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Hippocampus shapes entorhinal cortical output through a direct feedback circuit

Butola, Tanvi; Hernández-Frausto, Melissa; Blankvoort, Stefan; Flatset, Marcus Sandbukt; Peng, Lulu; Hairston, Ariel; Johnson, Cara Deanna; Elmaleh, Margot; Amilcar, Amanda; Hussain, Fabliha; Clopath, Claudia; Kentros, Clifford; Basu, Jayeeta
Our brains integrate sensory, cognitive and internal state information with memories to extract behavioral relevance. Cortico-hippocampal interactions likely mediate this interplay, but underlying circuit mechanisms remain elusive. Unlike the entorhinal cortex-to-hippocampus pathway, we know little about the organization and function of the hippocampus-to-cortex feedback circuit. Here we report in mice, two functionally distinct parallel hippocampus-to-entorhinal cortex feedback pathways: the canonical disynaptic route via layer 5 and a novel monosynaptic input to layer 2/3. Circuit mapping reveals that hippocampal input predominantly drives excitation in layer 5 but feed-forward inhibition in layer 2/3. Upon repetitive pairing with cortical layer 1 inputs, hippocampal inputs undergo homosynaptic potentiation in layer 5, but induce heterosynaptic plasticity and spike output in layer 2/3. Behaviorally, hippocampal inputs to layer 5 and layer 2/3 support object memory encoding versus recall, respectively. Two-photon imaging during navigation reveals hippocampal suppression reduces spatially tuned cortical axonal activity. We present a model, where hippocampal feedback could iteratively shape ongoing cortical processing.
PMID: 39966537
ISSN: 1546-1726
CID: 5823462

Adenosine metabolism and receptors in aging of the skin, musculoskeletal, immune and cardiovascular systems

Rabbani, Piul; Ramkhelawon, Bhama; Cronstein, Bruce N
Aging populations worldwide face an increasing burden of age-related chronic conditions, necessitating a deeper understanding of the underlying mechanisms. Purine metabolism has emerged as a crucial player in the pathophysiology of aging, affecting various tissues and organs. Dysregulation of purine metabolism, particularly alterations in extracellular adenosine levels and adenosine receptor signaling, contributes to age-related musculoskeletal problems, cardiovascular diseases, inflammation, and impaired immune responses. Changes in purine metabolism are associated with diminished tissue repair and regeneration, altered bone density, and impaired muscle regeneration. Mechanistically, age-related alterations in purine metabolism involve reductions in extracellular adenosine production, impaired autocrine signaling, and dysregulated expression of CD73 and CD39. Targeting adenosine receptors, such as A2A and A2B receptors, emerges as a promising therapeutic approach to mitigate age-related conditions, including sarcopenia, obesity, osteoarthritis, and impaired wound healing. Since we cannot reverse time, understanding the intricate molecular interplay between purine metabolism and aging-related pathologies holds significant potential for developing novel therapeutic strategies to improve the health and quality of life of aging populations. In this review, we compile the findings related to purine metabolism during aging in several tissues and organs and provide insights into how these signals can be manipulated to circumvent the deleterious effects of the passage of time on our body.
PMID: 39971100
ISSN: 1872-9649
CID: 5807852

Decoding Tertiary Lymphoid Structures in Hidradenitis Suppurativa: New Mechanistic Insights

Yu, Wei-Wen; Tong, Jie; Lu, Catherine P
PMID: 40152835
ISSN: 1523-1747
CID: 5817512

Long-Term Follow-Up Data on Flecainide Use as an Antiarrhythmic in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multicenter Study

