Biology subjects

Alenina, N.

Publications and source records attributed to Alenina, N..

8 recordsLinked to original sources

bioRxiv2024

Identification and characterization of alamandine-(1-5), a new component of the Renin-Angiotensin System with unique properties

The renin-angiotensin system (RAS) comprises a biochemical cascade that hydrolyzes angiotensinogen into several different bioactive peptides, which can activate different receptors promoting plenty of specific effects. The aim of this study was to evaluate the presence of the putative product of alamandine, the pentapeptide alamandine-(1-5) in the circulation and its biological activity. To accomplish this we have used mass spectrometry (MALDI/TOF/TOF, LC-MS/MS) and several methodologies including isolated blood vessels, isolated perfused hearts, isolated cardiomyocytes, blood pressure recording in freely-moving normotensive and hypertensive rats (SHR), high resolution echocardiography (VEVO 2100), central administration (ICV infusion and microinjection in the insular cortex), cell culture (endothelial cells and GPCR-transfected CHO cells) and wild type and Mas, MrgD or AT2R deficient mice. Our results show that alamandine-(1-5) circulates in the human and rodent blood and promotes many biological central and peripheral actions. More importantly, its plasma concentration is increased in pediatric nephropathic patients. A major role for plasma ACE activity in the formation of alamandine-(1-5) from alamandine was observed using plasma samples from Angiotensinogen-KO mice. Alamandine-(1-5) increased Baroreflex sensitivity and produced a long-lasting ([~]6 hours) anti-hypertensive effect in SHR, associated with a significant reduction in cardiac output. A particularly important effect of this pentapeptide was observed in isolated perfused heart and cardiomyocyte contractility (reduced inotropism). It was capable of stimulating NO production through all receptors from the renin-angiotensin protective arm, (MAS, MrgD and AT2R) in CHO-transfected cells. Our data shows that Alamandine-(1-5) exhibits selective actions that set it apart from traditional concepts of the vasodilatory axis of the RAS and that are possibly intricately linked to a complex interplay between Mas, MrgD and AT2 receptors. This novel finding suggests that RAS may possess a complexity that surpasses our current understanding.

physiology↗

bioRxiv2024

Serotonin drives aggression and social behaviours of laboratory mice in a semi-natural environment

Aggression is an adaptive social behaviour crucial for the stability and prosperity of social groups. When uncontrolled, aggression leads to pathological violence that disrupts group structure and individual well-being. The comorbidity of uncontrolled aggression across different psychopathologies makes it a potential endophenotype of mental disorders with the same neurobiological substrates. Serotonin plays a critical role in the regulation of impulsive and aggressive behaviours, and mice lacking brain serotonin, due to the ablation of a rate-limiting enzyme of serotonin synthesis (Tryptophan hydroxylase 2, TPH2), are a potential model of pathological aggression. Home cage monitoring allows for the continuous observation and quantification of social and non-social behaviours in group-housed, freely-moving mice. Using an ethological approach, we investigated the impact of central serotonin ablation on everyday expression of social and non-social behaviours and their correlations in undisturbed, group-living Tph2-deficient and wildtype mice. By training a machine learning algorithm on behavioural time series, "allogrooming", "struggling at feeder" and "eating" emerged as key behaviours dissociating one genotype from the other. Although Tph2-deficient mice showed characteristics of pathological aggression and decreased communication compared to wildtype animals they still showed affiliative behaviours to normal levels. Altogether, such distinct and dynamic phenotype of Tph2-deficient mice influenced the groups structure and the dynamic of its hierarchical organization which emerged later. These aspects were analyzed using social network analysis and the Glicko rating methods. This study demonstrates the importance of the ethological approach for understanding the global impact of pathological aggression on different aspects of life both at the individual and the group level. Home cage monitoring allows the observation of the natural behaviours of the mice in a semi-natural habitat and provides an accurate representation of real-world phenomena and pathological mechanisms. The results of this study provide insights into the neurobiological substrate of pathological aggression and their potential role in complex brain disorders.

neuroscience↗

bioRxiv2024

Poor decision making and sociability impairment following central serotonin reduction in inducible TPH2-knockdown rats

