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Effects of Cocaine on Nucleus Accumbens Core Astrocyte Calcium Dynamics and Control of Synaptic Plasticity
Get PDFPsychostimulant use disorders present a major public health concern within the United States. These drugs are associated with particularly high relapse vulnerability, and deaths associated with cocaine overdose have consistently increased since 2015. Despite this, there are currently no FDA-approved pharmacological treatments for psychostimulant use disorder. In order to develop more effective therapeutic interventions, it is imperative to develop a complete understanding of the changes in the brain that occur as a consequence of drug abuse. While much is known about neuronal changes that are observed with drug use and the development of dependence, relatively little is known about cocaine-mediated functional changes in astrocytes that affect synaptic transmission. Astrocytes form tripartite synapses with neuronal pre- and postsynapses, at which they respond to synaptic transmission with elevations in intracellular calcium and accordingly, respond by modulating synaptic function. Published data from the Reissner lab indicate that astrocytes in the nucleus accumbens (NAc) core exhibit significantly reduced structure and synaptic colocalization following long-access (LgA, 6 h/day, 10 days) cocaine self-administration and 45 days of abstinence, as evidenced by a ~40% reduction in surface area, volume, and synaptic colocalization (Kim et al., 2022). While these structural changes suggest reduced physical interaction between neurons and astrocytes, it remains unknown exactly how neuron-astrocyte communication is affected at NAc core tripartite synapses at the timepoint that corresponds with structural changes. Accordingly, experiments performed and described in this dissertation tested the overarching hypothesis that LgA cocaine self-administration and prolonged abstinence impairs the ability of astrocytes to “listen” and respond to synaptic activity via calcium responses, and in turn, “talk to” and regulate synaptic transmission. Specifically, the first aim examined astrocyte calcium dynamics and the ability of astrocytes to respond to synaptic transmission after LgA cocaine self-administration and abstinence. While astrocytes were not impaired in their ability to respond to glutamatergic input between cocaine and saline groups, astrocytes from the NAc core of the cocaine group exhibited significantly reduced microdomain calcium activity. Aim 2 examined astrocyte ability to regulate synaptic transmission following cocaine self-administration and abstinence. This experiment revealed hypoactivity at prelimbic to NAc core projections, as measured by paired-pulse ratio (PPR) and excitatory postsynaptic current (EPSC) amplitude. It further identified projection-specific and MSN subtype-specific cocaine-mediated changes in astrocyte regulation of synaptic transmission. Specifically at PL to NAc core synapses, astrocyte stimulation affected only PPR in D2-MSNs in saline rats. When astrocytes within the terminal field in the NAc core were stimulated, D1- and D2-MSN EPSC amplitude was significantly increased in both saline and cocaine rats. In summary, this dissertation identifies nuanced changes in neuron-astrocyte communication at the timepoint in abstinence from cocaine that corresponds with significant changes in astrocyte structure and synaptic colocalization in the NAc core. These data expand the understanding of astrocyte contributions to the neurobiological mechanisms underlying drug dependence and relapse vulnerability.Doctor of Philosoph
The Economics of Pharmaceutical Line Extensions and Regulatory Policy
Get PDFThis dissertation consists of two essays, a primary and a supplementary, on the economics of pharmaceutical line extensions. The FDA grants a three-year market exclusivity period for reformulated versions of existing drugs, known as line extensions, upon their approval. This policy can incentivize manufacturers to delay the launch of improved drugs until the original formulation's patent nears expiration, depriving patients of earlier access to better treatments. Chapter 1 considers a more detailed structural approach that captures the manufacturer's dynamic problem on when to introduce a line extension and how they should price their products, given the current policy. I develop a dynamic model to analyze manufacturer pricing and launch timing strategies under various policies, assessing how removing delay incentives impacts overall welfare. Applied to the dementia drug market, my findings show that a "no exclusivity" policy enhances consumer welfare, even though it introduces the risk that some line extensions might not be developed due to reduced profitability. In contrast, providing "full exclusivity" after