Scholarly Works, Fralin Biomedical Research Institute at VTC

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Cerebellar nuclei cells produce distinct pathogenic spike signatures in mouse models of ataxia, dystonia, and tremor
van der Heijden, Meike E.; Brown, Amanda M.; Kizek, Dominic J.; Sillitoe, Roy (eLife, 2024-07-29)
The cerebellum contributes to a diverse array of motor conditions, including ataxia, dystonia, and tremor. The neural substrates that encode this diversity are unclear. Here, we tested whether the neural spike activity of cerebellar output neurons is distinct between movement disorders with different impairments, generalizable across movement disorders with similar impairments, and capable of causing distinct movement impairments. Using in vivo awake recordings as input data, we trained a supervised classifier model to differentiate the spike parameters between mouse models for ataxia, dystonia, and tremor. The classifier model correctly assigned mouse phenotypes based on single-neuron signatures. Spike signatures were shared across etiologically distinct but phenotypically similar disease models. Mimicking these pathophysiological spike signatures with optogenetics induced the predicted motor impairments in otherwise healthy mice. These data show that distinct spike signatures promote the behavioral presentation of cerebellar diseases.
Converging and Diverging Cerebellar Pathways for Motor and Social Behaviors in Mice
van der Heijden, Meike E. (Springer, 2024-05-23)
Evidence from clinical and preclinical studies has shown that the cerebellum contributes to cognitive functions, including social behaviors. Now that the cerebellum’s role in a wider range of behaviors has been confirmed, the question arises whether the cerebellum contributes to social behaviors via the same mechanisms with which it modulates movements. This review seeks to answer whether the cerebellum guides motor and social behaviors through identical pathways. It focuses on studies in which cerebellar cells, synapses, or genes are manipulated in a cell-type specific manner followed by testing of the effects on social and motor behaviors. These studies show that both anatomically restricted and cerebellar cortex-wide manipulations can lead to social impairments without abnormal motor control, and vice versa. These studies suggest that the cerebellum employs different cellular, synaptic, and molecular pathways for social and motor behaviors. Future studies warrant a focus on the diverging mechanisms by which the cerebellum contributes to a wide range of neural functions.
More Than a Small Brain: The Importance of Studying Neural Function during Development
Dooley, James C.; van der Heijden, Meike E. (Society for Neuroscience, 2024-11-27)
The nervous system contains complex circuits comprising thousands of cell types and trillions of connections. Here, we discuss how the field of "developmental systems neuroscience" combines the molecular and genetic perspectives of developmental neuroscience with the (typically adult-focused) functional perspective of systems neuroscience. This combination of approaches is critical to understanding how a handful of cells eventually produce the wide range of behaviors necessary for survival. Functional circuit development typically lags behind neural connectivity, leading to intermediate stages of neural activity that are either not seen in adults or, if present, are considered pathophysiological. Developmental systems neuroscience examines these intermediate stages of neural activity, mapping out the critical phases and inflection points of neural circuit function to understand how neural activity and behavior emerge across development. Beyond understanding typical development, this approach provides invaluable insight into the pathophysiology of neurodevelopmental disorders by identifying when and how functional development diverges between health and disease. We argue that developmental systems neuroscience will identify important periods of neural development, reveal novel therapeutic windows for treatment, and set the stage to answer fundamental questions about the brain in health and disease.
