneration? In Aim 1 of this dissertation an inhibitor of colony stimulating factor 1 receptor (CSF1R) was used to partially deplete microglia within the context of the α-syn PFF rat model in order to determine whether degeneration of the nigrostriatal system can be attenuated. Despite significant microglial depletion, increased soma size and expression of major-histocompatibility complex-II (MHC-II) on microglia within the α-syn inclusion bearing substantia nigra pars compacta (SNpc) was maintained. Further, partial microglia depletion did not impact degeneration of dopaminergic neurons in the SNpc. Paradoxically, long term partial microglial depletion increased the soma size of remaining microglia in both control and PFF rats was associated with widespread MHC-IIir expression in extranigral regions. These results suggest that partial microglial depletion is not a promising anti-inflammatory therapeutic strategy for PD and that this approach may induce a heightened proinflammatory state in remaining microglia. Aim 2 of this dissertation built on a previous study RNA-Seq dataset that identified multiple upregulated innate and adaptive immune transcripts in the inclusion bearing SNpc in the PFF model. Complementary approaches of fluorescent in situ hybridization (FISH) and droplet digital PCR (ddPCR) were used. FISH results identified an a-syn aggregate associated microglial (a-SAM) phenotype that is characterized by upregulation of CD74, CXCl10, RT1-A2, GRN, CSF1R, Tyrobp, C3, C1qa and Fcer1g. ddPCR results identified additional neuroinflammatory genes, Cd4, Stat1, Casp 1, Axl and IL18, that are significantly upregulated in inclusion bearing nigral tissue. Collectively these findings implicate that the deposition of pathological α-syn inclusions in the SNpc is associated with perturbations in immune functions related to complement, inflammasome and T cell activation, phagocytosis, and interferon gamma signaling. Collectively, the findings of these dissertation experiments demonstrate that the microglial response to pathological α-syn aggregation is persistent and multifaceted. This comprehensive understanding of the multidimensional response of microglia to pathological α-syn aggregates may help to uncover novel therapeutic targets that could facilitate future anti-inflammatory, disease-modifying strategies for PD.
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Title: An investigation of cerebellar morphology in childhood stuttering
Creator: Johnson, Chelsea Anna
Date: 2022
Collection: Electronic Theses & Dissertations
Description: While many studies have connected structural and functional cerebellar differences to developmental stuttering, there are limited studies of cerebellar gray matter morphology in young children who stutter. These examinations include small sample sizes of children and use morphometry methods that might not be best suited for examining the cerebellum (e.g., Chang et al., 2008). This dissertation examines how the structure of specific cerebellar lobules differs in a larger cohort of children who...
Show moreWhile many studies have connected structural and functional cerebellar differences to developmental stuttering, there are limited studies of cerebellar gray matter morphology in young children who stutter. These examinations include small sample sizes of children and use morphometry methods that might not be best suited for examining the cerebellum (e.g., Chang et al., 2008). This dissertation examines how the structure of specific cerebellar lobules differs in a larger cohort of children who stutter and children who do not stutter as well as in persistent and recovered children who stutter. These data will provide evidence to better inform predictions of how the morphology of cerebellar areas are likely involved in aspects of speech motor control in developmental stuttering. In this study, gray matter morphology of the cerebellum was examined in children who do and do not stutter using voxel-based morphometry and a specialized toolbox and atlas for the cerebellum (Diedrichsen, 2006). Here we examined cerebellar gray matter volume (GMV) based on structural MRI data from children who stutter and children who do not stutter, 116 preschool-age children (stuttering N= 57) between the ages of 3-5 years, and a school-age cohort of 72 children (stuttering N=37) six years of age and up. This dissertation is the first study to examine cerebellar GMV in a large group of children who stutter using a specialized toolbox and atlas for the cerebellum. Results from this study showed that there were no overall significant group differences of lobular GMV between the stuttering and non-stuttering groups in any of the groups of children. There were significant age-related associations, however, that differentiated children who do and do not stutter in specific age ranges. In particular, the following cerebellar lobules differed significantly in GMV between children who do and do not stutter with age: 1) cerebellar lobule VII, which may correspond with cerebellar functions that support speech planning, 2) lobule VIII, which has been linked to various functions including corrections during perturbation studies, and 3) lobule IV which has been reported to be involved in feedforward control speech motor control processes. Notably, GMV of cerebellar lobule VI was associated negatively with Stuttering Severity Instrument (SSI) score in preschool-age persistent children who stutter. Associations between SSI score and GMV in cerebellar lobule VI may mean that feedforward control mechanisms are associated with the frequency of stuttering in children who stutter. In summary, significant findings of this investigation indicate that 1) children who do and do not stutter do not show an overall difference in cerebellar GMV, 2) GMV of the cerebellum is associated with SSI score, 3) age-related differences in GMV in the cerebellum differentiate children who do and do not stutter. The results from this study indicate that feedforward control is associated with disfluencies while age-related variations of cerebellar areas that may support both the feedback and feedforward control pathways are connected to aspects of stuttering, such as age.
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Title: Investigating Cognition in Howard Engel's Memory Book : Literary Interventions and Intercessions in Scientific Models of Memory
Creator: Cave, Kylene N.
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Crime fiction orbits around the concept of memory. At its core, crime narratives are concerned with reconstructing the past, bringing to light the events surrounding the criminal mystery. Memory also manifests in the genre’s detective figures, its modes of detection, and in the eyewitness testimonies used to solve the criminal mystery. In most crime narratives memory operates as a simplistic plot device used to temporarily complicate the mystery and, as such, it is rarely read beyond the...
