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Rationale Stress represents a major contributor to the development of mental illness. Accordingly, exposure of adult rats to chronic stress represents a valuable tool to investigate the ability of a pharmacological intervention to counteract the adverse effects produced by stress exposure. Objectives The aim of this study was to perform a time course analysis of the treatment with the antipsychotic drug lurasidone in normalizing the anhedonic phenotype in the chronic mild stress (CMS) model in order to identify early mechanisms that may contribute to its therapeutic activity. Methods Male Wistar rats were exposed to CMS or left undisturbed for 7 weeks. After two weeks of stress, both controls and CMS rats were randomly divided into two subgroups that received vehicle or lurasidone for five weeks. Weekly measures of sucrose intake were recorded to evaluate anhedonic behavior, and animals were sacrificed at different weeks of treatment for molecular analyses. Results We found that CMS-induced anhedonia was progressively improved by lurasidone treatment. Interestingly, after two weeks of lurasidone treatment, 50% of the animals showed a full recovery of the phenotype, which was associated with increased activation of the prefrontal and recruitment of parvalbumin-positive cells that may lead to a restoration of excitatory/inhibitory balance. Conclusion These results suggest that the capacity of lurasidone to normalize anhedonia at an early stage of treatment may depend on its ability to modulate the function of the prefrontal cortex.

Summary Rapastinel, formerly Glyx-13, is a novel positive allosteric modulator of the N-methyl-D-aspartate-receptor (NMDAR) that counteracts psychotomimetic actions of NMDAR antagonists. We set out to evaluate the effect of rapastinel alone or in combination with the global and GluN2B subunit–specific NMDAR antagonists MK-801 and Ro25-6981, respectively, on neuronal activation in relevant regions using c-fos brain mapping. Whereas rapastinel alone did not trigger significant c-fos expression beyond the prelimbic cortex, it strongly increased the c-fos expression induced by MK-801 in hippocampal, cingulate, and retrosplenial areas. Similar results were obtained when rapastinel was replaced by D-cycloserine. Our results reveal new interactions at network level between NMDAR modulators with possible implications regarding their therapeutic effects.

Animal models are useful preclinical tools for studying the pathogenesis of mental disorders and the effectiveness of their treatment. While it is not possible to mimic all symptoms occurring in humans, it is however possible to investigate the behavioral, physiological and neuroanatomical alterations relevant for these complex disorders in controlled conditions and in genetically homogeneous populations. Stressful and infection-related exposures represent the most employed environmental risk factors able to trigger or to unmask a psychopathological phenotype in animals. Indeed, when occurring during sensitive periods of brain maturation, including pre, postnatal life and adolescence, they can affect the offspring's neurodevelopmental trajectories, increasing the risk for mental disorders. Not all stressed or immune challenged animals, however, develop behavioral alterations and preclinical animal models can explain differences between vulnerable or resilient phenotypes. Our review focuses on different paradigms of stress (prenatal stress, maternal separation, social isolation and social defeat stress) and immune challenges (immune activation in pregnancy) and investigates the subsequent alterations in several biological and behavioral domains at different time points of animals' life. It also discusses the "double-hit" hypothesis where an initial early adverse event can prime the response to a second negative challenge. Interestingly, stress and infections early in life induce the activation of the hypothalamic-pituitary-adrenal (HPA) axis, alter the levels of neurotransmitters, neurotrophins and pro-inflammatory cytokines and affect the functions of microglia and oxidative stress. In conclusion, animal models allow shedding light on the pathophysiology of human mental illnesses and discovering novel molecular drug targets for personalized treatments.

Exercise has been shown to be beneficial in reducing symptoms of affective disorders and to increase the expression of brain-derived neurotrophic factor (BDNF). The BDNF Val66Met polymorphism is associated with reduced activity-dependent BDNF release and increased risk for anxiety and depression. Male and female Val66Met rats were given access to running wheels from 3 weeks of age and compared to sedentary controls. Anxiety- and depression-like behaviors were measured in adulthood using the elevated plus maze (EPM), open field (OF), and forced swim test (FST). Expression of BDNF and a number of stress-related genes, the glucocorticoid receptor (Nr3c1), serum/glucocorticoid-regulated kinase 1 (Sgk1), and FK506 binding protein 51 (Fkbp5) in the hippocampus were also measured. Rats given access to running wheels developed high levels of voluntary exercise, decreased open-arm time on the EPM and center-field time in the OF, reduced overall exploratory activity in the open field, and increased immobility time in the FST with no differences between genotypes. Chronic exercise induced a significant increase in Bdnf mRNA and BDNF protein levels in the hippocampus with some of these effects being genotype specific. Exercise decreased the expression of Nr3c1 and Sgk1, but increased the expression of Fkbp5. These results suggest that chronic running-wheel exercise from adolescence increased anxiety and depression-like phenotypes in adulthood, independent of BDNF Val66Met genotype. Further studies are required to confirm that increased indices of anxiety-like behavior are independent from reduced overall locomotor activity.