Gaine, Sean; Rolland, Thomas; Asatryan, Babken; Laredo, Mikael; Sampognaro, James; Carrick, Richard T; Peretto, Giovanni; Muller, Steven; Villatore, Andrea; Murray, Brittney; Tichnell, Crystal; Te Riele, Anneline S J M; Loh, Peter; Compagnucci, Paolo; Casella, Michela; Martini, Marika; Schiavone, Marco; Tondo, Claudio; Cappelletto, Chiara; Sinagra, Gianfranco; Merlo, Marco; Jankelson, Lior; Delmar, Mario; Targetti, Mattia; Pieroni, Maurizio; Olivotto, Iacopo; Calò, Leonardo; Graziosi, Maddalena; Biagini, Elena; Tandri, Harikrishna; Bauce, Barbara; James, Cynthia; Cerrone, Marina; Calkins, Hugh; Gandjbakhch, Estelle; Gasperetti, Alessio
BACKGROUND:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy associated with a high risk of ventricular arrhythmia (VA). Several animal models have been used to postulate a therapeutic role of the inhibition of the ryanodine 2 receptor via the use of flecainide for this disease. Clinical data describing its use are scarce, however, especially in patients without implantable cardioverter-defibrillators or with left ventricular (LV) involvement. OBJECTIVES/OBJECTIVE:This study sought to report safety and effectiveness long-term, multicenter data on the impact of flecainide therapy on arrhythmic outcomes in patients with a definite diagnosis of ARVC. METHODS:Patients with definite ARVC receiving flecainide at 12 academic institutions were enrolled in the study. Baseline was defined as the time of flecainide initiation. Premature ventricular complex burdens, nonsustained ventricular tachycardia (NSVT) rates, and sustained VA yearly/rates were collected and compared while on and off flecainide. Side effects and flecainide discontinuation were tracked. Analyses were performed in the overall cohort as well as stratifying for genotype (gene positive vs negative; plakohpillin-2 [PKP-2] vs non PKP-2) and for LV involvement. RESULTS:; LV ejection fraction 55.9 ± 7.3%; right ventricular ejection fraction 44.5 ± 10.5% at baseline) were enrolled, with 66 patients (34.6%) showing LV involvement. The median dose of flecainide was 200 mg/d [150-200 mg/d], with 166 patients (86.9%) also taking a beta-blocker. The median follow-up time on flecainide was 4.2 years [1.9-6.3 years]. Flecainide was well tolerated, with a low (7.9%) discontinuation rate. After flecainide initiation, a significant reduction in the 24-hour premature ventricular complex burden and in the rate of nonsustained ventricular tachycardia was observed (2,190 vs 418; P < 0.001; 35.1% vs 21.5%; P = 0.003). For patients with prior VA events, a significant reduction in the amount of VA episodes/y (1.1 [0.4-1.6] episodes/y vs 0 [0-0.3] episodes/y; P < 0.001) was observed. These safety and effectiveness findings were consistent across genotype subgroups, as well as in patients with and without LV involvement. CONCLUSIONS:Flecainide use had a favorable safety profile and was associated with an observed to a significant reduction in arrhythmic burden in patients with ARVC, irrespective of the underlying genotype or LV involvement.
PMID: 40243965
ISSN: 2405-5018
CID: 5828602

Defining the molecular identity and morphology of glia limitans superficialis astrocytes in vertebrates

Hasel, Philip; Cooper, Melissa L; Marchildon, Anne E; Rufen-Blanchette, Uriel; Kim, Rachel D; Ma, Thong C; Groh, Adam M R; Hill, Emily J; Lewis, Eleanor M; Januszewski, Michał; Light, Sarah E W; Smith, Cody J; Stratton, Jo Anne; Sloan, Steven A; Kang, Un Jung; Chao, Moses V; Liddelow, Shane A
Astrocytes are a highly abundant glial cell type and perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogeneous subtypes. The subtype identity and functions are, at least in part, associated with their anatomical location and can be highly restricted to strategically important anatomical domains. Here, we report that astrocytes forming the glia limitans superficialis, the outermost border of the brain and spinal cord, are a highly specialized astrocyte subtype and can be identified by a single marker: myocilin (Myoc). We show that glia limitans superficialis astrocytes cover the entire brain and spinal cord surface, exhibit an atypical morphology, and are evolutionarily conserved from zebrafish, rodents, and non-human primates to humans. Identification of this highly specialized astrocyte subtype will advance our understanding of CNS homeostasis and potentially be targeted for therapeutic intervention to combat peripheral inflammatory effects on the CNS.
PMID: 39982817
ISSN: 2211-1247
CID: 5814472