Serotonin is an essential neuromodulator for mental health and animals socio-cognitive abilities. However, we previously found that a constitutive depletion of central serotonin did not impair rat cognitive abilities in stand-alone tests. Here we investigated how a mild and acute decrease of brain serotonin would affect rats cognitive abilities. Using a novel rat model of inducible serotonin depletion via the genetic knock-down of tryptophan hydroxylase 2 (TPH2), we achieved 20% decrease of serotonin levels in the hypothalamus after three weeks of non-invasive oral doxycycline administration. Decision making in the Rat Gambling Task and the Probability Discounting Task, cognitive flexibility and social recognition memory were tested in low-serotonin (Tph2-kd) and control rats. Our results showed that the Tph2-kd rats were more prone to choose disadvantageously on the long term (poor decision making) and that only the low-serotonin poor decision makers were more sensitive to probabilistic discounting and had poorer social recognition memory than other low-serotonin and control individuals. Flexibility was unaffected by the acute brain serotonin reduction. Poor social recognition memory was the most central characteristic of the behavioral network of low-serotonin poor decision makers, suggesting a key role of social recognition in expression of their profile. The acute decrease of brain serotonin appeared to specifically amplify cognitive impairments of the subgroup of individuals also identified as poor decision makers in the population. This study highlights the great opportunity Tph2-kd rat model offers to study inter-individual susceptibilities to develop cognitive impairment following mild variations of brain serotonin in otherwise healthy individuals. These transgenic and differential approaches together could be critical for the identification of translational markers and vulnerabilities in the development of mental disorders.

neuroscience↗

bioRxiv2023

Serotonin transporter-dependent histone serotonylation in placenta contributes to the neurodevelopmental transcriptome

Brain development requires appropriate regulation of serotonin (5-HT) signaling from distinct tissue sources across embryogenesis. At the maternal-fetal interface, the placenta is thought to be an important contributor of offspring brain 5-HT and is critical to overall fetal health. Yet, how placental 5-HT is acquired, and the mechanisms through which 5-HT influences placental functions, are not well understood. Recently, our group identified a novel epigenetic role for 5-HT, in which 5-HT can be added to histone proteins to regulate transcription, a process called H3 serotonylation. Here, we show that H3 serotonylation undergoes dynamic regulation during placental development, corresponding to gene expression changes that are known to influence key metabolic processes. Using transgenic mice, we demonstrate that placental H3 serotonylation largely depends on 5-HT uptake by the serotonin transporter (SERT/SLC6A4). SERT deletion robustly reduces enrichment of H3 serotonylation across the placental genome, and disrupts neurodevelopmental gene networks in early embryonic brain tissues. Thus, these findings suggest a novel role for H3 serotonylation in coordinating placental transcription at the intersection of maternal physiology and offspring brain development.

molecular biology↗

bioRxiv2021

Constitutive depletion of brain serotonin differentially affects rats' social and cognitive abilities

BackgroundCentral serotonin is an essential neuromodulator for mental disorders. It appears a promising transdiagnostic marker of distinct psychiatric disorders and a common modulator of some of their key behavioral symptoms. We aimed to identify the behavioral markers of serotonergic function in rats and compare them to human deficits. MethodsWe applied a comprehensive profiling approach in adult male Tph2-/- rats constitutively lacking central serotonin. Under classical and ethological testing conditions, we tested each individuals cognitive, social and non-social abilities and characterized the group organization (i.e. social network, hierarchy). Using unsupervised machine learning, we identified the functions most dependent on central serotonin. ResultsIn classical procedures, Tph2-/- rats presented an unexpected normal cognitive profile. Under the complex and experimenter-free conditions of their home-cage, the same Tph2-/- rats presented drastic changes in their daily life. Brain serotonin depletion induced compulsive aggression and sexual behavior, hyperactive and hypervigilant stereotyped behavior, reduced self-care and body weight, and exacerbated corticosterone levels. Group-housed Tph2-/- rats showed strong social disorganization with disrupted social networks and hierarchical structure, which may arise from communication deficits and cognitive blunting. ConclusionsSerotonin depletion induced a profile reminiscent of the symptomatology of impulse control and anxiety disorders. Serotonin was necessary for behavioral adaptation to dynamic social environments. In classical testing conditions, our animal model challenged the concept of an essential role of serotonin in decision-making, flexibility, and impulsivity, although developmental compensations may have occurred. These contrasting findings highlight the need to generalize the evaluation of animal models multidimensional functions within the complexity of the social living environment.

animal behavior and cognition↗

bioRxiv2020

Myogenic Vasoconstriction Requires Canonical Gq/11 Signaling of Angiotensin II Type 1a Receptor in Murine Vasculature

