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Mimicking the Structure and Polymerization Behavior of Clathrin Using DNA Origami
No full textDNA origami is a recently developed nanotechnology paradigm that has demonstrated significant convenience and utility for its ability to self-assemble nanostructures with exquisite control over shape and behavior. Controlling the polymerization and self-assembly properties of DNA origami monomers and polymers would allow for the triggered assembly of large-scale structures with applications in diagnostics and nanofabrication. To that end, we developed a DNA origami system that mimics the structure and polymerization activity of the cellular protein clathrin, which is known for its finely tuned nucleation behavior based on interactions between non-nearest neighbor monomers. We designed triskelion-shaped DNA origami monomers that folded into clathrin-shaped structures with polymerization functionality and multiple distinct binding domains that could engage in non-nearest neighbor interactions. We experimentally verified multi-domain monomer folding using agarose gel electrophoresis and transmission electron microscopy. Guided by a set of abstract models and physical intuitions that incorporated principles from thermodynamics and graph theory, we then designed polymers to recreate the hexagonal lattices formed by clathrin, and progressively improved lattice formation using an iterative process. Hexagonal clathrin-like polymer lattices were successfully formed using a set of 14 rationally designed and unique monomers. This research lays key groundwork for expanding the control that can be exerted over nanoscale self-assembly and nucleation behavior in a biologically inspired fashion.Biomedical Engineering A
The Role of Trade Imbalance and Asymmetry in Interstate Wars
Get PDFWhile liberal international relations theory often emphasizes that trade interdependence fosters peace, recent patterns of violent interstate conflicts challenge this assumption. According to the Global Peace Index 2024, there are currently 56 active conflicts globally, most of which are ongoing since the end of WWII, and with fewer conflicts being resolved (The Institute for Economics & Peace, 2024).
This thesis investigates the complex relationship between trade interdependence and interstate conflict, with particular attention to how imbalances and asymmetries in bilateral trade (dyads) can exacerbate rather than reduce conflict risks. Drawing on the Hague Centre for Strategic Studies’ (HCSS) dangerous dyads model and the Heidelberg Institute for International Conflict Research’s (HIIK) Conflict Barometer 2023, the study examines six high-risk dyads: Russia - Ukraine, Russia - Georgia, Afghanistan - Pakistan, China - India, Rwanda - Uganda, and Syria - Türkiye.
The findings of this thesis challenge the liberal assumption that economic interdependence universally fosters peace and demonstrate that trade interdependence is not inherently pacifying. A hypothesis is proposed to explain the various political, economic, and social conditions under which trade interdependence transitions from peace to conflict. This thesis also contributes to the broader debate on trade and peace by suggesting that trade positions and outlooks are critical in understanding whether economic ties stabilize or destabilize interstate relations.Extension Studie
Inferring dynamic extracellular matrix composition of the thymus: towards a biomimetic scaffold for T cell culture
Get PDFImmunotherapy is a pioneering approach using T lymphocytes (T cells) to fight cancer and immune deficiency, which together affect millions of patients in the US. Current clinical therapies require patient- or donor-derived T cells, leading to manufacturing delays and limited supply. While stem cell-derived T cells offer a scalable strategy to meet growing demand and increase accessibility to therapy, generating mature and clinically usable T cells through this method is challenging and cell yields remain low.
In the body, T cell maturation relies on cell migration through thymic structures that change chemically and physically over time; the extracellular matrix (ECM) has a role in shaping these evolving niches. Existing solutions to producing “off the shelf” engineered T cells use mouse thymic epithelial cell lines and native ECM to adapt key in vivo components of the T differentiation process. However, these solutions are not fully synthetic, limiting their scalability and potential therapeutic use. Additionally, these models of the thymic ECM overlook developmental shifts in thymic structure that might advance an understanding of T cell maturation.