Gradient descent optimization of acoustic holograms for transcranial focused ultrasound
Sallam, Ahmed; Cengiz, Ceren; Pewekar, Mihir; Hoffmann, Eric; Legon, Wynn; Vlaisavljevich, Eli; Shahab, Shima (AIP Publishing, 2024-10-08)
Acoustic holographic lenses, also known as acoustic holograms, can change the phase of a transmitted wavefront in order to shape and construct complex ultrasound pressure fields, often for focusing the acoustic energy on a target region. These lenses have been proposed for transcranial focused ultrasound (tFUS) to create diffraction-limited focal zones that target specific brain regions while compensating for skull aberration. Holograms are currently designed using time-reversal approaches in full-wave time-domain numerical simulations. Such simulations need time-consuming computations, which severely limits the adoption of iterative optimization strategies. In the time-reversal method, the number and distribution of virtual sources can significantly influence the final sound field. Because of the computational constraints, predicting these effects and determining the optimal arrangement is challenging. This study introduces an efficient method for designing acoustic holograms using a volumetric holographic technique to generate focused fields inside the skull. The proposed method combines a modified mixed-domain method for ultrasonic propagation with a gradient descent iterative optimization algorithm. The findings are further validated in underwater experiments with a realistic 3D-printed skull phantom. This approach enables substantially faster holographic computation than previously reported techniques. The iterative process uses explicitly defined loss functions to bias the ultrasound field’s optimization parameters to specific desired characteristics, such as axial resolution, transversal resolution, coverage, and focal region uniformity, while eliminating the uncertainty associated with virtual sources in time-reversal techniques. The proposed techniques enable more rapid hologram computation and more flexibility in tailoring ultrasound fields for specific therapeutic requirements.
Spatial Transcriptomics and Single-Nucleus Multi-Omics Analysis Revealing the Impact of High Maternal Folic Acid Supplementation on Offspring Brain Development
Xu, Xiguang; Lin, Yu; Yin, Liduo; Serpa, Priscila da Silva; Conacher, Benjamin; Pacholec, Christina; Carvallo, Francisco; Hrubec, Terry; Farris, Shannon; Zimmerman, Kurt; Wang, Xiaobin; Xie, Hehuang (MDPI, 2024-11-07)
Background: Folate, an essential vitamin B9, is crucial for diverse biological processes, including neurogenesis. Folic acid (FA) supplementation during pregnancy is a standard practice for preventing neural tube defects (NTDs). However, concerns are growing over the potential risks of excessive maternal FA intake. Objectives/Methods: Here, we employed a mouse model and spatial transcriptomic and single-nucleus multi-omics approaches to investigate the impact of high maternal FA supplementation during the periconceptional period on offspring brain development. Results: Maternal high FA supplementation affected gene pathways linked to neurogenesis and neuronal axon myelination across multiple brain regions, as well as gene expression alterations related to learning and memory in thalamic and ventricular regions. Single-nucleus multi-omics analysis revealed that maturing excitatory neurons in the dentate gyrus (DG) are particularly vulnerable to high maternal FA intake, leading to aberrant gene expressions and chromatin accessibility in pathways governing ribosomal biogenesis critical for synaptic formation. Conclusions: Our findings provide new insights into specific brain regions, cell types, gene expressions and pathways that can be affected by maternal high FA supplementation.
Glycosphingolipids in Cardiovascular Disease: Insights from Molecular Mechanisms and Heart Failure Models
Huang, Sarah; Abutaleb, Karima; Mishra, Sumita (MDPI, 2024-10-08)
This review explores the crucial role of glycosphingolipids (GSLs) in the context of cardiovascular diseases (CVDs), focusing on their biosynthesis, metabolic pathways, and implications for clinical outcomes. GSLs are pivotal in regulating a myriad of cellular functions that are essential for heart health and disease progression. Highlighting findings from both human cohorts and animal models, this review emphasizes the potential of GSLs as biomarkers and therapeutic targets. We advocate for more detailed mechanistic studies to deepen our understanding of GSL functions in cardiovascular health, which could lead to innovative strategies for diagnosis, treatment, and personalized medicine in cardiovascular care.