BackgroundThe myogenic response is an inherent vasoconstrictive property of resistance arteries to keep blood flow constant in response to increases in intravascular pressure. Angiotensin II (Ang II) type 1 receptors (AT1R) are broadly distributed, mechanoactivated receptors, which have been proposed to transduce myogenic vasoconstriction. However, the AT1R subtype(s) involved and their downstream G protein- and {beta}-arrestin-mediated signaling pathways are still elusive. ObjectiveTo characterize the function of AT1aR and AT1bR in the regulation of the myogenic response of resistance size arteries and possible downstream signaling cascades mediated by Gq/11 and/or {beta}-arrestins. MethodsWe used Agtr1a-/-, Agtr1b-/- and tamoxifen-inducible smooth muscle-specific AT1aR knockout mice (SM-Agtr1a mice). FR900359, [Sar1, Ile4, Ile8] Ang II (SII) and TRV120055 were used as selective Gq/11 protein inhibitor and biased agonists to activate non-canonical {beta}-arrestin and canonical Gq/11 signaling of the AT1R, respectively. ResultsMyogenic and Ang II-induced vasoconstrictions were diminished in the perfused renal vasculature of Agtr1a-/- and SM-Agtr1a mice. Similar results were observed in isolated pressurized mesenteric and cerebral arteries. Myogenic tone and Ang II-induced vasoconstrictions were normal in arteries from Agtr1b-/- mice. The Gq/11 blocker FR900359 decreased myogenic tone and Ang II vasoconstrictions while selective biased targeting of AT1R {beta}-arrestin signaling pathways had no effects. ConclusionThe present study demonstrates that myogenic arterial constriction requires Gq/11-dependent signaling pathways of mechanoactivated AT1aR but not G protein-independent, noncanonical alternative signaling pathways in the murine mesenteric, cerebral and renal circulation.

physiology↗

bioRxiv2019

Inter-individual and inter-strain differences in cognitive and social abilities of Dark Agouti and Wistar Han rats

BackgroundHealthy animals showing extreme behaviours spontaneously that resemble human psychiatric symptoms are relevant models to study the natural psychobiological processes of maladapted behaviours. Healthy poor decision makers (PDMs) identified using a Rat Gambling Task, co-express a combination of cognitive and reward-based characteristics similar to symptoms observed in human patients with impulse-control disorders. The main goals of this study were to 1) confirm the existence of PDMs and their unique behavioural phenotypes in the Dark Agouti (DA) and Wistar Han (WH), 2) to extend the behavioural profile of the PDMs to probability-based decision-making and social behaviours and 3) to discuss how the key traits of each strain could be relevant for biomedical research.\n\nMethodsWe compared cognitive abilities, natural behaviours and physiological responses in DA and WH rats using several tests. We analysed the results at the strain and the individual level.\n\nResultsPrevious findings in WH rats were reproduced and could be generalized to DA. Each PDM of either strain displayed a similar, naturally occurring, combination of behavioural traits, including possibly higher social rank, but no deficits in probability-based decision-making. A Random forest analysis revealed interesting discriminating traits between WH and DA.\n\nConclusionThe reproducibility and conservation of the socio-cognitive and behavioural phenotypes of GDM (good decision maker) and PDM individuals in the two genetically different strains of WH and DA support a good translational validity of these phenotypes. Both DA and WH rat strains present large phenotypic variations in behaviour pertinent for the study of the underlying mechanisms of poor decision making and associated disorders.

animal behavior and cognition↗

bioRxiv2018

Targeted genomic integration of EGFP under tubulin beta 3 class III promoter and mEos2 under tryptophan hydroxylase 2 promoter does not produce sufficient levels of reporter gene expression

Neuronal tracing is a modern technology that is based on the expression of fluorescent proteins under the control of cell type-specific promoters. However, random genomic integration of the reporter construct often leads to incorrect spatial and temporal expression of the marker protein. Targeted integration (or knock-in) of the reporter coding sequence is supposed to provide better expression control by exploiting endogenous regulatory elements. Here we describe the generation of two fluorescent reporter systems: EGFP under pan-neural marker class III {beta}-tubulin (Tubb3) promoter and mEos2 under serotonergic neuron specific tryptophan hydroxylase 2 (Tph2) promoter. Differentiation of Tubb3-EGFP ES cells into neurons revealed that though Tubb3-positive cells express EGFP, its expression level is not sufficient for the neuronal tracing by routine fluorescent microscopy. Similarly, the expression levels of mEos2-TPH2 in differentiated ES cells was very low and could be detected only on mRNA level using PCR-based methods. Our data shows that the use of endogenous regulatory elements to control transgene expression is not always beneficial compared to random genomic integration.

developmental biology↗