40 results on '"Richetto J"'
Search Results
2. Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency
- Author
-
Labouesse, M A, Lassalle, O, Richetto, J, Iafrati, J, Weber-Stadlbauer, U, Notter, T, Gschwind, T, Pujadas, L, Soriano, E, Reichelt, A C, Labouesse, C, Langhans, W, Chavis, P, and Meyer, U
- Published
- 2017
- Full Text
- View/download PDF
3. Transgenerational transmission and modification of pathological traits induced by prenatal immune activation
- Author
-
Weber-Stadlbauer, U, Richetto, J, Labouesse, M A, Bohacek, J, Mansuy, I M, and Meyer, U
- Published
- 2017
- Full Text
- View/download PDF
4. Abstract # 3223 Influence of poly(I:C) variability on thermoregulation, immune responses and pregnancy outcomes in mouse models of maternal immune activation
- Author
-
Mueller, F.S., primary, Richetto, J., additional, Hayes, L., additional, Zambon, A., additional, Pollak, D., additional, Sawa, A., additional, Meyer, U., additional, and Weber-Stadlbauer, U., additional
- Published
- 2019
- Full Text
- View/download PDF
5. Abstract # 3224 Role of microglia deficiency in brain maturation and behaviors relevant to neurodevelopmental disorders
- Author
-
Schalbetter, S.M., primary, Notter, T., additional, Müller, F., additional, Scarborough, J., additional, Mattei, D., additional, Weber, U., additional, Richetto, J., additional, and Meyer, U., additional
- Published
- 2019
- Full Text
- View/download PDF
6. Abstract #4387 Modeling prenatal depression in mice: Behavioral and molecular consequences and the impact of antidepressant treatment
- Author
-
Scarborough, J., primary, Müller, F.S., additional, Cattaneo, A., additional, Meyer, U., additional, and Richetto, J., additional
- Published
- 2019
- Full Text
- View/download PDF
7. Abstract # 3212 Maternal immune activation induces transgenerational effects on prefrontal cortex structure and function
- Author
-
Weber-Stadlbauer, U., primary, Notter, T., additional, Richetto, J., additional, and Meyer, U., additional
- Published
- 2019
- Full Text
- View/download PDF
8. S.26.01 Modeling prenatal depression in mice: Behavioural and molecular consequences and the impact of antidepressant treatment
- Author
-
Richetto, J., primary
- Published
- 2019
- Full Text
- View/download PDF
9. Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency
- Author
-
Labouesse, M A, primary, Lassalle, O, additional, Richetto, J, additional, Iafrati, J, additional, Weber-Stadlbauer, U, additional, Notter, T, additional, Gschwind, T, additional, Pujadas, L, additional, Soriano, E, additional, Reichelt, A C, additional, Labouesse, C, additional, Langhans, W, additional, Chavis, P, additional, and Meyer, U, additional
- Published
- 2016
- Full Text
- View/download PDF
10. Behavioral effects of the benzodiazepine-positive allosteric modulator SH-053-2'F-S-CH3 in an immune-mediated neurodevelopmental disruption model
- Author
-
Richetto, J, Labouesse, M A, Poe, M M, Cook, J M, Grace, A A, Riva, M A, Meyer, U, University of Zurich, and Meyer, U
- Subjects
2738 Psychiatry and Mental Health ,3004 Pharmacology ,570 Life sciences ,biology ,2736 Pharmacology (medical) ,10079 Institute of Veterinary Pharmacology and Toxicology - Published
- 2015
11. Preventive effects of minocycline in a neurodevelopmental two-hit model with relevance to schizophrenia
- Author
-
Giovanoli, S, Engler, H, Engler, A, Richetto, J, Feldon, J, Riva, M A, Schedlowski, M, Meyer, Urs, Giovanoli, S, Engler, H, Engler, A, Richetto, J, Feldon, J, Riva, M A, Schedlowski, M, and Meyer, Urs
- Abstract
Maternal immune activation can increase the vulnerability of the offspring to develop neuroimmune and behavioral abnormalities in response to stress in puberty. In offspring of immune-challenged mothers, stress-induced inflammatory processes precede the adult onset of multiple behavioral dysfunctions. Here, we explored whether an early anti-inflammatory intervention during peripubertal stress exposure might prevent the subsequent emergence of adult behavioral pathology. We used an environmental two-hit model in mice, in which prenatal maternal administration of the viral mimetic poly(I:C) served as the first hit, and exposure to sub-chronic unpredictable stress during peripubertal maturation as the second hit. Using this model, we examined the effectiveness of the tetracycline antibiotic minocycline (MINO) given during stress exposure to block stress-induced inflammatory responses and to prevent subsequent behavioral abnormalities. We found that combined exposure to prenatal immune activation and peripubertal stress caused significant deficits in prepulse inhibition and increased sensitivity to the psychotomimetic drugs amphetamine and dizocilpine in adulthood. MINO treatment during stress exposure prevented the emergence of these behavioral dysfunctions. In addition, the pharmacological intervention blocked hippocampal and prefrontal microglia activation and interleukin-1β expression in offspring exposed to prenatal infection and peripubertal stress. Together, these findings demonstrate that presymptomatic MINO treatment can prevent the subsequent emergence of multiple behavioral abnormalities relevant to human neuropsychiatric disorders with onset in early adulthood, including schizophrenia. Our epidemiologically informed two-hit model may thus encourage attempts to explore the use of anti-inflammatory agents in the early course of brain disorders that are characterized by signs of central nervous system inflammation during development.
