Scholarly Works, Fralin Biomedical Research Institute at VTC

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  • Lateral hypothalamic proenkephalin neurons drive threat-induced overeating associated with a negative emotional state
    You, In-Jee; Bae, Yeeun; Beck, Alec R.; Shin, Sora (Nature Research, 2023-10-28)
    Psychological stressors, like the nearby presence of a predator, can be strong enough to induce physiological/hormonal alterations, leading to appetite changes. However, little is known about how threats can alter feeding-related hypothalamic circuit functions. Here, we found that proenkephalin (Penk)- expressing lateral hypothalamic (LHPenk) neurons of mice exposed to predator scent stimulus (PSS) show sensitized responses to high-fat diet (HFD) eating, whereas silencing of the same neurons normalizes PSS-induced HFD overconsumption associated with a negative emotional state. Downregulation of endogenous enkephalin peptides in the LH is crucial for inhibiting the neuronal and behavioral changes developed after PSS exposure. Furthermore, elevated corticosterone after PSS contributes to enhance the reactivity of glucocorticoid receptor (GR)-containing LHPenk neurons to HFD, whereas pharmacological inhibition of GR in the LH suppresses PSS-induced maladaptive behavioral responses. We have thus identified the LHPenk neurons as a critical component in the threat-induced neuronal adaptation that leads to emotional overconsumption.
  • Development of a Dihydroquinoline-Pyrazoline GluN2C/2D-Selective Negative Allosteric Modulator of the N-Methyl-d-aspartate Receptor
    D'Erasmo, Michael P.; Akins, Nicholas S.; Ma, Peipei; Jing, Yao; Swanger, Sharon A.; Sharma, Savita K.; Bartsch, Perry W.; Menaldino, David S.; Arcoria, Paul J.; Bui, Thi-Thien; Pons-Bennaceur, Alexandre; Le, Phuong; Allen, James P.; Ullman, Elijah Z.; Nocilla, Kelsey A.; Zhang, Jing; Perszyk, Riley E.; Kim, Sukhan; Acker, Timothy M.; Taz, Azmain; Burton, Samantha L.; Coe, Kevin; Fritzemeier, Russell G.; Burnashev, Nail; Yuan, Hongjie; Liotta, Dennis C.; Traynelis, Stephen F. (American Chemical Society, 2023-08-11)
    Subunit-selective inhibition of N-methyl-d-aspartate receptors (NMDARs) is a promising therapeutic strategy for several neurological disorders, including epilepsy, Alzheimer’s and Parkinson’s disease, depression, and acute brain injury. We previously described the dihydroquinoline-pyrazoline (DQP) analogue 2a (DQP-26) as a potent NMDAR negative allosteric modulator with selectivity for GluN2C/D over GluN2A/B. However, moderate (<100-fold) subunit selectivity, inadequate cell-membrane permeability, and poor brain penetration complicated the use of 2a as an in vivo probe. In an effort to improve selectivity and the pharmacokinetic profile of the series, we performed additional structure-activity relationship studies of the succinate side chain and investigated the use of prodrugs to mask the pendant carboxylic acid. These efforts led to discovery of the analogue (S)-(−)-2i, also referred to as (S)-(−)-DQP-997-74, which exhibits >100- and >300-fold selectivity for GluN2C- and GluN2D-containing NMDARs (IC50 0.069 and 0.035 μM, respectively) compared to GluN2A- and GluN2B-containing receptors (IC50 5.2 and 16 μM, respectively) and has no effects on AMPA, kainate, or GluN1/GluN3 receptors. Compound (S)-(−)-2i is 5-fold more potent than (S)-2a. In addition, compound 2i shows a time-dependent enhancement of inhibitory actions at GluN2C- and GluN2D-containing NMDARs in the presence of the agonist glutamate, which could attenuate hypersynchronous activity driven by high-frequency excitatory synaptic transmission. Consistent with this finding, compound 2i significantly reduced the number of epileptic events in a murine model of tuberous sclerosis complex (TSC)-induced epilepsy that is associated with upregulation of the GluN2C subunit. Thus, 2i represents a robust tool for the GluN2C/D target validation. Esterification of the succinate carboxylate improved brain penetration, suggesting a strategy for therapeutic development of this series for NMDAR-associated neurological conditions.
