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Neuron-astrocyte calcium dynamics in fear learning and memory
(2024) Suthard, Rebecca L.; Ramirez, Steve
Memory is one of the most extensively-studied phenomenon in neuroscience as it provides the basis for our day-to-day human experience. A continued unmet need is understanding how memory processing can go wrong, whether in the degeneration of our ability to form or access memories (i.e. dementia) or in maladaptive memory processing (i.e. Post-Traumatic Stress Disorder). Animal models have enabled tremendous insight into the molecular and systems-level underpinnings of healthy and pathological memory states that advance our understanding of the human condition. Within the memory field, the primary focus has traditionally been on how neuronal activity within regions such as the hippocampus enable the formation, consolidation, maintenance, and extinction of episodic memories, i.e. the memories of our personally experienced events defined along what-where-when dimensions. While the majority of this work has focused on neurons despite extensive work indicating that memories recruit heterogenous cell types, recent work has supported the idea that astrocytes, a type of glial cell, are active modulators of learning and memory processes ranging from fear encoding to spatial navigation. To expand upon this growing literature, we investigated the role of astrocytic calcium dynamics using multiple imaging modalities within the amygdala and hippocampus, in an effort to understand how they may be intimately interacting with neurons to enable higher-level cognitive processing.To that end, my thesis puts forth three experiments that link the activity of neurons and astrocytes to cognition and behavior. In the first experiment, we recorded real-time astrocytic calcium dynamics in the basolateral amygdala (BLA) across contextual fear conditioning (CFC), recall and extinction using single-color fiber photometry. We showed that BLA astrocytes robustly responded to foot shock during CFC, resulting in persistent changes in calcium activity across subsequent days compared to controls. Additionally, astrocytic calcium dynamics became correlated with freezing epochs during CFC and recall only in mice that received foot shocks, and this activity became uncoupled across extinction days. Further, chemogenetic inhibition of BLA fear ensembles had no effect on astrocytic calcium activity or freezing behavior. The results of our first experiment revealed that astrocytes play a real-time role in the acquisition and maintenance of contextual fear as it relates to behavior. Our second experiment then sought to understand how artificial stimulation of fear affects intra-hippocampal neuron-astrocyte dynamics as well as their behavioral consequences. Here, we utilized a combination of activity-dependent labeling strategies in the dentate gyrus (DG) and in vivo fiber photometry of neurons and astrocytes in ventral CA1 of the hippocampus (vCA1) across fear acquisition, natural recall and artificial reactivation of a fear memory or engram. In line with our first experiment, both cell types in vCA1 displayed shock-responsiveness during CFC, with astrocytic calcium events uniquely modulated. Optogenetic activation of a DG-mediated fear engram was sufficient to induce calcium dynamics in neurons and astrocytes that were akin to those displayed during natural recall. Further, these dynamics in both cell types were coupled to fear-related behaviors, such as freezing, during both natural and artificial reactivation of fear. These findings provide the first evidence of neuron-astrocytic coupling as a shared mechanism that enables both natural and artificially-induced memory retrieval, as well as the behavioral expression of fear. The final experiments sought to investigate how astrocytes contribute to contextual fear learning and memory at the single-cell level, enabling a higher-resolution understanding of our previous findings. To accomplish this, we performed freely-moving one-photon calcium recording of dorsal CA1 (dCA1) astrocytes as mice underwent CFC and a subsequent day of contextual recall (Context A; Cxt A) or novel context exposure (Context B; Cxt B). Further, we performed the first longitudinal registration of astrocytes using one-photon imaging to enable analysis of their dynamics across learning. We showed that astrocytes respond to aversive foot shock with sequential calcium activity, akin to that displayed by hippocampal time cells. Notably, these sequences reappear during contextual recall (Cxt A) but not novel exposure (Cxt B), and seem to be driven by reactivated astrocytes across days. Our ongoing work will characterize these sequences across days and explore how they may be coupled with the behavioral expression of fear. These preliminary findings suggest that astrocytes may be involved in temporal coding and provide the first evidence that sequential activity during recall may serve as a memory-specific retrieval process. In summary, my dissertation work presents evidence for the active role of amygdalar and hippocampal astrocytic calcium in the real-time processing of fear learning and memory as it relates to behavior.