Stressful experiences early in life, especially in the prenatal period, can increase the risk to develop depression during adolescence. However, there may be important qualitative and quantitative differences in outcome of prenatal stress (PNS), where some individuals exposed to PNS are vulnerable and develop a depressive-like phenotype, while others appear to be resilient. PNS exposure, a well-established rat model of early life stress, is known to increase vulnerability to depression and a recent study demonstrated a strong interaction between transforming growth factor-β1 (TGF-β1) gene and PNS in the pathogenesis of depression. Moreover, it is well-known that the exposure to early life stress experiences induces brain oxidative damage by increasing nitric oxide levels and decreasing antioxidant factors. In the present work, we examined the role of TGF-β1 pathway in an animal model of adolescent depression induced by PNS obtained by exposing pregnant females to a stressful condition during the last week of gestation. We performed behavioral tests to identify vulnerable or resilient subjects in the obtained litters (postnatal day, PND > 35) and we carried out molecular analyses on hippocampus, a brain area with a key role in the pathogenesis of depression. We found that female, but not male, PNS adolescent rats exhibited a depressive-like behavior in forced swim test (FST), whereas both male and female PNS rats showed a deficit of recognition memory as assessed by novel object recognition test (NOR). Interestingly, we found an increased expression of type 2 TGF-β1 receptor (TGFβ-R2) in the hippocampus of both male and female resilient PNS rats, with higher plasma TGF-β1 levels in male, but not in female, PNS rats. Furthermore, PNS induced the activation of oxidative stress pathways by increasing inducible nitric oxide synthase (iNOS), NADPH oxidase 1 (NOX1) and NOX2 levels in the hippocampus of both male and female PNS adolescent rats. Our data suggest that high levels of TGF-β1 and its receptor TGFβ-R2 can significantly increase the resiliency of adolescent rats to PNS, suggesting that TGF-β1 pathway might represent a novel pharmacological target to prevent adolescent depression in rats.

Neuroinflammation has emerged as an important factor in the molecular underpinnings of major depressive disorder (MDD) pathophysiology and in the mechanism of action of antidepressants. Among the inflammatory mediators dysregulated in depressed patients, interleukin (IL)-6 has recently been proposed to play a crucial role. IL-6 activates a signaling pathway comprising the JAK/STAT proteins and characterized by a specific negative feedback loop exerted by the cytoplasmic protein suppressor of cytokine signalling-3 (SOCS3). On these bases, here, we explored the potential involvement of IL-6 signaling in the ability of the antidepressant drug agomelatine to normalize the anhedonic-like phenotype induced in the rat by chronic stress exposure. To this aim, adult male Wistar rats were subjected to the chronic mild stress (CMS) paradigm and chronically treated with vehicle or agomelatine. The behavioral evaluation was assessed by the sucrose consumption test, whereas molecular analyses were performed in the prefrontal cortex. We found that CMS was able to stimulate IL-6 production and signaling, including SOCS3 gene and protein expression, but the SOCS3-mediated feedback-loop inhibition failed to suppress the IL-6 cascade in stressed animals. Conversely, agomelatine treatment normalized the stress-induced decrease in sucrose consumption and restored the negative modulation of the IL-6 signaling via SOCS3 expression and activity. Our results provide additional information about the pleiotropic mechanisms that contribute to agomelatine's therapeutic effects.

We report the implemented architecture for monitoring the health and the quality of the Son Of X-Shooter (SOXS) spectrograph for the New Technology Telescope in La Silla at the European Southern Observatory. Briefly, we report on the innovative no-SQL database approach used for storing time-series data that best suits for automatically triggering alarm, and report high-quality graphs on the dashboard to be used by the operation support team. The system is designed to constantly and actively monitor the Key Performance Indicators (KPI) metrics, as much automatically as possible, reducing the overhead on the support and operation teams. Moreover, we will also detail about the interface designed to inject quality checks metrics from the automated SOXS Pipeline (Young et al. 2022).