Therefore, dynamic biological and chemical properties in the thymic microenvironment are important in efficiently producing mature T cells in vivo. This project constructs a proof-of- concept biomimetic platform for immune cell differentiation from stem cells based on these changing characteristics of the thymic extracellular matrix. Using single-cell RNA sequencing data to quantify gene expression levels, the extracellular matrix composition of the thymus at different developmental stages is computationally characterized, and characteristic ratios of key extracellular matrix components (fibronectin, collagen, and laminin) are identified at these different stages. These ratios are then used to engineer a stage-specific alginate-based hydrogel for cell culture, designed to replicate thymic tissue stiffness and viscoelasticity with tunable properties that reflect different developmental stages. Using this stage-specific platform, researchers can investigate how T cell differentiation, activation, and toxicity are influenced by the thymus's developmental stage. Additionally, this platform could allow for the identification of the optimal stage of thymic development to mimic in T cell culture scaffolds, enabling more scalable T cell expansion.Engineering Sciences S
Developing new chemoproteomic platforms to decode and perturb the degradome
No full textProteins are the functional units of the cell, orchestrating virtually every biological process from cellular metabolism and signal transduction to structural support and immune defense. The precise and temporal regulation of protein abundance is critical to maintain cellular homeostasis and, by extension, human health. Dysregulation of protein homeostasis can lead to many diseases including cancer, neurodegeneration, and metabolic disorders, which highlights the importance of understanding how exactly a protein is degraded. Doing so opens new opportunities to therapeutically harness and reprogram protein homeostasis.
A subset of the human proteome is remarkably short-lived, with some proteins persisting for just minutes. Despite their brief existence, these proteins play fundamental regulatory roles, controlling key cellular processes and enabling rapid responses to external stimuli. Previous proteomic studies from our lab using cycloheximide pulse-chase experiments have revealed that approximately 5–10% of the human proteome consists of such short-lived proteins (SLPs). These proteins are enriched in functionally important protein classes, including transcription factors, ubiquitin ligases, and membrane-bound signaling receptors. Their transient nature reflects the cell’s need to tightly regulate their abundance, often through active degradation pathways. In a way, dissecting the mechanisms of SLP degradation provides a direct line of sight into the mind of the proteostasis network itself. The ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway (ALP) constitute a highly coordinated network of proteins responsible for maintaining protein homeostasis through the regulated degradation and stabilization of nearly all expressed proteins. Given their central role in cellular protein quality control and overall cellular function, it is striking how little is known about the turnover mechanisms of a substantial portion of the proteome. Despite these knowledge gaps, therapeutic strategies targeting the UPS have already yielded FDA-approved drugs effective in treating various cancers. These successes validate the UPS as a therapeutically tractable target and underscore the importance and opportunity of understanding natural protein regulatory mechanisms to better treat human disease. Key substrate-ligase pairs—such as NRF2-KEAP1, HIF1A-VHL, and TP53-MDM2—serve as paradigms for how the successful decoding of how an SLP protein is degraded can be exploited for drug development. Aside from these select few examples, however, the precise mechanisms underlying the degradation of the overwhelming majority of SLPs remain poorly understood. This raises fundamental questions that I sought to answer during my PhD: through which cellular pathways are these proteins degraded? What intrinsic features of a protein determine their specific degradation routes? Can we exploit our SLP degradome map to identify therapeutic pinch points to target historically ‘undruggable’ proteins like transcription factors? And lastly, can we build new discovery platforms to find molecules that precisely modulate the degradome?
Mass spectrometry–based proteomics provides a unique opportunity to capture a comprehensive snapshot of the entire proteome in a single experiment. With chemical multiplexing using tandem mass tag (TMT) reagents, researchers can now label and analyze up to 35 samples simultaneously in one combined run. By leveraging multiplexed mass spectrometry–based proteomics, I recognized a unique opportunity to uncover the mechanisms underlying the degradation of hundreds of short-lived proteins (SLPs), to elucidate how the oncogenic transcription factor ASCL1 is regulated by its endogenous ligase, and to build a complementary drug discovery platform for identifying molecules that target the proteostasis network.