Detection, Isolation and Quantification of Myocardial Infarct with Four Different Histological Staining Techniques
Wu, Xiaobo; Meier, Linnea; Liu, Tom X.; Toldo, Stefano; Poelzing, Steven; Gourdie, Robert G. (MDPI, 2024-10-18)
Background/Objectives: The precise quantification of myocardial infarction is crucial for evaluating therapeutic strategies. We developed a robust, color-based semi-automatic algorithm capable of infarct region detection, isolation and quantification with four different histological staining techniques, and of the isolation and quantification of diffuse fibrosis in the heart. Methods: Our method is developed based on the color difference in the infarct and non-infarct regions after histological staining. Mouse cardiac tissues stained with Masson’s trichrome (MTS), hematoxylin and eosin (H&E), 2,3,5-Triphenyltetrazolium chloride and picrosirius red were included to demonstrate the performance of our method. Results: We demonstrate that our algorithm can effectively identify and produce a clear visualization of infarct tissue in the four staining techniques. Notably, the infarct region on an H&E-stained tissue section can be clearly visualized after processing. The MATLAB-based program we developed holds promise for infarct quantification. Additionally, our program can isolate and quantify diffuse fibrotic elements from an MTS-stained cardiac section, which suggests the algorithm’s potential for evaluating pathological cardiac fibrosis in diseased cardiac tissues. Conclusions: We demonstrate that this color-based algorithm is capable of accurately identifying, isolating and quantifying cardiac infarct regions with different staining techniques, as well as diffuse and patchy fibrosis in MTS-stained cardiac tissues.
Connexin 43 regulates intercellular mitochondrial transfer from human mesenchymal stromal cells to chondrocytes
Irwin, Rebecca M.; Thomas, Matthew A.; Fahey, Megan J.; Mayán, María D.; Smyth, James W.; Delco, Michelle L. (2024-10-10)
Background: The phenomenon of intercellular mitochondrial transfer from mesenchymal stromal cells (MSCs) has shown promise for improving tissue healing after injury and has potential for treating degenerative diseases like osteoarthritis (OA). Recently MSC to chondrocyte mitochondrial transfer has been documented, but the mechanism of transfer is unknown. Full-length connexin 43 (Cx43, encoded by GJA1) and the truncated, internally translated isoform GJA1-20k have been implicated in mitochondrial transfer between highly oxidative cells, but have not been explored in orthopaedic tissues. Here, our goal was to investigate the role of Cx43 in MSC to chondrocyte mitochondrial transfer. In this study, we tested the hypotheses that (a) mitochondrial transfer from MSCs to chondrocytes is increased when chondrocytes are under oxidative stress and (b) MSC Cx43 expression mediates mitochondrial transfer to chondrocytes. Methods: Oxidative stress was induced in immortalized human chondrocytes using tert-Butyl hydroperoxide (t-BHP) and cells were evaluated for mitochondrial membrane depolarization and reactive oxygen species (ROS) production. Human bone-marrow derived MSCs were transduced for mitochondrial fluorescence using lentiviral vectors. MSC Cx43 expression was knocked down using siRNA or overexpressed (GJA1 + and GJA1-20k+) using lentiviral transduction. Chondrocytes and MSCs were co-cultured for 24 h in direct contact or separated using transwells. Mitochondrial transfer was quantified using flow cytometry. Co-cultures were fixed and stained for actin and Cx43 to visualize cell-cell interactions during transfer. Results: Mitochondrial transfer was significantly higher in t-BHP-stressed chondrocytes. Contact co-cultures had significantly higher mitochondrial transfer compared to transwell co-cultures. Confocal images showed direct cell contacts between MSCs and chondrocytes where Cx43 staining was enriched at the terminal ends of actin cellular extensions containing mitochondria in MSCs. MSC Cx43 expression was associated with the magnitude of mitochondrial transfer to chondrocytes; knocking down Cx43 significantly decreased transfer while Cx43 overexpression significantly increased transfer. Interestingly, GJA1-20k expression was highly correlated with incidence of mitochondrial transfer from MSCs to chondrocytes. Conclusions Overexpression of GJA1-20k in MSCs increases mitochondrial transfer to chondrocytes, highlighting GJA1-20k as a potential target for promoting mitochondrial transfer from MSCs as a regenerative therapy for cartilage tissue repair in OA.