- Published
- 2016
12. Preventive effects of minocycline in a neurodevelopmental two-hit model with relevance to schizophrenia
- Author
-
Giovanoli, S, primary, Engler, H, additional, Engler, A, additional, Richetto, J, additional, Feldon, J, additional, Riva, M A, additional, Schedlowski, M, additional, and Meyer, U, additional
- Published
- 2016
- Full Text
- View/download PDF
13. Transgenerational transmission and modification of pathological traits induced by prenatal immune activation
- Author
-
Weber-Stadlbauer, U, primary, Richetto, J, additional, Labouesse, M A, additional, Bohacek, J, additional, Mansuy, I M, additional, and Meyer, U, additional
- Published
- 2016
- Full Text
- View/download PDF
14. Microglia undergo molecular and functional adaptations to dark and light phases in male laboratory mice.
- Author
-
Mattei D, Ivanov A, Hammer J, Ugursu B, Schalbetter S, Richetto J, Weber-Stadlbauer U, Mueller F, Scarborough J, Wolf SA, Kettenmann H, Wollscheid B, Beule D, and Meyer U
- Subjects
- Animals, Male, Mice, Mice, Inbred C57BL, Photoperiod, Brain metabolism, Adaptation, Physiological physiology, Sleep physiology, Light, Microglia metabolism, Circadian Rhythm physiology
- Abstract
Microglia are increasingly recognized to contribute to brain health and disease. Preclinical studies using laboratory rodents are essential to advance our understanding of the physiological and pathophysiological roles of these cells in the central nervous system. Rodents are nocturnal animals, and they are mostly maintained in a defined light-dark cycle within animal facilities, with many laboratories investigating the molecular and functional profiles of microglia exclusively during the animals' light (sleep) phase. However, only a few studies have considered possible differences in microglial functions between the active and sleep phases. Based on initial evidence suggesting that microglial intrinsic clock genes can affect their phenotypes, we sought to investigate differences in transcriptional, proteotype and functional profiles of microglia between light (sleep) and dark (active) phases, and how these changes are affected in pathological models. We found marked transcriptional and proteotype differences between microglia harvested from male mice during the light or dark phase. Amongst others, these differences related to genes and proteins associated with immune responses, motility, and phagocytosis, which were reflected by functional alterations in microglial synaptic pruning and response to bacterial stimuli. Possibly accounting for such changes, we found RNA and protein regulation in SWI/SNF and NuRD chromatin remodeling complexes between light and dark phases. Importantly, we also show that the time of microglial sample collection influences the nature of microglial transcriptomic changes in a model of immune-mediated neurodevelopmental disorders. Our findings emphasize the importance of considering diurnal factors in studying microglial cells and indicate that implementing a circadian perspective is pivotal for advancing our understanding of their physiological and pathophysiological roles in brain health and disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