In my first project, I developed a multiplexed chemoproteomics platform to systematically profile the degradome of a cell line of interest. This was achieved through a simple assay in which cells were treated with potent inhibitors targeting the proteasome (Bortezomib), lysosome (Bafilomycin A1), ubiquitin system (TAK243), neddylation system (MLN4924), and translation machinery (cycloheximide). By quantifying protein accumulation in response to inhibitor treatment relative to DMSO, I could determine a protein’s pathway dependencies and whether it is short-lived in one unified proteomics-based assay. The specific patterns of accumulation in response to these inhibitors allowed me to then categorize the short-lived proteome into mechanistically distinct pathways. Of the SLPs that responded to chemical inhibition of the proteostasis network, I found that proteins are either degraded by the proteasome (~70%), lysosome (~25%), or by both pathways (~5%). Within these main degradation categories, proteins can further be subcategorized based on their ubiquitin-dependency (ubiquitin-dependent/CRL-independent, ubiquitin-dependent/CRL-dependent, and ubiquitin-independent). In total, I binned proteins into 9 mechanistically distinct degradation pathways. Interestingly, there were a subset of proteins that could not be binned into any one of the previously mentioned categories. This was either because a protein did not meet statistical cutoffs, or more interestingly, due to potentially being regulated by a protease or even an alternative pathway that may cause the acute depletion of these proteins. For SLPs degraded by the proteasome, I found that virtually all these proteins are degraded in a ubiquitin-dependent manner (~95%) with a slight bias toward non-CRL mediated degradation, which was the predominant mechanism of degradation of most transcription factors. A small subset of proteasomal substrates (~5%) are degraded through ubiquitin-independent mechanisms. These proteins defy the canonical model in which substrates are first ubiquitinated and then delivered to the proteasome via shuttling factors or through direct recognition by one of the proteasome’s many ubiquitin receptors. Notable examples included ODC1—a pioneering case that established the concept of ubiquitin-independent degradation by the 26S proteasome—and MIDN, a recently characterized substrate that has reignited major interest in this degradation pathway. These ubiquitin-independent proteasome substrates exhibit the fastest rate of degradation and are significantly smaller than SLPs that are eliminated by other pathways. Lysosomal proteins are degraded equally in a ubiquitin-dependent (mostly membrane-bound signaling receptors) and ubiquitin-independent manner (mostly structural proteins). Virtually all ubiquitin-dependent lysosomal degradation occurs in a CRL-independent manner. For proteins degraded by both pathways, the vast majority are targeted through a ubiquitin-dependent yet CRL-independent mechanism. These substrates are enriched at the endoplasmic reticulum, reflecting the unique mechanisms of degradation that occur at this organelle. Overall, the findings from this atlas can inform therapeutic strategies to modulate SLP abundance through the proteostasis network. This multiplexed degradomics assay can be extended to include additional selective inhibitors against other key nodes of the proteostasis network, such as heat shock proteins, p97/VCP, and specific proteasome subspecies. Expanding the scope in this way will add granularity and resolution to our degradome map, providing deeper insight into how these short-lived yet important proteins are regulated by the proteostasis network.