The connexin 43 carboxyl terminal mimetic peptide αCT1 prompts differentiation of a collagen scar matrix in humans resembling unwounded skin
Montgomery, Jade; Richardson, William J.; Marsh, Spencer; Rhett, J. Matthew; Bustos, Francis; Degen, Katherine; Ghatnekar, Gautam S.; Grek, Christina L.; Jourdan, L. Jane; Holmes, Jeffrey W.; Gourdie, Robert G. (Wiley, 2021-07-10)
Phase II clinical trials have reported that acute treatment of surgical skin wounds with the therapeutic peptide alpha Connexin Carboxy-Terminus 1 (αCT1) improves cutaneous scar appearance by 47% 9-month postsurgery. While Cx43 and ZO-1 have been identified as molecular targets of αCT1, the mode-of-action of the peptide in scar mitigation at cellular and tissue levels remains to be further characterized. Scar histoarchitecture in αCT1 and vehicle-control treated skin wounds within the same patient were compared using biopsies from a Phase I clinical trial at 29-day postwounding. The sole effect on scar structure of a range of epidermal and dermal variables examined was that αCT1-treated scars had less alignment of collagen fibers relative to control wounds—a characteristic that resembles unwounded skin. The with-in subject effect of αCT1 on scar collagen order observed in Phase I testing in humans was recapitulated in Sprague–Dawley rats and the IAF hairless guinea pig. Transient increase in histologic collagen density in response to αCT1 was also observed in both animal models. Mouse NIH 3T3 fibroblasts and primary human dermal fibroblasts treated with αCT1 in vitro showed more rapid closure in scratch wound assays, with individual cells showing decreased directionality in movement. An agent-based computational model parameterized with fibroblast motility data predicted collagen alignments in simulated scars consistent with that observed experimentally in human and the animal models. In conclusion, αCT1 prompts decreased directionality of fibroblast movement and the generation of a 3D collagen matrix postwounding that is similar to unwounded skin—changes that correlate with long-term improvement in scar appearance.
Tmem65 is critical for the structure and function of the intercalated discs in mouse hearts
Teng, Allen C. T.; Gu, Liyang; Di Paola, Michelle; Lakin, Robert; Williams, Zachary J.; Au, Aaron; Chen, Wenliang; Callaghan, Neal; Zadeh, Farigol Hakem; Zhou, Yu-Qing; Fatah, Meena; Chatterjee, Diptendu; Jourdan, L. Jane; Liu, Jack; Simmons, Craig A.; Kislinger, Thomas; Yip, Christopher M.; Backx, Peter H.; Gourdie, Robert G.; Hamilton, Robert M.; Gramolini, Anthony O. (Nature Portfolio, 2022-10-18)
The intercalated disc (ICD) is a unique membrane structure that is indispensable to normal heart function, yet its structural organization is not completely understood. Previously, we showed that the ICD-bound transmembrane protein 65 (Tmem65) was required for connexin43 (Cx43) localization and function in cultured mouse neonatal cardiomyocytes. Here, we investigate the functional and cellular effects of Tmem65 reductions on the myocardium in a mouse model by injecting CD1 mouse pups (3–7 days after birth) with recombinant adeno-associated virus 9 (rAAV9) harboring Tmem65 shRNA, which reduces Tmem65 expression by 90% in mouse ventricles compared to scrambled shRNA injection. Tmem65 knockdown (KD) results in increased mortality which is accompanied by eccentric hypertrophic cardiomyopathy within 3 weeks of injection and progression to dilated cardiomyopathy with severe cardiac fibrosis by 7 weeks post-injection. Tmem65 KD hearts display depressed hemodynamics as measured echocardiographically as well as slowed conduction in optical recording accompanied by prolonged PR intervals and QRS duration in electrocardiograms. Immunoprecipitation and super-resolution microscopy demonstrate a physical interaction between Tmem65 and sodium channel β subunit (β1) in mouse hearts and this interaction appears to be required for both the establishment of perinexal nanodomain structure and the localization of both voltage-gated sodium channel 1.5 (NaV1.5) and Cx43 to ICDs. Despite the loss of NaV1.5 at ICDs, whole-cell patch clamp electrophysiology did not reveal reductions in Na+ currents but did show reduced Ca2+ and K+ currents in Tmem65 KD cardiomyocytes in comparison to control cells. We conclude that disrupting Tmem65 function results in impaired ICD structure, abnormal cardiac electrophysiology, and ultimately cardiomyopathy.