Systems Engineering requires the involvement of different engineering disciplines: Software, Electronics, Mechanics (often nowadays together as Mechatronics), Optics etc. Systems Engineering of Astronomical Instrumentation is no exception to this. A critical point is the handling of the different point of view introduced by these disciplines often related to different tools and cultures. Model Based Systems Engineering (MBSE) approach can help the Systems Engineer to always have a complete view of the full system. Moreover, in an ideal situation, all of the information resides in the model thus allowing different views of the System without having to resort to different sources of information, often outdated. In the real world, however, this does not happen because the different actors (Optical Designers, Mechanical Engineers, Astronomers etc.) should adopt the same language and this is clearly, at least nowadays and for the immediate future, close to impossible. In the Italian Astronomical Community, we are developing methodologies and tools to share the expertise in this field among the different projects. In this paper we present the status of this activity that aims to deliver to the community proper tools and template to enable a uniformed use of MBSE (friendly name Astro MBSE) among different projects (ground and space based, …). We will analyze here different software and different approaches. The target and synthesis of this work will be a support framework for the MBSE based system Engineering activity to the Italian Astronomical Community (INAF).

Exposure to stress during early development may lead to altered neurobiological functions, thus increasing the risk for psychiatric illnesses later in life. One potential mechanism associated with those outcomes is the disruption of glial density and morphology, despite results from rodent studies have been conflicting. To address that we performed a systematic review and meta-analysis of rodent studies that investigated the effects of prenatal stress (PNS) and early life stress (ELS) on microglia, astrocyte, and oligodendrocyte density and morphology within the offspring. Our meta-analysis demonstrates that animals exposed to PNS or ELS showed significant increase in microglia density, as well as decreased oligodendrocyte density. Moreover, ELS exposure induced an increase in microglia soma size. However, we were unable to identify significant effects on astrocytes. Meta-regression indicated that experimental stress protocol, sex, age, and type of tissue analyzed are important covariates that impact those results. Importantly, PNS microglia showed higher estimates in young animals, while the ELS effects were stronger in adult animals. This set of data reinforces that alterations in glial cells could play a role in stress-induced dysfunctions throughout development.

The exposure to adverse environmental situations during sensitive periods of development may induce re-organizational effects on different systems and increase the vulnerability to develop psychiatric disorders later in life. The adolescent period has been demonstrated extremely susceptible to stressful events. However, most of the studies focused on the immediate effects of stress exposure and few of them investigated sex differences. This raised the question if these modulations might also be long-lasting and how the differential maturational events taking place during adolescence between males and females might have a role in the detrimental effects of stress. Given the importance of social play for the right maturation of behavior during adolescence, we used the preclinical model of social deprivation, based on the lack of all social contacts, for four weeks after weaning, followed by re-socialization until adulthood. We found that both male and female animals reared in isolation during adolescence developed an anhedonic phenotype at adulthood, without any impairments in the cognitive domain. At molecular level, these functional changes were associated with sex-specific impairments in the expression of neuroplastic markers as well as of hypothalamic-pituitary-adrenal axis-related genes. Lastly, we also reported anatomically-selective changes associated with the enduring effects of social isolation.

Background Sheep (Ovis aries) have been largely used as animal models in a multitude of specialties in biomedical research. The similarity to human brain anatomy in terms of brain size, skull features, and gyrification index, gives to ovine as a large animal model a better translational value than small animal models in neuroscience. Despite this evidence and the availability of advanced imaging techniques, morphometric brain studies are lacking. We herein present the morphometric ovine brain indexes and anatomical measures developed by two observers in a double-blinded study and validated via an intra- and inter-observer analysis. Results For this retrospective study, T1-weighted Magnetic Resonance Imaging (MRI) scans were performed at 1.5 T on 15 sheep, under general anaesthesia. The animals were female Ovis aries, in the age of 18-24 months. Two observers assessed the scans, twice time each. The statistical analysis of intra-observer and inter-observer agreement was obtained via the Bland-Altman plot and Spearman rank correlation test. The results are as follows (mean ± Standard deviation): Indexes: Bifrontal 0,338 ± 0,032 cm; Bicaudate 0,080 ± 0,012 cm; Evans’ 0,218 ± 0,035 cm; Ventricular 0,241 ± 0,039 cm; Huckman 1693 ± 0,174 cm; Cella Media 0,096 ± 0,037 cm; Third ventricle ratio 0,040 ± 0,007 cm. Anatomical measures: Fourth ventricle length 0,295 ± 0,073 cm; Fourth ventricle width 0,344 ± 0,074 cm; Left lateral ventricle 4175 ± 0,275 cm; Right lateral ventricle 4182 ± 0,269 cm; Frontal horn length 1795 ± 0,303 cm; Interventricular foramen left 1794 ± 0,301 cm; Interventricular foramen right 1,78 ± 0,317 cm. Conclusions The present study provides baseline values of linear indexes of the ventricles in the ovine models. The acquisition of these data contributes to filling the knowledge void on important anatomical and morphological features of the sheep brain.

