Scholarly Works, Fralin Biomedical Research Institute at VTC

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Research articles, presentations, and other scholarship


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  • Coordination of rhythmic RNA synthesis and degradation orchestrates 24-and 12-h RNA expression patterns in mouse fibroblasts
    Unruh, Benjamin A.; Weidemann, Douglas E.; Miao, Lin; Kojima, Shihoko (National Academy of Sciences, 2024)
    Circadian RNA expression is essential to ultimately regulate a plethora of downstream rhythmic biochemical, physiological, and behavioral processes. Both transcriptional and posttranscriptional mechanisms are considered important to drive rhythmic RNA expression; however, the extent to which each regulatory process contributes to the rhythmic RNA expression remains controversial. To systematically address this, we monitored RNA dynamics using metabolic RNA labeling technology during a circadian cycle in mouse fibroblasts. We find that rhythmic RNA synthesis is the primary contributor of 24-h RNA rhythms, while rhythmic degradation is more important for 12-h RNA rhythms. These rhythms were predominantly regulated by Bmal1 and/or the core clock mechanism, and the interplay between rhythmic synthesis and degradation has a significant impact in shaping rhythmic RNA expression patterns. Interestingly, core clock RNAs are regulated by multiple rhythmic processes and have the highest amplitude of synthesis and degradation, presumably critical to sustain robust rhythmicity of cell-autonomous circadian rhythms. Our study yields invaluable insights into the temporal dynamics of both 24-and 12-h RNA rhythms in mouse fibroblasts.
  • Dopamine and serotonin in human substantia nigra track social context and value signals during economic exchange
    Batten, Seth R.; Bang, Dan; Kopell, Brian H.; Davis, Arianna N.; Heflin, Matthew; Fu, Qixiu; Perl, Ofer; Ziafa, Kimia; Hashemi, Alice; Saez, Ignacio; Barbosa, Leonardo S.; Twomey, Thomas; Lohrenz, Terry; White, Jason P.; Dayan, Peter; Charney, Alexander W.; Figee, Martijn; Mayberg, Helen S.; Kishida, Kenneth T.; Gu, Xiaosi; Montague, P. Read (Nature Research, 2024-02-26)
    Dopamine and serotonin are hypothesized to guide social behaviours. In humans, however, we have not yet been able to study neuromodulator dynamics as social interaction unfolds. Here, we obtained subsecond estimates of dopamine and serotonin from human substantia nigra pars reticulata during the ultimatum game. Participants, who were patients with Parkinson’s disease undergoing awake brain surgery, had to accept or reject monetary offers of varying fairness from human and computer players. They rejected more offers in the human than the computer condition, an effect of social context associated with higher overall levels of dopamine but not serotonin. Regardless of the social context, relative changes in dopamine tracked trial-by-trial changes in offer value—akin to reward prediction errors—whereas serotonin tracked the current offer value. These results show that dopamine and serotonin fluctuations in one of the basal ganglia’s main output structures reflect distinct social context and value signals.
  • Neuromuscular Dysfunction Precedes Cognitive Impairment in a Mouse Model of Alzheimer's Disease
    Brisendine, Matthew H.; Nichenko, Anna S.; Bandara, Aloka B.; Willoughby, Orion S.; Amiri, Niloufar; Weingrad, Zach; Specht, Kalyn S.; Bond, Jacob M.; Addington, Adele; Jones III, Ronald G.; Murach, Kevin A.; Poelzing, Steven; Craige, Siobhan M.; Grange, Robert W.; Drake, Joshua C. (Oxford University Press, 2023-12-04)
    Alzheimer's disease (AD) develops along a continuum that spans years prior to diagnosis. Decreased muscle function and mitochondrial respiration occur years earlier in those that develop AD; however, it is unknown what causes these peripheral phenotypes in a disease of the brain. Exercise promotes muscle, mitochondria, and cognitive health and is proposed to be a potential therapeutic for AD, but no study has investigated how skeletal muscle adapts to exercise training in an AD-like context. Utilizing 5xFAD mice, an AD model that develops ad-like pathology and cognitive impairments around 6 mo of age, we examined in vivo neuromuscular function and exercise adapations (mitochondrial respiration and RNA sequencing) before the manifestation of overt cognitive impairment. We found 5xFAD mice develop neuromuscular dysfunction beginning as early as 4 mo of age, characterized by impaired nerve-stimulated muscle torque production and compound nerve action potential of the sciatic nerve. Furthermore, skeletal muscle in 5xFAD mice had altered, sex-dependent, adaptive responses (mitochondrial respiration and gene expression) to exercise training in the absence of overt cognitive impairment. Changes in peripheral systems, specifically neural communication to skeletal muscle, may be harbingers for AD and have implications for lifestyle interventions, like exercise, in AD.