Attachment and borderline personality disorder as the dance unfolds: A quantitative analysis of a novel paradigm
Mancinelli, Federico; Nolte, Tobias; Griem, Julia; Lohrenz, Terry; Feigenbaum, Janet; Casas, Brooks; Montague, P. Read; Fonagy, Peter; Mathys, Christoph (Elsevier, 2024-04-17)
Current research on personality disorders strives to identify key behavioural and cognitive facets of patient functioning, to unravel the underlying root causes and maintenance mechanisms. This process often involves the application of social paradigms — however, these often only include momentary affective depictions rather than unfolding interactions. This constitutes a limitation in our capacity to probe core symptoms, and leaves potential findings uncovered which could help those who are in close relationships with affected individuals. Here, we deployed a novel task in which subjects interact with four unknown virtual partners in a turn-taking paradigm akin to a dance, and report on their experience with each. The virtual partners embody four combinations of low/high expressivity of positive/negative mood. Higher scores on our symptomatic measures of attachment anxiety, avoidance, and borderline personality disorder (BPD) were all linked to a general negative appraisal of all the interpersonal experiences. Moreover, the negative appraisal of the partner who displayed a high negative/low positive mood was tied with attachment anxiety and BPD symptoms. The extent to which subjects felt responsible for causing partners’ distress was most strongly linked to attachment anxiety. Finally, we provide a fully-fledged exploration of move-by-move action latencies and click distances from partners. This analysis underscored slower movement initiation from anxiously attached individuals throughout all virtual interactions. In summary, we describe a novel paradigm for second-person neuroscience, which allowed both the replication of established results and the capture of new behavioural signatures associated with attachment anxiety, and discuss its limitations.
Linking mentalizing capacity, shame, and depressive symptoms in the context of childhood maltreatment
Schwarzer, Nicola-Hans; Nolte, Tobias; Fonagy, Peter; Feigenbaum, Janet; Casas, Brooks; Rüfenacht, Eva; Gingelmaier, Stephan; Leibowitz, Judy; Pilling, Steve; Montague, P. Read (Elsevier, 2024-08-01)
Background: Experiences of childhood maltreatment have been shown to be a crucial predictor of depressive symptoms. Objective: This study investigated the association between a history of maltreatment and depressive symptoms in a mixed sample of adults, exploring whether feelings of shame and impairments in mentalizing mediate this association and potentially represent health-affecting factors associated with an increase in depressive symptoms. Further, the association between feelings of shame and depressive symptoms was expected to be moderated by impairments in mentalizing. Participants and setting: A mixed sample of 796 adults, including clinical and non-clinical participants, completed questionnaires assessing retrospectively rated experiences of childhood maltreatment, feelings of shame, mentalizing capacities, and current depressive symptoms in a cross-sectional design. Methods: The hypotheses were tested using structural equation modelling. Results: Associations were found between childhood maltreatment, feelings of shame, impairments in mentalizing, and depressive symptoms. Impairments in mentalizing and feelings of shame partially mediated the link between maltreatment and depressive symptoms. However, impairments in mentalizing did not moderate the link between shame and depressive symptoms. Conclusion: The current study provides evidence for the role of metacognitive processes that affect mental health problems in the domain of depression. Psychological treatments that promote mentalizing capacities might be helpful in reducing feelings of shame, and consequently in reducing depressive symptoms.