  • Enhancing Brain Flow Visualization with Automated 3D Data Processing: A Study on DCE-MRI Data from Mice with Tumors
    Mohammed, Ayat; Polys, Nicholas F.; Cunningham, Jessica; Munson, Jennifer M.; Chutkowski, James; Liang, Hun; Park, Daniel; Rockne, Russell; Woodall, Ryan; Esparza, Cora (ACM, 2023-10-09)
    Enhancing the process of generating entirely automated visualization schemes of complex fluid flow patterns within brain tumors is critical for gaining insights into their movements and behaviors. This study focused on optimizing and automating the processing of 3D volumetric and vector field data sets obtained from DCE-MRI (Dynamic Contrast-Enhanced Magnetic Resonance Imaging) scans. It is crucial to maintain performance, preserve data quality and resolution, and provide an accessible platform for biomedical scientists. In this paper, we represent an innovative approach to enhance fluid flow visualization of brain tumors through scalable visualization techniques. New techniques have been designed, benchmarked, and authenticated to produce X3D visualizations in Web3D environments using Python, and ParaView. The proposed approach does not only enhance fluid flow visualization in the context of brain tumor research but also provides a reproducible and transparent framework for future studies with both human and mouse scans.
  • Noradrenaline tracks emotional modulation of attention in human amygdala
    Bang, Dan; Luo, Yi; Barbosa, Leonardo S.; Batten, Seth R.; Hadj-Amar, Beniamino; Twomey, Thomas; Melville, Natalie; White, Jason P.; Torres, Alexis; Celaya, Xavier; Ramaiah, Priya; McClure, Samuel M.; Brewer, Gene A.; Bina, Robert W.; Lohrenz, Terry; Casas, Brooks; Chiu, Pearl H.; Vannucci, Marina; Kishida, Kenneth T.; Witcher, Mark R.; Montague, P. Read (Elsevier, 2023-11-20)
    The noradrenaline (NA) system is one of the brain’s major neuromodulatory systems; it originates in a small midbrain nucleus, the locus coeruleus (LC), and projects widely throughout the brain. The LC-NA system is believed to regulate arousal and attention and is a pharmacological target in multiple clinical conditions. Yet our understanding of its role in health and disease has been impeded by a lack of direct recordings in humans. Here, we address this problem by showing that electrochemical estimates of sub-second NA dynamics can be obtained using clinical depth electrodes implanted for epilepsy monitoring. We made these recordings in the amygdala, an evolutionarily ancient structure that supports emotional processing, and receives dense LC-NA projections, while patients (n = 3) performed a visual affective oddball task. The task was designed to induce different cognitive states, with the oddball stimuli involving emotionally evocative images, which varied in terms of arousal (low versus high) and valence (negative versus positive). Consistent with theory, the NA estimates tracked the emotional modulation of attention, with a stronger oddball response in a high-arousal state. Parallel estimates of pupil dilation, a common behavioral proxy for LC-NA activity, supported a hypothesis that pupil-NA coupling changes with cognitive state, with the pupil and NA estimates being positively correlated for oddball stimuli in a high-arousal but not a lowarousal state. Our study provides proof of concept that neuromodulator monitoring is now possible using depth electrodes in standard clinical use.
  • 3D models of glioblastoma interaction with cortical cells
    Abedin, Md Joynal; Michelhaugh, Sharon K.; Mittal, Sandeep; Berdichevsky, Yevgeny (Frontiers, 2023-03-09)
    Introduction: Glioblastoma (GBM) invasiveness and ability to infiltrate deep into the brain tissue is a major reason for the poor patient prognosis for this type of brain cancer. Behavior of glioblastoma cells, including their motility, and expression of invasion-promoting genes such as matrix metalloprotease-2 (MMP2), are strongly influenced by normal cells found in the brain parenchyma. Cells such as neurons may also be influenced by the tumor, as many glioblastoma patients develop epilepsy. In vitro models of glioblastoma invasiveness are used to supplement animal models in a search for better treatments, and need to combine capability for high-throughput experiments with capturing bidirectional interactions between GBM and brain cells.Methods: In this work, two 3D in vitro models of GBM-cortical interactions were investigated. A matrix-free model was created by co-culturing GBM and cortical spheroids, and a matrix-based model was created by embedding cortical cells and a GBM spheroid in Matrigel.Results: Rapid GBM invasion occurred in the matrix-based model, and was enhanced by the presence of cortical cells. Little invasion occurred in the matrix-free model. In both types of models, presence of GBM cells resulted in a significant increase in paroxysmal neuronal activity.Discussion: Matrix-based model may be better suited for studying GBM invasion in an environment that includes cortical cells, while matrix-free model may be useful in investigation of tumor-associated epilepsy.
