Chronic adolescent stress increases exploratory behavior but does not appear to change the acute stress response in adult male C57BL/6 mice

Chronic stress exposure in adolescence can lead to a lasting change in stress responsiveness later in life and is associated with increased mental health issues in adulthood. Here we investigate whether the Chronic Social Instability (CSI) paradigm influences the behavioral and molecular responses to novel acute stressors in mice, and whether it alters physiological responses influenced by the noradrenergic system. Using large cohorts of mice, we show that CSI mice display a persistent increase in exploratory behaviors in the open field test alongside small but widespread transcriptional changes in the ventral hippocampus. However, both the transcriptomic and behavioral responses to novel acute stressors are indistinguishable between groups. In addition, the pupillometric response to a tail shock, known to be mediated by the noradrenergic system, remains unaltered in CSI mice. Ultra-high performance liquid chromatography analysis of monoaminergic neurotransmitter levels in the ventral hippocampus also shows no differences between control or CSI mice at baseline or in response to acute stress. We conclude that CSI exposure during adolescence leads to persistent changes in exploratory behavior and gene expression in the hippocampus, but it does not alter the response to acute stress in adulthood and is unlikely to alter the function of the noradrenergic system

A complete pupillometry toolbox for real-time monitoring of locus coeruleus activity in rodents

The locus coeruleus (LC) is a region in the brainstem that produces noradrenaline and is involved in both normal and pathological brain function. Pupillometry, the measurement of pupil diameter, provides a powerful readout of LC activity in rodents, primates and humans. The protocol detailed here describes a miniaturized setup that can screen LC activity in rodents in real-time and can be established within 1–2 d. Using low-cost Raspberry Pi computers and cameras, the complete custom-built system costs only ~300 euros, is compatible with stereotaxic surgery frames and seamlessly integrates into complex experimental setups. Tools for pupil tracking and a user-friendly Pupillometry App allow quantification, analysis and visualization of pupil size. Pupillometry can discriminate between different, physiologically relevant firing patterns of the LC and can accurately report LC activation as measured by noradrenaline turnover. Pupillometry provides a rapid, non-invasive readout that can be used to verify accurate placement of electrodes/fibers in vivo, thus allowing decisions about the inclusion/exclusion of individual animals before experiments begin

Diagnosis, treatment and prevention of pediatric obesity: consensus position statement of the Italian Society for Pediatric Endocrinology and Diabetology and the Italian Society of Pediatrics

The Italian Consensus Position Statement on Diagnosis, Treatment and Prevention of Obesity in Children and Adolescents integrates and updates the previous guidelines to deliver an evidence based approach to the disease. The following areas were reviewed: (1) obesity definition and causes of secondary obesity; (2) physical and psychosocial comorbidities; (3) treatment and care settings; (4) prevention.The main novelties deriving from the Italian experience lie in the definition, screening of the cardiometabolic and hepatic risk factors and the endorsement of a staged approach to treatment. The evidence based efficacy of behavioral intervention versus pharmacological or surgical treatments is reported. Lastly, the prevention by promoting healthful diet, physical activity, sleep pattern, and environment is strongly recommended since the intrauterine phase

The locus coeruleus noradrenergic system in stress: Shaping the pupillary and transcriptomic stress response