Spontaneous pneumothorax etiology and the efficacy of interventional surgery as first-line treatment
(2024) Bolger, Ian; Tornheim, Keith; Young, Aaron William
Spontaneous pneumothorax presents as a prevalent health problem across the globe with rates of occurrence being higher in young adults and males. The occurrence is clinically defined as air outside of the lung and in the pleural space. This presence of air in the pleural cavity occurs due to many possible etiologies, including genetics, bullae formation, morphological body characteristics, and underlying disease. Air in the pleural space disrupts pressure gradients in the thoracic cavity and puts pressure on the lung, causing collapse and interference with normal breathing support. Two major types of pneumothorax occur: primary and secondary. Primary spontaneous pneumothorax (PSP) occurs due to no direct or known cause with no concurrent pathology. A major aspect of the clinical significance of PSP stems from highly prevalent recurrence rates after the first episode. Many patients who receive conservative treatment return with repeated pneumothorax events, pushing for a more definitive strategy at initial stages. Current treatment methodologies provide an inconsistent first-line approach with shifts in focus between symptoms first and the level of respiratory distress. Guidelines provide no clear emphasis on long term success with initial treatments that promote a reduction in recurrence rate. Numerous treatments exist today, beginning with conservative observation and simple bedside needle aspiration or chest tube placement to promote lung reinflation. More lasting treatments extend into interventional thoracoscopic surgery that works to not only remove intrapleural air but also remove blebs or bullae present on the visceral pleura surface. Additionally, a pleurodesis or pleurectomy procedure may be performed to support adherence of the pleural layers to prevent future rupture or collapse. The various treatment approaches are evaluated based on an array of patient factors. Physicians today have no widespread consensus on the best treatment decision for first-time primary spontaneous pneumothorax occurrences. Many continue to observe the conservative management strategy with a focus on observation and minimally invasive steps to achieve lung reinflation. These steps often do not consider long term outcomes and the numerous patient-specific factors that can contribute to elevated recurrence possibilities, such as morphological body type, genetic features, and the possibility of underlying pathology. Other physician teams follow a more interventional approach from onset with outcomes displaying lower rates of recurrence and shorter hospital lengths of stay. Evaluation of current literature surrounding primary spontaneous pneumothorax incidence, etiology, and initial treatment choices has been undertaken to compare the long-term efficacies of conservative versus interventional approaches. Comparison of results from several studies supports indications for the most efficacious first-line treatment that maximizes the success of long-term patient outcomes.
Brain dynamics of behavioral state transitions across sleep and wakefulness
(2024) Setzer, Beverly; Lewis, Laura D.
Virtually every organism with a nervous system must enter a reversible state of quiescence, namely sleep, to maintain brain function. Sleep contributes to major aspects of cognition - including mood, attention, learning, memory, and decision making - and almost all neuropsychiatric disorders are associated with altered sleep. Though this state of decreased arousal is crucial for health and life quality, much remains unknown about how the brain traverses through high and low arousal states. To address this question, we systematically evaluated the relationship between brain activity and arousal state from two angles. First, we centered on the moment that behavioral responsiveness returns with awakening and delineated how activity unfolds in key brain networks during this state switch. Then, we reversed our analysis approach and zoomed into moments that brain activity changed, investigating how behavioral arousal state fluctuates with intrinsic brain-wide dynamics that are prevalent in restfulness and light sleep. Awakening from sleep reflects a profound transformation in neural activity and behavior. The thalamus is a key controller of arousal state, but whether its diverse nuclei exhibit coordinated or distinct activity at transitions in behavioral arousal state is unknown. Using fast functional magnetic resonance imaging (fMRI) at ultra-high field (7 Tesla), we measured sub-second activity across thalamocortical networks and within nine thalamic nuclei to delineate these dynamics during spontaneous transitions in behavioral arousal state. We discovered a stereotyped sequence of activity across thalamic nuclei and cingulate cortex that preceded behavioral arousal after a period of inactivity, followed by widespread deactivation. These thalamic dynamics were linked to whether participants subsequently fell back into unresponsiveness, with unified thalamic activation reflecting maintenance of behavior. These results provide an outline of the complex interactions across thalamocortical circuits that orchestrate behavioral arousal state transitions, and additionally, demonstrate that fast fMRI can resolve sub-second subcortical dynamics in the human brain.