  • Social, clinical, and policy implications of ultra-processed food addiction
    Gearhardt, Ashley N.; Bueno, Nassib B.; DiFeliceantonio, Alexandra G.; Roberto, Christina A.; Jiménez-Murcia, Susana; Fernandez-Aranda, Fernando (BMJ, 2023-10)
    The scientific understanding of addiction is evolving. Although addiction to certain foods is not included in diagnostic frameworks such as the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), research on this topic has grown rapidly in the past 20 years. Much of this research uses the Yale Food Addiction Scale (YFAS), which was developed to measure food addiction by assessing DSM-5 criteria for substance use disorder in the context of food intake (box 1). A recent analysis of two systematic reviews including 281 studies from 36 different countries found the overall pooled prevalence of food addiction using YFAS was 14% in adults and 12% in children. This reported prevalence is similar to the levels of addiction seen for other legal substances in adults (eg, 14% for alcohol and 18% for tobacco), but the level of implied addiction in children is unprecedented. In populations with defined clinical diagnoses, YFAS identified prevalence of food addiction reaches 32% in people with obesity having bariatric surgery,12 and over 50% in those with binge eating disorder. Food addiction based on the YFAS is also associated with core mechanisms of addiction, such as reward related neural dysfunction, impulsivity, and emotion dysregulation, as well as poorer physical and mental health and lower quality of life. Thus, there is converging and consistent support for the validity and clinical relevance of food addiction; what remains a more open question is the types of foods that are addictive. Despite the uncertainty, classifying foods as addictive could stimulate research and shift attitudes to regulation.
  • 3D electron microscopy and volume-based bouton sorting reveal the selectivity of inputs onto geniculate relay cell and interneuron dendrite segments
    Maher, Erin E.; Briegel, Alex C.; Imtiaz, Shahrozia; Fox, Michael A.; Golino, Hudson; Erisir, Alev (Frontiers, 2023-03)
    IntroductionThe visual signals evoked at the retinal ganglion cells are modified and modulated by various synaptic inputs that impinge on lateral geniculate nucleus cells before they are sent to the cortex. The selectivity of geniculate inputs for clustering or forming microcircuits on discrete dendritic segments of geniculate cell types may provide the structural basis for network properties of the geniculate circuitry and differential signal processing through the parallel pathways of vision. In our study, we aimed to reveal the patterns of input selectivity on morphologically discernable relay cell types and interneurons in the mouse lateral geniculate nucleus. MethodsWe used two sets of Scanning Blockface Electron Microscopy (SBEM) image stacks and Reconstruct software to manually reconstruct of terminal boutons and dendrite segments. First, using an unbiased terminal sampling (UTS) approach and statistical modeling, we identified the criteria for volume-based sorting of geniculate boutons into their putative origins. Geniculate terminal boutons that were sorted in retinal and non-retinal categories based on previously described mitochondrial morphology, could further be sorted into multiple subpopulations based on their bouton volume distributions. Terminals deemed non-retinal based on the morphological criteria consisted of five distinct subpopulations, including small-sized putative corticothalamic and cholinergic boutons, two medium-sized putative GABAergic inputs, and a large-sized bouton type that contains dark mitochondria. Retinal terminals also consisted of four distinct subpopulations. The cutoff criteria for these subpopulations were then applied to datasets of terminals that synapse on reconstructed dendrite segments of relay cells or interneurons. ResultsUsing a network analysis approach, we found an almost complete segregation of retinal and cortical terminals on putative X-type cell dendrite segments characterized by grape-like appendages and triads. On these cells, interneuron appendages intermingle with retinal and other medium size terminals to form triads within glomeruli. In contrast, a second, presumed Y-type cell displayed dendrodendritic puncta adherentia and received all terminal types without a selectivity for synapse location; these were not engaged in triads. Furthermore, the contribution of retinal and cortical synapses received by X-, Y- and interneuron dendrites differed such that over 60% of inputs to interneuron dendrites were from the retina, as opposed to 20% and 7% to X- and Y-type cells, respectively. ConclusionThe results underlie differences in network properties of synaptic inputs from distinct origins on geniculate cell types.