We present development progress of the scheduler for the Son Of X-Shooter (SOXS) instrument at the ESO-NTT 3.58 meter telescope. SOXS will be a single object spectroscopic facility, consisting of a two-arms high-efficiency spectrograph covering the spectral range 350-2000 nanometer with a mean resolving power R$\approx$4500. SOXS will be uniquely dedicated to the UV-visible and near infrared follow up of astrophysical transients, with a very wide pool of targets available from the streaming services of wide-field telescopes, current and future. This instrument will serve a variety of scientific scopes in the astrophysical community, with each scope eliciting its specific requirements for observation planning, that the observing scheduler has to meet. Due to directions from the European Southern Observatory (ESO), the instrument will be operated only by La Silla staff, with no astronomer present on the mountain. This implies a new challenge for the scheduling process, requiring a fully automated algorithm that should be able to present the operator not only with and ordered list of optimal targets, but also with optimal back-ups, should anything in the observing conditions change. This imposes a fast-response capability to the scheduler, without compromising the optimization process, that ensures good quality of the observations. In this paper we present the current state of the scheduler, that is now almost complete, and of its web interface., Accepted for publication in SPIE Astronomical Telescope and Instrumentation Conference proceedings - Montreal (Canada) July 2022

Systems Engineering requires the involvement of different engineering disciplines: Software, Electronics, Mechanics (often nowadays together as Mechatronics), Optics etc. Astronomical Instrumentation is no exception to this. A critical point is the handling of the requirements, their tracing, flow down and the interaction with stakeholders (flow up) and subsystems (flow down) in order to have traceable and methodical evolution and management. In the Italian Astronomical Community, we are developing methodologies and tools to share the expertise in this field among the different projects. In this paper we will focus on the requirement management approach among different projects (ground and space based, …). The target and synthesis of tis work will be a support framework for the Requirement management of the Italian Astronomical Community (INAF) projects.

The common brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with reduced activity-dependent BDNF release and increased risk for anxiety disorders and PTSD. Here we behaviorally phenotyped a novel Val66Met rat model with an equivalent valine to methionine substitution in the rat Bdnf gene (Val68Met). In a three-day fear conditioning protocol of fear learning and extinction, adult rats with the Met/Met genotype demonstrated impaired fear memory compared to Val/Met rats and Val/Val controls, with no genotype differences in fear learning or extinction. This deficit in fear memory occurred irrespective of the sex of the animals and was not seen in adolescence (4 weeks of age). There were no changes in open-field locomotor activity or anxiety measured in the elevated plus maze (EPM) nor in other types of memory measured using the novel-object recognition test or Y-maze. BDNF exon VI expression in the dorsal hippocampus was higher and BDNF protein level in the ventral hippocampus was lower in female Val/Met rats than female Val/Val rats, with no other genotype differences, including in total BDNF, BDNF long, or BDNF IV mRNA. These data suggest a specific role for the BDNF Met/Met genotype in fear memory in rats. Further studies are required to investigate gene–environment interactions in this novel animal model.

The Son-Of-XShooter (SOXS) is a single object spectrograph (UV-VIS & NIR) and acquisition camera scheduled to be mounted on the ESO 3.58-m New Technology Telescope at the La Silla Observatory. Although the underlying data reduction processes to convert raw detector data to fully-reduced science ready data are complex and multi-stepped, we have designed the SOXS Data Reduction pipeline with the core aims of providing end-users with a simple-to-use, well-documented command-line interface while also allowing the pipeline to be run in a fully automated state; streaming reduced data into the ESO Science Archive Facility without need for human intervention. To keep up with the stream of data coming from the instrument, there is the requirement to optimise the software to reduce each observation block of data well within the typical observation exposure time. The pipeline is written in Python 3 and has been built with an agile development philosophy that includes CI and adaptive planning., 10 pages, 7 figures, published in SPIE proceedings volume 12189. arXiv admin note: substantial text overlap with arXiv:2012.12678

Antipsychotics represent the mainstay of schizophrenia pharmacological therapy, and their role has been expanded in the last years to mood disorders treatment. Although introduced in 1952, many years of research were required before an accurate picture of how antipsychotics work began to emerge. Despite the well-recognized characterization of antipsychotics in typical and atypical based on their liability to induce motor adverse events, their main action at dopamine D2R to elicit the "anti-psychotic" effect, as well as the multimodal action at other classes of receptors, their effects on intracellular mechanisms starting with receptor occupancy is still not completely understood. Significant lines of evidence converge on the impact of these compounds on multiple molecular signaling pathways implicated in the regulation of early genes and growth factors, dendritic spine shape, brain inflammation, and immune response, tuning overall the function and architecture of the synapse. Here we present, based on PRISMA approach, a comprehensive and systematic review of the above mechanisms under a translational perspective to disentangle those intracellular actions and signaling that may underline clinically relevant effects and represent potential targets for further innovative strategies in antipsychotic therapy.