In light sleep and drowsiness, the brain exhibits low-frequency oscillations that are linked to changes in arousal state. It is unknown if specific spatiotemporal properties of these infraslow brain dynamics have functional relevance for arousal state. To address this gap in knowledge, we used fast fMRI to capture brain-wide activity while subjects performed a simple, self-paced behavioral task and transitioned in and out of behavioral unresponsiveness. We found that behavioral arousal state fluctuates with ongoing, infraslow fMRI activity. We determined that specific spatiotemporal features (magnitude, frequency, and propagation dynamics) are linked to various arousal state dynamics. We found that larger-amplitude, slower, peaks with greater lags across the brain were more likely to be associated with a change in arousal state than smaller-amplitude, faster, more tightly coupled activations across the brain. We found that peak magnitude was directly coupled to greater transitions in arousal state, and that frequency was coupled to baseline arousal state levels. Additionally, we found that thalamic and global peaks may contribute differently to behavioral arousal state transitions. Therefore, peaks in infraslow fMRI activity are linked to behavior and electroencephalography (EEG) rhythms in a state-dependent manner, with changes in behavior and EEG rhythms occurring more strongly in peaks with specific features. This study reveals functional differences in oscillatory blood oxygen level dependent (BOLD) signal activity linked to drowsiness and light sleep.
Overall, this work elucidates key brain dynamics that underlie changes in arousal state, providing a foundational understanding of the basic network mechanisms underlying transitions between active behavior and unresponsiveness.
Atopic dermatitis: pathogenesis and therapeutic interventions
(2024) Akinjaiyeju, Tioluwa; Offner, Gwynneth; Symes, Karen
Atopic dermatitis (AD), often called eczema, is the most common chronic inflammatory skin disease. Over two hundred million people worldwide have eczema, which mainly begins in early childhood by showing dermatological signs, including rashes, itchiness, redness, inflammation, and dry, cracked skin. As the skin condition is becoming more widespread, research shows that genetic and environmental factors, among others, are all involved in the mechanism of this disease and how to manage and treat it in the future. There is no exact etiology of atopic dermatitis. However, clinicians believe that studying the various contributors, such as genetic predispositions, immune dysfunction, and environmental factors, will provide an analysis of the development of the heterogeneous disease.
The effects of a new class of glaucoma treatment drug netarsudil on cellular connections of Schlemm’s canal endothelium
(2024) Ahmadian, Bijan; Gong, Haiyan; Foley, Jeannine
BACKGROUND: Primary Open Angle Glaucoma (POAG) is a subclass of glaucoma. It is the second most common cause of blindness, within the United States. This disease is characterized by its link to one of its major risk factors, increasing intraocular pressure (IOP). High IOP causes neuronal death of the optic nerve, progressively reducing the visual field until total blindness. IOP elevation is due to an obstruction somewhere along the trabecular outflow pathway, the primary route of drainage for the aqueous humor. One of the most effective treatments to mitigate the progress of POAG involves lowering IOP, by using medicine, laser and surgery. Netarsudil, is one of Rho-Kinase inhibitors, which is a relatively new medication to lower IOP in glaucoma and ocular hypertension. A previous study in Dr. Gong’s lab found that Netarsudil increased outflow facility in human eyes; it induced trabecular meshwork expansion and episcleral vein dilation, which results in an increase in active flow area, consequently increasing outflow facility. However, the effect of Netarsudil on the inner wall endothelial cells has not been carefully studied.
AIM: The purpose of this study was to test the hypothesis that one of mechanisms that Netarsudil increases outflow facility is through reduction of connectivity between the inner wall (IW) endothelial cells of Schlemm’s canal (SC) and their underlying juxtacanalicular cells (JCT) and matrix.