Show moreCrime fiction orbits around the concept of memory. At its core, crime narratives are concerned with reconstructing the past, bringing to light the events surrounding the criminal mystery. Memory also manifests in the genre’s detective figures, its modes of detection, and in the eyewitness testimonies used to solve the criminal mystery. In most crime narratives memory operates as a simplistic plot device used to temporarily complicate the mystery and, as such, it is rarely read beyond the cursory scope of trauma. This dissertation, however, argues that crime narratives depicting extreme and rare cases of memory—like amnesia—help trace the boundaries around average functioning memory and reveal useful ways for conceptualizing how memory functions, and what disciplines have the impetus to do so. In this dissertation I argue that Howard Engel’s novel, Memory Book (2005), examines the complexities of memory by accomplishing three narratological tasks, distinguishing it from other crime fiction narratives and their more traditional handling of issues of memory and recall. The first task involves placing memory at the center of the narrative and elevating the mystery of the mind to the forefront of the plot. In placing memory at its center, the novel pushes back against traditional and widely popular scientific models of memory as merely the process of remembering and forgetting, advocating for a theory that is more complex and heterogenous. The second narratological task involves the novel’s ability to act as a literary intercessor on behalf of the sciences to translate and disseminate theories of memory to the layperson. Within this task, however, I assert that the novel not only passively intercedes, but actively intervenes in the study of memory by highlighting the inherent limitations of purely scientific or medical models of memory. In exposing these constraints, the novel also suggests a blended, transdisciplinary approach to conceptualizing human memory function and the mind. Lastly, the final task asserts that Memory Book is distinct because its narrative is infused with elements of lived experience, elements the scientific method is incapable of capturing in its probing of memory and cognition. Pointing specifically to Engel’s authorship and the circumstances surrounding the narrative’s composition following a stroke, I argue that the text intentionally blurs the boundaries between reality and fiction as a way of investigating the real-world implications of wrestling with memory loss and brain-injury based amnesia. Each of these narratological tasks is systematically analyzed by engaging with the Howard Engel’s memoir—The Man Who Forgot How to Read—deeply engaging with the novel’s paratextual elements, and through a detailed close reading of the novel.
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Title: AGGRESSION AND THE GUT-BRAIN AXIS
Creator: Kwiatkowski, Christine Carole
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Violence is a widespread public health and justice system problem with far-reaching consequences for victims, offenders, and their communities. Aggression, the cognitive and behavioral antecedent to violent action, is mainly understood in terms of the psychosocial risk factors that increase the likelihood of aggressive behavioral strategies. Neighborhood context is a principal risk factor for violent crime perpetration, but the mechanisms that mediate the effect of the environment on...
Show moreViolence is a widespread public health and justice system problem with far-reaching consequences for victims, offenders, and their communities. Aggression, the cognitive and behavioral antecedent to violent action, is mainly understood in terms of the psychosocial risk factors that increase the likelihood of aggressive behavioral strategies. Neighborhood context is a principal risk factor for violent crime perpetration, but the mechanisms that mediate the effect of the environment on individual-level aggression behavior are poorly understood, especially the biological factors that may contribute to our understanding of violent behavior. In order to gain a better understanding of mechanisms that precipitate violence in specific geographic contexts, this dissertation explores the relationship between aggression behavior and the gut microbiome, a spatially determined physiological system that affects human health and behavior. Preclinical experiments elucidate the role of the gut microbiome in territorial, reactive aggression behavior in mice. Results show significant differences in gut microbiome composition across the spectrum of murine aggression behavior. Moreover, manipulation of the gut microbiome via administration of short-term antibiotics and sodium butyrate, a short-chain fatty acid byproduct of microbial fermentation, increases aggression behavior. The overall goal of this research is to use basic science findings in mice to better understand how environmental exposures could influence human health and behavior, thus revealing how community health affects individuals and supplying a potential target for future intervention.
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Title: Structural connectivity of an interoception network in schizophrenia
Creator: Yao, Beier
Date: 2022
Collection: Electronic Theses & Dissertations
Description: Interoception refers to the processing, integration, and interpretation of bodily signals by the brain. Interoception is key to not only basic survival, but also many cognitive processes, especially motivational and affective functioning. There is emerging evidence suggesting altered interoception in schizophrenia, but its neural underpinning has not been examined. The current study aims to investigate the structural connectivity of a putative interoception network in schizophrenia, and its...
Show moreInteroception refers to the processing, integration, and interpretation of bodily signals by the brain. Interoception is key to not only basic survival, but also many cognitive processes, especially motivational and affective functioning. There is emerging evidence suggesting altered interoception in schizophrenia, but its neural underpinning has not been examined. The current study aims to investigate the structural connectivity of a putative interoception network in schizophrenia, and its relationship with affective functioning and clinical symptoms. Thirty-five participants with schizophrenia (SZ) and 36 healthy control participants (HC) underwent diffusion tensor imaging (DTI) and performed tasks measuring emotional functioning. Probabilistic tractography was used to identify white matter tracts connecting the key hubs forming the interoception network (i.e., rostral and caudal anterior cingulate cortex, ventral anterior insula, dorsal mid and posterior insula, and amygdala). Microstructural integrity of these tracts was compared across groups and correlated with measures of emotional functioning and symptom severity. I found that SZ exhibited altered structural connectivity in the putative interoception network, compared to HC. The structural connectivity of the network was correlated with emotion recognition in HC, supporting a link between the interoception network and emotional functioning. However, this correlation was much weaker in SZ, suggesting less reliance on this network. I did not find a correlation between the structural connectivity and clinical symptoms in SZ. These findings suggest that altered interoception may play a role in illness mechanisms of schizophrenia, especially in relation to emotional deficits.