High-Resolution Imaging of Human Cancer Proteins Using Microprocessor Materials
Solares, Maria J.; Jonaid, G. M.; Luqiu, William Y.; Berry, Samantha; Khadela, Janki; Liang, Yanping; Evans, Madison C.; Pridham, Kevin J.; Dearnaley, William J.; Sheng, Zhi; Kelly, Deborah F. (Wiley-V C H , 2022-07-14)
Mutations in tumor suppressor genes, such as Tumor Protein 53 (TP53), are heavily implicated in aggressive cancers giving rise to gain- and loss-of-function phenotypes. While individual domains of the p53 protein have been studied extensively, structural information for full-length p53 remains incomplete. Functionalized microprocessor chips (microchips) with properties amenable to electron microscopy permitted us to visualize complete p53 assemblies for the first time. The new structures revealed p53 in an inactive dimeric state independent of DNA binding. Residues located at the protein-protein interface corresponded with modification sites in cancer-related hot spots. Changes in these regions may amplify the toxic effects of clinical mutations. Taken together, these results contribute advances in technology and imaging approaches to decode native protein models in different states of activation.
A machine-learning approach for differentiating borderline personality disorder from community participants with brain-wide functional connectivity
Lahnakoski, Juha M.; Nolte, Tobias; Solway, Alec; Vilares, Iris; Hula, Andreas; Feigenbaum, Janet; Lohrenz, Terry; Casas, Brooks; Fonagy, Peter; Montague, P. Read; Schilbach, Leonhard (Elsevier, 2024-05-26)
Background: Functional connectivity has garnered interest as a potential biomarker of psychiatric disorders including borderline personality disorder (BPD). However, small sample sizes and lack of within-study replications have led to divergent findings with no clear spatial foci. Aims: Evaluate discriminative performance and generalizability of functional connectivity markers for BPD. Method: Whole-brain fMRI resting state functional connectivity in matched subsamples of 116 BPD and 72 control individuals defined by three grouping strategies. We predicted BPD status using classifiers with repeated cross-validation based on multiscale functional connectivity within and between regions of interest (ROIs) covering the whole brain—global ROI-based network, seed-based ROI-connectivity, functional consistency, and voxel-to-voxel connectivity—and evaluated the generalizability of the classification in the left-out portion of non-matched data. Results: Full-brain connectivity allowed classification (∼70 %) of BPD patients vs. controls in matched inner cross-validation. The classification remained significant when applied to unmatched out-of-sample data (∼61–70 %). Highest seed-based accuracies were in a similar range to global accuracies (∼70–75 %), but spatially more specific. The most discriminative seed regions included midline, temporal and somatomotor regions. Univariate connectivity values were not predictive of BPD after multiple comparison corrections, but weak local effects coincided with the most discriminative seed-ROIs. Highest accuracies were achieved with a full clinical interview while self-report results remained at chance level. Limitations: The accuracies vary considerably between random sub-samples of the population, global signal and covariates limiting the practical applicability. Conclusions: Spatially distributed functional connectivity patterns are moderately predictive of BPD despite heterogeneity of the patient population.