METHODS: Human eyes were perfused with or without Netarsudil for three hours, and perfusion-fixed prior to the onset of this study. Since outflow is not uniform, high- and non-flow regions of each eye were identified and processed for serial block-face scanning electron microscopy (SBF- SEM). SBF-SEM images of these eyes were produced by the Cleveland clinic and returned to the Gong Lab for study. Images of 20 cells from both high- and non-flow regions of the Netarsudi-treated and control groups were analyzed, five cells from each group. Cellular connectivity was counted manually using a software program known as Reconstruct. Raw Data was input into spreadsheets for statistical analysis. Data was then normalized to account for the difference in cellular length. Statistical analyses were performed using Prism.
RESULTS: Netarsudil significantly reduced the total cell-cell (C-C) and cell-matrix (C-M) connections compared to the control. When normalized, a similar reduction is exhibited. When control and treated groups were separated into flow regions, a significant decrease in mean number of total connections was evident in the high-flow region, but not in non-flow region. Once normalized, however, no significant decrease could be noted. When further comparing the effects of Netarsudil on mean C-M connections, between the non- and high-flow regions, no significant findings were evident. When normalized, there were also no significant differences. Analysis of Netarsudil’s effects on C-C connections between treated and control flow regions show no significant difference could be observed for the mean C-C count and normalized means. Cell-cell counts were further specified for 6 different type distributions and compared between high- and non- flow regions of treated and controls. There was a significant decrease in type 2 connections with the Netarsudil administration, while other types (3-7) did not exhibit significant differences in mean connection count in non-flow regions. When normalized, it appears Netarsudil enacted a significant decrease in type 2 connections, and a significant increase in type 5 connections. Type 2 connections were significantly decreased in high-flow regions. Normalization re-affirmed that Netarsudil decreased type 2 connections in high-flow regions.
CONCLUSION: Netarsudil significantly reduced the total cell-cell (C-C) and cell-matrix (C-M) connections compared to the controls, and specifically, Netarsudil significantly decreased type 2 cellular connections. Our data supports our hypothesis. Netarsudil exhibits this relaxing effect on the IW cells of SC and promotes outflow facility by minimization of adherence at the junction of the IW/JCT, resulting in ECM expansion and more uniform flow. The limitation of this study was a small sample size. An increase in sample size would greatly add to the significance and validity of the data and help to reaffirm the findings with more confidence. In addition to what could have been done to improve this study, more work can be done to analyze this effect in the low-flow regions of the TM as well, to develop a more coherent and cohesive understanding of the treatment effects across the entire TM.
Examining whether prior knowledge of cervical cancer can lead to positive attitudes and behaviors towards cancer prevention
(2024) Acker, Adam; Tornheim, Keith; Pierre-Joseph, Natalie
PURPOSE: Cervical cancer poses a significant global health challenge, ranking as the fourth most common cancer among women worldwide, according to the World Health Organization. The aim of this study is to examine the impact of prior knowledge of cervical cancer on attitudes and behaviors toward cancer prevention.
SUBJECT AND METHODS: We conducted a cross-sectional study of 100 participants who completed surveys assessing their knowledge of Human papillomavirus (HPV), cervical cancer causes, risk reduction strategies, vaccines, screening methods, and perceived cancer risk and vaccination behaviors. The population for this study comprised parents whose children were enrolled in the clinical trial titled "An Exploratory Open-Label Clinical Trial Evaluating the Immunogenicity and Safety of the 9vHPV 2-Dose Vaccine Regimen in Children Aged 4–8 Years” at Boston Medical Center.
RESULTS: The average age of the participants was 35.65 years (SD = 8.58, n = 98). Regarding gender distribution, 14.58% identified as male, 84.38% as female, and 1.04% as non-binary (n = 96). The ethnic composition of the sample was diverse, with 57.14% identifying as African American, 15.31% as Hispanic, 2.04% as Asian, 5.10% as White, and 14.29% as Other (n = 98). 2.04% reporting no education, 1.02% primary education, 41.84% middle school education, 12.24% high school education, 41.84% obtaining a GED, and 1.02% having some college education (n = 98). The results revealed several statistically significant associations. Prior knowledge of the cause of cervical cancer was significantly associated with the perceived importance of cancer prevention (χ2 = 15.2538, p = 0.0184). Similarly, knowledge of cervical cancer risk reduction was significantly associated with the perceived importance of cancer prevention (χ2 = 23.2341, p = 0.0007). Knowledge of the cervical cancer vaccine was also significantly associated with the perceived importance of cancer prevention (χ2 = 12.5993, p = 0.0499). Additionally, knowledge of Pap smears was significantly associated with the perceived importance of cancer prevention (χ2 = 15.3223, p = 0.0041). The study found a significant association between knowledge of HPV cervical cancer risk and HPV vaccine reception (Fisher's Exact Test, p < 0.0001), as well as between knowledge of HPV-related genital warts and HPV vaccine reception (Fisher's Exact Test, p = 0.0407). Furthermore, knowledge of HPV causing cervical cancer was significantly associated with perceived cancer risk (Fisher's Exact Test, p = 0.0319). CONCLUSION: Enhancing tailored knowledge about HPV and cervical cancer is pivotal in increasing HPV vaccination rates and reducing the burden of cervical cancer. This study underscores the critical role of targeted education in shaping perceptions and behaviors related to cervical cancer prevention among susceptible communities. Future interventions should address knowledge gaps and improve vaccine acceptance through multifaceted approaches.
