Cyclotraxin-B, the First Highly Potent and Selective TrkB Inhibitor, Has Anxiolytic Properties in Mice

In the last decades, few mechanistically novel therapeutic agents have been developed to treat mental and neurodegenerative disorders. Numerous studies suggest that targeting BDNF and its TrkB receptor could be a promising therapeutic strategy for the treatment of brain disorders. However, the development of potent small ligands for the TrkB receptor has proven to be difficult. By using a peptidomimetic approach, we developed a highly potent and selective TrkB inhibitor, cyclotraxin-B, capable of altering TrkB-dependent molecular and physiological processes such as synaptic plasticity, neuronal differentiation and BDNF-induced neurotoxicity. Cyclotraxin-B allosterically alters the conformation of TrkB, which leads to the inhibition of both BDNF-dependent and -independent (basal) activities. Finally, systemic administration of cyclotraxin-B to mice results in TrkB inhibition in the brain with specific anxiolytic-like behavioral effects and no antidepressant-like activity. This study demonstrates that cyclotraxin-B might not only be a powerful tool to investigate the role of BDNF and TrkB in physiology and pathology, but also represents a lead compound for the development of new therapeutic strategies to treat brain disorders

Beneficial behavioural and neurogenic effects of agomelatine in a model of depression/anxiety

Abstract Agomelatine (S20098) is a novel antidepressant drug with melatonergic agonist and 5-HT 2C receptor antagonist properties, displaying antidepressant/anxiolytic-like properties in animal models and in humans. In a depression/anxiety-like mouse model in which the response of the HPA axis is blunted, we investigated whether agomelatine could reverse behavioural deficits related to depression/anxiety compared to the classical selective serotonin reuptake inhibitor, fluoxetine. Adult mice were treated for 8 wk with either vehicle or corticosterone (35 mg/ml.d) via drinking water. During the final 4 wk, animals were treated with vehicle, agomelatine (10 or 40 mg/kg i.p.) or fluoxetine (18 mg/kg i.p.) and tested in several behavioural paradigms and also evaluated for home-cage activity. Our results showed that the depressive/anxiety-like phenotype induced by corticosterone treatment is reversed by either chronic agomelatine or fluoxetine treatment. Moreover, agomelatine increased the dark/light ratio of home-cage activity in vehicle-treated mice and reversed the alterations in this ratio induced by chronic corticosterone, suggesting a normalization of disturbed circadian rhythms. Finally, we investigated the effects of this new antidepressant on neurogenesis. Agomelatine reversed the decreased cell proliferation in the whole hippocampus in corticosterone-treated mice and increased maturation of newborn neurons in both vehicle-and corticosterone-treated mice. Overall, the present study suggests that agomelatine, with its distinct mechanism of action based on the synergy between the melatonergic agonist and 5-HT 2C antagonist properties, provides a distinct antidepressant/anxiolytic spectrum including circadian rhythm normalization

S 38093, a histamine H3 antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice

Strategies designed to increase adult hippocampal neurogenesis (AHN) may have therapeutic potential for reversing memory impairments. H3 receptor antagonists/inverse agonists also may be useful for treating cognitive deficits. However, it remains unclear whether these ligands have effects on AHN. The present study aimed to investigate the effects of a 28-day treatment with S 38093, a novel brain-penetrant antagonist/inverse agonist of H3 receptors, on AHN (proliferation, maturation and survival) in 3-month-old and in aged 16-month-old mice. In addition, the effects of S 38093 treatment on 7-month-old APPSWE Tg2576 transgenic mice, a model of Alzheimer’s disease, were also assessed. In all tested models, chronic treatment with S 38093 stimulated all steps of AHN. In aged animals, S 38093 induced a reversal of age-dependent effects on hippocampal brain-derived neurotrophic factor (BDNF) BDNF-IX, BDNF-IV and BDNF-I transcripts and increased vascular endothelial growth factor (VEGF) expression. Finally, the effects of chronic administration of S 38093 were assessed on a neurogenesis-dependent “context discrimination (CS) test” in aged mice. While ageing altered mouse CS, chronic S 38093 treatment significantly improved CS. Taken together, these results provide evidence that chronic S 38093 treatment increases adult hippocampal neurogenesis and may provide an innovative strategy to improve age-associated cognitive deficits

Altered Gene Synchrony Suggests a Combined Hormone-Mediated Dysregulated State in Major Depression