  • Mechanisms of mGluR-dependent plasticity in hippocampal area CA2
    Samadi, Mahsa; Hales, Claire A.; Lustberg, Daniel J.; Farris, Shannon; Ross, Madeleine R.; Zhao, Meilan; Hepler, John R.; Harbin, Nicholas H.; Robinson, Emma S. J.; Banks, Paul J.; Bashir, Zafar I.; Dudek, Serena M. (Wiley, 2023-06)
    Pyramidal cells in hippocampal area CA2 have synaptic properties that are distinct from the other CA subregions. Notably, this includes a lack of typical long-term potentiation of stratum radiatum synapses. CA2 neurons express high levels of several known and potential regulators of metabotropic glutamate receptor (mGluR)-dependent signaling including Striatal-Enriched Tyrosine Phosphatase (STEP) and several Regulator of G-protein Signaling (RGS) proteins, yet the functions of these proteins in regulating mGluR-dependent synaptic plasticity in CA2 are completely unknown. Thus, the aim of this study was to examine mGluR-dependent synaptic depression and to determine whether STEP and the RGS proteins RGS4 and RGS14 are involved. Using whole cell voltage-clamp recordings from mouse pyramidal cells, we found that mGluR agonist-induced long-term depression (mGluR-LTD) is more pronounced in CA2 compared with that observed in CA1. This mGluR-LTD in CA2 was found to be protein synthesis and STEP dependent, suggesting that CA2 mGluR-LTD shares mechanistic processes with those seen in CA1, but in addition, RGS14, but not RGS4, was essential for mGluR-LTD in CA2. In addition, we found that exogenous application of STEP could rescue mGluR-LTD in RGS14 KO slices. Supporting a role for CA2 synaptic plasticity in social cognition, we found that RGS14 KO mice had impaired social recognition memory as assessed in a social discrimination task. These results highlight possible roles for mGluRs, RGS14, and STEP in CA2-dependent behaviors, perhaps by biasing the dominant form of synaptic plasticity away from LTP and toward LTD in CA2.
  • Pericyte Progenitor Coupling to the Emerging Endothelium during Vasculogenesis via Connexin43
    Payne, Laura Beth; Tewari, Bhanu P.; Dunkenberger, Logan; Bond, Samantha; Savelli, Alyssa; Darden, Jordan; Zhao, Huaning; Willi, Caroline; Kanodia, Ronak; Gude, Rosalie; Powell, Michael D.; Oestreich, Kenneth J.; Sontheimer, Harald; Dal-Pra, Sophie; Chappell, John C. (Lippincott Williams & Wilkins, 2022-04-01)
    Background: Vascular pericytes stabilize blood vessels and contribute to their maturation, while playing other key roles in microvascular function. Nevertheless, relatively little is known about involvement of their precursors in the earliest stages of vascular development, specifically during vasculogenesis. Methods: We combined high-power, time-lapse imaging with transcriptional profiling of emerging pericytes and endothelial cells in reporter mouse and cell lines. We also analyzed conditional transgenic animals deficient in Cx43/Gja1 (connexin 43/gap junction alpha-1) expression within Ng2+ cells. Results: A subset of Ng2-DsRed+ cells, likely pericyte/mural cell precursors, arose alongside endothelial cell differentiation and organization and physically engaged vasculogenic endothelium in vivo and in vitro. We found no overlap between this population of differentiating pericyte/mural progenitors and other lineages including hemangiogenic and neuronal/glial cell types. We also observed cell-cell coupling and identified Cx43-based gap junctions contributing to pericyte-endothelial cell precursor communication during vascular assembly. Genetic loss of Cx43/Gja1 in Ng2+ pericyte progenitors compromised embryonic blood vessel formation in a subset of animals, while surviving mutants displayed little-to-no vessel abnormalities, suggesting a resilience to Cx43/Gja1 loss in Ng2+ cells or potential compensation by additional connexin isoforms. Conclusions: Together, our data suggest that a distinct pericyte lineage emerges alongside vasculogenesis and directly communicates with the nascent endothelium via Cx43 during early vessel formation. Cx43/Gja1 loss in pericyte/mural cell progenitors can induce embryonic vessel dysmorphogenesis, but alternate connexin isoforms may be able to compensate. These data provide insight that may reshape the current framework of vascular development and may also inform tissue revascularization/vascularization strategies.
  • A review of the literature: How does prenatal opioid exposure impact placental health and fetal brain development?