Tetraspanin CD37 regulates platelet hyperreactivity and thrombosis

Sowa, Marcin A; Hannemann, Carmen; Pinos Cabezas, Ivan; Ferreira, Elissa; Biwas, Bharti; Dai, Min; Corr, Emma M; Cornwell, Macintosh G; Drenkova, Kamelia; Lee, Angela H; Spruill, Tanya; Reynolds, Harmony R; Hochman, Judith; Ruggles, Kelly V; Campbell, Robert A; van Solingen, Coen; Wright, Mark D; Moore, Kathryn J; Berger, Jeffrey S; Barrett, Tessa J
AIM/OBJECTIVE:To investigate how psychosocial stress contributes to accelerated thrombosis, focusing on platelet activation and hyperreactivity. The specific objective was to identify novel platelet regulators involved in stress-mediated thrombosis, with a particular emphasis on the tetraspanin CD37. METHODS AND RESULTS/RESULTS:To explore how stress contributes to platelet hyperreactivity, platelets were isolated from (1) mice that experienced chronic variable stress and stress-free controls (n=8/group) and (2) human subjects with self-reported high and no stress levels (n=18/group), followed by RNA-sequencing. By comparing mutually expressed transcripts, a subset of genes differentially expressed following psychosocial stress was identified in both human and mouse platelets. In both mice and humans, platelet CD37 positively associates with platelet aggregation responses that underlie thrombosis, with Cd37-/- platelets exhibiting impaired integrin αIIbβ3 signaling, characterized by reduced platelet fibrinogen spreading and decreased agonist-induced αIIbβ3 activation. Consistent with a role for CD37 in regulating platelet activation responses, chimeric mice that received Cd37-/- bone marrow experienced a significantly increased time to vessel occlusion in the carotid artery FeCl3 model compared to mice reconstituted with wild-type bone marrow. CD37 deficiency did not alter hemostasis, as platelet count, coagulation metrics, prothrombin time, and partial thromboplastin time did not differ in Cd37-/- mice relative to wild-type mice. Consistent with this, bleeding time did not differ between wild-type and Cd37-/- mice following tail tip transection. CONCLUSIONS:This study provides new insights into the platelet-associated mechanisms underlying stress-mediated thrombosis. Identifying CD37 as a novel regulator of platelet activation responses offers potential therapeutic targets for reducing the thrombotic risk associated with psychosocial stress. The findings also contribute to understanding how psychosocial stress accelerates thrombotic events and underscore the importance of platelet activation in this process.
PMID: 40126944
ISSN: 1755-3245
CID: 5814722

Astrocytes in the mouse brain respond bilaterally to unilateral retinal neurodegeneration

Cooper, Melissa L; Gildea, Holly K; Selles, Maria Clara; Katafygiotou, Eleni; Liddelow, Shane A; Chao, Moses V
Glaucomatous optic neuropathy, or glaucoma, is the world's primary cause of irreversible blindness. Glaucoma is comorbid with other neurodegenerative diseases, but how it might impact the environment of the full central nervous system to increase neurodegenerative vulnerability is unknown. Two neurodegenerative events occur early in the optic nerve, the structural link between the retina and brain: loss of anterograde transport in retinal ganglion cell (RGC) axons and early alterations in astrocyte structure and function. Here, we used whole-mount tissue clearing of full mouse brains to image RGC anterograde transport function and astrocyte responses across retinorecipient regions early in a unilateral microbead occlusion model of glaucoma. Using light sheet imaging, we found that RGC projections terminating specifically in the accessory optic tract are the first to lose transport function. Although degeneration was induced in one retina, astrocytes in both brain hemispheres responded to transport loss in a retinotopic pattern that mirrored the degenerating RGCs. A subpopulation of these astrocytes in contact with large descending blood vessels were immunopositive for LCN2, a marker associated with astrocyte reactivity. Together, these data suggest that even early stages of unilateral glaucoma have broad impacts on the health of astrocytes across both hemispheres of the brain, implying a glial mechanism behind neurodegenerative comorbidity in glaucoma.
PMID: 40063795
ISSN: 1091-6490
CID: 5809062

Cryo-ET reveals the in situ architecture of the polar tube invasion apparatus from microsporidian parasites