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Title: THE ROLE OF α-SYNUCLEIN IN CHOLINERGIC NEUROTRANSMISSION IN THE ENTERIC NERVOUS SYSTEM
Creator: Yelleswarapu, Narayana KrishnaChaithanya
Date: 2021
Collection: Electronic Theses & Dissertations
Description: Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder that is manifested by significant motor impairments that decrease the quality of life and increase mortality in our elderly population. Non-motor symptoms in PD are common in patients and occur up to 2 decades prior to the onset of motor symptoms. Gastrointestinal (GI) complications, specifically constipation, is seen in over 50% of patients with PD and can be debilitating and result in malnutrition and weight loss....
Show moreParkinson’s disease (PD) is a slowly progressive neurodegenerative disorder that is manifested by significant motor impairments that decrease the quality of life and increase mortality in our elderly population. Non-motor symptoms in PD are common in patients and occur up to 2 decades prior to the onset of motor symptoms. Gastrointestinal (GI) complications, specifically constipation, is seen in over 50% of patients with PD and can be debilitating and result in malnutrition and weight loss. There is a need to elucidate the underlying mechanisms the lead to gut dysmotility in PD. Moreover, the pathologic event that causes cell death of dopaminergic neurons within the central nervous system (CNS) is observed with the enteric nervous system (ENS) decades prior to pathology in the CNS. This pathologic event is the toxic conversion and aggregation of a presynaptic terminal protein, α-synuclein (αSyn), into Lewy bodies. αSyn plays an important functional role in various cellular processes, including but not limited to, mitochondrial, lysosomal, synaptic vesicle regulation, and protease function. Therefore, we can predict the cascade of events that occur when this protein is no longer functional. Within the ENS, acetylcholine is the primary vesicular neurotransmitter involved in smooth muscle contractions. In this work I aimed to elucidate the role of pathologic αSyn on slow colonic transit disrupting cholinergic neurotransmission. In Chapter 2, we used two mouse models of hαSyn overexpression to target ENS pathology. In Chapter 3, we used a gene knockout of αSyn to further establish a functional role for the protein in cholinergic neurotransmission. We performed immunofluorescence, fecal pellet output, whole gut transit, colonic migrating motor complexes, studied longitudinal smooth muscle contractions, and junctional potentials to put together a thorough picture connecting phenotype to circuitry within the ENS. Our findings discussed in this dissertation shed light on 1) αSyn’s role in cholinergic neurotransmission, and 2) whether αSyn is necessary for normal colonic function and motility. Overall, cholinergic neurotransmission warrants a closer inspection in the ENS in PD. Strong evidence has continued to associate αSyn pathology to cholinergic neurons. Understanding this mechanism may allow for development of therapeutics that may alleviate GI symptoms in the PD population and help focus on discovering an early biomarker in diagnosing PD.
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Title: NEUROTECHNOLOGY DESIGN FEATURES’ IMPACT ON THE FUNCTION AND IDENTITY OF REACTIVE ASTROCYTES
Creator: Riggins, Ti'Air
Date: 2021
Collection: Electronic Theses & Dissertations
Description: Implantable neurotechnology offers substantial promise to improve the condition of many neurodegenerative diseases. Microelectrode arrays implanted in the brain have the capability to stimulate or record electrical activity from neighboring cells. However, shortly after implantation, a foreign body response occurs, which is what researchers believe decreases the electrical recording stability and longevity of signal detection of these devices. Established biomarkers such as astrogliosis, and...
Show moreImplantable neurotechnology offers substantial promise to improve the condition of many neurodegenerative diseases. Microelectrode arrays implanted in the brain have the capability to stimulate or record electrical activity from neighboring cells. However, shortly after implantation, a foreign body response occurs, which is what researchers believe decreases the electrical recording stability and longevity of signal detection of these devices. Established biomarkers such as astrogliosis, and stimuli such as the mechanical mismatch at the device-tissue interface, have been studied to understand the tissue response to the devices. However, the relationship of these factors with device performance is not well understood. Astrocytes play an important role in the brain’s immune system and recently, RNA analysis has confirmed transcriptional profiles of reactive astrocytes which are associated with specific injury states and neurodegenerative diseases. In this dissertation, I have investigated new biomarkers of astroglial reactivity at the electrode interface and characterized the surface topography and bending stiffness of devices. I induced two types of inflammatory astrocytic cell culture models, and I characterize each model’s reactivity in comparison to gene expression surrounding electrodes implanted in rat tissue. Atomic microscope microscopy (AFM) techniques were also used to measure surface roughness and bending stiffness as it may predict cellular adhesion and device performance. I aim to elucidate pathways in the neurological foreign body response which will give researchers new potential biomarkers to target to improve recording performance, motivating improved designs for implantable neurotechnology. The research presented in this dissertation investigates how design features influence the tissue interface and asks questions about possible ways to mitigate tissue response: (1) by exploring and summarizing the design space as a whole, suggesting ways to characterize designs and evaluating each designs’ successes and limitations (2) using a cutting edge imaging technique to image and measure material properties of three commonly used materials, (3) and creating a reactive tissue culture model, comparing its proteomic and genetic expression to the established rat model. Chapter 2 describes surface characterization techniques that could be used to better classify device features to predict performance and explores next generation probes from a design and performance standpoint. Chapter 3 uses atomic force microscopy to image and measure surface roughness on device surfaces while also measuring the bending stiffness to help determine possible micromotion in the brain. Here, we speculate what these findings mean for the performance and longevity of current probe design. Chapter 4 develops an astroglial culture model to mimic foreign body response in the brain and compare the genomic results to tissue culture near and far from the implanted device. Here, we report the transcriptomic results of the model in comparison to brain transcriptomic results, and what these biomarkers may implicate regarding tissue response and neurodegenerative signaling. This body of work uncovers knowledge recapitulating important factors of device features that affects tissue signaling at the tissue device interface, and biomarkers that play a role and cell signaling. Future directions aim at developing a more physiologically relevant tissue culture model that can predict clinical outcomes, and use high throughput screening techniques to help researchers address the challenge of long term suboptimal device performance.