the original patent expires leads to significantly higher drug costs for insurers with minimal gains for consumers. Simulations indicate that line extensions with only minor quality improvements are most at risk of not being developed under a no exclusivity policy, which limits consumer welfare losses. Chapter 2 describes a simpler model that provides a high-level approximation of the costs of developing line extensions at a broader scale across all therapeutic classes. This work offers empirical estimates on the cost of developing line extensions but does not make use of the more sophisticated approach, at the cost of not explicitly modeling the individual manufacturer's timing trade-off. The benefit of this approach is that it allows for analysis across the universe of line extensions, rather than focusing on a specific case study. I view this analysis as a good starting point that helps policy makers address the question at hand in a timelier fashion, while still allowing for analysis that approximately captures the main objects of interest well. Both chapters provide a blueprint to potentially combine the two approaches used, to provide a richer analysis as to the consequences alternative reward policies may have if implemented. I believe this is a great avenue for future research, as more detailed data becomes available for researchers and policy makers, and these chapters provide a framework to allow the richer analysis to be conducted.Doctor of Philosoph
ARE YOU FREE OR ENSLAVED?: FREE PEOPLE OF COLOR MAINTAINING FREEDOM THROUGH DOCUMENTATION 1793-1860
Get PDFFrom 1793 to the American Civil War, the Free Negro Register was used as a tool by the Virginia state government to keep surveillance on the growing free people of color population. They were supposed to prove their freedom by registering every three years and carrying freedom papers showing their registration. The Free Negro Register, however, never worked as intended. Many free people of color simply did not register. Others registered once, but did not re-register every three years as the law required, the penalties of doing so could include fines, indefinite jail time, and re-enslavement. The free colored population, however, did not follow the law in mass. This thesis argues that free people of color were able to maintain their freedom when not following laws that racially targeted them and theoretically that could reenslave them if convicted. Other forms of documentation could be used in place of the Free Negro Register, allowing these free colored people to maintain their freedom while at worse, having to pay a fine and face jail time until they gained the necessary documentation from the Free Negro Register. This argument presents the power that documents had in the slave empire of the American South, but also the decisions of free people of color as they worked to stay free.Master of Art
SPECTROSCOPIC AND ELECTROCHEMICAL CHARACTERIZATION OF ENERGY CAPTURE AND STORAGE MATERIALS
Get PDFQuantum confined semiconductor nanocrystals (NCs), such as quantum dots and nanoplatelets, are promising materials for energy capture technologies because of their size-dependent optoelectronic properties that arise from confinement of charge carriers at sizes below the material’s exciton Bohr radius. Because of their high surface-to-volume ratios, the NC surface plays a key role in their performance for numerous applications. Surface defects such as undercoordinated surface ions trap charge carriers, hindering NC optoelectronic properties. Although surface modification has been demonstrated to counteract surface defects, the limited understanding of ligand exchange mechanisms and lack of a molecular-level understanding of the NC surface obstructs the optimal performance of NCs.To tackle this conundrum, the work presented in this dissertation outlines efforts to elucidate reactivity at NC surfaces. Two projects focused on enhancing molecular-level understanding of the NC surface are discussed. First, the surface reactivity of oleate-capped PbS NCs with primary amines as non-native L-type ligands is assessed. This work resolves the mechanisms through which primary amines bind to the NC surface and displace native Z-type ligands and identifies the robust electronic structure of PbS NCs that persists through significant surface changes. Ligand binding motifs and thermochemistry at the NC surface are subsequently probed by quantifying the self-exchange of oleic acid ligands in PbS NCs. In a parallel project, electrochemical modulation of the energetics of hybridized states arising from nanoplatelets coupled with light in an optical cavity are investigated, highlighting the versatility of NCs for diverse applications.Coupled with energy capture technologies, redox-flow batteries (RFBs) are a promising alternative for storing large amounts of energy through electrolyte reservoirs. In a final project, the electrochemical properties of quinone and quinone derivatives are investigated as potential RFB electrolytes extracted from naturally occurring fungi. Their electrochemical and chemical reversibility were identified under neutral and buffered conditions, gauging the impact of different conditions in the stability of potential RFB electrolytes. The work described herein serves as a collection of characterization methods to develop design principles for improved energy capture and storage materials, paving the way to combine different systems for a sustainable energy economy.Doctor of Philosoph
