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Psychedelics produce enduring behavioral effects and functional plasticity through mechanisms independent of structural plasticity
No full textActivation of serotonin 2A (5-HT2A) receptors is thought to underly the long-lasting antidepressant effects of psychedelics such as psilocybin, but beyond that, the molecular and cellular mechanisms involved are not well understood. Recent preclinical studies using mice have primarily examined relatively short time points after psychedelic administration, which does not address the long-lasting effects of psilocybin in humans (i.e., several months or more). We utilized a rat experimental system to demonstrate that both psilocybin and the selective 5-HT2A receptor agonist 25CN-NBOH reduce immobility in the forced swim test without a decrease in effect size for at least three months after a single administration of the psychedelic. There were no overt behavioral differences between psilocybin and 25CN-NBOH treated animals, suggesting 5-HT2A receptor activation is sufficient to produce long-lasting behavioral changes. Functional cellular plasticity in neurons from the medial prefrontal cortex (mPFC) of these animals was assessed using brain slice electrophysiology. Functional plasticity was evident for both psychedelics several months after treatment, and Layer 5 excitatory pyramidal neurons demonstrated significant changes in resting membrane potential, firing rates, and synaptic excitation. Recorded neurons were examined by microscopy for synaptic density and spine classification, which found no differences between control and psychedelic-treated. Gene expression studies for several presynaptic and postsynaptic markers in the mPFC indicated no differences in expression between groups. Together, our results indicate a single treatment with a psychedelic is sufficient to elicit very long-lasting behavioral and cellular changes through enduring function plasticity rather than structural plasticity
In situ-generated volumetric dried plasma spots for the analysis of edaravone and metabolites in animal models
No full textIn this study, for the first time rat plasma microsampling was carried out by means of in situ-generated volumetric dried plasma spot (vDPS) technology and applied to the determination of the neuroprotective agent edaravone and its sulphate and glucuronide metabolites. Sampling was performed using Telimmune® plasma separation cards (vPSC), which allow the formation of volumetrically accurate dried plasma spots (3 µL) from blood drops deposited on them. After accelerated forced drying and solvent extraction in methanol, drying and redissolution, analytes were baseline separated and quantified through an original HPLC-MS/MS analytical method. Validation assays provided excellent results, with detection limits between 0.7 and 1.7 ng/mL, and quantitation limits between 2.0 and 5.0 ng/mL. Extraction yields were higher than 81 % and precision was lower than 14.1 % (relative standard deviation, RSD). The volumetric microsampling approach offers a much less invasive and stressful sampling. The vPSC technology offers a simple, cost-effective alternative method to produce a volumetric plasma sample that is stable when dried and eliminates requirements for both cold-chain and biohazard transport. The developed analytical workflow appears suitable for advantageous application to pharmacokinetic and toxicokinetic animal studies of edaravone and its metabolites
Trypanosoma cruzi infection-induced changes in cardiac microvascular endothelial cell morphology and function
No full textIntroduction. Six to seven million individuals are infected with Trypanosoma cruzi, the causative agent of Chagas disease. With 12,000 deaths annually, chronic Chagas disease remains a significant global health challenge due to persistent vector transmission, increasing non-vector transmission and limited therapeutic options. Chronic Chagas cardiomyopathy is a leading cause of morbidity and mortality, yet the underlying mechanisms remain poorly understood.Gap Statement. Since its initial description more than 100 years ago, research efforts into the cardiomyopathy found in chronic Chagas disease have primarily focused on the contributions of immune cells, cardiomyocytes and cardiac fibroblasts, leaving a significant gap in understanding the role of microvascular endothelial dysfunction in disease progression.Aim. The aim of this study was to identify any morphological or functional changes to cardiac microvascular endothelial cells induced by T. cruzi infection with the potential to contribute to the pathologies found in chronic Chagas disease.Methodology. We cultured primary cardiac microvascular endothelial cell monolayers in vitro and infected them with T. cruzi trypomastigotes or exposed them to conditioned media collected from control or infected endothelial cells. Cells were analysed for changes in morphology and proliferation, by wound healing assays for measurements of migratory capacity and by tube-forming assay to characterize their ability to form capillary-like structures.Results. We show that T. cruzi infection leads to the development of hypertrophic multinuclear cells, inhibits endothelial proliferation, increases endothelial migration and results in changes in several aspects of angiogenesis.Conclusion. We present data to demonstrate morphological and functional changes in cardiac endothelial cells that occur as a result of T. cruzi infection and propose that these changes may contribute to endothelial dysfunction and the development of chronic Chagas cardiomyopathy
epDevAtlas: mapping GABAergic cells and microglia in the early postnatal mouse brain