Major depressive disorder (MDD) is a complex mental disorder where the neurochemical, neuroendocrine, immune, and metabolic systems are impaired. The microbiota-gut-brain axis is a bidirectional network where the central and enteric nervous systems are linked through the same endocrine, immune, neural, and metabolic routes dysregulated in MDD. Thus, gut-brain axis abnormalities in MDD patients may, at least in part, account for the symptomatic features associated with MDD. Recent investigations have suggested that the oral microbiome also plays a key role in this complex molecular picture of relationships. As on one hand there is a lot of what we know and on the other hand little of what we still need to know, we structured this review focusing, in the first place, on putting all pieces of this complex puzzle together, underlying the endocrine, immune, oxidative stress, neural, microbial neurotransmitters, and metabolites molecular interactions and systems lying at the base of gut microbiota (GM)–brain-depression interphase. Then, we focused on promising but still under-explored areas of research strictly linked to the GM and potentially involved in MDD development: (i) the interconnection of GM with oral microbiome that can influence the neuroinflammation-related processes and (ii) gut phageome (bacteria-infecting viruses). As conclusions and future directions, we discussed potentiality but also pitfalls, roadblocks, and the gaps to be bridged in this exciting field of research. By the development of a broader knowledge of the biology associated with MDD, with the inclusion of the gut/oral microbiome, we can accelerate the growth toward a better global health based on precision medicine.

Rationale Although the occurrence of stressful events is very common during life, their impact may be different depending on the experience severity and duration. Specifically, acute challenges may trigger adaptive responses and even improve the individual’s performance. However, such a physiological positive coping can only take place if the underlying molecular mechanisms are properly functioning. Indeed, if these systems are compromised by genetic factors or previous adverse conditions, the response set in motion by an acute challenge may be maladaptive and even cause the insurgence or the relapse of stress-related psychiatric disorders. Objectives On these bases, we evaluated in the rat brain the role of the antioxidant component of the redox machinery on the acute stress responsiveness and its modulation by potential detrimental or beneficial events. Methods The expression of several antioxidant enzymes was assessed in different brain areas of adult male rats exposed to acute stress 3 weeks after a chronic immobilization paradigm with or without a concomitant treatment with the antipsychotic lurasidone. Results The acute challenge was able to trigger a marked antioxidant response that, despite the washout period, was impaired by the previous adverse experience and restored by lurasidone in an anatomical-specific manner. Conclusions We found that a working antioxidant machinery takes part in acute stress response and may be differentially affected by other experiences. Given the essential role of stress responsiveness in almost every life process, the identification of the underlying mechanisms and their potential pharmacological modulation add further translational value to our data.

Exposure to early adverse experiences induces persistent changes in physiological, emotional and behavioural functions predisposing the individual to an enhanced vulnerability to develop different disorders during lifespan. The adverse outcomes depend upon the timing of the stressful experiences, and in this contest, adolescence represents a key sensitive period for brain development. Among the biological systems involved, gut microbiota has recently been proposed to act on the interplay between the stress response, brain functions and immune system, through the gut-brain axis communication. In the current study we aimed to evaluate, in a preclinical model, changes over time in the microbiota community structure in physiological condition and in response to stress during adolescence. We also aimed to correlate the microbiota composition to the inflammatory status in brain. We used the preclinical model of social deprivation in rats during adolescence, based on the lack of all social contacts, for four weeks after weaning, followed by re-socialization until adulthood. We collected fecal samples at different post-natal days to investigate the short- and long-lasting effects of social isolation on gut microbiota composition and we collected brain areas (dorsal and ventral hippocampus) samples at killing to measure a panel of inflammatory and microglia activation markers. 16 S metataxonomic sequencing analysis revealed that microbial changes were influenced by age in both isolated and controls rats, regardless of sex, whereas social isolation impacted the microbial composition in a sex-dependent manner. A multivariate analysis showed that social isolation induced short-term gut microbiota alterations in females but not in males. We also identified several stress-related genera associated with social isolation condition. In brain areas we found a specific inflammatory pattern, in dorsal and ventral hippocampus, that significantly correlated with gut microbiota composition. Overall, in this study we reported a novel sex-specific association between gut microbiota composition and inflammatory response related to social isolation paradigm during adolescence, suggesting that stressful experiences during this sensitive period could have a long-lasting impact on the development of different biological systems that could in turn influence the vulnerability to develop mental disorders later in life.