Usmani, Mahrukh; Coudray, Nicolas; Riggi, Margot; Raghu, Rishwanth; Ramchandani, Harshita; Bobe, Daija; Kopylov, Mykhailo; Zhong, Ellen D; Iwasa, Janet H; Ekiert, Damian C; Bhabha, Gira
Microsporidia are divergent fungal pathogens that employ a unique harpoon-like apparatus called the polar tube (PT) to invade host cells. The long PT is fired out of the microsporidian spore over the course of just a few hundred milliseconds. Once fired, the PT is thought to pierce the plasma membrane of a target cell and act as a conduit for the transfer of the parasite into the host cell, which initiates infection. The PT architecture and its association with neighboring organelles within the parasite cell remain poorly understood. Here, we use cryoelectron tomography to investigate the structural cell biology of the PT in dormant spores from the human-infecting microsporidian species, Encephalitozoon intestinalis. Segmentation and subtomogram averaging of the PT reveal at least four layers: two protein-based layers surrounded by a membrane layer and filled with a dense core. Regularly spaced protein filaments form the structural skeleton of the PT. Combining cryoelectron tomography with cellular modeling, we propose a model for the three-dimensional organization of the polaroplast, an organelle that surrounds the PT and is continuous with the outermost, membranous layer of the PT. Our results reveal the ultrastructure of the microsporidian invasion apparatus in situ, laying the foundation for understanding infection mechanisms.
PMID: 40067903
ISSN: 1091-6490
CID: 5808352

A survey study of urban retailers selling alkyl nitrites ("poppers") in the New York City area which led to public health interventions

Olinde, Abigail; Hayman, Chelsea; Ivanov, Ivan; Schwartz, Lauren; Bloom, Joshua; Su, Mark K; Biary, Rana
INTRODUCTION/UNASSIGNED:Alkyl nitrites ("poppers") are used recreationally for sexual enhancement, muscle relaxation, and euphoria. However, they can be toxic and cause adverse reactions such as methemoglobinemia. While inhalation is the typical route of usage, the New York City Poison Center has noted an increase in calls related to ingestion. Given the uncertainty of usage instructions at the point of sale, our study aimed to assess instructions provided to consumers about alkyl nitrite use and to evaluate the proximity and co-sale of alkyl nitrites with similarly appearing energy drink shots. METHODS/UNASSIGNED:We conducted a cross-sectional convenience sample survey of smoke shops, cannabis dispensaries, and exotic shops within the catchment area of an urban poison center. Plain clothes "investigators" (i.e., the researchers) visited these retailers and followed a predetermined protocol and script to request information regarding the availability and usage of alkyl nitrites. Additionally, the researchers attempted to visually assess the proximity of alkyl nitrites to similarly appearing energy drink shots during their visit. RESULTS/UNASSIGNED:drinks and alkyl nitrites were located near these energy drink shots in twenty (39%) of these fifty-one stores. DISCUSSION/UNASSIGNED:Many commercial alkyl nitrite retailers in our survey area lack knowledge or provide potentially inaccurate information regarding the use of alkyl nitrites. Additionally, alkyl nitrites are often sold alongside commercial energy drinks, potentially increasing the risk of incidental ingestion. CONCLUSIONS/UNASSIGNED:Further research is necessary to determine the impact of these patterns of sale and potential misinformation. Discussing preliminary results of our survey with the New York City Department of Health led to the rapid creation of an informational poster and local outreach. Clinicians should report cases of alkyl nitrite use to their regional poison center to allow for more targeted and timely public health intervention.
PMID: 40072897
ISSN: 1556-9519
CID: 5808512

Oxytocin induces embryonic diapause

Minder, Jessica L; Winokur, Sarah B; Stephens, Janaye; Tong, Jie; Cassel, Naomi L; Schuster, Luisa; Issa, Habon A; Cammer, Michael; Khatri, Latika; Moisan, Gaia; Alvarado-Torres, Maria; Aristizábal, Orlando; Wadghiri, Youssef Z; Kim, Sang Yong; Valtcheva, Silvana; Lu, Catherine Pei-Ju; Chao, Moses V; Froemke, Robert C
Embryonic development in many species, including case reports in humans, can be temporarily halted before implantation during a process called diapause. Facultative diapause occurs under conditions of maternal metabolic stress such as nursing. While molecular mechanisms of diapause have been studied, a natural inducing factor has yet to be identified. Here, we show that oxytocin induces embryonic diapause in mice. We show that gestational delays were triggered during nursing or optogenetic stimulation of oxytocin neurons simulating nursing patterns. Mouse blastocysts express oxytocin receptors, and oxytocin induced delayed implantation-like dispersion in cultured embryos. Last, oxytocin receptor-knockout embryos transferred into wild-type surrogates had low survival rates during diapause. Our results indicate that oxytocin coordinates timing of embryonic development with uterine progression through pregnancy, providing an evolutionarily conserved mechanism for ensuring successful reproduction.
PMCID:11881891
PMID: 40043121
ISSN: 2375-2548
CID: 5809752