15. Prenatal and postnatal influences on behavioral development in a mouse model of preconceptional stress.
- Author
-
Scarborough J, Iachizzi M, Schalbetter SM, Müller FS, Weber-Stadlbauer U, and Richetto J
- Abstract
Depression during pregnancy is detrimental for the wellbeing of the expectant mother and can exert long-term consequences on the offspring's development and mental health. In this context, both the gestational environment and the postpartum milieu may be negatively affected by the depressive pathology. It is, however, challenging to assess whether the contributions of prenatal and postnatal depression exposure are distinct, interactive, or cumulative, as it is unclear whether antenatal effects are due to direct effects on fetal development or because antenatal symptoms continue postnatally. Preclinical models have sought to answer this question by implementing stressors that induce a depressive-like state in the dams during pregnancy and studying the effects on the offspring. The aim of our present study was to disentangle the contribution of direct stress in utero from possible changes in maternal behavior in a novel model of preconceptional stress based on social isolation rearing (SIR). Using a cross-fostering paradigm in this model, we show that while SIR leads to subtle changes in maternal behavior, the behavioral changes observed in the offspring are driven by a complex interaction between sex, and prenatal and postnatal maternal factors. Indeed, male offspring are more sensitive to the prenatal environment, as demonstrated by behavioral and transcriptional changes driven by their birth mother, while females are likely affected by more complex interactions between the pre and the postpartum milieu, as suggested by the important impact of their surrogate foster mother. Taken together, our findings suggest that male and female offspring have different time-windows and behavioral domains of susceptibility to maternal preconceptional stress, and thus underscore the importance of including both sexes when investigating the mechanisms that mediate the negative consequences of exposure to such stressor., Competing Interests: None, (© 2024 The Authors.)
- Published
- 2024
- Full Text
- View/download PDF
16. A novel murine model to study the impact of maternal depression and antidepressant treatment on biobehavioral functions in the offspring.
- Author
-
Scarborough J, Mueller FS, Weber-Stadlbauer U, Mattei D, Opitz L, Cattaneo A, and Richetto J
- Subjects
- Animals, Antidepressive Agents pharmacology, Antidepressive Agents therapeutic use, Disease Models, Animal, Female, Fluoxetine pharmacology, Fluoxetine therapeutic use, Mice, Pregnancy, Stress, Psychological drug therapy, Depression drug therapy, Prenatal Exposure Delayed Effects drug therapy
- Abstract
Antenatal psychopathology negatively affects obstetric outcomes and exerts long-term consequences on the offspring's wellbeing and mental health. However, the precise mechanisms underlying these associations remain largely unknown. Here, we present a novel model system in mice that allows for experimental investigations into the effects of antenatal depression-like psychopathology and for evaluating the influence of maternal pharmacological treatments on long-term outcomes in the offspring. This model system in based on rearing nulliparous female mice in social isolation prior to mating, leading to a depressive-like state that is initiated before and continued throughout pregnancy. Using this model, we show that the maternal depressive-like state induced by social isolation can be partially rescued by chronic treatment with the selective serotonin reuptake inhibitor, fluoxetine (FLX). Moreover, we identify numerous and partly sex-dependent behavioral and molecular abnormalities, including increased anxiety-like behavior, cognitive impairments and alterations of the amygdalar transcriptome, in offspring born to socially isolated mothers relative to offspring born to mothers that were maintained in social groups prior to conception. We also found that maternal FLX treatment was effective in preventing some of the behavioral and molecular abnormalities emerging in offspring born to socially isolated mothers. Taken together, our findings suggest that the presence of a depressive-like state during preconception and pregnancy has sex-dependent consequences on brain and behavioral functions in the offspring. At the same time, our study highlights that FLX treatment in dams with a depression-like state can prevent abnormal behavioral development in the offspring., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
17. Symptomatic and preventive effects of the novel phosphodiesterase-9 inhibitor BI 409306 in an immune-mediated model of neurodevelopmental disorders.
- Author
-
Scarborough J, Mattei D, Dorner-Ciossek C, Sand M, Arban R, Rosenbrock H, Richetto J, and Meyer U
- Subjects
- Adult, Animals, Behavior, Animal, Disease Models, Animal, Female, Humans, Phosphodiesterase Inhibitors, Phosphoric Diester Hydrolases, Pregnancy, Pyrazoles, Pyrimidines, Neurodevelopmental Disorders, Prenatal Exposure Delayed Effects
- Abstract
BI 409306, a phosphodiesterase-9 inhibitor under development for treatment of schizophrenia and attenuated psychosis syndrome (APS), promotes synaptic plasticity and cognition. Here, we explored the effects of BI 409306 treatment in the polyriboinosinic-polyribocytidilic acid (poly[I:C])-based mouse model of maternal immune activation (MIA), which is relevant to schizophrenia and APS. In Study 1, adult offspring received BI 409306 0.2, 0.5, or 1 mg/kg or vehicle to establish an active dose. In Study 2, adult offspring received BI 409306 1 mg/kg and/or risperidone 0.025 mg/kg, risperidone 0.05 mg/kg, or vehicle, to evaluate BI 409306 as add-on to standard therapy for schizophrenia. In Study 3, offspring received BI 409306 1 mg/kg during adolescence only, or continually into adulthood to evaluate preventive effects of BI 409306. We found that BI 409306 significantly mitigated MIA-induced social interaction deficits and amphetamine-induced hyperlocomotion, but not prepulse inhibition impairments, in a dose-dependent manner (Study 1). Furthermore, BI 409306 1 mg/kg alone or in combination with risperidone 0.025 mg/kg significantly reversed social interaction deficits and attenuated amphetamine-induced hyperlocomotion in MIA offspring (Study 2). Finally, we revealed that BI 409306 1 mg/kg treatment restricted to adolescence prevented adult deficits in social interaction, whereas continued treatment into adulthood also significantly reduced amphetamine-induced hyperlocomotion (Study 3). Taken together, our findings suggest that symptomatic treatment with BI 409306 can restore social interaction deficits and dopaminergic dysfunctions in a MIA model of neurodevelopmental disruption, lending preclinical support to current clinical trials of BI 409306 in patients with schizophrenia. Moreover, BI 409306 given during adolescence has preventive effects on adult social interaction deficits in this model, supporting its use in people with APS.