Background: Stress represents one of the main precipitating factors for psychiatric diseases, characterised by an altered function of glucocorticoid receptors (GR), known to play a role in mood and cognitive function. We investigated the ability of the antipsychotic lurasidone to modulate the involvement of genomic and non-genomic GR signalling in the behavioural alterations due to chronic stress exposure Methods: Male Wistar rats were exposed to seven weeks of chronic mild stress (CMS) and treated with lurasidone (3 mg/kg/day) starting from the second week of stress for more five weeks. Gene expression and protein analyses were conducted in dorsal hippocampus. Results: Seven weeks of CMS induced anhedonia and cognitive impairment, which were normalised by lurasidone. At molecular level, CMS rats showed an increase of GR protein levels by 60% ( pConclusion: Our results further support the role of glucocorticoid signalling in the dysfunction associated with stress exposure. We provide novel insights on the mechanism of lurasidone, suggesting its effectiveness on different domains associated with psychiatric disorders.

Cariprazine is a new atypical antipsychotic drug (APD) with a unique pharmacodynamic profile, different from both typical and atypical APDs. Specifically, cariprazine acts as a partial agonist at the dopamine (DA) D2and D3receptors and serotonin 5-HT1Areceptors, and as an antagonist at the 5-HT2Breceptors. Moreover, it shows moderate affinities for adrenergic, histaminergic, and cholinergic receptors that are involved in mediating the side effects characteristic of typical APDs. In this review, we discuss the contribution of DA D3receptors (D3Rs) in the etiology and pathophysiology of schizophrenia and the potential benefits that may be associated with a more selective targeting of D3R by APDs, as compared to other dopaminergic and non-dopaminergic receptor subtypes. Cariprazine, by acting on D3Rs, ameliorates anhedonia and cognitive deficits in animal models based on environmental or pharmacological manipulation. The reviewed results support the potential benefits of cariprazine in treating negative symptoms and cognitive deficits of schizophrenia, and therefore representing a promising approach in addressing the unmet clinical needs for the improved treatment of this serious neuropsychiatric disorder.

Vortioxetine is a novel multimodal antidepressant approved in 2013 by the Food and Drug Administration and the European Medicines Agency for the treatment of major depressive disorder (MDD). It combines the modulation of serotonin receptors activity with the inhibition of serotonin transporter (SERT). In this study, we aim at establishing the effect of chronic vortioxetine treatment (5 mg/kg twice/daily) in modulating neuroplastic mechanisms as well as hypothalamic pituitary adrenal axis (HPA) activity under basal condition and in response to an acute challenge. We found that prolonged vortioxetine administration significantly increased total Bdnf expression in the dorsal and ventral hippocampus of adult male rats and affected the stress-induced modulation of the immediate early genes Arc and Zif268, mainly in the ventral sub-region. Moreover, we also found that, within this brain area, chronic drug treatment was able to modulate glucocorticoid responsiveness at genomic level by enhancing the translocation of the glucocorticoid receptor (GR) in the nuclear compartment in response to the acute stress. Interestingly, this effect was mirrored by the up-regulation of different GR responsive-genes. Taken together, our data suggest that repeated exposure to vortioxetine specifically targets the ventral hippocampus by improving the ability to cope with stressful conditions. Moreover, its ability to facilitate HPA axis function might provide an indication to use this drug in patients characterized by glucocorticoid resistance.

Exposure to adverse events during gestation has detrimental effects on the maturation of specific brain networks, triggering changes in the expression of several stress-related mechanisms that may lead to long-lasting functional consequences, including cognitive deterioration. On these bases, the aim of the present study was to investigate the effects of early-life stress exposure on cognition and to explore potential molecular mechanisms contributing to the long-term functional impairment. We found that exposure to prenatal stress, a well-established animal model of early-life adversity, produces a significant disruption in the novel object recognition test both in male and female adult rats, although such impairment was more pronounced in females. Furthermore, the cognitive dysfunction observed during the behavioral test appears to be sustained by a disrupted activation of key networks of genes that may be required for proper cognitive performance. In particular, within the dorsal hippocampus, a brain region critical for cognition, the glucocorticoid, the inflammatory, and the protein kinase A signaling pathways are regulated by the novel object recognition test in an opposite manner in animals previously exposed to prenatal stress, when compared with control animals. These data further support the evidence that early-life stress exposure prompts cognitive impairment and suggest that this is the consequence of inability to activate the proper transcriptional machinery required for the cognitive performance.