  • Noninvasive neuromodulation of subregions of the human insula differentially affect pain processing and heart-rate variability: a within-subjects pseudo-randomized trial
    Legon, Wynn; Strohman, Andrew; In, Alexander; Payne, Brighton (Wolters Kluwer Health, Inc., 2024-02-01)
    The insula is an intriguing target for pain modulation. Unfortunately, it lies deep to the cortex making spatially specific noninvasive access difficult. Here, we leverage the high spatial resolution and deep penetration depth of low-intensity focused ultrasound (LIFU) to nonsurgically modulate the anterior insula (AI) or posterior insula (PI) in humans for effect on subjective pain ratings, electroencephalographic (EEG) contact heat–evoked potentials, as well as autonomic measures including heart-rate variability (HRV). In a within-subjects, repeated-measures, pseudo-randomized trial design, 23 healthy volunteers received brief noxious heat pain stimuli to the dorsum of their right hand during continuous heart-rate, electrodermal, electrocardiography and EEG recording. Low-intensity focused ultrasound was delivered to the AI (anterior short gyrus), PI (posterior longus gyrus), or under an inert Sham condition. The primary outcome measure was pain rating. Low-intensity focused ultrasound to both AI and PI similarly reduced pain ratings but had differential effects on EEG activity. Low-intensity focused ultrasound to PI affected earlier EEG amplitudes, whereas LIFU to AI affected later EEG amplitudes. Only LIFU to the AI affected HRV as indexed by an increase in SD of N-N intervals and mean HRV low-frequency power. Taken together, LIFU is an effective noninvasive method to individually target subregions of the insula in humans for site-specific effects on brain biomarkers of pain processing and autonomic reactivity that translates to reduced perceived pain to a transient heat stimulus.
  • Hedgehog-interacting protein acts in the habenula to regulate nicotine intake
    Caligiuri, Stephanie P. B.; Howe, William M.; Wills, Lauren; Smith, Alexander C. W.; Lei, Ye; Bali, Purva; Heyer, Mary P.; Moen, Janna K.; Ables, Jessica L.; Elayouby, Karim S.; Williams, Maya; Fillinger, Clementine; Oketokoun, Zainab; Lehmann, Vanessa E.; DiFeliceantonio, Alexandra G.; Johnson, Paul M.; Beaumont, Kristin; Sebra, Robert P.; Ibanez-Tallon, Ines; Kenny, Paul J. (National Academy of Sciences, 2022-11-08)
    Hedgehog-interacting protein (HHIP) sequesters Hedgehog ligands to repress Smoothened (SMO)-mediated recruitment of the GLI family of transcription factors. Allelic variation in HHIP confers risk of chronic obstructive pulmonary disease and other smoking-related lung diseases, but underlying mechanisms are unclear. Using single-cell and cell-type-specific translational profiling, we show that HHIP expression is highly enriched in medial habenula (MHb) neurons, particularly MHb cholinergic neurons that regulate aversive behavioral responses to nicotine. HHIP deficiency dysregulated the expression of genes involved in cholinergic signaling in the MHb and disrupted the function of nicotinic acetylcholine receptors (nAChRs) through a PTCH-1/cholesterol-dependent mechanism. Further, CRISPR/Cas9-mediated genomic cleavage of the Hhip gene in MHb neurons enhanced the motivational properties of nicotine in mice. These findings suggest that HHIP influences vulnerability to smoking-related lung diseases in part by regulating the actions of nicotine on habenular aversion circuits.