Coordinated gene transcript levels across tissues (denoted “gene synchrony”) reflect converging influences of genetic, biochemical and environmental factors; hence they are informative of the biological state of an individual. So could brain gene synchrony also integrate the multiple factors engaged in neuropsychiatric disorders and reveal underlying pathologies? Using bootstrapped Pearson correlation for transcript levels for the same genes across distinct brain areas, we report robust gene transcript synchrony between the amygdala and cingulate cortex in the human postmortem brain of normal control subjects (n = 14; Control/Permutated data, p<0.000001). Coordinated expression was confirmed across distinct prefrontal cortex areas in a separate cohort (n = 19 subjects) and affected different gene sets, potentially reflecting regional network- and function-dependent transcriptional programs. Genewise regional transcript coordination was independent of age-related changes and array technical parameters. Robust shifts in amygdala-cingulate gene synchrony were observed in subjects with major depressive disorder (MDD, denoted here “depression”) (n = 14; MDD/Permutated data, p<0.000001), significantly affecting between 100 and 250 individual genes (10–30% false discovery rate). Biological networks and signal transduction pathways corresponding to the identified gene set suggested putative dysregulated functions for several hormone-type factors previously implicated in depression (insulin, interleukin-1, thyroid hormone, estradiol and glucocorticoids; p<0.01 for association with depression-related networks). In summary, we showed that coordinated gene expression across brain areas may represent a novel molecular probe for brain structure/function that is sensitive to disease condition, suggesting the presence of a distinct and integrated hormone-mediated corticolimbic homeostatic, although maladaptive and pathological, state in major depression

Intérêt du (+-)-pindolol en co-administration avec un antidépresseur sérotoninergique (étude du rôle des récepteurs 1A et 1B de la sérotonine)

Le (+-)-pindolol serait efficace pour raccourcir le long délai d'action (4-6 semaines) des inhibiteurs sélectifs de la recapture de la sérotonine dans le traitement de la dépression chez l'Homme. Ne connaissant pas précisément les sites d'action centraux du pindolol, nous avons tenté de les identifier à l'aide de tests comportementaux (test de la nage forcée) et neurochimiques (microdialyse intracérébrale in vivo) en utilisant une approche pharmacologique (utilisation de ligands des R5-HT1A) et génétique (utilisation de souris "knock-out" [KO] pour le récepteur 5-HT1A et/ou du récepteur 5-HT1B). Les études neurochimiques révèlent une activité agoniste partielle du pindolol sur les récepteurs 5-HT1A du noyau du raphé dorsal. Par contre, ses effets comportementaux seraient médiés par une action antagoniste sur les récepteurs 5-HT1B postsynaptiques. Enfin, la génération des souris KO 5-HT1A/1B constitueraient un nouveau modèle physiopathologique murin d'anxiété sensible aux anxiolytiques.(+-)-pindolol seems to be useful to shorten the onset of action (4-6 weeks) of selective serotonin reuptake inhibitors in the treatment of human depression. As the precise mechanism of action of pindolol is still unknown, we tried to highlight it using behavourial (forced swimming test) and neurochemical (in vivo intracerebral microdialysis) tests with a pharmacological and genetical approaches (using 5-HT1A receptor antagonists and 5-HT1A and/or 5-HT1B receptor knockout [KO] mice, respectively). Neurochemical experiments showed a partial agonist activity of pindolol on 5-HT1A presynaptic receptors in the dorsal raphé nucleus. In contrary, its behavioural effects may be related to its antagonistic activity at 5-HT1B postsynaptic receptors. Finally, 5-HT1A/1B receptors knockout mice might be a new model of anxiety to test the putative anxiolytic-like activity of new drugs.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

MiniCACTUS: Sub-100 ps timing with depleted MAPS

International audienceMiniCACTUS is a monolithic CMOS sensor demonstrator designed for time tagging individual Minimum Ionizing Particles with an accuracy better than 100ps. The sensor features an active array of 2 × 4 pixels surrounded by guard-rings used to bias the high-resistivity substrate, an analog and digital front-end per pixel, a slow control interface and internal programmable biases through DACs. The baseline pixel sizes are 1.0mm2 and 0.5mm2. The sensing element is a deep n-well/p-substrate diode without internal amplification. The analog front-ends and the discriminators for each pixel have been implemented outside the pixel, at the column level. After fabrication, the sensors have been thinned to 200µm and 100µm and then post-processed for backside biasing. As such, this sensor is a demonstrator chip for future large scale timing detectors, like upgrades of timing detectors at LHC, or future high energy physics detector projects. Measurements of noise, response to X and γ-rays are presented, as well as time resolution measurements using β decays from 90Sr. Some preliminary results from a test-beam campaign are also mentioned