Exposure to traumatic experience represents one of the key environmental factors influencing the risk for several psychiatric disorders, in particular when suffered during childhood, a critical period for brain development, characterized by a high level of neuroplasticity. Abnormalities affecting neurotrophic factors might play a fundamental role in the link between childhood trauma (CT) and early life stress (ELS) and psychiatric disorders.A systematic review was conducted, considering genetic, biochemical and expression studies along with cognitive and brain structure imaging investigations, based on PubMed and Web of Science databases (available up until November 2021), to identify potential neuroplasticity related biomarkers associated both with CT/ELS and psychiatric disorders. The search was followed by data abstraction and study quality assessment (Newcastle-Ottawa Scale).103 studies met our eligibility criteria. Among them, 65 were available for genetic, 30 for biochemical and 3 for mRNA data; 45 findings were linked to specific symptomatology/pathologies, 16 with various cognitive functions, 19 with different brain areas, 6 on methylation and 36 performed on control subjects for the Brain Derived Neurotrophic Factor (BDNF); whereas 4 expression/biochemical studies covered Neurotrophin 4 (NT-4), Vascular Endothelium Growth Factor (VEGF), Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), and Transforming Growth Factor β1 (TGF-β1).Heterogeneity of assessments (biological, psychological, of symptomatology, and CT/ELS), age range and ethnicity of samples for BDNF studies; limited studies for other neurotrophins.Results support the key role of BDNF (in form of Met allele) as biomarker, both at genetic and biochemical level, in mediating the effect of CT/ELS in psychiatric disorders, passing through specific cognitive functions and specific brain region architecture.

Epigenetics is one of the mechanisms by which environmental factors can alter brain function and may contribute to central nervous system disorders. Alterations of DNA methylation and miRNA expression can induce long-lasting changes in neurobiological processes. Hence, we investigated the effect of chronic stress, by employing the chronic mild stress (CMS) and the chronic restraint stress protocol, in adult male rats, on the glucocorticoid receptor (GR) function. We focused on DNA methylation specifically in the proximity of the glucocorticoid responsive element (GRE) of the GR responsive genes Gadd45β, Sgk1, and Gilz and on selected miRNA targeting these genes. Moreover, we assessed the role of the antipsychotic lurasidone in modulating these alterations. Chronic stress downregulated Gadd45β and Gilz gene expression and lurasidone normalized the Gadd45β modification. At the epigenetic level, CMS induced hypermethylation of the GRE of Gadd45β gene, an effect prevented by lurasidone treatment. These stress-induced alterations were still present even after a period of rest from stress, indicating the enduring nature of such changes. However, the contribution of miRNA to the alterations in gene expression was moderate in our experimental conditions. Our results demonstrated that chronic stress mainly affects Gadd45β expression and methylation, effects that are prolonged over time, suggesting that stress leads to changes in DNA methylation that last also after the cessation of stress procedure, and that lurasidone is a modifier of such mechanisms.

Epidemiological studies have shown that environmental insults and maternal stress during pregnancy increase the risk of several psychiatric disorders in the offspring. Converging lines of evidence from humans, as well as from rodent models, suggest that prenatal stress (PNS) interferes with fetal development, ultimately determining changes in brain maturation and function that may lead to the onset of neuropsychiatric disorders. From a molecular standpoint, transcriptional alterations are thought to play a major role in this context and may contribute to the behavioral phenotype by shifting the expression of genes related to excitatory and inhibitory (E/I) transmission balance. Nevertheless, the exact neurophysiological mechanisms underlying the enhanced vulnerability to psychopathology following PNS exposure are not well understood. In the present study, we used a model of maternal stress in rats to investigate the distal effects of PNS on the expression of genes related to glutamatergic and GABAergic neurotransmissions. We inspected two critical brain regions involved in emotion regulation, namely, the prefrontal cortex (PFC) and the amygdala (AMY), which we show to relate with the mild behavioral effects detected in adult rat offspring. We observed that PNS exposure promotes E/I imbalance in the PFC of adult males only, by dysregulating the expression of glutamatergic-related genes. Moreover, such an effect is accompanied by increased expression of the activity-dependent synaptic modulator gene Npas4 specifically in the PFC parvalbumin (PV)-positive interneurons, suggesting an altered regulation of synapse formation promoting higher PV-dependent inhibitory transmission and increased overall circuit inhibition in the PFC of males. In the AMY, PNS more evidently affects the transcription of GABAergic-related genes, shifting the balance toward inhibition. Collectively, our findings suggest that the E/I dysregulation of the PFC-to-AMY transmission may be a long-term signature of PNS and may contribute to increase the risk for mood disorder upon further stress.