From my short-lived protein degradation atlas, I found that ASCL1 is degraded by the proteasome in a ubiquitin-dependent, but CRL-independent manner. ASCL1 is normally a lineage-defining master regulator of neuronal cell identity, and it drives most small cell lung cancers (SCLCs). It is one of the deadliest cancers with limited treatment options. In close collaboration with Dr. Keita Masuzawa from Dr. Matthew Oser’s lab, we found that ASCL1 exhibits the “Goldilocks” effect in small cell lung cancers (SCLCs) whereby levels must be precisely maintained—too much or too little of this transcription factor are deleterious to ASCL1-dependent SCLC cells. This suggested that there may be a therapeutic opportunity to modulate ASCL1 levels through enhancing or inhibiting its natural turnover by its endogenous ligase. To mechanistically dissect this regulatory axis, we employed a combination of proteomic, functional genomics, in silico structural analysis, genetic deletion and chemical studies. From this work, we identified that the HECT E3 ligase HUWE1 recognizes the phosphorylated C-terminus of ASCL1 to mediate its destruction. We demonstrate that the C-terminus is necessary for recognition and degradation by HUWE1 and conversely, we show that this C-terminal sequence is sufficient to induce the rapid HUWE1-dependent degradation of GFP upon transplantation. Strikingly, C-terminal mutants demonstrate increased interactions with histones and the epigenetic machinery. This observation was corroborated via ChIP-seq experiments. Interestingly, despite significantly prolonging ASCL1 half-life and accumulating at canonical E-box binding motifs, C-terminal deletion mutants could not rescue survival defects when expressed in an ASCL1 knockout background. These results suggest that the C-terminus may serve a dual role as both a potent degron and a region essential for normal function. We performed a saturating base-editing screen to identify HUWE1 mutations that modulate ASCL1 degradation. Charge-flipping mutations within a helix enhanced degradation, nominating a region we term the bouncer helix. Although unresolved in prior cryo-EM structures and predicted to be disordered, AlphaFold 3 modeling revealed that the bouncer helix packs tightly against a positively charged pocket, termed the donut, where phosphorylated DDIT4 was previously shown to bind. In the apo structure, the bouncer blocks the donut, but structural modeling suggests it is displaced to permit substrate engagement. In an orthogonal base-editing screen, we show that these bouncer helix mutations also lead to enhanced degradation of MYCL, which we recently found to be another HUWE1 substrate based on complementary expression proteomic and functional genomic studies. Cells expressing these bouncer helix mutations exhibited shorter ASCL1 half-lives and enhanced ASCL1 ubiquitination compared to WT cells. Collectively, these results reveal new druggable interaction between the oncogenic transcription factor ASCL1 and its ligase HUWE1. We also propose a generalizable mechanism by which HUWE1 recognizes its substrates. Lastly, we propose that targeting molecules to the donut region of HUWE1 could enable selective gluing and enhanced degradation of ASCL1 as a therapeutic strategy for SCLC.
For my third project, I developed a live-cell, targeted covalent drug discovery platform to identify functional binders. Ubiquitin-mediated degradation depends on a dedicated network of proteins that transfer ubiquitin onto substrates for proteasomal turnover. Both catalytic and allosteric cysteines within these proteins are critical for activity, and modulating these sites can fine-tune substrate levels. HUWE1, for example, contains a catalytic cysteine in its active site that is amenable to covalent inhibition via cysteine-targeting electrophiles. Activity-based protein profiling (ABPP) is a powerful, unbiased approach to assess proteome-wide electrophile reactivity. However, ABPP datasets often suffer from missing values, limiting their utility when the goal is to find inhibitors for a specific target. To address this, I developed CysDig, a targeted chemoproteomics platform designed to overcome the missing data problem by enabling drug hunters to easily generate targeted proteomic assays for covalent drug discovery. Through integration with GoDig, a TMT-based targeted proteomics strategy developed in our lab, CysDig allows users to select up to 300 targets of interest. Unlike conventional approaches, CysDig bypasses cysteine enrichment. In doing so, the entire proteome remains available for quantification. Collectively, these innovations enable hybrid targeted assays in which covalent target engagement can be measured in parallel with changes in substrate abundance. This makes CysDig particularly well-suited for discovering small molecule binders against the proteostasis network, where simultaneous assessment of compound engagement with UPS proteins and corresponding substrate abundance changes is especially informative at the screening level.
Using CysDig, I identified 31 covalent inhibitors that engage the HUWE1 active site. I prioritized CL129 for follow-up due to its relative specificity for HUWE1 over other HECT E3 ligase family members, UBE3A and UBE3C. Direct detection of the covalent adduct on HUWE1 and covalent docking studies confirmed target engagement. In cells, CL129 treatment caused a dose-dependent accumulation of known HUWE1 substrates—DDIT4, MCL1, SCNM1, and C16orf72/HAPSTR1. Importantly, in SCLC lines, CL129 increased ASCL1 levels at baseline and extended its half-life in a HUWE1-dependent manner.