Widespread exposure to SARS-CoV-2 in wildlife communities
Goldberg, Amanda R.; Langwig, Kate E.; Brown, Katherine L.; Marano, Jeffrey M.; Rai, Pallavi; King, Kelsie M.; Sharp, Amanda K.; Ceci, Alessandro; Kailing, Christopher D.; Kailing, Macy J.; Briggs, Russell; Urbano, Matthew G.; Roby, Clinton; Brown, Anne M.; Weger-Lucarelli, James; Finkielstein, Carla V.; Hoyt, Joseph R. (Springer, 2024-07-29)
Pervasive SARS-CoV-2 infections in humans have led to multiple transmission events to animals. While SARS-CoV-2 has a potential broad wildlife host range, most documented infections have been in captive animals and a single wildlife species, the white-tailed deer. The full extent of SARS-CoV-2 exposure among wildlife communities and the factors that influence wildlife transmission risk remain unknown. We sampled 23 species of wildlife for SARS-CoV-2 and examined the effects of urbanization and human use on seropositivity. Here, we document positive detections of SARS-CoV-2 RNA in six species, including the deer mouse, Virginia opossum, raccoon, groundhog, Eastern cottontail, and Eastern red bat between May 2022–September 2023 across Virginia and Washington, D.C., USA. In addition, we found that sites with high human activity had three times higher seroprevalence than low human-use areas. We obtained SARS-CoV-2 genomic sequences from nine individuals of six species which were assigned to seven Pango lineages of the Omicron variant. The close match to variants circulating in humans at the time suggests at least seven recent human-to-animal transmission events. Our data support that exposure to SARS-CoV-2 has been widespread in wildlife communities and suggests that areas with high human activity may serve as points of contact for cross-species transmission.
Developing medical simulations for opioid overdose response training: A qualitative analysis of narratives from responders to overdoses
Edwards, G. Franklin; Mierisch, Cassandra; Mutcheson, Brock; Coleman, Keel; Horn, Kimberly; Parker, Sarah Henrickson (PLOS, 2024-03-28)
Medical simulation offers a controlled environment for studying challenging clinical care situations that are difficult to observe directly. Overdose education and naloxone distribution (OEND) programs aim to train potential rescuers in responding to opioid overdoses, but assessing rescuer performance in real-life situations before emergency medical services arrive is exceedingly complex. There is an opportunity to incorporate individuals with firsthand experience in treating out-of-hospital overdoses into the development of simulation scenarios. Realistic overdose simulations could provide OEND programs with valuable tools to effectively teach hands-on skills and support context-sensitive training regimens. In this research, semi-structured interviews were conducted with 17 individuals experienced in responding to opioid overdoses including emergency department physicians, first responders, OEND program instructors, and peer recovery specialists. Two coders conducted qualitative content analysis using open and axial thematic coding to identify nuances associated with illicit and prescription opioid overdoses. The results are presented as narrative findings complemented by summaries of the frequency of themes across the interviews. Over 20 hours of audio recording were transcribed verbatim and then coded. During the open and axial thematic coding process several primary themes, along with subthemes, were identified, highlighting the distinctions between illicit and prescription opioid overdoses. Distinct contextual details, such as locations, clinical presentations, the environment surrounding the patient, and bystanders’ behavior, were used to create four example simulations of outof- hospital overdoses. The narrative findings in this qualitative study offer context-sensitive information for developing out-of-hospital overdose scenarios applicable to simulation training. These insights can serve as a valuable resource, aiding instructors and researchers in systematically creating evidence-based scenarios for both training and research purposes.
Temporal dynamics of the multi-omic response to endurance exercise training
MoTrPAC Study Group; Yan, Zhen (Nature Research, 2024-05-01)
Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository (https://motrpac-data.org/).
Editorial: Effects of performing arts training on the brain, (socio)cognitive and motor functions across the lifespan
Kausel, Leonie; Basso, Julia C.; Grinspun, Noemí; Alain, Claude (Frontiers Media, 2023-12-06)
Performing arts are a cultural expression that is ubiquitous around the world and consists of arts that are performed for an audience, such as music, dance, and drama. In recent years, there has been a growing interest in understanding how this expressive, and in essence social activity, impacts brain development and plasticity. This topic aimed to collect evidence on how the brain and (socio)cognitive and motor functions are influenced by performing arts training along the lifespan, deepening the current knowledge on this subject and helping to unravel the neurobiological mechanisms that underlie these changes. The five articles presented in this Research Topic explore research on an acting intervention, cover matters related to dance training, identify variables related to music sophistication, and focus on performing arts and musical training.