- Published
- 2021
- Full Text
- View/download PDF
18. Neuronal activity increases translocator protein (TSPO) levels.
- Author
-
Notter T, Schalbetter SM, Clifton NE, Mattei D, Richetto J, Thomas K, Meyer U, and Hall J
- Subjects
- Animals, Mice, Microglia, Neurons, Positron-Emission Tomography, Endothelial Cells, Receptors, GABA genetics
- Abstract
The mitochondrial protein, translocator protein (TSPO), is a widely used biomarker of neuroinflammation, but its non-selective cellular expression pattern implies roles beyond inflammatory processes. In the present study, we investigated whether neuronal activity modifies TSPO levels in the adult central nervous system. First, we used single-cell RNA sequencing to generate a cellular landscape of basal TSPO gene expression in the hippocampus of adult (12 weeks old) C57BL6/N mice, followed by confocal laser scanning microscopy to verify TSPO protein in neuronal and non-neuronal cell populations. We then quantified TSPO mRNA and protein levels after stimulating neuronal activity with distinct stimuli, including designer receptors exclusively activated by designer drugs (DREADDs), exposure to a novel environment and acute treatment with the psychostimulant drug, amphetamine. Single-cell RNA sequencing demonstrated a non-selective and multi-cellular gene expression pattern of TSPO at basal conditions in the adult mouse hippocampus. Confocal laser scanning microscopy confirmed that TSPO protein is present in neuronal and non-neuronal (astrocytes, microglia, vascular endothelial cells) cells of cortical (medial prefrontal cortex) and subcortical (hippocampus) brain regions. Stimulating neuronal activity through chemogenetic (DREADDs), physiological (novel environment exposure) or psychopharmacological (amphetamine treatment) approaches led to consistent increases in TSPO gene and protein levels in neurons, but not in microglia or astrocytes. Taken together, our findings show that neuronal activity has the potential to modify TSPO levels in the adult central nervous system. These findings challenge the general assumption that altered TSPO expression or binding unequivocally mirrors ongoing neuroinflammation and emphasize the need to consider non-inflammatory interpretations in some physiological or pathological contexts., (© 2020. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
19. Oral application of clozapine-N-oxide using the micropipette-guided drug administration (MDA) method in mouse DREADD systems.
- Author
-
Schalbetter SM, Mueller FS, Scarborough J, Richetto J, Weber-Stadlbauer U, Meyer U, and Notter T
- Subjects
- Animals, Brain, Mice, Neurons, Oxides, Clozapine, Designer Drugs
- Abstract
The designer receptor exclusively activated by designer drugs (DREADD) system is one of the most widely used chemogenetic techniques to modulate the activity of cell populations in the brains of behaving animals. DREADDs are activated by acute or chronic administration of their ligand, clozapine-N-oxide (CNO). There is, however, a current lack of a non-invasive CNO administration technique that can control for drug timing and dosing without inducing substantial distress for the animals. Here, we evaluated whether the recently developed micropipette-guided drug administration (MDA) method, which has been used as a non-invasive and minimally stressful alternative to oral gavages, may be applied to administer CNO orally to activate DREADDs in a dosing- and timing-controlled manner. Unlike standard intraperitoneal injections, administration of vehicle substances via MDA did not elevate plasma levels of the major stress hormone, corticosterone, and did not attenuate exploratory activity in the open field test. At the same time, however, administration of CNO via MDA or intraperitoneally was equally efficient in activating hM3D
Gq -expressing neurons in the medial prefrontal cortex, as evident by time-dependent increases in mRNA levels of neuronal immediate early genes (cFos, Arc and Zif268) and cFos-immunoreactive neurons. Compared to vehicle given via MDA, oral administration of CNO via MDA was also found to potently increase locomotor activity in mice that express hM3DGq in prefrontal neurons. Taken together, our study confirms the effectiveness of CNO given orally via MDA and provides a novel method for non-stressful, yet well controllable CNO treatments in mouse DREADD systems.- Published
- 2021
- Full Text
- View/download PDF
20. Increased levels of midbrain immune-related transcripts in schizophrenia and in murine offspring after maternal immune activation.