Taken together, this work provides the research community with three key contributions. First, my degradome atlas maps the mechanisms of short-lived protein degradation for hundreds of proteins, offering new opportunities to further dissect the exact mechanisms of degradation and to use that understanding to inform therapeutic discovery. Second, in collaboration with Dr. Keita Masuzawa from Dr. Matt Oser’s lab, we decoded how ASCL1 is degraded by its endogenous ligase, HUWE1. Zooming out, we developed a generalizable framework for translating the initial mechanistic insights provided by my degradome atlas into a detailed understanding of how exactly a protein is regulated. We believe that the experiments outlined in this chapter can be generalized to any protein found to be regulated by the proteostasis network. Third, the CysDig platform enables targeted screening of cysteine-reactive compounds against the UPS. Its utility will scale with our increasing knowledge of how proteins are degraded by the proteostasis machinery. Collectively, my thesis presents a blueprint to decode endogenous degradation pathways and contributes a new drug discovery platform that is specifically tailored for proteostasis-centric drug discovery.Biological and Biomedical Science
Genes required for maintaining fidelity of Plasmodium daughter cell formation
No full textApicomplexan parasites utilize a divergent set of cell division mechanisms to replicate and form daughter cells that are morphologically distinct between different genera and even between different lifecycle stages within a species. Within a specific lifecycle stage, the parasites usually generate many daughter cells at once from a single parent. This, coupled with the complexity of the parasite life cycle across different hosts, presents a unique challenge for the parasite to ensure the successful inheritance of the replicated organelles and genetic material for each individual daughter cell. One such parasite that contributes to severe global health burden is Plasmodium falciparum, the causative agent of the deadliest form of malaria. This thesis aims to advance our understanding of the divergent cell division modes of Plasmodium using advanced microscopy techniques, focusing specifically on proteins involved in nuclear inheritance and their profound impact on the overall fidelity of daughter cells.
The mode of asexual replication in the vertebrate host red blood cells (RBCs) is known as schizogony, and the mode of replication at the mosquito host midgut is called sporogony. In both cases, the daughter cell building materials including the nucleus, other organelles, and critical cytoskeletal components are replicated several times before a single round of cytokinesis forms many daughter cells. In Chapter 2, we demonstrate the importance of the two Plasmodium striated fiber assemblin (SFA) homologs, SFA1 and SFA2, and the rootlet fiber they form in these processes using super-resolution light microscopy and electron microscopy, filling a critical knowledge gap of Plasmodium cell biology.
In Chapter 3, we use co-immunoprecipitation with an SFA protein as bait followed by mass spectrometry to discover potential interacting or associated proteins of the SFA rootlet fiber. We discuss the hits with known function or characterized orthologs and provide the list of proteins for future characterization. Then, we characterize three hits of unknown function from the list, PF3D7_1339700/PfPEARL, PF3D7_1307900/PfBBx, and PF3D7_0703600. Using immunofluorescence and ultrastructure expansion microscopy, we illustrate their localization relative to the SFA rootlet fiber and elucidate and/or hypothesize their roles during the erythrocytic asexual cycle. We find that all three proteins are important for asexual replication in RBCs and discuss future directions for deeper probing into their functions.
Overall, our studies paint a more detailed picture of Plasmodium cell division, providing novel insights into the mediators of high-fidelity daughter cell formation. Characterizing the functions of SFAs and associated proteins has allowed us to delineate the structural and molecular framework that underpins nuclear inheritance and apical organelle formation in Plasmodium. These findings not only enhance our understanding of the fundamental biology of this deadly parasite but also open avenues for targeting parasite-specific division mechanisms in future antimalarial development.Biological and Biomedical Science
Advancing Therapeutic Gene Editing through Development of Novel Delivery Modalities and Gene Editing Strategies
No full textSince the landmark discovery of CRISPR-Cas9 system in 2012, the field of gene editing has rapidly expanded its toolkit. Advances such as base editors (BEs) and prime editors (PEs) now enable precise and permanent DNA modifications. These technologies hold promise not only for correcting a broad spectrum of genetic diseases, but also for innovative applications in common diseases, such as cancer and autoimmune disorders. However, realizing the therapeutic potential of gene editing technologies requires overcoming several key challenges. In this thesis, I describe the development of novel delivery modalities and gene editing strategies to advance the therapeutic applications of CRISPR-based precision gene editing technologies.