  • Cardiovascular aging: from cellular and molecular changes to therapeutic interventions
    Vakka, Angeliki; Warren, Junco S.; Drosatos, Konstantinos (OAE Publishing, 2023-07-01)
    Progressive age-induced deterioration in the structure and function of the cardiovascular system involves cardiac hypertrophy, diastolic dysfunction, myocardial fibrosis, arterial stiffness, and endothelial dysfunction. These changes are driven by complex processes that are interconnected, such as oxidative stress, mitochondrial dysfunction, autophagy, inflammation, fibrosis, and telomere dysfunction. In recent years, the advances in research of cardiovascular aging, including the wide use of animal models of cardiovascular aging, elucidated an abundance of cell signaling pathways involved in these processes and brought into sight possible interventions, which span from pharmacological agents, such as metformin, sodium-glucose cotransporter 2-inhibitors, rapamycin, dasatinib and quercetin, to lifestyle changes.
  • PERM1 regulates energy metabolism in the heart via ERR alpha/PGC-1 alpha axis
    Oka, Shin-ichi I.; Sreedevi, Karthi; Shankar, Thirupura S.; Yedla, Shreya; Arowa, Sumaita; James, Amina; Stone, Kathryn G.; Olmos, Katia; Sabry, Amira D.; Horiuchi, Amanda; Cawley, Keiko M.; O'very, Sean A.; Tong, Mingming; Byun, Jaemin; Xu, Xiaoyong; Kashyap, Sanchita; Mourad, Youssef; Vehra, Omair; Calder, Dallen; Lunde, Ty; Liu, Tong; Li, Hong; Mashchek, J. Alan; Cox, James; Saijoh, Yukio; Drakos, Stavros G.; Warren, Junco S. (Frontiers, 2022-11-07)
    Aims: PERM1 is a striated muscle-specific regulator of mitochondrial bioenergetics. We previously demonstrated that PERM1 is downregulated in the failing heart and that PERM1 positively regulates metabolic genes known as targets of the transcription factor ERRα and its coactivator PGC-1α in cultured cardiomyocytes. The aims of this study were to determine the effect of loss of PERM1 on cardiac function and energetics using newly generated Perm1-knockout (Perm1–/–) mice and to investigate the molecular mechanisms of its transcriptional control. Methods and results: Echocardiography showed that ejection fraction and fractional shortening were lower in Perm1–/– mice than in wild-type mice (both p < 0.05), and the phosphocreatine-to-ATP ratio was decreased in Perm1–/– hearts (p < 0.05), indicating reduced contractile function and energy reserves of the heart. Integrated proteomic and metabolomic analyses revealed downregulation of oxidative phosphorylation and upregulation of glycolysis and polyol pathways in Perm1–/– hearts. To examine whether PERM1 regulates energy metabolism through ERRα, we performed co-immunoprecipitation assays, which showed that PERM1 bound to ERRα in cardiomyocytes and the mouse heart. DNA binding and reporter gene assays showed that PERM1 was localized to and activated the ERR target promoters partially through ERRα. Mass spectrometry-based screening in cardiomyocytes identified BAG6 and KANK2 as potential PERM1’s binding partners in transcriptional regulation. Mammalian one-hybrid assay, in which PERM1 was fused to Gal4 DNA binding domain, showed that the recruitment of PERM1 to a gene promoter was sufficient to activate transcription, which was blunted by silencing of either PGC-1α, BAG6, or KANK2. Conclusion: This study demonstrates that PERM1 is an essential regulator of cardiac energetics and function and that PERM1 is a novel transcriptional coactivator in the ERRα/PGC-1α axis that functionally interacts with BAG6 and KANK2.