Antipsychotic drugs represent a fundamental aid for the treatment of schizophrenia and other psychiatric disorders. However, the definition of antipsychotics includes molecules that are extremely heterogeneous when considering their mechanism of action and the clinical implications. While in the first part of this review the major critical issues in the treatment of schizophrenia will be highlighted, the attention will then focus on the major pharmacological 'innovation' in recent years, which is represented by the development of partial agonists for the D2 and D3 receptors, a strategy that may guarantee a 'stabilization' of impaired dopaminergic function in the schizophrenic patient. One such drug is cariprazine that differs from other molecules due to its greater affinity for the dopaminergic D3 receptor. Next, it will be described receptor and functional mechanisms that characterize the action of cariprazine, both with respect to other partial agonists as well as with respect to second-generation antipsychotics. More specifically, it will be highlighted the peculiarities of cariprazine and how these mechanisms could modify the functionality of specific brain circuits associated with major functional domains that are altered in schizophrenia. The activity of partial agonist at dopaminergic D3 receptors, which is dominant as compared to other receptor mechanisms, represents the mechanism that is most likely associated with the improvement of negative symptoms and of specific components such as motivational deficits. Furthermore, this mechanism together with the binding to other receptors is also compatible with a positive effect on cognitive deficits, often associated with reduced functionality of the prefrontal cortex, as well as in the substance abuse, a relevant problem of co-morbidity with schizophrenia.

The treatment of schizophrenia includes the control of symptoms, the prevention of relapses, and amelioration of adaptive skills for patient re-integration into society. Antipsychotic drugs are the agents of choice for the treatment of schizophrenia, as they reduce the positive symptoms of psychosis. Lurasidone is a second-generation antipsychotic drug representing a novel and useful clinical tool for the management of schizophrenia. A board consisting of a panel of Italian expert psychiatrists was organized with the following aims: (a) defining the current modalities of use of lurasidone, highlighted through 17 specific questions; (b) defining and agreeing the main features of the drug and the principal reasons to suggest its administration. We established that lurasidone is suggested at any age, with no gender difference, at all stages of the disease. The switch from previous treatments is done primarily because of lack of efficacy as well as poor adherence/tolerability. Lurasidone is among the best-tolerated antipsychotics, and its use is indicated in the presence of different comorbidities. A wide range of dosages is available, allowing safe titration in particular cases, with the highest dose (148 mg) generally used for the treatment of the acute phase. The discontinuation rate due to poor tolerability, low compliance, and interactions with other drugs is very low. Akathisia is the most reported adverse event, but it may be controlled by dose reduction. Lurasidone does not possess a marked sedative action but, in agitated patients, can be associated with sedative drugs, such as benzodiazepines. The most frequent reason for switching to other therapies is the need for long-acting formulations, as in patients at risk of very low adherence or suicide. Lurasidone does not strongly impact metabolism or the cardiovascular system (QT interval), and does not influence the metabolism of other drugs, showing good efficacy and tolerability.

Prenatal stress (PNS) affects foetal programming and, through an interaction with subsequent challenges, can increase vulnerability to mood and metabolic disorders. We have previously shown that, following PNS, adult male rats are characterized by increased vulnerability to a metabolic stressor experienced at adulthood (8-week-high-fat diet-HFD). In this study, we specifically assessed whether PNS might interact with an adult metabolic challenge to induce an inflammatory phenotype. Changes in the expression levels of inflammatory (Il-1β, Tnf-α, Il-6) and of stress response mediators (Nr3c1, Fkbp5) as well as of mood and metabolic regulators (Bdnf, Ghs-R) were investigated in the hippocampus, prefrontal cortex and hypothalamus, brain regions involved in the pathogenesis of depression and prone to inflammation in response to stress. Overall, PNS reduced the expression of Bdnf and Tnf-α, while HFD administered at adulthood counteracted this effect suggesting that PNS impinges upon the same pathways regulating responses to a metabolic challenge at adulthood. Furthermore, HFD and PNS affected the expression of both Nr3c1 and Fkbp5, two neuroendocrine mediators involved in the response to stress, metabolic challenges and in the modulation of the emotional profile (as shown by the correlation between Fkbp5 and the time spent in the open arms of the elevated plus-maze). Overall, these results indicate that the same metabolic and neuroendocrine effectors engaged by PNS are affected by metabolic challenges at adulthood, providing some mechanistic insight into the well-known comorbidity between mood and metabolic disorders.

BACKGROUND The brain of sheep has primarily been used in neuroscience as an animal model because of its similarity to the human brain, in particular if compared to other models such as the lissencephalic rodent brain. Their brain size also makes sheep an ideal model for the development of neurosurgical techniques using conventional clinical CT/MRI scanners and stereotactic systems for neurosurgery. METHODS In this study, we present the design and validation of a new CT/MRI compatible head frame for the ovine model and software, with its assessment under two real clinical scenarios. RESULTS Ex-vivo and in vivo trial results report an average linear displacement of the ovine head frame during conventional surgical procedures of 0.81 mm for ex-vivo trials and 0.68 mm for in vivo tests, respectively. CONCLUSIONS These trial results demonstrate the robustness of the head frame system and its suitability to be employed within a real clinical setting.