In Chapter 1, I review the current state of gene editing technologies, highlighting CRISPR-based precision gene editing tools, existing delivery modalities with a focus on in vivo delivery, and key preclinical and ongoing clinical applications.
In Chapter 2, I describe the development of an engineered virus-like particle (eVLP) system for the in vivo delivery of PE components. PE is a versatile gene editor capable of introducing any base substitution as well as small insertions and deletions, but its large size and complex guide RNA (gRNA) structure pose challenges for efficient delivery. eVLPs represent a promising delivery modality that combine the advantages of viral and non-viral delivery modalities. Through iterative rounds of PE protein and gRNA engineering, along with eVLP construct optimization, we generated PE-eVLPs with substantially improved cargo packaging, thereby enhancing potency. In this chapter, I describe the engineering campaigns that improved the PE-eVLP potency and demonstrate their applications in mouse models for efficient transient delivery of PE cargo in vivo.
In Chapter 3, I describe the development of a gene editing strategy to target prion disease, a fatal and rapidly progressing neurodegenerative disease with no effective treatments. Reducing endogenous prion protein has been proposed as a promising therapeutic hypothesis to delay disease onset or progression. To this end, we developed a base editing approach to permanently install a premature stop codon in the gene encoding prion protein, thereby reducing endogenous prion protein levels. Through delivery of base editing components via adeno-associated virus (AAV), we achieved significant lifespan extension in a mouse model of prion disease. In this chapter, I describe the development of base editing strategy as a potential treatment for prion disease.
In Chapter 4, I describe the progress in developing a base editing strategy to treat Hutchinson-Gilford Progeria Syndrome (hereafter referred to as Progeria). In 2021, our lab reported a base editing strategy delivered by a dual-AAV system that corrected the pathogenic mutation causing Progeria, achieving efficient editing in key tissues such as the heart and descending aorta, and extending lifespan in a mouse model of Progeria. To advance this strategy toward clinical translation, we developed a base editing system that can be delivered with a single AAV, which may improve both in vivo efficacy and manufacturability. In this chapter, I describe the development and characterization of this single-AAV strategy for Progeria.
Finally, in Chapter 5, I conclude by discussing the future directions of each project and the broader outlook for therapeutic gene editing.Chemistry and Chemical Biolog
Connecting Dietary Intake, Health Outcomes, and Environmental Shocks in Southwestern Madagascar
No full textEnvironmental and human health are increasingly understood as interrelated; yet more
research is needed to understand how extreme weather events impact diet quality and individual
health outcomes. There is also a need for context-specific research to understand how extreme
weather events affect diet quality and health outcomes in areas with high levels of malnutrition
and high vulnerability to climate change. Individuals living in southern Madagascar face
extremely high levels of poverty and malnutrition driven by underlying social and ecological
conditions, exacerbated by climate-change-related drought and food insecurity. Before
interventions can improve nutritional well-being, there must be an understanding of dietary
intake patterns in the region, how these patterns relate to human health outcomes, and their
relationship to environmental events such as drought, cyclones, heavy winds, and floods. This
study harnesses a longitudinal cohort of 1,702 individuals living in southwestern Madagascar,
from 12 villages along the Bay of Ranobe, to analyze the role of environmental factors in
shaping dietary patterns and diet quality and subsequent impacts on overweight and obesity-related health outcomes.
In chapter one, we conducted a dietary pattern analysis to characterize dietary patterns in
the diets of individuals living on or near the Bay of Ranobe, Madagascar, and examined the
socio-economic characteristics and diet quality of individuals in each dietary pattern group.