  • Pregnancy-induced remodeling of the murine reproductive tract: a longitudinal in vivo magnetic resonance imaging study
    Suarez, Aileen C.; Gimenez, Clara J.; Russell, Serena R.; Wang, Maosen; Munson, Jennifer M.; Myers, Kristin M.; Miller, Kristin S.; Abramowitch, Steven D.; De Vita, Rafaella (Springer, 2024-01-05)
    Mammalian pregnancy requires gradual yet extreme remodeling of the reproductive organs to support the growth of the embryos and their birth. After delivery, the reproductive organs return to their non-pregnant state. As pregnancy has traditionally been understudied, there are many unknowns pertaining to the mechanisms behind this remarkable remodeling and repair process which, when not successful, can lead to pregnancy-related complications such as maternal trauma, pre-term birth, and pelvic floor disorders. This study presents the first longitudinal imaging data that focuses on revealing anatomical alterations of the vagina, cervix, and uterine horns during pregnancy and postpartum using the mouse model. By utilizing advanced magnetic resonance imaging (MRI) technology, T1-weighted and T2-weighted images of the reproductive organs of three mice in their in vivo environment were collected at five time points: non-pregnant, mid-pregnant (gestation day: 9–10), late pregnant (gestation day: 16–17), postpartum (24–72 h after delivery) and three weeks postpartum. Measurements of the vagina, cervix, and uterine horns were taken by analyzing MRI segmentations of these organs. The cross-sectional diameter, length, and volume of the vagina increased in late pregnancy and then returned to non-pregnant values three weeks after delivery. The cross-sectional diameter of the cervix decreased at mid-pregnancy before increasing in late pregnancy. The volume of the cervix peaked at late pregnancy before shortening by 24–72 h postpartum. As expected, the uterus increased in cross-sectional diameter, length, and volume during pregnancy. The uterine horns decreased in size postpartum, ultimately returning to their average non-pregnant size three weeks postpartum. The newly developed methods for acquiring longitudinal in vivo MRI scans of the murine reproductive system can be extended to future studies that evaluate functional and morphological alterations of this system due to pathologies, interventions, and treatments.
  • Endurance Exercise Training Mitigates Diastolic Dysfunction in Diabetic Mice Independent of Phosphorylation of Ulk1 at S555
    Guan, Yuntian; Zhang, Mei; Lacy, Christie; Shah, Soham; Epstein, Frederick H.; Yan, Zhen (MDPI, 2024-01-03)
    Millions of diabetic patients suffer from cardiovascular complications. One of the earliest signs of diabetic complications in the heart is diastolic dysfunction. Regular exercise is a highly effective preventive/therapeutic intervention against diastolic dysfunction in diabetes, but the underlying mechanism(s) remain poorly understood. Studies have shown that the accumulation of damaged or dysfunctional mitochondria in the myocardium is at the center of this pathology. Here, we employed a mouse model of diabetes to test the hypothesis that endurance exercise training mitigates diastolic dysfunction by promoting cardiac mitophagy (the clearance of mitochondria via autophagy) via S555 phosphorylation of Ulk1. High-fat diet (HFD) feeding and streptozotocin (STZ) injection in mice led to reduced endurance capacity, impaired diastolic function, increased myocardial oxidative stress, and compromised mitochondrial structure and function, which were all ameliorated by 6 weeks of voluntary wheel running. Using CRISPR/Cas9-mediated gene editing, we generated non-phosphorylatable Ulk1 (S555A) mutant mice and showed the requirement of p-Ulk1at S555 for exercise-induced mitophagy in the myocardium. However, diabetic Ulk1 (S555A) mice retained the benefits of exercise intervention. We conclude that endurance exercise training mitigates diabetes-induced diastolic dysfunction independent of Ulk1 phosphorylation at S555.