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Title: TOWARD PRECISION MEDICINE : EFFECTS OF THE COMMON VAL66MET BDNF VARIANT IN THE AGING BRAIN AND IMPLICATIONS FOR THE FUTURE OF PARKINSON’S DISEASE THERAPEUTICS
Creator: Mercado-Idziak, Natosha Marie
Date: 2021
Collection: Electronic Theses & Dissertations
Description: The rs6265 (Val66Met) single nucleotide polymorphism in the gene for brain-derived neurotrophic factor (BDNF) is a common genetic variant that has been shown to alter therapeutic responses in patients with Parkinson’s disease (PD). Possession of the variant Met allele results in decreased activity-dependent release of BDNF by disrupting BDNF transport and sorting into synaptic vesicles. In the experiments detailed in this thesis, I examine the effects of the Val66Met SNP, and its interaction...
Show moreThe rs6265 (Val66Met) single nucleotide polymorphism in the gene for brain-derived neurotrophic factor (BDNF) is a common genetic variant that has been shown to alter therapeutic responses in patients with Parkinson’s disease (PD). Possession of the variant Met allele results in decreased activity-dependent release of BDNF by disrupting BDNF transport and sorting into synaptic vesicles. In the experiments detailed in this thesis, I examine the effects of the Val66Met SNP, and its interaction with aging, on therapeutic efficacy and the development of aberrant side-effects following primary dopamine (DA) neuron transplantation, a restorative experimental therapeutic approach for PD that is currently experiencing a robust revitalization following a decade-long worldwide moratorium. In particular, I hypothesized that rs6265-mediated dysfunctional BDNF signaling is an unrecognized contributor to the limited clinical benefit observed in a subpopulation of individuals with PD despite robust survival of grafted DA neurons and extensive integration into the host brain. I also hypothesized that this genetic variant contributes to the development of graft-induced dyskinesias (GID). To test these hypotheses, we generated a novel CRISPR knock-in rat model of the rs6265 BDNF SNP to investigate for the first time the influence of a common genetic polymorphism on graft survival, functional efficacy, and side-effect burden in subjects grafted with embryonic ventral mesencephalic DA neurons. In two sister studies, I compared these primary endpoints between wild-type (Val/Val) rats and those homozygous for the variant Met allele (Met/Met), in both young adult (8 m.o. at grafting) and middle-aged (15 m.o. at grafting) cohorts. In each study, rats were rendered unilaterally parkinsonian with intranigral 6-hydroxydopamine and primed with levodopa (12 mg/kg M-Fr) to induce stable expression of levodopa-induced dyskinesias (LID), the primary behavioral endpoint for assessing graft function. After levodopa priming, rats received an intrastriatal graft of embryonic ventral mesencephalic neurons (200,000 cells in young adult rats, 400,000 cells in middle-aged rats; E14 wild-type donors) or a sham graft. LID were evaluated for 9-10 weeks post-engraftment, and GID were assessed 24-48 hr prior to sacrifice. In young adult graft recipients, this research demonstrates that: 1) Met/Met rats display enhanced graft efficacy and paradoxically enriched graft-derived neurite outgrowth compared to Val/Val rats, and 2) the Met allele is strongly linked to GID development and this behavioral phenotype is correlated with neurochemical signatures of glutamatergic neurotransmission by grafted DA neurons. In middle-aged graft recipients, this research indicates that: 1) behavioral enhancement associated with the Met allele is maintained with advancing age, and 2) advanced age is associated with the induction of GID in rats of both genotypes despite the presence of widespread intrastriatal grafts. In this rapidly evolving era of precision medicine, understanding mechanisms underlying the beneficial versus detrimental impact of the Val66Met polymorphism, and/or its interaction with aging, will aid in the development of safe and optimized therapeutic approaches for remodeling the parkinsonian striatum.
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Title: PERTURBATION OF ASTROCYTIC KEAP1-NRF2-ARE PATHWAY AND GLUTAMATE TRANSPORTER EXPRESSION IN SPINAL ASTROCYTIC DEGENERATION
Creator: Wiwatratana, Duanghathai
Date: 2021
Collection: Electronic Theses & Dissertations
Description: Several cellular mechanisms are known to be involved in methylmercury (MeHg) induced central nervous system (CNS) toxicity, including the dysregulation of intracellular Ca2+, redox, and glutamate homeostasis. However, the factors that make particular neurons susceptible to MeHg toxicity, and the latency period of neurological signs and symptoms, have not yet been clearly delineated. For example, the spinal dorsal root ganglia (DRG) is the primary target of MeHg. Mercury (Hg) granules are...