No full textDuring development, brain regions follow encoded growth trajectories. Compared to classical brain growth charts, high-definition growth charts could quantify regional volumetric growth and constituent cell types, improving our understanding of typical and pathological brain development. Here, we create high-resolution 3D atlases of the early postnatal mouse brain, using Allen CCFv3 anatomical labels, at postnatal days (P) 4, 6, 8, 10, 12, and 14, and determine the volumetric growth of different brain regions. We utilize 11 different cell type-specific transgenic animals to validate and refine anatomical labels. Moreover, we reveal region-specific density changes in γ-aminobutyric acid-producing (GABAergic) neurons, cortical layer-specific cell types, and microglia as key players in shaping early postnatal brain development. We find contrasting changes in GABAergic neuronal densities between cortical and striatal areas, stabilizing at P12. Moreover, somatostatin-expressing and vasoactive intestinal peptide-expressing cortical interneurons undergo regionally distinct density changes. Remarkably, microglia transition from high density in white matter tracks to gray matter at P10, and show selective density increases in sensory processing areas that correlate with the emergence of individual sensory modalities. Lastly, we create an open-access web-visualization ( https://kimlab.io/brain-map/epDevAtlas ) for cell-type growth charts and developmental atlases for all postnatal time points
Rebound Bursting Selectively Enables Fast Dynamics in Dopamine Midbrain Neurons Projecting to the Dorsolateral Striatum
No full textDopamine (DA) midbrain neurons are involved in a wide array of key brain functions including movement control and reward-based learning. They are also critical for major brain disorders such as Parkinson\u27s disease or schizophrenia. DA neurons projecting to distinct striatal territories are diverse with regard to their molecular makeup and cellular physiology, which are likely to contribute to the observed differences in temporal DA dynamics. Among these regions, the dorsolateral striatum (DLS) displays the fastest DA dynamics, which might control the moment-to-moment vigor and variability of voluntary movements. However, the underlying mechanisms for these DLS-specific fast DA fluctuations are unresolved. Here, we show that DLS-projecting DA neurons in the substantia nigra (SN) possess a unique biophysical profile allowing immediate 10-fold accelerations in discharge frequency via rebound bursting. By using a combination of in vitro patch-clamp recordings in projection-defined DA SN subpopulations from adult male mice and developing matching projection-specific computational models, we demonstrate that a strong interaction of Ca3 and SK channels specific for DLS-projecting Aldh1a1-positive DA SN (DLS-DA) neurons controls the gain of fast rebound bursting, while K4 and HCN channels mediate timing of rebound excitability. In addition, GIRK channels activated by D2 and GABA receptors prevent rebound bursting in these DLS-DA neurons. Furthermore, our in vivo patch-clamp recordings and matching in vivo computational models provide evidence that these unique rebound properties might be preserved in the intact brain, where they might endow specific computational properties well suited for the generation of fast DA dynamics present in DLS
Dupuytren\u27s Disease: Current and Emerging Techniques
No full textDupuytren’s disease (DD) is a fibroproliferative disorder that affects the palmar aponeurosis and causes flexure contractures of the digits. Treatment is typically advised with flexion contracture of at least 30 degrees at the metacarpophalangeal (MCP) or proximal interphalangeal (PIP) joints [1]. Surgical excision of the diseased tissue has been the gold standard treatment [2]. However, surgery can be costly with potential for wound breakdown, infection, recurrence, and risk for neurovascular injury. Thus, nonsurgical options have been explored that can be implemented in an office-based setting, decrease morbidity, decrease cost and recovery time, but still improve function and quality of life [3]. Collagenase Clostridium histolyticum (CCH) injections have become a popular nonsurgical treatment option that have shown excellent outcomes in properly selected patients [4]. Xiaflex[[sup]]®[[/sup]], a commercial CCH specifically designed for medical purposes, was FDA approved in 2010 and has clear guidelines for appropriate use to optimize benefits and reduce risks
Rare Presentation of Mucous Membrane Pemphigoid With Pemphigoid of the Pulmonary System in 10-Month-Old Female
No full textWe present a 10-month-old girl with diffuse mucous membrane pemphigoid (MMP) and pemphigoid of the pulmonary system (POPS). Systemic corticosteroids, intravenous immunoglobulin, cyclophosphamide, rituximab, and mycophenolate mofetil led to improvement in cutaneous and mucosal lesions. However, she had progressively worsening airway involvement refractory to immunosuppression and ultimately died from respiratory failure
Ivermectin: a therapeutic strategy to treat patients with resistant epilepsy
No full textDrug-resistant epilepsy (DRE) remains a major clinical challenge, with up to one-third of patients experiencing uncontrolled seizures despite polytherapy. Ivermectin (IVM), a macrocyclic lactone with antiparasitic, neuromodulatory, and anti-inflammatory properties, has recently emerged as a candidate adjunctive therapy. We conducted an observational study including 146 patients with highly refractory epilepsy treated with IVM in addition to standard antiseizure medication (ASM). Clinical outcomes were assessed before and after IVM initiation, with seizure frequency recorded from patient diaries and seizure control classified according to International League Against Epilepsy criteria. IVM was administered orally, dissolved in propylene glycol, at doses ranging from 30 to 280 mg/week. After treatment, mean annual seizure frequency decreased by 88.9%, with consistent benefits across subgroups, including patients with cluster seizures (86.4% reduction). More than 90% of participants achieved seizure freedom, and all patients reported some degree of seizure reduction. Concomitant ASM burden decreased by 22%, reflecting improved tolerability and adherence, and no major safety concerns were observed. Mechanistically, the antiseizure potential of IVM may involve modulation of neuronal excitability, neuroinflammatory pathways, and blood-brain barrier transport dynamics, as supported by experimental evidence. These findings align with epidemiological data on onchocerciasis-associated epilepsy and recent controlled trials of IVM formulations in focal epilepsy. While further randomized studies are needed to confirm optimal dosing, safety monitoring, and mechanistic correlates, our results provide real-world evidence that IVM represents a promising adjunctive option for the management of refractory epilepsy