  • The Impact of Weight Bias and Stigma on the 24 h Dietary Recall Process in Adults with Overweight and Obesity: A Pilot Study
    Howes, Erica M.; Parker, Molly K.; Misyak, Sarah A.; DiFeliceantonio, Alexandra G.; Davy, Brenda M.; Brown, Letisha Engracia Cardoso; Hedrick, Valisa E. (MDPI, 2024-01-06)
    People with overweight and obesity tend to both underreport dietary energy intake and experience weight stigma. This exploratory pilot study aimed to determine the relationship between weight bias and weight stigma and energy intake reporting accuracy. Thirty-nine weight-stable adults with BMI ≥ 25 completed three 24 h dietary recalls; indirect calorimetry to measure resting metabolic rate; a survey measuring weight stigma, psychosocial constructs, and physical activity; and a semi-structured qualitative interview. Multiple linear regression was used to determine if weight bias internalization, weight bias toward others, and experiences of weight stigma were predictive of the accuracy of energy reporting. A thematic analysis was conducted for the qualitative interviews. Weight stigma was reported by 64.1% of the sample. Weight stigma constructs did not predict the accuracy of energy intake reporting. People with obesity underreported by a mean of 477 kcals (p = 0.02). People classified as overweight overreported by a mean of 144 kcals, but this was not significant (p = 0.18). Participants reported a desire to report accurate data despite concerns about reporting socially undesirable foods. Future research should quantify the impact of weight stigma on energy reporting in 24 h recalls using a larger, more diverse sample size and objective measures like doubly labeled water for validation.
  • Resident Support for the Federally Mandated Smoke-Free Rule in Public Housing: 2018-2022
    Dearfield, Craig T.; Ulfers, Margaret; Horn, Kimberly; Bernat, Debra H. (MDPI, 2024-01-17)
    This study examines support for the Department of Housing and Urban Development’s (HUD) mandatory smoke-free rule up to four years post-rule among smokers and non-smokers. A repeated cross-sectional design was used where District of Columbia public housing residents aged 18+ (n = 529) completed surveys during three time points: July 2018 (pre-rule), November 2018–March 2020 (post-rule), and September 2020–December 2022 (post-rule + COVID-19). Full support for the rule was indicated by agreeing that smoking should not be allowed in all indoor locations and within 25 feet of buildings. Descriptive statistics showed significant differences in support across time for smokers (5.3%, 30.7%, and 22.5%, respectively) and similar support across time for nonsmokers (48.2%, 52.2%, and 40.0%, respectively). In unstratified regression analysis, pre-rule support was lower than when the rule was in effect (aOR = 0.47, 95% CI = 0.25, 0.90), and tobacco users were less likely to support the rule (aOR = 0.34, 95% CI = 0.23, 0.50). Stratified logistic regression results showed that pre-rule support was lower among smokers compared to post-rule support (aOR = 0.14, 95% CI = 0.03, 0.59); support among nonsmokers did not vary by time. Findings overall indicate low support for the smoke-free rule up to 4 years post-implementation. Engaging residents with the rule and promoting health and well-being may further enhance policy effectiveness and acceptance.
  • Semaglutide and Tirzepatide reduce alcohol consumption in individuals with obesity
    Quddos, Fatima; Hubshman, Zachary; Tegge, Allison; Sane, Daniel; Marti, Erin; Kablinger, Anita S.; Gatchalian, Kirstin M.; Kelly, Amber L.; DiFeliceantonio, Alexandra G.; Bickel, Warren K. (Nature Portfolio, 2023)
    Alcohol Use Disorder (AUD) contributes significantly to global mortality. GLP-1 (Glucagon-like peptide-1) and GLP-1/GIP (Glucose-dependent Insulinotropic Polypeptide) agonists, FDA-approved for managing type 2 diabetes and obesity, where the former has shown to effectively reduce the consumption of alcohol in animal models but no reports exist on the latter. In this report, we conducted two studies. In the first study, we conducted an analysis of abundant social media texts. Specifically, a machine-learning based attribution mapping of ~ 68,250 posts related to GLP-1 or GLP-1/GIP agonists on the Reddit platform. Secondly, we recruited participants (n = 153; current alcohol drinkers; BMI ≥ 30) who self-reported either taking Semaglutide (GLP-1 agonist), Tirzepatide (the GLP-1/GIP combination) for ≥ 30 days or, as a control group; no medication to manage diabetes or weight loss for a within and between subject remote study. In the social media study, we report 8 major themes including effects of medications (30%); diabetes (21%); and Weight loss and obesity (19%). Among the alcohol-related posts (n = 1580), 71% were identified as craving reduction, decreased desire to drink, and other negative effects. In the remote study, we observe a significantly lower self-reported intake of alcohol, drinks per drinking episode, binge drinking odds, Alcohol Use Disorders Identification Test (AUDIT) scores, and stimulating, and sedative effects in the Semaglutide or Tirzepatide group when compared to prior to starting medication timepoint (within-subjects) and the control group (between-subjects). In summary, we provide initial real-world evidence of reduced alcohol consumption in people with obesity taking Semaglutide or Tirzepatide medications, suggesting potential efficacy for treatment in AUD comorbid with obesity.