Distinct pathways of osteoclastogenesis in inflammatory arthritis
(2023) Savchenko, Alisa; Wisco, Jonathan; Jacome-Galarza, Christian E.
Inflammatory arthritis results from infiltration of inflammatory cells into the synovial tissue surrounding diarthrodial joints. These cell infiltrates produce cytokines and other factors causing inflammation and the formation of bone resorbing osteoclasts which cause destruction of cartilage and bone1. Osteoclasts are large multinucleated cells that are key in the development and maintenance of the skeleton4. They allow for the modelling of bone and tooth eruption in early life, and the maintenance and remodeling of bone during adulthood in healthy individuals12. Two distinct osteoclast lineages have been reported. During embryogenesis, osteoclasts that colonize developing ossification centers of long bones derived from erythromyeloid progenitors (EMPs); after birth hematopoietic stem cell (HSCs)-derived progenitors fuse with pre-existing EMP-derived osteoclasts and gradually replace them, however each lineage contribution is critical to maintain osteoclast function throughout life12. Jacome-Galarza C.E., et al., 2019, generated mice that lack either EMP-derived osteoclasts (Tnfrsf11aCre;Csf1rfl/fl, lethal after birth), or mice that lacked HSC-derived osteoclast (Flt3Cre;Tnfrsf11afl/fl) which are born normally but develop osteopetrosis with age12.Osteoclasts are normally found in long bones associated to trabecular bone but are absent in healthy synovial tissues, however, under inflammatory conditions, osteoclasts are found on bone periosteal surfaces that are in contact with the inflamed synovium, leading to bone erosions along all surface of bone. The diagnosis of bone erosions in inflammatory arthritis is essential to the prognosis of the disease3. Osteoclasts develop from the cell fusion of osteoclast precursors, which depend on M-CSF and RANKL for cell survival and differentiation6. The resorption capacity of osteoclasts has been suggested to activate independent of RANK signaling in inflammatory conditions and shown to depend on inflammatory cytokines expressed in inflamed synovium including TNF, IL-6, and IL-19. Some reports indicate that macrophages can differentiate into osteoclasts under these conditions24, however, the lineage of origin is unknown. We hypothesize that osteoclasts derived from both HSC- and EMP-derived precursors differentiate in inflamed synovium. To test this hypothesis, a conditional KO mouse which genetically deletes Tnfrsf11a (which codes for RANK) in all HSC-derived cells expressing Flt3 and can also expressed YFP for cell lineage tracing was developed (Flt3Cre; Tnfrsf11afl/fl;Rosa26LSL-YFP). In these mice, under arthritic conditions, HSC-derived osteoclasts were reduced in the inflamed synovium of hind paws. Interestingly, the majority of osteoclasts identified in the inflamed synovium in the absence of RANK (deleted in HSC-derived cells) were potentially consequent from EMP-derived cells and were capable of causing bone erosion.
In addition, inflammatory Ly6C+ monocytes, which are precursors of osteoclasts in the bone marrow, were quantified in the inflamed synovium of hind paws in Flt3Cre; Tnfrsf11afl/fl;Rosa26LSL-YFP KO mice and found to be reduced in inflamed synovium when compared to WT littermates, suggesting that deletion of RANK in these cells prevents their differentiation to osteoclasts in inflamed synovium. Although inconclusive, these preliminary results suggest that in inflammatory arthritis, osteoclasts might originate from at least two different cell sources that are also different in origin and regulated by distinct signaling pathways.