A NEW TYPE OF NONSUPPRESSIBLE VIREMIA: HIV-1 CONSTITUTIVELY PRODUCED FROM INFECTED MACROPHAGES
Get PDFThe effectiveness of antiretroviral therapy against HIV-1 can be quantified by a decrease in HIV-1 RNA in the plasma. Individuals experience virological failure when the plasma viral load does not decrease, does not fully suppress below the limit of quantification, or returns after being suppressed. Here we describe three study participants who experienced an unusual form of virological failure, where a drug sensitive virus persisted despite adherence to ART. The persistent viral population was diverse, and macrophage-tropic, while CD4+ T cell-tropic viral populations were suppressed by ART. This viral population was rare or absent from PBMC DNA and found to have defects in the viral accessory protein Vpr. These participants have a rare presentation of macrophage-tropic virus, which is normally isolated in immune privileged compartments, suggesting the production by a large systemic population of infected macrophages that are more slowly cleared by immune cells when compared to CD4+ T cells.Master of Scienc
Novel Privacies: Surveillance and Enclosure in 1960s American Fiction
Get PDFThis dissertation presents three interrelated claims. First, that American novels of the 1960s exhibit a literary formation that I call enclosure. At the same time that they conspicuously display their characters’ subjection to various forms of surveillance, novelists from this period produce formal and thematic spaces that appear beyond the reach of other characters, the reader, and even, occasionally, the author. Second, that these enclosures constitute the American novel’s response to contemporary developments in surveillance technology, facilitated, in part, by the invention of the transistor in the late 1940s. The authors I analyze present the novel as a hopeful haven of privacy that persists even under the conditions of pervasive surveillance that these new technologies enable. Third, that there exists a reciprocity between these novelists’ turn to enclosure and contemporary changes in American privacy law. Each responds to the emergence and proliferation of audio bugs, peephole cameras, and even LSD by conceptualizing new forms of privacy, collapsing distinctions between mental content and physical spaces in images of enclosure. By bringing archival materials related to electronics miniaturization, government surveillance programs, and privacy law to bear on close readings of contemporary novels, this dissertation clarifies that underlying this new literary formation is a pursuit of individual enclosure in a world beset by paranoia and official acts of invasion. Each chapter examines the use of new formal techniques—or refashioned old ones—deployed to the ends of resisting, redirecting, accommodating to, or exploiting subjection to pervasive exposure. Novel Privacies thus tells a new story about the novel’s response to a quantitatively unprecedented and qualitatively distinct regime of surveillance.Doctor of Philosoph
Prescription for Savings? Disclosure in the Drug Market
Get PDFThe market for prescription drugs in the United States is complex and rising costs are cause for concern. Recent regulatory efforts to rein in drug prices have targeted pharmacy benefits managers, or PBMs. These opaque middlemen negotiate with drug makers on behalf of health plans and hence hold private information about the true cost of drugs. I study the effectiveness of two types of disclosure regulation in reducing drugs costs for patients and health plans: disclosure from PBMs to other firms in the drug market (inter-firm disclosure) and disclosure from PBMs to government regulators. I find inter-firm PBM disclosure increases prescription drug costs for health plans but decreases costs for patients. Cross-sectional tests reveal the effect depends on the specific user of the disclosure: health plans use PBM disclosures to negotiate lower costs for monopoly drugs, while drug manufacturers use PBM disclosures to minimize aggressive discounting for competitive drugs, leading to higher costs. I find no average effect of PBM disclosure to regulators, but cross sectional tests reveal a decrease in drug costs in areas of increased regulator attention. My results suggest PBM disclosure regulation can affect prescription drug spending by billions of dollars in a single year, providing timely evidence for regulators and policy-makers as they address rising drug costs.Doctor of Philosoph