  • Brain Similarity as a Protective Factor in the Longitudinal Pathway Linking Household Chaos, Parenting, and Substance Use
    Kim-Spoon, Jungmeen; Lee, Tae-Ho; Clinchard, Claudia; Lindenmuth, Morgan; Brieant, Alexis; Steinberg, Laurence; Deater-Deckard, Kirby; Casas, Brooks (Elsevier, 2023-04-29)
    Background: Socioecological factors such as family environment and parenting behaviors contribute to the development of substance use. While biobehavioral synchrony has been suggested as the foundation for resilience that can modulate environmental effects on development, the role of brain similarity that attenuates deleterious effects of environmental contexts has not been clearly understood. We tested whether parent-adolescent neural similarity—the level of pattern similarity between parent-adolescent functional brain connectivity representing the level of attunement within each dyad—moderates the longitudinal pathways in which household chaos (a stressor) predicts adolescent substance use directly and indirectly via parental monitoring. Methods: In a sample of 70 parent-adolescent dyads, similarity in resting-state brain activity was identified using multipattern connectivity similarity estimation. Adolescents and parents reported on household chaos and parental monitoring, and adolescent substance use was assessed at a 1-year follow-up. Results: The moderated mediation model indicated that for adolescents with low neural similarity, but not high neural similarity, greater household chaos predicted higher substance use over time directly and indirectly via lower parental monitoring. Our data also indicated differential susceptibility in the overall association between household chaos and substance use: Adolescents with low neural similarity exhibited high substance use under high household chaos but low substance use under low household chaos. Conclusions: Neural similarity acts as a protective factor such that the detrimental effects of suboptimal family environment and parenting behaviors on the development of adolescent health risk behaviors may be attenuated by neural similarity within parent-adolescent bonds.
  • Early Childhood Education that Promotes Lifelong Learning, Health, and Social Well-being: The Abecedarian Project and its Replications
    Ramey, Craig T.; Ramey, Sharon L. (European Society of Medicine, 2023-11-30)
    Introduction: The Abecedarian Project was a randomized controlled trial (RCT) that tested the effects of 5 years of early education combined with social and health supports on learning and cognitive development in infants from high-risk environments. This article provides a reflective review of its key findings from 50 years along with results from variations also tested in RCTs. Methods: The Abecedarian Project and its replications all used a comparative efficacy RCT design. The Early Education treatment group received systematic early education with pediatric health care, early nutritional enhancement, and family social services while the Health/Social Services comparison group received health and family supports but not the formal early education program. In childhood, key outcomes were cognition and school-age academic achievement; in adulthood, assessments included post-high school educational attainment, employment, income/assets, adult family relationships, brain development, and social decision-making. Results: At all tested ages after 12 months of age, the Abecedarian Early Education was associated with significant benefits in children’s cognitive development, school and educational achievements, and multiple indicators of positive health and indicators of adult social adjustment. Collectively, the major replication studies provide affirmation of the positive impact of high-quality early education, although the breadth and magnitude of benefits vary with the child’s environmental risks and dosage of the early education intervention. Some unexpected long-term associations include enhanced caring and future planning in social decision-making, positive relationships with parents, altered brain structure, and improved cardiovascular health. Conclusions: This series of RCTs improved developmental trajectories of infants born into multi-risk social, economic, and biological life circumstances, thus strongly resolving that human malleability is achievable. The challenge ahead concerns how to effectively disseminate and practically use these findings to realize widespread benefits. We nominate both a guiding conceptual framework to help plan and measure strategic interventions as well as a set of hallmarks associated with successful community implementation of effective child and family programs.
  • 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.