Topological recursion, quantum airy structures, and the generalized volume conjecture
(2023) Potter, Greyson; Kimura, Takashi
The goal of the present thesis is to develop a computational approach to analyzing the generalized volume conjecture, which relates topological recursion and Chern-Simons theory for hyperbolic 3-manifolds with torus boundary. The conjecture states that there is an equality between two series in a formal parameter h: the non-perturbative wave function from topological recursion and a state-integral model for SL(2,C) Chern-Simons theory. Both series are expressible as sums over graphs. We develop algorithms for efficiently computing the graph sum for the non-perturbative wave function via quantum Airy structures and a software package, called qairy, which implements our algorithms. We further develop tools and techniques which are widely applicable to the calculation and analysis of the non-perturbative wave functions associated to genus one spectral curves. Using these tools, we are able to verify the conjecture in several cases up to much higher order in h than was previously accessible as well as analyze the arithmetic aspects of the conjecture.
Textiles in New England II : four centuries of material life
(Boston : Boston University, 1999)
Keynote address: In the garrets and ratholes of old houses / Laurel Thatcher Ulrich -- Four perspectives on a bed rug / Laurel Thatcher Ulrich ... [et al.] -- "A dull business alone": cooperative quilting in New England, 1750-1850 / Lynne Zacek Bassett -- "A bed and curtains and all things thereto belonging": context, value, and scarcity in eighteenth-century Massachusetts / M. Michelle Jarrett Morris -- A rare set of eighteenth-century bed hangings / Joyce Geary Volk -- Mary Anne Warriner, Rhode Island milliner / Melinda Talbot -- Rag carpet weaving in Connecticut, 1850-1880 / Sandra Rux -- The mystery of the Connecticut chair wheel / Florence Feldman-Wood -- The Hibbert-Townsend latch needle mystery unraveled: patent control and nineteenth-century American knitting machines / Richard M. Candee -- Canterbury shaker textile production / Mary Rose Boswell -- Having it both ways: the needlework table cover of Mercy Otis Warren / Jill Maney and Jonathan Maney
The accounts of Tryphena Newton Cooke: work, family, and community in Hadley, Massachusetts, 1780-1805 / Marla R. Miller -- "Some work ... to be kept": textiles and memories of Victorian domesticity / Kathryn Clippinger Kosto -- Textile commemoratives and broadsides from New England's mid-nineteenth century / Diane L. Fagan Affleck -- Stories from her needle: colonial revival samplers of Mary Saltonstall Parker / Paula Bradstreet Richter -- "I shall cut my cote after my cloth": reproducing the dress of the pilgrims / Jill M. Hall.
Health coverage for pregnant people who are undocumented in the United States
(2024) DiMeo, Amanda Florian; Weinstein, John; Molina, Rose
The United States continues to experience one of the highest maternal mortality rates of all high-income nations with stark and significant racial and ethnic inequities in outcomes. Concurrently, the U.S. is also experiencing divisive changes in immigration policy. The U.S. has a large immigrant population with almost one quarter of those undocumented, without legal documentation regarding their residency status. At the intersection of these two major health crises, little is known about pregnant people who are undocumented. Health care coverage and access to pregnancy care for people who are undocumented is variable from state-to-state, existing as a patchwork of both federal and state-led mechanisms. This thesis aims to explore the labyrinth of healthcare coverage that exists for the population of pregnant people who are undocumented, providing context into both federal and state-level policy mechanisms. Coverage includes state- based Child Health Insurance Program (CHIP) programming to cover prenatal care under the “unborn child” program and optional postpartum care. Some states have expanded Medicaid to include this population. There also exist other innovative programs, including subsidies for private insurance. This thesis proposes a study that assesses national coverage through a data collection tool that allows a snapshot of current national policy that may be utilized over time. A clear comprehension of coverage is necessary for policymakers and researchers alike as it provides a baseline of which future policy can be improved to include this population. It is critical that undocumented immigrants are included in maternal health programming that aims to reduce disparities and improve outcomes.