In chapter two, we analyzed the association between dietary pattern group membership
and overweight- and obesity-related health outcomes, including overweight Body Mass Index,
abdominal obesity, and hypertension.
In chapter three, we evaluated the relationship between diet quality and the self-reported
experience of environmental shocks, including droughts, cyclones, heavy winds, and floods and
heavy rains.
Together, these research results elucidate the mechanistic pathways linking
environmental conditions to diet quality and subsequent health outcomes in southwestern
Madagascar, thereby informing public health policy and targeted nutritional and planetary health
interventionsPopulation Health Science
Functional and molecular organization of threat processing in lateral septum cells and circuits
No full textSurvival depends on an animal’s ability to rapidly detect, evaluate, and respond to threats while balancing exploration essential for resources against potential risks. The lateral septum (LS), an inhibitory nucleus within the limbic forebrain, is uniquely positioned to integrate external sensory information with internal states and prior experiences to regulate adaptive behavioral outcomes. Despite extensive evidence implicating the LS in threat processing, the specific neuronal subpopulations, circuits, and computational mechanisms that guide defensive behaviors and exploratory actions remain poorly understood.
In this dissertation, I investigate how LS neurons expressing the type 2 corticotropin-releasing hormone receptor (LSCrhr2) orchestrate critical computations that shape behavioral responses to threats and novel environments. First, using single-cell calcium imaging, molecular sequencing, and circuit tracing, I identify distinct LSCrhr2 neuronal subclasses characterized by unique molecular profiles, spatial organization, and selective afferent connectivity. I find that the activity dynamics of each subclass collectively encodes diverse features of threat stimuli to drive cue-evoked defensive behaviors. Next, by monitoring the activity of precise LSCrhr2 afferents, I find that the LSCrhr2 population integrates cognitive signals from the hippocampus related to sensory context and cue-outcome associations, together with motivational signals from the hypothalamus linked to physiological arousal and stimulus salience. Together, these findings establish a multifeatured organizational principle that underlies how LS mediates motivated behaviors in response to learned discrete threats.
Next, I identify a critical hypothalamic-septal circuit originating from the supramamillary nucleus (SuM) critical for responses to uncertain threats. First, I show that LSCrhr2 population dynamics are intricately tied to the exploratory behavior of the animal and the salience of the environment or stimulus they are exposed to. As the most abundant hypothalamic input to the LSCrhr2 population, we find that the SuM is a primary source of salience and arousal signals to LS. Activation of SuM-LS projections is aversive and imposes a bottom-up brake on exploration through recruitment of LSCrhr2 neurons, promoting arousal and avoidance in environments where threats are uncertain. I show that SuM axons in LS encode the aversive salience of an environment and relays these signals to LSCrhr2 neurons to constrain exploration. The activity of this circuit predicts the vigor of avoidance and thus provides a substrate by which a dynamic internal state can guide exploratory behavior in diverse environments.
Together, these findings define the LSCrhr2 neuronal population and its hypothalamic and hippocampal inputs as essential conduits by which the delicate balance between defensive responses and exploratory behavior is achieved. This dissertation thus reveals general principles for how limbic circuits dynamically integrate internal and external signals to adaptively shape complex motivated behaviors in uncertain or explicitly dangerous environments.Neuroscienc
Essays on Max Weber and Friedrich Nietzsche
No full textThis dissertation compares two diagnoses of problems facing Europe in the late nineteenth and early twentieth centuries, the first offered by Max Weber and the second by Friedrich Nietzsche. The dissertation is composed of three papers. The first paper asks why Weber locates a threat to Germany in the growing entrenchment of a “bureaucratic caste.” Weber argues that the increasing complexity of modern technology and social organization requires a deep division of labor and specialization which insulate the state bureaucracy from democratic control. To counter this and promote “co-rule” among citizens, he advocates for a strong parliament to keep the public informed about the bureaucracy which has such extraordinary power over its daily life. But Weber also argues for a national “plebiscitary leader” elected directly by the people rather than by parliament. Only such a figure, backed by the “trust of the masses,” would have the power to wrestle the bureaucracy into submission and thereby exert a kind of democratic control over it. He attempts to strike a delicate balance between a plebiscitary leader sufficiently powerful for this task and a parliament sufficiently powerful to check the “plebiscitary dictator” and prevent a slide into “Caesarism.” Weber insists on equal suffrage, excoriating proposals which would deny soldiers returning from the First World War a say in the affairs of the state whose existence they have preserved. His defense of equal suffrage is based not on natural rights but on a sense of “political decency” toward the returning soldiers and on reasons of national unity, especially that required for future military mobilization. In this paper I argue that it would be a mistake to understand Weber as paving the way to a kind of proto-fascism, as some have argued.