    Humphries, Audrey; Simcox, Kim; Howell, Brittany (Wiley, 2023-04)
    In recent years, there has been a sixfold increase in the number of pregnant people with opioid use disorder (OUD). Rates of neonatal opioid withdrawal syndrome (NOWS), previously known as neonatal abstinence syndrome (NAS), have significantly increased in virtually every state and demographic group (Healthcare Cost Utilization Project, HCUP, 2010). NOWS is a condition resulting from chronic exposure to either therapeutic opioid use (e.g., medication for OUD, chronic pain conditions) or nonprescribed opioid use. To date, there is no known prenatal treatment to help decrease the risk of infants developing NOWS and subsequent neurodevelopmental outcomes. Given the increasing support for how placental signaling, or placental programming, may play a role in downstream pathology, prospective research investigating how the placenta is affected by chronic opioid exposure morphologically, histologically, and at the cellular level may open up potential treatment opportunities in this field. In this review, we discuss literature exploring the physiological roles of nitric oxide and dopamine not only in the vascular development of the placenta, but also in fetal cerebral blood flow, neurogenesis, neuronal differentiation, and neuronal activity. We also discuss histological preclinical studies that suggest chronic opioid exposure to induce some combination of placental dysfunction and hypoxia in a manner similar to other well-known placental pathologies, as denoted by the compensatory neovascularization and increased utilization of the placenta's supply of trophoblast cells, which play an essential role in placental angiogenesis. Overall, we found that the current literature, while limited, suggests chronic opioid exposure negatively impacts placental function and fetal brain development on a cellular and histopathological level. We conclude that it is worthwhile to consider the placenta as a therapeutic target with the ultimate goal of decreasing the incidence of NOWS and the long-term impacts of prenatal opioid exposure.
  • Collagen XIX is required for pheromone recognition and glutamatergic synapse formation in mouse accessory olfactory bulb
    Amos, Chase; Fox, Michael A.; Su, Jianmin (Frontiers, 2023-04)
    In mammals, the accessory olfactory bulb (AOB) receives input from vomeronasal sensory neurons (VSN) which detect pheromones, chemical cues released by animals to regulate the physiology or behaviors of other animals of the same species. Cytoarchitecturally, cells within the AOB are segregated into a glomerular layer (GL), mitral cell layer (MCL), and granule cell layer (GCL). While the cells and circuitry of these layers has been well studied, the molecular mechanism underlying the assembly of such circuitry in the mouse AOB remains unclear. With the goal of identifying synaptogenic mechanisms in AOB, our attention was drawn to Collagen XIX, a non-fibrillar collagen generated by neurons in the mammalian telencephalon that has previously been shown to regulate the assembly of synapses. Here, we used both a targeted mouse mutant that lacks Collagen XIX globally and a conditional allele allowing for cell-specific deletion of this collagen to test if the loss of Collagen XIX causes impaired synaptogenesis in the mouse AOB. These analyses not only revealed defects in excitatory synapse distribution in these Collagen XIX-deficient mutants, but also showed that these mutant mice exhibit altered behavioral responses to pheromones. Although this collagen has been demonstrated to play synaptogenic roles in the telencephalon, those roles are at perisomatic inhibitory synapses, results here are the first to demonstrate the function of this unconventional collagen in glutamatergic synapse formation.
  • Development of a Synthetic, Injectable Hydrogel to Capture Residual Glioblastoma and Glioblastoma Stem-Like Cells with CXCL12-Mediated Chemotaxis
    Khan, Zerin Mahzabin; Munson, Jennifer M.; Long, Timothy E.; Vlaisavljevich, Eli; Verbridge, Scott S. (Wiley, 2023-06)
    Glioblastoma (GBM), characterized by high infiltrative capacity, is the most common and deadly type of primary brain tumor in adults. GBM cells, including therapy-resistant glioblastoma stem-like cells (GSCs), invade the healthy brain parenchyma to form secondary tumors even after patients undergo surgical resection and chemoradiotherapy. New techniques are therefore urgently needed to eradicate these residual tumor cells. A thiol-Michael addition injectable hydrogel for compatibility with GBM therapy is previously characterized and optimized. This study aims to develop the hydrogel further to capture GBM/GSCs through CXCL12-mediated chemotaxis. The release kinetics of hydrogel payloads are investigated, migration and invasion assays in response to chemoattractants are performed, and the GBM-hydrogel interactions in vitro are studied. With a novel dual-layer hydrogel platform, it is demonstrated that CXCL12 released from the synthetic hydrogel can induce the migration of U251 GBM cells and GSCs from the extracellular matrix microenvironment and promote invasion into the synthetic hydrogel via amoeboid migration. The survival of GBM cells entrapped deep into the synthetic hydrogel is limited, while live cells near the surface reinforce the hydrogel through fibronectin deposition. This synthetic hydrogel, therefore, demonstrates a promising method to attract and capture migratory GBM cells and GSCs responsive to CXCL12 chemotaxis.