Show moreSeveral cellular mechanisms are known to be involved in methylmercury (MeHg) induced central nervous system (CNS) toxicity, including the dysregulation of intracellular Ca2+, redox, and glutamate homeostasis. However, the factors that make particular neurons susceptible to MeHg toxicity, and the latency period of neurological signs and symptoms, have not yet been clearly delineated. For example, the spinal dorsal root ganglia (DRG) is the primary target of MeHg. Mercury (Hg) granules are first detected in spinal cord motor neurons (SMNs) in the non-symptomatic phase, whereas Hg granules are detected in glia later, following with neurological symptoms (Møller-Madsen, 1991). This finding suggested that the latent period (non-symptomatic phase) is associated with Hg accumulation in neurons, while the symptomatic phase occurs following Hg accumulation in glia, and the susceptibility is not associated with Hg granule accumulation in cells (Møller-Madsen, 1991). Astrocytes generally provide glutathione (GSH) for neurons to detoxify toxic insult. In the spinal cord, MeHg might perturb the antioxidant pathway, Keap1-Nrf2-ARE pathway in the spinal cord astrocytes (SCAs) consequently contribute to DRG or SMN susceptibility to MeHg toxicity. In this study, the comparative responses of different SCAs maturity to a non-toxic MeHg concentration (0.1 μM) suggested that the fully mature SCAs (Day in vitro 30; DIV30), were more susceptible to MeHg than SCAs on DIV14. The perturbation of the Keap1-Nrf2-ARE pathway in SCAs (DIV 30) during exposure to sub-toxic MeHg concentration (0.50 μM) caused a biphasic increase in antioxidant genes such as Keap1, Nrf2, Gclc, Abcc1 mRNAs expression. The concomitant increase of glutamate transporter Slc7a11 encoded for the system Xc-, and Slc1a3 encoded for EAAT1, and Slc1a2 encoded for EAAT2 expression during MeHg exposure might suggest the cooperative expression or function of these glutamate transporters. This concomitant expression was further demonstrated in studies using Nrf2-knockout (Nrf2-KO) derived SCAs. The increase of basal Slc7a11 mRNA, was concurrent to the increase of basal Slc1a3 and Slc1a2 mRNA expressions in Nrf2-KO derived SCA. The function of time of MeHg exposure indicated that Nrf2-KO derived SCAs were more susceptible to MeHg than the wild-type (WT)-derived SCAs. The pronounced susceptibility of Nrf2-KO derived SCAs was mainly due to the loss of GSH) metabolism and transport genes Gclc, GPx1, GPx4, and Abcc1 mRNAs in this genotype. MeHg significantly reduced these mRNA expressions in both genotypes. However, not all Nrf2-ARE regulated genes were affected by MeHg in similar ways in these genotypes. For example, MeHg induced the increase of Slc7a11 mRNA expression in WT-derived SCAs, but it appears to cause the reduction of this mRNA expression in Nrf2 KO-derived SCAs. Administration of antioxidant N-acetyl-L-cystine (NAC) in pretreatment (NP), co-treatment (CO), and post-treatment of MeHg (MP) prevented the reduction of SCAs metabolic functions for over 160h. The mechanism of NAC action in preventing MeHg induced SCAs degeneration is primarily due to its thiol antioxidant property.In conclusion, this study suggests that age and genetic predisposition contribute to SCAs susceptibility to MeHg toxicity. The dysregulation of the antioxidant pathways and glutamate homeostasis in SCAs potentially contributes to SMNs or DRG susceptible to MeHg.
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Title: Delineation of Delta FosB's in vivo redox sensitivity
Creator: Lynch, Haley Marie
Date: 2021
Collection: Electronic Theses & Dissertations
Description: Many neurodegenerative diseases, including Alzheimer’s disease (AD), are driven by altered reduction/oxidation (redox) balance in the brain. Moreover, cognitive decline in AD is caused by neuronal dysfunction that precedes cell death, and this dysfunction is in part produced by altered gene expression. However, the mechanisms by which redox state controls gene expression in neurons are not well understood. Delta FosB is a neuronally enriched transcription factor critical for orchestrating...
Show moreMany neurodegenerative diseases, including Alzheimer’s disease (AD), are driven by altered reduction/oxidation (redox) balance in the brain. Moreover, cognitive decline in AD is caused by neuronal dysfunction that precedes cell death, and this dysfunction is in part produced by altered gene expression. However, the mechanisms by which redox state controls gene expression in neurons are not well understood. Delta FosB is a neuronally enriched transcription factor critical for orchestrating gene expression underlying memory, mood, and motivated behaviors and is dysregulated in AD. Delta FosB regulates gene expression by dimerizing with JunD to form activator protein 1 (AP-1) which binds the promoter regions of target genes to control transcription. In controlled in vitro conditions, AP-1 complex formation and DNA binding are modulated by redox-sensitive disulfide bonds and related redox-sensitive conformational changes in Delta FosB. Here, we show that the redox-dependence of the structure-function relationship of Fos-family proteins found in vitro is also conserved in Delta FosB in cells and in the mouse brain. Under oxidizing conditions, Delta FosB cysteine residues can form disulfide bridges, including at C222 and C172, which can stabilize its interaction with a partner protein; however, these conditions reduce complex binding to AP-1 consensus sequence DNA, specifically when C172 is oxidized. We present evidence that this effect occurs in cells and in mouse brain, altering Delta FosB target gene expression during redox stress. This evidence supports Delta FosB as an important mediator of oxidative stress-driven changes in gene expression seen in neurological conditions and implicates Delta FosB as a possible therapeutic target for intervention in diseases of oxidative stress like AD.