In an ever-changing environment, we are constantly presented with new challenging and stressful situations. Within all organisms, specific molecular, physiological and behavioral adaptations have evolved to perceive, assess and execute appropriate stress responses. A rapid and adequate response not only increases the chance of immediate survival, but also promotes long-term adaptations to improve future outcomes. However, maladaptation to stress has also been associated with the development of various neurological disorders, such as depression, anxiety and post-traumatic stress disorder. A better understanding of the underlying mechanisms is therefore essential to fully grasp how stress responses lead to maladaptation. Various systems across peripheral and central organs have evolved to mediate responses to stress. The central nervous system mainly governs the perception, assessment and execution of stress responses. This includes the complementary actions of various brain areas and neurotransmitter systems; however, the locus coeruleus (LC) noradrenergic system has been proven to play a key role in facilitating responses to stress. Here, I present our research on the LC noradrenergic system and how it shapes pupillary and molecular responses in mice. First, we demonstrate how pupillometry, the measurement of pupil diameter, can be easily applied to rodents and how it can complement electric, chemogenetic and optogenetic manipulations of the locus coeruleus. Thus, pupillometry provides a rapid, non-invasive and translationally relevant tool to facilitate locus coeruleus research. Secondly, long-term adaptations to stress are based on molecular changes in the brain; however, the role of noradrenaline (NA) in this is still barely understood. To this end, we investigated and characterized how stress-dependent activation of the LC-NA system affects transcriptomic responses in the hippocampus, a stress-sensitive projection region of the LC. By combining RNA-sequencing with selective pharmacological, chemogenetic, and optogenetic manipulations of the LC-NA system, we show that NA-release during stress exposure reliably regulates a set of genes in the hippocampus via β-adrenergic receptors. The identity of the gene set suggests LC-mediated mobilization of astrocytic energy and thyroid hormone metabolism as essential mediators of LC function in the hippocampus. I further expand on current models of LC function and propose that these astrocytic pathways underlie LC-mediated facilitation of long-term adaptations to stress and thus offer prominent targets for further research investigating the role of the LC-NA system in health and disease

Spatial immunization to abate disease spreading in transportation hubs

Proximity social interactions are crucial for infectious diseases transmission. Crowded agglomerations pose serious risk of triggering superspreading events. Locations like transportation hubs (airports and stations) are designed to optimize logistic efficiency, not to reduce crowding, and are characterized by a constant in and out flow of people. Here, we analyze the paradigmatic example of London Heathrow, one of the busiest European airports. Thanks to a dataset of anonymized individuals' trajectories, we can model the spreading of different diseases to localize the contagion hotspots and to propose a spatial immunization policy targeting them to reduce disease spreading risk. We also detect the most vulnerable destinations to contagions produced at the airport and quantify the benefits of the spatial immunization technique to prevent regional and global disease diffusion. This method is immediately generalizable to train, metro and bus stations and to other facilities such as commercial or convention centers

Spatial immunization: a temporal network approach to counteract epidemic outbreaks in airports

Trabajo presentado en la NetSci Conference, celebrada online del 17 al 25 de septiembre de 2020

A complete pupillometry toolbox for real-time monitoring of locus coeruleus activity in rodents

The locus coeruleus (LC) is a region in the brainstem that produces noradrenaline and is involved in both normal and pathological brain function. Pupillometry, the measurement of pupil diameter, provides a powerful readout of LC activity in rodents, primates and humans. The protocol detailed here describes a miniaturized setup that can screen LC activity in rodents in real-time and can be established within 1–2 d. Using low-cost Raspberry Pi computers and cameras, the complete custom-built system costs only ~300 euros, is compatible with stereotaxic surgery frames and seamlessly integrates into complex experimental setups. Tools for pupil tracking and a user-friendly Pupillometry App allow quantification, analysis and visualization of pupil size. Pupillometry can discriminate between different, physiologically relevant firing patterns of the LC and can accurately report LC activation as measured by noradrenaline turnover. Pupillometry provides a rapid, non-invasive readout that can be used to verify accurate placement of electrodes/fibers in vivo, thus allowing decisions about the inclusion/exclusion of individual animals before experiments begin

Distinct Proteomic, Transcriptomic, and Epigenetic Stress Responses in Dorsal and Ventral Hippocampus