The second paper contrasts Weber and Nietzsche by comparing their attitudes toward “national political ambition.” Weber insists that participation in great power politics both requires and promotes the “political maturity” of the citizens by confronting them with weighty decisions of international commerce, diplomacy, war, and peace. Only a nation in which citizens are co-rulers rather than subjects of a bureaucratic caste has the right to participate in world politics, and in turn this participation offers an essential political education in citizen co-rule. Because of its specific historical circumstances leading up to the First World War, including its position as a Machtstaat (power-state), Germany has a “tragic” duty to defend the Germanic peoples of central and northern Europe against English and Russian encroachment. This reflects Weber’s view that politics should aim to preserve a distinct national character and should resist universal political moralities such as utilitarianism. He understands Germany’s “fate” to require the sacrifice of “other cultural possibilities,” including artistic values, as the nation directs its most talented individuals into politics and war. The paper here turns to Nietzsche, who agrees with Weber that the pursuit of national power politics will produce a culture antithetical to the creation of great art and philosophy. But Nietzsche disagrees with Weber’s conclusion, warning that the “political blossoming of a people almost inevitably brings with it a spiritual impoverishment and exhaustion.” He asks whether the “coarse and gaudy flower of the nation” is worth the sacrifice of the nation’s “more noble, more delicate, more spiritual plants and growths.” The remainder of the paper explores Nietzsche’s hostility toward national political ambition and public life more broadly, with particular attention to his understanding of the role of solitude in the creation of art and philosophy. It attempts to say why Nietzsche thinks “anything great in the cultural sense is apolitical, even anti-political.”
The third paper explores why Nietzsche thinks solitude is important here, and why he suspects that modern moral psychology risks insisting that “all solitude is guilt.” The paper pays particular attention to Nietzsche’s understanding of the genesis of guilt in modern morality, especially its evolution within Christianity under the concept of “sin.” The dissertation concludes by offering reflections on the supposed connection between Nietzsche and twentieth-century fascism. My view is that it would be misguided to understand Nietzsche as preparing the ground for Nazism, primarily due to his hostility to the “petty provincialism” of nationalism and to any form of mass politics. But it would be equally misguided to use his ideas for egalitarian or democratic ends, and here the contrast with Weber, who defends a kind of democratic nationalism, is most stark.Governmen
Building Communities of Upward Mobility
No full textAround 3.5 billion people, 44 percent of the global population, remain poor (below
$6.85 per day) (World Bank, 2022). Alleviaitng poverty requires finding ways of
upward mobility. I study 3 such ways.
The first and main paper in my dissertation found that uniting teachers, parents and
principals around the protection of children's rights is a powerful way of fostering a
loving environment for more than 200 000 children from low-income backgrounds
to thrive.
The second paper in my dissertation suggests that fostering connections between
high- and low-income individuals is essential for lower-income individuals' upward
mobility, potentially through higher income individuals acting as role models,
information sources, and providers of job referrals to lower income individuals.
The third paper in my dissertation suggests that hiring passionate young graduates
as teachers in shcools in low-income rural areas can give access to a decent
education to low-income children who might not have one otherwise.Economic