  • Naturalistic Hyperscanning with Wearable Magnetoencephalography
    Holmes, Niall; Rea, Molly; Hill, Ryan M.; Boto, Elena; Leggett, James; Edwards, Lucy J.; Rhodes, Natalie; Shah, Vishal; Osborne, James; Fromhold, T. Mark; Glover, Paul; Montague, P. Read; Brookes, Matthew J.; Bowtell, Richard (MDPI, 2023-06-09)
    The evolution of human cognitive function is reliant on complex social interactions which form the behavioural foundation of who we are. These social capacities are subject to dramatic change in disease and injury; yet their supporting neural substrates remain poorly understood. Hyperscanning employs functional neuroimaging to simultaneously assess brain activity in two individuals and offers the best means to understand the neural basis of social interaction. However, present technologies are limited, either by poor performance (low spatial/temporal precision) or an unnatural scanning environment (claustrophobic scanners, with interactions via video). Here, we describe hyperscanning using wearable magnetoencephalography (MEG) based on optically pumped magnetometers (OPMs). We demonstrate our approach by simultaneously measuring brain activity in two subjects undertaking two separate tasks—an interactive touching task and a ball game. Despite large and unpredictable subject motion, sensorimotor brain activity was delineated clearly, and the correlation of the envelope of neuronal oscillations between the two subjects was demonstrated. Our results show that unlike existing modalities, OPM-MEG combines high-fidelity data acquisition and a naturalistic setting and thus presents significant potential to investigate neural correlates of social interaction.
  • Evidence for Using ACQUIRE Therapy in the Clinical Application of Intensive Therapy: A Framework to Guide Therapeutic Interactions
    DeLuca, Stephanie C.; Trucks, Mary Rebekah; Wallace, Dorian; Ramey, Sharon L. (MDPI, 2023-06-07)
    Intensive therapies have become increasingly popular for children with hemiparesis in the last two decades and are specifically recommended because of high levels of scientific evidence associated with them, including multiple randomized controlled trials and systematic reviews. Common features of most intensive therapies that have documented efficacy include: high dosages of therapy hours; active engagement of the child; individualized goal-directed activities; and the systematic application of operant conditioning techniques to elicit and progress skills with an emphasis on success-oriented play. However, the scientific protocols have not resulted in guiding principles designed to aid clinicians with understanding the complexity of applying these principles to a heterogeneous clinical population, nor have we gathered sufficient clinical data using intensive therapies to justify their widespread clinical use beyond hemiparesis. We define a framework for describing moment-by-moment therapeutic interactions that we have used to train therapists across multiple clinical trials in implementing intensive therapy protocols. We also document outcomes from the use of this framework during intensive therapies provided clinically to children (7 months–20 years) from a wide array of diagnoses that present with motor impairments, including hemiparesis and quadriparesis. Results indicate that children from a wide array of diagnostic categories demonstrated functional improvements.
  • Mapping established psychopathology scales onto the Hierarchical Taxonomy of Psychopathology (HiTOP)
    Wendt, Leon P.; Jankowsky, Kristin; Schroeders, Ulrich; Nolte, Tobias; Fonagy, Peter; Montague, P. Read; Zimmermann, Johannes; Olaru, Gabriel (Wiley, 2023-05)
    The Hierarchical Taxonomy of Psychopathology (HiTOP) organizes phenotypes of mental disorder based on empirical covariation, offering a comprehensive organizational framework from narrow symptoms to broader patterns of psychopathology. We argue that established self-report measures of psychopathology from the pre-HiTOP era should be systematically integrated into HiTOP to foster cumulative research and further the understanding of psychopathology structure. Hence, in this study, we mapped 92 established psychopathology (sub)scales onto the current HiTOP working model using data from an extensive battery of self-report assessments that was completed by community participants and outpatients (N = 909). Content validity ratings of the item pool were used to select indicators for a bifactor-(S-1) model of the p factor and five HiTOP spectra (i.e., internalizing, thought disorder, detachment, disinhibited externalizing, and antagonistic externalizing). The content-based HiTOP scales were validated against personality disorder diagnoses as assessed by standardized interviews. We then located established scales within the taxonomy by estimating the extent to which scales reflected higher-level HiTOP dimensions. The analyses shed light on the location of established psychopathology scales in HiTOP, identifying pure markers and blends of HiTOP spectra, as well as pure markers of the p factor (i.e., scales assessing mentalizing impairment and suspiciousness/epistemic mistrust).