BACKGROUND Acutely stressful experiences can trigger neuropsychiatric disorders and impair cognitive processes by altering hippocampal function. Although the intrinsic organization of the hippocampus is highly conserved throughout its long dorsal-ventral axis, the dorsal (anterior) hippocampus mediates spatial navigation and memory formation, whereas the ventral (posterior) hippocampus is involved in emotion regulation. To understand the molecular consequences of stress, detailed genome-wide screens are necessary and need to distinguish between dorsal and ventral hippocampal regions. While transcriptomic screens have become a mainstay in basic and clinical research, proteomic methods are rapidly evolving and hold even greater promise to reveal biologically and clinically relevant biomarkers. METHODS Here, we provide the first combined transcriptomic (RNA sequencing) and proteomic (sequential window acquisition of all theoretical mass spectra [SWATH-MS]) profiling of dorsal and ventral hippocampus in mice. We used three different acute stressors (novelty, swim, and restraint) to assess the impact of stress on both regions. RESULTS We demonstrated that both hippocampal regions display radically distinct molecular responses and that the ventral hippocampus is particularly sensitive to the effects of stress. Separately analyzing these structures greatly increased the sensitivity to detect stress-induced changes. For example, protein interaction cluster analyses revealed a stress-responsive epigenetic network around histone demethylase Kdm6b restricted to the ventral hippocampus, and acute stress reduced methylation of its enzymatic target H3K27me3. Selective Kdm6b knockdown in the ventral hippocampus led to behavioral hyperactivity/hyperresponsiveness. CONCLUSIONS These findings underscore the importance of considering dorsal and ventral hippocampus separately when conducting high-throughput molecular analyses, which has important implications for fundamental research as well as clinical studies

Distinct Proteomic, Transcriptomic, and Epigenetic Stress Responses in Dorsal and Ventral Hippocampus

Background Acutely stressful experiences can trigger neuropsychiatric disorders and impair cognitive processes by altering hippocampal function. Although the intrinsic organization of the hippocampus is highly conserved throughout its long dorsal-ventral axis, the dorsal (anterior) hippocampus mediates spatial navigation and memory formation, whereas the ventral (posterior) hippocampus is involved in emotion regulation. To understand the molecular consequences of stress, detailed genome-wide screens are necessary and need to distinguish between dorsal and ventral hippocampal regions. While transcriptomic screens have become a mainstay in basic and clinical research, proteomic methods are rapidly evolving and hold even greater promise to reveal biologically and clinically relevant biomarkers. Methods Here, we provide the first combined transcriptomic (RNA sequencing) and proteomic (sequential window acquisition of all theoretical mass spectra [SWATH-MS]) profiling of dorsal and ventral hippocampus in mice. We used three different acute stressors (novelty, swim, and restraint) to assess the impact of stress on both regions. Results We demonstrated that both hippocampal regions display radically distinct molecular responses and that the ventral hippocampus is particularly sensitive to the effects of stress. Separately analyzing these structures greatly increased the sensitivity to detect stress-induced changes. For example, protein interaction cluster analyses revealed a stress-responsive epigenetic network around histone demethylase Kdm6b restricted to the ventral hippocampus, and acute stress reduced methylation of its enzymatic target H3K27me3. Selective Kdm6b knockdown in the ventral hippocampus led to behavioral hyperactivity/hyperresponsiveness. Conclusions These findings underscore the importance of considering dorsal and ventral hippocampus separately when conducting high-throughput molecular analyses, which has important implications for fundamental research as well as clinical studies.ISSN:0006-3223ISSN:1873-240

Chronic adolescent stress increases exploratory behavior but does not appear to change the acute stress response in adult male C57BL/6 mice

Chronic stress exposure in adolescence can lead to a lasting change in stress responsiveness later in life and is associated with increased mental health issues in adulthood. Here we investigate whether the Chronic Social Instability (CSI) paradigm influences the behavioral and molecular responses to novel acute stressors in mice, and whether it alters physiological responses influenced by the noradrenergic system. Using large cohorts of mice, we show that CSI mice display a persistent increase in exploratory behaviors in the open field test alongside small but widespread transcriptional changes in the ventral hippocampus. However, both the transcriptomic and behavioral responses to novel acute stressors are indistinguishable between groups. In addition, the pupillo-metric response to a tail shock, known to be mediated by the noradrenergic system, remains unaltered in CSI mice. Ultra-high performance liquid chromatography analysis of monoaminergic neurotransmitter levels in the ventral hippocampus also shows no differences between control or CSI mice at baseline or in response to acute stress. We conclude that CSI exposure during adolescence leads to persistent changes in exploratory behavior and gene expression in the hippocampus, but it does not alter the response to acute stress in adulthood and is unlikely to alter the function of the noradrenergic system.ISSN:2352-289