MiniCACTUS: A 65 ps Time Resolution Depleted Monolithic CMOS Sensor

International audienceMiniCACTUS is a monolithic sensor prototype optimized for timing measurement of charged particles. It has been designed in a standard 150 nm CMOS process without dedicated amplification layer. It is intended as a demonstrator chip for future large-scale timing detectors, like upgrades of timing detectors at LHC, or future high-energy physics detector projects. The sensor features an active array of $2\times4$ diodes, analog and digital front-ends (FEs), a slow control interface, and bias circuitry programmable through internal DACs. The sensing element is a deep n-well/p-substrate diode. Thanks to the optimized guard-rings surrounding the whole chip, it is possible to apply safely more than −450 V on the high-resistivity substrate allowing fast charge collection. The baseline pixel dimensions are $1.0\times1.0$ mm and $0.5\times1.0$ mm. The analog FEs and the discriminators for each pixel are implemented outside the pixel, at the column level. The power consumption is approximately 300 mW/cm2, which is compatible with cooling infrastructure available at LHC experiments, and making integration of this concept viable in future high-energy physics experiments. After fabrication, the sensors have been thinned to 100, 200, and $300~\mu \text{m}$ total thickness and then postprocessed for backside biasing. The time resolution of several sensors with different thicknesses has been measured in three testbeam campaigns using high-energy muons minimum ionizing particles (MIPs) at CERN SPS in 2021 and 2022. A resolution of 65.3 ps has been measured with ON-chip FE and discriminator. This article will focus on the results of these testbeam campaigns

MiniCACTUS: A 65 ps Time Resolution Depleted Monolithic CMOS Sensor

International audienceMiniCACTUS is a monolithic sensor prototype optimised for timing measurement of charged particles. It has been designed in a standard 150 nm CMOS process without dedicated amplification layer. It is intended as a demonstrator chip for future large scale timing detectors, like upgrades of timing detectors at LHC, or future high energy physics detector projects. The sensor features an active array of 2 x 4 diodes, analog and digital Front-Ends (FEs), a slow control interface, and bias circuitry programmable through internal DACs. The sensing element is a deep n-well/p-substrate diode. Thanks to the optimized guard-rings surrounding the whole chip, it is possible to apply safely more than 450 V on the high-resistivity substrate allowing fast charge collection. The baseline pixel dimensions are 1.0 mm x 1.0 mm and 0.5 mm x 1.0 mm. The analog FEs and the discriminators for each pixel are implemented outside the pixel, at the column level. The power consumption is approximately 300 mW/cm$\mathbf {^2}$, which is compatible with cooling infrastructure available at LHC experiments, and making integration of this concept viable in future high energy physics experiments. After fabrication, the sensors have been thinned to 100 $\mu$m, 200 $\mu$m and 300 $\mu$m total thickness and then post-processed for backside biasing. The time resolution of several sensors with different thicknesses has been measured in 3 test-beam campaigns using high energy muons (Minimum Ionizing Particles) at CERN SPS in 2021 and 2022. A resolution of 65.3 ps has been measured with on-chip FE and discriminator. This paper will focus on the results of these test-beam campaigns

Cognitive Dysfunction in Major Depressive Disorder. A Translational Review in Animal Models of the Disease

Major Depressive Disorder (MDD) is the most common psychiatric disease, affecting millions of people worldwide. In addition to the well-defined depressive symptoms, patients suffering from MDD consistently complain about cognitive disturbances, significantly exacerbating the burden of this illness. Among cognitive symptoms, impairments in attention, working memory, learning and memory or executive functions are often reported. However, available data about the heterogeneity of MDD patients and magnitude of cognitive symptoms through the different phases of MDD remain difficult to summarize. Thus, the first part of this review briefly overviewed clinical studies, focusing on the cognitive dysfunctions depending on the MDD type. As animal models are essential translational tools for underpinning the mechanisms of cognitive deficits in MDD, the second part of this review synthetized preclinical studies observing cognitive deficits in different rodent models of anxiety/depression. For each cognitive domain, we determined whether deficits could be shared across models. Particularly, we established whether specific stress-related procedures or unspecific criteria (such as species, sex or age) could segregate common cognitive alteration across models. Finally, the role of adult hippocampal neurogenesis in rodents in cognitive dysfunctions during MDD state was also discussed