  • Development of cognitive control during adolescence: The integrative effects of family socioeconomic status and parenting behaviors
    Li, Mengjiao; Lindenmuth, Morgan; Tarnai, Kathryn; Lee, Jacob; Casas, Brooks; Kim-Spoon, Jungmeen; Deater-Deckard, Kirby (Elsevier, 2022-10)
    Cognitive control is of great interest to researchers and practitioners. The concurrent association between family socioeconomic status (SES) and adolescent cognitive control is well-documented. However, little is known about whether and how SES relates to individual differences in the development of adolescent cognitive control. The current four-year longitudinal investigation (N = 167, 13-14 years at Wave 1) used multi-source interference task performance (reaction time in interference correct trials minus neutral correct trials) and corresponding neural activities (blood oxygen level dependent contrast of interference versus neutral conditions) as measures of cognitive control. SES and parenting behaviors (warmth, monitoring) were measured through surveys. We examined direct and indirect effects of earlier SES on the development of cognitive control via parenting behaviors; the moderating effect of parenting also was explored. Results of latent growth modeling (LGM) revealed significant interactive effects between SES and parenting predicting behavioral and neural measures of cognitive control. Lower family SES was associated with poorer cognitive performance when coupled with low parental warmth. In contrast, higher family SES was associated with greater improvement in performance, as well as a higher intercept and steeper decrease in frontoparietal activation over time, when coupled with high parental monitoring. These findings extend prior cross-sectional evidence to show the moderating effect of the parenting environment on the potential effects of SES on developmental changes in adolescent cognitive control.
  • A Soluble Platelet-Derived Growth Factor Receptor-β Originates via Pre-mRNA Splicing in the Healthy Brain and Is Upregulated during Hypoxia and Aging
    Payne, Laura Beth; Abdelazim, Hanaa; Hoque, Maruf; Barnes, Audra; Mironovova, Zuzana; Willi, Caroline E.; Darden, Jordan; Houk, Clifton; Sedovy, Meghan W.; Johnstone, Scott R.; Chappell, John C. (MDPI, 2023-04-21)
    The platelet-derived growth factor-BB (PDGF-BB) pathway provides critical regulation of cerebrovascular pericytes, orchestrating their investment and retention within the brain microcirculation. Dysregulated PDGF Receptor-beta (PDGFRβ) signaling can lead to pericyte defects that compromise blood-brain barrier (BBB) integrity and cerebral perfusion, impairing neuronal activity and viability, which fuels cognitive and memory deficits. Receptor tyrosine kinases such as PDGF-BB and vascular endothelial growth factor-A (VEGF-A) are often modulated by soluble isoforms of cognate receptors that establish signaling activity within a physiological range. Soluble PDGFRβ (sPDGFRβ) isoforms have been reported to form by enzymatic cleavage from cerebrovascular mural cells, and pericytes in particular, largely under pathological conditions. However, pre-mRNA alternative splicing has not been widely explored as a possible mechanism for generating sPDGFRβ variants, and specifically during tissue homeostasis. Here, we found sPDGFRβ protein in the murine brain and other tissues under normal, physiological conditions. Utilizing brain samples for follow-on analysis, we identified mRNA sequences corresponding to sPDGFRβ isoforms, which facilitated construction of predicted protein structures and related amino acid sequences. Human cell lines yielded comparable sequences and protein model predictions. Retention of ligand binding capacity was confirmed for sPDGFRβ by co-immunoprecipitation. Visualizing fluorescently labeled sPDGFRβ transcripts revealed a spatial distribution corresponding to murine brain pericytes alongside cerebrovascular endothelium. Soluble PDGFRβ protein was detected throughout the brain parenchyma in distinct regions, such as along the lateral ventricles, with signals also found more broadly adjacent to cerebral microvessels consistent with pericyte labeling. To better understand how sPDGFRβ variants might be regulated, we found elevated transcript and protein levels in the murine brain with age, and acute hypoxia increased sPDGFRβ variant transcripts in a cell-based model of intact vessels. Our findings indicate that soluble isoforms of PDGFRβ likely arise from pre-mRNA alternative splicing, in addition to enzymatic cleavage mechanisms, and these variants exist under normal physiological conditions. Follow-on studies will be needed to establish potential roles for sPDGFRβ in regulating PDGF-BB signaling to maintain pericyte quiescence, BBB integrity, and cerebral perfusion—critical processes underlying neuronal health and function, and in turn, memory and cognition.