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Title: An examination of between- and within-subject effects of stress on emotional eating over 49 consecutive days in women
Creator: Fowler, Natasha
Date: 2021
Collection: Electronic Theses & Dissertations
Description: Objective: Stress is associated with emotional eating (EE) in women cross-sectionally (between-subject). However, few studies have examined stress longitudinally limiting our understanding of how within-subject variations in stress level influence risk for EE over time and whether stress is in fact a risk factor or consequence of EE (within-subject). This study used an intensive, longitudinal study design to examine between- and within-subject effects of major life stress, daily stress impact...
Show moreObjective: Stress is associated with emotional eating (EE) in women cross-sectionally (between-subject). However, few studies have examined stress longitudinally limiting our understanding of how within-subject variations in stress level influence risk for EE over time and whether stress is in fact a risk factor or consequence of EE (within-subject). This study used an intensive, longitudinal study design to examine between- and within-subject effects of major life stress, daily stress impact, and cortisol on EE in women. Methods: An archival sample of 477 women aged 15-30 years recruited from the Michigan State University Twin Registry provided daily ratings of EE and stress impact for 49 consecutive days, along with self-reports of major life stress in the last 12 months and hair cortisol concentration (HCC), a longitudinal measure of cortisol secretion. Mixed linear models examined main and interactive effects of each stress variable on EE. Results: Both between- and within-subject analyses showed that daily stress more strongly predicted EE than major life stress. Specifically, women engaged in higher levels of EE when they experienced higher levels of daily stress impact relative to other women (between-subject) and their own daily stress levels (within-subject). There was a tendency for lower HCC to predict increased levels of EE (between-subject). Discussion: Findings confirm longitudinal associations between daily stress impact and cortisol with EE in women. Results also highlight the importance of within-subject shifts in a woman’s stress level in her risk for EE and suggest that stress management techniques may a be useful tool for treatment.
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Title: Heterogeneous Thalamic Reticular Nucleus Neurons and Their Functional Role in Thalamocortical Processing
Creator: Harding-Jackson, Laura
Date: 2021
Collection: Electronic Theses & Dissertations
Description: The thalamic reticular nucleus (TRN) is an integral regulator of information flow between the thalamus and cortex. The TRN receives synaptic inputs from both cortical and thalamic regions and based upon this information it selectively inhibits thalamic activity. TRN neurons produce action potentials in two distinct modes: a fast, transient burst discharge from a hyperpolarized state, and a prolonged, tonic discharge from a relatively depolarized state. While previous studies have...
Show moreThe thalamic reticular nucleus (TRN) is an integral regulator of information flow between the thalamus and cortex. The TRN receives synaptic inputs from both cortical and thalamic regions and based upon this information it selectively inhibits thalamic activity. TRN neurons produce action potentials in two distinct modes: a fast, transient burst discharge from a hyperpolarized state, and a prolonged, tonic discharge from a relatively depolarized state. While previous studies have characterized burst discharge as a transient high frequency discharge (> 250 Hz), these electrophysiological studies reveal a highly variable range of burst frequencies (4- 342 Hz). In these studies, I aim to discover the mechanisms underlying these highly variable burst frequencies, as well as their functional role in thalamocortical processing.In chapter two, I found that bursts from TRN neurons with relatively higher frequency discharge (>100 Hz) contain more action potentials per burst. These neurons also have higher input resistances, broader action potentials, higher action potential thresholds, and larger somas. The amplitude of the T-type calcium channel-mediated low-threshold spike, which underlies the burst discharge, is positively correlated with both the burst discharge frequency and the number of action potentials per burst. I next investigated whether small conductance calcium-activated potassium channels (SK channels) could mediate the differences in burst firing rate and action potential number. Blocking SK channels increased the frequency and duration of the burst but did not increase the amplitude of the underlying T-type calcium current. Prior studies suggest that T-type calcium channels are distributed along the dendrites in TRN neurons with high frequency burst discharge. In chapter three, I examine the distribution of dendritic calcium activity within the lower frequency bursting neurons. While the calcium signal was lower in these neurons all along the dendrites, the calcium signal was evenly distributed across proximal, intermediate, and distal dendritic regions. Investigation of SK channel activity revealed significant location-specific effects. In lower frequency bursting neurons, SK channels had the greatest influence at proximal and distal locations. In higher frequency bursting neurons, SK channels had the greatest influence at proximal and intermediate dendritic locations. Heterogeneous TRN burst discharge frequencies may represent a diverse cell population with unique dendritic ion channel composition and distribution. These results may improve our understanding of the mechanisms of TRN neuron afferent synaptic integration as well as modulation of thalamocortical inhibition. In chapter four I investigate whether intrinsic properties of TRN neurons are altered in the Fmr1-KO mouse model of Fragile X Syndrome (FXS). Individuals with FXS experience a variety of comorbidities that could involve TRN function, such as altered sensory perceptions, sleep disorders, and epilepsy. Analysis of intrinsic cellular properties revealed no differences in TRN neuron properties. Further investigation of synaptic plasticity, which is an abnormal finding in several other brain regions in FXS, also revealed no pathology. These findings suggest that TRN dysfunction does not contribute to FXS pathology.