ELECTRO-FLUID-MECHANICAL COMPUTATIONAL MODELS OF THE HUMAN HEART
Get PDFComputational models that integrate key anatomical and functional components of the heart are an important tool in understanding the complex electrophysiological mechanisms governing cardiac activation. This thesis presents novel approaches for modeling both the whole heart and atrial electrophysiology, with a focus on the cardiac conduction system and patient-specific fiber architecture. In Chapters 2 and 3, we develop an electrophysiology-driven immersed finite element-difference framework featuring a network-based Purkinje fiber system and a detailed representation of the sinoatrial node, enabling bidirectional coupling between the conduction system and myocardium. Additionally, we introduce a computationally efficient monodomain-monodomain coupling algorithm to integrate one-dimensional conduction pathways, such as the Purkinje network, with three-dimensional myocardial tissue. This methodology is applied to patient-specific whole-heart simulations, demonstrating physiologically relevant activation patterns. In Chapter 4, we develop a semi-automated rule-based algorithm for generating left atrial fiber orientation, addressing the challenge of complex muscle arrangement and its influence on electrical propagation. Using harmonic fields that satisfy carefully selected boundary conditions, this approach robustly reconstructs multilayer fiber architecture across diverse anatomical variants, as demonstrated in a cohort of atrial fibrillation patients. Electrophysiology simulations highlight the importance of detailed fiber representation in capturing complex activation patterns. Together, these contributions advance computational heart modeling by improving the representation of cardiac conduction, and providing a framework for investigating pathophysiological conditions such as bundle branch block and atrial fibrillation.Doctor of Philosoph
PLATFORM COMPETITION IN TWO-SIDED MARKETS
Get PDFUnderstanding what drives competition between platforms in two-sided markets is essentialfor antitrust authorities and policymakers, especially as platform interactions diverge from thosein traditional markets. This paper explores the role of product differentiation in shaping platformcompetition within the vacation rental industry, using a rich dataset of properties in coastal NorthCarolina. Differentiation stems from features such as oceanfront access, number of bedrooms,bathrooms, and pet-friendliness. I develop and estimate a consumer choice model that accountsfor the dynamic nature of availability, where each booking alters the options available to futureconsumers. The model reveals that consumers are willing to pay 118 for an extra bedroom, 18 for an extra bathroom. I find a negativerelationship between product differentiation and platform market concentration, supported byboth preliminiary and structural analyses. Counterfactual analysis further suggests that, in thisindustry, the benefit of sellers listing alongside similar properties—by attracting more interestedconsumers—outweighs the downside of intensified price competition, driving the observed negativerelationship.Doctor of Philosoph
INTERAGENCY DISCLOSURE USE IN GOVERNMENT ENFORCEMENT
Get PDFI examine how government agencies use other agencies’ public disclosures in their enforcement decisions, which I refer to as interagency disclosure use. I assess the role of interagency disclosure use in two settings. First, I find that after the EPA makes its enforcement data publicly available, the SEC is more likely to investigate firms with EPA enforcement actions, consistent with the SEC using EPA disclosures to select firms to investigate. However, I find that EPA disclosures have no substantive effect on SEC investigation outcomes or duration. Second, using a novel measure of IRS audits from a generative AI model, I find that after an SEC-mandated disclosure on tax uncertainty, the IRS is more likely to audit firms that disclose tax uncertainty than those that do not. I further find evidence suggesting that SEC-mandated tax disclosures causally affect IRS audits using plausibly exogenous variation in firms’ fiscal year ends. Finally, I find that the tax disclosures have no significant effect on audit settlements but increase audit duration. Overall, the results suggest that government agencies use interagency disclosures to select firms to investigate, shedding light on an important input to the regulatory enforcement process.Doctor of Philosoph