  • A Phase 1b Adaptive Androgen Deprivation Therapy Trial in Metastatic Castration Sensitive Prostate Cancer
    Zhang, Jingsong; Gallaher, Jill; Cunningham, Jessica J.; Choi, Jung W.; Ionescu, Filip; Chatwal, Monica S.; Jain, Rohit; Kim, Youngchul; Wang, Liang; Brown, Joel S.; Anderson, Alexander R.; Gatenby, Robert A. (MDPI, 2022-11)
    Simple Summary Despite early utilization of new hormonal agents (NHA, i.e., abiraterone, enzalutamide and apalutamide) for combined androgen deprivation therapy (ADT) for metastatic prostate cancer, increasingly more men are dying from this disease. While continued development of new drugs is needed, we propose that improved survival of metastatic prostate cancer can be obtained through evolutionarily informed treatment strategies that adjust patient-specific-dosing to their current and past Prostate Specific Antigen (PSA) levels. Compared to the conventional treat-until-progression paradigm, our previous study in metastatic castration resistant prostate cancer (NCT02415621) showed that an on-and-off abiraterone therapy adapted to an individual's PSA response dynamics provided better cancer control with less drug usage. Here, we report the feasibility of applying this strategy to newly diagnosed metastatic prostate cancer. On-and-off ADTs with luteinizing hormone releasing hormone (LHRH) analog, an NHA, or in combination were based on individual's testosterone and PSA levels. The current study represents the foundation for future efforts to validate our adaptive therapy in randomized controlled studies for metastatic prostate cancer. Background: We hypothesize that cancer survival can be improved through adapting treatment strategies to cancer evolutionary dynamics and conducted a phase 1b study in metastatic castration sensitive prostate cancer (mCSPC). Methods: Men with asymptomatic mCSPC were enrolled and proceeded with a treatment break after achieving > 75% PSA decline with LHRH analog plus an NHA. ADT was restarted at the time of PSA or radiographic progression and held again after achieving >50% PSA decline. This on-off cycling of ADT continued until on treatment imaging progression. Results: At data cut off in August 2022, only 2 of the 16 evaluable patients were off study due to imaging progression at 28 months from first dose of LHRH analog for mCSPC. Two additional patients showed PSA progression at 12.4 and 20.5 months and remain on trial. Since none of the 16 patients developed imaging progression at 12 months, the study succeeded in its primary objective of feasibility. The secondary endpoints of median time to PSA progression and median time to radiographic progression have not been reached at a median follow up of 26 months. Conclusions: It is feasible to use an individual's PSA response and testosterone levels to guide intermittent ADT in mCSPC.
  • Tobacco use among Appalachian adolescents: An urgent need for virtual scale out of effective interventions
    Horn, Kimberly; Schoenberg, Nancy; Rose, Shyanika; Romm, Katelyn; Berg, Carla (European Publishing, 2022-11)
    Tobacco use, typically initiated during adolescence, can escalate into young adulthood, even among experimenting or intermittent users. Despite declines in cigarette smoking among US adolescents, use of other tobacco products and poly-tobacco are on the rise among Appalachian adolescents. Unfortunately, Appalachian adolescent tobacco users also are less likely to receive effective tobacco interventions due to various barriers: a) accessibility (e.g. service and provider shortages, affordability, and transportation; b) acceptability (e.g. issues of privacy and stigma); and c) cultural relevance. The present review provides critical considerations synthesized from an extensive body of literature on the suitability of virtual tobacco interventions, the need for well-timed interventions that address complex tobacco use, and the rationale for leveraging and scaling evidence-based interventions inform novel interventions for Appalachian adolescent tobacco users. Borrowing strength from existing in-person evidence-based adolescent tobacco interventions and state-of-the-art virtual health services, a well-planned virtual scale out of tobacco interventions holds potential to minimize barriers unique to Appalachia.
  • Sonic hedgehog-dependent recruitment of GABAergic interneurons into the developing visual thalamus
    Somaiya, Rachana Deven; Stebbins, Katelyn; Gingrich, Ellen C.; Xie, Hehuang; Campbell, John N.; Garcia, A. Denise R.; Fox, Michael A. (Elife Sciences, 2022-11)
    Axons of retinal ganglion cells (RGCs) play critical roles in the development of inhibitory circuits in visual thalamus. We previously reported that RGC axons signal astrocytes to induce the expression of fibroblast growth factor 15 (FGF15), a motogen required for GABAergic interneuron migration into visual thalamus. However, how retinal axons induce thalamic astrocytes to generate Fgf15 and influence interneuron migration remains unknown. Here, we demonstrate that impairing RGC activity had little impact on interneuron recruitment into mouse visual thalamus. Instead, our data show that retinal-derived sonic hedgehog (SHH) is essential for interneuron recruitment. Specifically, we show that thalamus-projecting RGCs express SHH and thalamic astrocytes generate downstream components of SHH signaling. Deletion of RGC-derived SHH leads to a significant decrease in Fgf15 expression, as well as in the percentage of interneurons recruited into visual thalamus. Overall, our findings identify a morphogen-dependent neuron-astrocyte signaling mechanism essential for the migration of thalamic interneurons.