Granular retrosplenial cortex layer 2/3 generates high-frequency oscillations dynamically coupled with hippocampal rhythms across brain states
Arndt, Kaiser C.; Gilbert, Earl T.; Klaver, Lianne M.F.; Kim, Jongwoon; Buhler, Chelsea M.; Basso, Julia C.; McKenzie, Sam; English, Daniel Fine (CellPress, 2024-03-26)
The granular retrosplenial cortex (gRSC) exhibits high-frequency oscillations (HFOs; ~150 Hz), which can be driven by a hippocampus-subiculum pathway. How the cellular-synaptic and laminar organization of gRSC facilitates HFOs is unknown. Here, we probe gRSC HFO generation and coupling with hippocampal rhythms using focal optogenetics and silicon-probe recordings in behaving mice. ChR2-mediated excitation of CaMKII-expressing cells in L2/3 or L5 induces HFOs, but spontaneous HFOs are found only in L2/3, where HFO power is highest. HFOs couple to CA1 sharp wave-ripples (SPW-Rs) during rest and the descending phase of theta. gRSC HFO current sources and sinks are the same for events during both SPW-Rs and theta oscillations. Independent component analysis shows that high gamma (50–100 Hz) in CA1 stratum lacunosum moleculare is comodulated with HFO power. HFOs may thus facilitate interregional communication of a multisynaptic loop between the gRSC, hippocampus, and medial entorhinal cortex during distinct brain and behavioral states.
Examining the Effect of Increased Aerobic Exercise in Moderately Fit Adults on Psychological State and Cognitive Function
Basso, Julia C.; Oberlin, Douglas J.; Satyal, Medha K.; O’Brien, Catherine E.; Crosta, Christen; Psaras, Zach; Metpally, Anvitha; Suzuki, Wendy A. (Frontiers Media, 2022-07-12)
Regular physical exercise can decrease the risk for obesity, diabetes, and cardiovascular disease, increase life expectancy, and promote psychological health and neurocognitive functioning. Cross-sectional studies show that cardiorespiratory fitness level (VO₂ max) is associated with enhanced brain health, including improved mood state and heightened cognitive performance. Interventional studies are consistent with these cross-sectional studies, but most have focused on low-fit populations. Few such studies have asked if increasing levels of physical activity in moderately fit people can significantly enhance mood, motivation, and cognition. Therefore, the current study investigated the effects of increasing aerobic exercise in moderately fit individuals on psychological state and cognitive performance.We randomly assigned moderately fit healthy adults, 25–59 years of age, who were engaged in one or two aerobic exercise sessions per week to either maintain their exercise regimen (n = 41) or increase their exercise regimen (i.e., 4–7 aerobic workouts per week; n = 39) for a duration of 3 months. Both before and after the intervention, we assessed aerobic capacity using a modified cardiorespiratory fitness test, and hippocampal functioning via various neuropsychological assessments including a spatial navigation task and the Mnemonic Similarity Task as well as self-reported measures including the Positive and Negative Affect Scale, Beck Anxiety Inventory, State-Trait Anxiety Inventory, Perceived Stress Scale, Rumination Scale, Eating Disorders Examination, Eating Attitudes Test, Body Attitudes Test, and Behavioral Regulation of Exercise Questionnaire. Consistent with our initial working hypotheses, we found that increasing exercise significantly decreased measures of negative affect, including fear, sadness, guilt, and hostility, as well as improved body image. Further, we found that the total number of workouts was significantly associated with improved spatial navigation abilities and body image as well as reduced anxiety, general negative affect, fear, sadness, hostility, rumination, and disordered eating. In addition, increases in fitness levels were significantly associated with improved episodic memory and exercise motivation as well as decreased stress and disordered eating. Our findings are some of the first to indicate that in middle-aged moderately-fit adults, continuing to increase exercise levels in an already ongoing fitness regimen is associated with additional benefits for both psychological and cognitive health.

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