1,720,956 research outputs found
Mechanism of action and neuroplastic potential of the 5-HT2A serotonin receptor agonist psilocin
No full textMajor depressive disorder (MDD) is a debilitating illness characterized by depressed mood, anhedonia, and impaired cognitive function. In the last few years, several compounds from various pharmacological classes emerged as promising rapid-onset antidepressant agents, including serotoninergic agonists. These drugs, collectively known as fast-acting antidepressants, demonstrate clinical effectiveness within 24 hours from the first administration and their effects persist long after the compounds have been eliminated from the bloodstream. It is believed that this clinical effect is driven by the promotion of long-term structural and functional neuroplasticity in the prefrontal cortex (PFC), a brain region known to experience neuronal atrophy in patients with MDD. Among all these molecules, a great interest garnered around the therapeutic potential of serotonergic psychedelics, especially psilocybin and its active metabolite psilocin. Psilocin is a partial agonists of the serotonin receptor 5-HT2A (5-HT2AR). 5-HT2ARs are G-protein coupled receptors that are densely expressed by post-synaptic neurons of the PFC, where they promote the excitatory effects of serotonin via the activation of the Gq/11 signaling cascade. Despite the role of 5-HT2ARs in the hallucinogenic effect of these molecules is well documented, their involvement in the neuroplastic effect, and whether this action is mediated by the canonical Gq/11 signaling pathway originating at the plasma membrane or by different signal transduction routes, is still unclear.
The work described in this thesis is conceived within a collaboration with MGGM LLC, a company interested in the clinical development of psilocybin and its derivates. Notably, MGGM LLC recently submitted a clinical trial application for a preliminary Phase 1 study of a new, extended-release psilocybin formulation. The aim of the project is to investigate the mechanism of action and neuroplastic potential of molecules targeting 5-HT2ARs. A recent study suggests that psilocin, after entering neurons, might promote neuroplasticity through the activation of intracellular 5-HT2ARs. An intriguing idea is that psilocin becomes protonated and trapped in acidic compartments, accumulating and explaining its prolonged effects. To investigate this possibility, we developed a fluorescent-labeled psilocin derivative that we used as a probe for exploring the intracellular distribution of psilocin.
By testing the new probe on primary cortical neurons and neuronal cells, we demonstrated that it mirrors the biological activity of psilocin in terms of 5-HT2AR activation and dendritic spine plasticity, endorsing its use as a strategic tool to explore psilocin mechanism of action. Using various microscopy imaging techniques, results obtained with this probe allowed us to shed new light on the intracellular distribution of psilocin. Preliminary data, aimed at assessing the role of psilocin accumulation in the neuroplastic outcome, suggest that psilocin retention inside acidic compartments might indeed contribute to prolong its neuroplastic action even upon a brief, transient stimulation. If confirmed, these data would explain why psilocin and other protonable membrane-permeable psychedelics promote long-term clinical effect after a single dose.
Our approach, that we are currently implementing with ex vivo and in vivo methodologies, represents a novel, powerful strategy to comprehend the contribution of intracellular acidic compartments in the pharmacology of other fast-acting antidepressants. This will also lay the groundwork for the rational design of new serotoninergic agonists that leverage drug retention within acidic compartments
Emerging mechanisms of psilocybin-induced neuroplasticity
No full textPsilocybin, a serotonergic psychedelic, is gaining attention for its rapid and sustained therapeutic effects in depression and other hard-to-treat neuropsychiatric conditions, potentially through its capacity to enhance neuronal plasticity. While its neuroplastic and therapeutic effects are commonly attributed to serotonin 2A (5-HT2A) receptor activation, emerging evidence reveals a more nuanced pharmacological profile involving multiple serotonin receptor subtypes and nonserotonergic targets such as TrkB. This review integrates current findings on the molecular interactome of psilocin (psilocybin active metabolite), emphasizing receptor selectivity, biased agonism, and intracellular receptor localization. Together, these insights offer a refined framework for understanding psilocybin's enduring effects and guiding the development of next-generation neuroplastogens with improved specificity and safety
Lighting Up Ca2+ Dynamics in Animal Models
Get PDFCalcium (Ca2+) signaling coordinates are crucial processes in brain physiology. Particularly, fundamental aspects of neuronal function such as synaptic transmission and neuronal plasticity are regulated by Ca2+, and neuronal survival itself relies on Ca2+-dependent cascades. Indeed, impaired Ca2+ homeostasis has been reported in aging as well as in the onset and progression of neurodegeneration. Understanding the physiology of brain function and the key processes leading to its derangement is a core challenge for neuroscience. In this context, Ca2+ imaging represents a powerful tool, effectively fostered by the continuous amelioration of Ca2+ sensors in parallel with the improvement of imaging instrumentation. In this review, we explore the potentiality of the most used animal models employed for Ca2+ imaging, highlighting their application in brain research to explore the pathogenesis of neurodegenerative diseases
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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