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Title: NOVEL IMPACTS OF HOST-ENVIRONMENT INTERACTIONS IN ENTERIC GLIA THROUGH SEQUENCING AND IN-SITU EXPRESSION
Creator: Ponnampalam, Christine Dharshika
Date: 2021
Collection: Electronic Theses & Dissertations
Description: The enteric nervous system (ENS) is comprised of enteric neurons and glia that facilitate essential gastrointestinal (GI) function including motility, visceral sensation, absorption, and gut permeability. Enteric neurons and glia are responsive to environmental cues and stressors ranging from the local gut microenvironment to the host’s psychosocial state and understanding how the ENS integrates these cues to modulate local and systemic function is critical. Novel roles for enteric neurons in...
Show moreThe enteric nervous system (ENS) is comprised of enteric neurons and glia that facilitate essential gastrointestinal (GI) function including motility, visceral sensation, absorption, and gut permeability. Enteric neurons and glia are responsive to environmental cues and stressors ranging from the local gut microenvironment to the host’s psychosocial state and understanding how the ENS integrates these cues to modulate local and systemic function is critical. Novel roles for enteric neurons in host-environmental interactions have been discovered using specialized sequencing technologies but these tools have not yet readily investigated enteric glia. The goal of this dissertation was to develop and utilize genetic technologies to characterize enteric glial responses to environmental mediators. First we adapted existing genetic tools to study molecular changes in the ENS and specifically enteric glia. We developed effective means of characterizing enteric glial expression within complex in vivo models using the RiboTag model with RNA-sequencing and subsequently visualized changes in gene expression within enteric ganglia in situ. We then utilized these techniques to investigate sex-specific responses to early life stress in enteric glia. Enteric glia from male and female mice have contrasting expression profiles including differences in GPCR signaling that could contribute to sex-specific ENS signaling mechanisms and ultimately GI disease outcomes. This supports recent findings of sexual dimorphism in glial functional connectivity and may highlight a critical difference in the way enteric glia communicate with other cell types between males and females. Additionally enteric glia from male mice ‘feminize’ following iiiearly life stress through altered expression of GI and neurological disease genes including mechanisms of glial-immune communication like type I interferon signaling. Together these data highlight striking differences in the physiologic molecular patterns and nature of stress response in enteric glia between males and females that likely contribute to sexually dimorphic GI disease patterns and symptom presentation. Next we investigated ENS type I interferon responses through the stimulator of interferon genes (STING) pathway. STING responds to both microbial and host mediators to contribute to GI inflammation. However the role of STING signaling in the gut is complex and can either exacerbate or ameliorate inflammation likely dependent on complex microenvironmental factors. We provide the first known investigation of STING expression and signaling within the ENS. STING is expressed in both enteric neurons and glia but IFNB is only expressed in enteric neurons. ENS STING is activated by its canonical ligands toproduce type I interferons. However this is likely primarily mediated through canonical activation of enteric neuronal STING and the contribution of enteric glial STING to type I IFN response is minor. Additionally enteric glial STING does not alter gastrointestinal outcomes during acute colitis within the DSS colitis model. Taken together these findings suggest enteric glia do not utilize STING for canonical type I IFN signaling or contribute to disease pathology in acute DSS colitis. Enteric glial STING may instead utilize primordial and specialized signaling pathways that more selectively alter local function. Together our data provide novel genetic tools and data to further uncover molecular functions in enteric glia and their role in GI and systemic health. Using these we discovered entirely novel molecular interaction effects between sex and early life stress that shift the framework of these risk factors in GI disease. Furthermore we highlight a novel potential mediator of ENS-microbe communication with STING. Our findings further characterize the molecular patterns used by glia in response to complex environmental factors and highlight unique heterogeneity in glial intercellular communication.
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Title: ROLE OF VENTRAL TEGMENTAL AREA NEUROTENSIN RECEPTOR-1 NEURONS IN ENERGY BALANCE
Creator: Perez-Bonilla, Patricia
Date: 2021
Collection: Electronic Theses & Dissertations
Description: Dopamine (DA) neurons in the ventral tegmental area (VTA) modulate physical activity and feeding behaviors that are disrupted in obesity. Although the heterogeneity of VTA DA neurons has hindered determination of which ones might be leveraged to support weight loss, we have characterized a subset of VTA DA neurons that express NtsR1 (VTA NtsR1 neurons) that are involved in the coordination of energy balance. We hypothesized that 1) increased activity VTA NtsR1 neurons might promote weight...
Show moreDopamine (DA) neurons in the ventral tegmental area (VTA) modulate physical activity and feeding behaviors that are disrupted in obesity. Although the heterogeneity of VTA DA neurons has hindered determination of which ones might be leveraged to support weight loss, we have characterized a subset of VTA DA neurons that express NtsR1 (VTA NtsR1 neurons) that are involved in the coordination of energy balance. We hypothesized that 1) increased activity VTA NtsR1 neurons might promote weight loss behaviors, and that 2) deleting NtsR1 specifically from VTA DA neurons would promote weight gain by increasing food intake and decreasing physical activity. We first used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to activate VTA NtsR1 neurons in normal weight and diet-induced obese mice.Acute activation of VTA NtsR1 neurons (24hr) significantly decreased body weight in normal weight and obese mice by reducing food intake and increasing physical activity. Moreover, daily activation of VTA NtsR1 neurons in obese mice sustained weight loss over 7 days. Activating VTA NtsR1 neurons also suppressed how much mice worked to obtain sucrose rewards, even when there was high motivation to consume. However, VTA NtsR1 neural activation was not reinforcing, nor did it invoke anxiety, vasodepressor responses or hypothermia. We then used newly generated NtsR1 flox/flox mice to study NtsR1 deletion in both development and adulthood. Curiously, developmental deletion of VTA NtsR1 (by crossing DAT Cre mice with NtsR1 flox/flox mice) had no impact on feeding or body weight. Adult deletion of the receptor (by injecting adeno associated Cre into VTA of adult NtsR1 flox/flox mice), however, resulted in lower body weight and DA-dependent food intake. Altogether, these data suggest that modulating NtsR1 expression in the adult VTA may be useful to safely promote weight loss, and that NtsR1 is worth further exploration for managing obesity.
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Title: MIND-BODY STATE LITERACY : A PEDAGOGICAL APPROACH THAT USES MINDFULNESS AND BRAIN LITERACY TO SUPPORT LEARNING AND RELATIONAL NARRATIVE WORK
Creator: Schaefer, Erin Elizabeth
Date: 2020
Collection: Electronic Theses & Dissertations
Description: Mind-Body State Literacy: A Pedagogical Approach that uses Mindfulness and Neuroscience to Support Learning and Relational Narrative Work describes the literacies necessary to develop the habits of minds presented in the Framework for Success in Postsecondary Writing: “curiosity, openness, engagement, creativity, persistence, responsibility, flexibility and metacognition” (WPA, NCTE, & NWP, 2011, par. 2). Such habits, because they deal with students’ openness in the learning process, are key...
Show moreMind-Body State Literacy: A Pedagogical Approach that uses Mindfulness and Neuroscience to Support Learning and Relational Narrative Work describes the literacies necessary to develop the habits of minds presented in the Framework for Success in Postsecondary Writing: “curiosity, openness, engagement, creativity, persistence, responsibility, flexibility and metacognition” (WPA, NCTE, & NWP, 2011, par. 2). Such habits, because they deal with students’ openness in the learning process, are key to students’ ability to receive a liberal education. I suggest that before instructors or students can develop these habits, they need to learn to develop an open mind-body state, defined as the ability to let one’s narrative incorporate other narratives/perspectives through listening. The Mind-Body State model is comprised of three facets: brainwaves, narratives, and emotions. The Mind-Body State Literacy (MBSL) approach suggests that students develop literacies related to these three facets, drawing primarily from mindfulness practices and philosophies the center the body and compassion. I anchor my presentation of the MBSL by suggesting why it might be especially relevant as students engage in personal narrative writing in the Rhetoric and Writing classroom.
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Title: Biomaterial and genetic tools to influence neuronal network formation, excitability, and maturity at the electrode interface
Creator: Setien-Grafals, Monica B.
Date: 2020
Collection: Electronic Theses & Dissertations
Description: Understanding brain function remains a grand challenge of our time. Likewise, when neurodegeneration occurs, repair efforts are limited due to the highly heterogeneous and interconnected nature of the cerebral cortex. The drive to better understand normal brain function and pathological states has intensified demand for new technologies which can interrogate the nervous system with enhanced spatiotemporal resolution. Implanted brain electrodes are being used and developed to provide a deeper...
Show moreUnderstanding brain function remains a grand challenge of our time. Likewise, when neurodegeneration occurs, repair efforts are limited due to the highly heterogeneous and interconnected nature of the cerebral cortex. The drive to better understand normal brain function and pathological states has intensified demand for new technologies which can interrogate the nervous system with enhanced spatiotemporal resolution. Implanted brain electrodes are being used and developed to provide a deeper understanding for neurological injury and neurodegeneration. However, issues with biological integration come into play and potentially interfere with signal stability over time. Here, this work provides innovative tools that can be used to interface and control the tissue-electrode interface. In particular, we are interested in exploring surface chemistries, genetic tools, and electrode materials which favor neural regeneration around implanted electrodes. The research presented in this dissertation describes the exploration of biomaterial and genetic tools for interfacing the tissue-electrode interface: (1) characterization of surface chemistries presented to differentiating neural progenitors, and an understanding of the conditions which promote neurite outgrowth and electrophysiological maturation, (2) a blue-light inducible gene expression system, which could potentially be used to control gene expression at the implanted electrode interface, and (3) testing the impacts of "next-generation" electrode materials, such as diamond, as candidates for neural interfacing. Chapter 2 uncovers the study of various common substrates and their effects on rat neural progenitor cells, which can be used to create unique morphologies. Chapter 3 explores the use of an optogenetic system from a bacterial transcription factor (EL222) that allows for blue light-dependent transcriptional activation. Here, we validated the use of EL222 for spatial patterning of fluorescent reporter genes and developed stable expression in HEK293 cells, which can be used long-term for developing approaches for light-driven regeneration of neural circuitry. Chapter 4 reveals material and genetic factors that can affect cell structure and function. Here, we report the results of an initial characterization of the biocompatibility of the novel diamond-based materials, including conductive boron-doped polycrystalline diamond (BDD) and insulating polycrystalline diamond (PCD). The results presented will inform the transfer of the novel diamond substrate materials to sensing applications in the in vivo environment, where we expect to leverage the positive performance characteristics of the diamond materials displayed in vitro. Taken together, these chapters offer significant development of material and biological tools and that will help manage and mitigate challenges presented at the tissue-electrode interface. Future directions aim at exploring synergistic effects of electrode material and optogenetic control for controlling excitability and identity of cells at the interface, effectively bridging the divide between electronics and tissue.
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