- Author
-
Purves-Tyson TD, Weber-Stadlbauer U, Richetto J, Rothmond DA, Labouesse MA, Polesel M, Robinson K, Shannon Weickert C, and Meyer U
- Subjects
- Animals, Behavior, Animal, Disease Models, Animal, Female, Mesencephalon, Mice, Microglia, Pregnancy, Prenatal Exposure Delayed Effects, Schizophrenia genetics
- Abstract
The pathophysiology of dopamine dysregulation in schizophrenia involves alterations at the ventral midbrain level. Given that inflammatory mediators such as cytokines influence the functional properties of midbrain dopamine neurons, midbrain inflammation may play a role in schizophrenia by contributing to presynaptic dopamine abnormalities. Thus, we quantified inflammatory markers in dopaminergic areas of the midbrain of people with schizophrenia and matched controls. We also measured these markers in midbrain of mice exposed to maternal immune activation (MIA) during pregnancy, an established risk factor for schizophrenia and other psychiatric disorders. We found diagnostic increases in SERPINA3, TNFα, IL1β, IL6, and IL6ST transcripts in schizophrenia compared with controls (p < 0.02-0.001). The diagnostic differences in these immune markers were accounted for by a subgroup of schizophrenia cases (~ 45%, 13/28) showing high immune status. Consistent with the human cohort, we identified increased expression of immune markers in the midbrain of adult MIA offspring (SERPINA3, TNFα, and IL1β mRNAs, all p ≤ 0.01), which was driven by a subset of MIA offspring (~ 40%, 13/32) with high immune status. There were no diagnostic (human cohort) or group-wise (mouse cohort) differences in cellular markers indexing the density and/or morphology of microglia or astrocytes, but an increase in the transcription of microglial and astrocytic markers in schizophrenia cases and MIA offspring with high inflammation. These data demonstrate that immune-related changes in schizophrenia extend to dopaminergic areas of the midbrain and exist in the absence of changes in microglial cell number, but with putative evidence of microglial and astrocytic activation in the high immune subgroup. MIA may be one of the contributing factors underlying persistent neuroimmune changes in the midbrain of people with schizophrenia.
- Published
- 2021
- Full Text
- View/download PDF
21. Epigenetic Modifications in Schizophrenia and Related Disorders: Molecular Scars of Environmental Exposures and Source of Phenotypic Variability.
- Author
-
Richetto J and Meyer U
- Subjects
- Biological Variation, Population, Cicatrix, DNA Methylation, Environmental Exposure, Epigenesis, Genetic, Humans, Schizophrenia genetics
- Abstract
Epigenetic modifications are increasingly recognized to play a role in the etiology and pathophysiology of schizophrenia and other psychiatric disorders with developmental origins. Here, we summarize clinical and preclinical findings of epigenetic alterations in schizophrenia and relevant disease models and discuss their putative origin. Recent findings suggest that certain schizophrenia risk loci can influence stochastic variation in gene expression through epigenetic processes, highlighting the intricate interaction between genetic and epigenetic control of neurodevelopmental trajectories. In addition, a substantial portion of epigenetic alterations in schizophrenia and related disorders may be acquired through environmental factors and may be manifested as molecular "scars." Some of these scars can influence brain functions throughout the entire lifespan and may even be transmitted across generations via epigenetic germline inheritance. Epigenetic modifications, whether caused by genetic or environmental factors, are plausible molecular sources of phenotypic heterogeneity and offer a target for therapeutic interventions. The further elucidation of epigenetic modifications thus may increase our knowledge regarding schizophrenia's heterogeneous etiology and pathophysiology and, in the long term, may advance personalized treatments through the use of biomarker-guided epigenetic interventions., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
22. Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation.
- Author
-
Mueller FS, Scarborough J, Schalbetter SM, Richetto J, Kim E, Couch A, Yee Y, Lerch JP, Vernon AC, Weber-Stadlbauer U, and Meyer U
- Subjects
- Animals, Disease Models, Animal, Female, Mice, Mice, Inbred C57BL, Pregnancy, Social Behavior, Behavior, Animal, Prenatal Exposure Delayed Effects
- Abstract
Infectious or noninfectious maternal immune activation (MIA) is an environmental risk factor for psychiatric and neurological disorders with neurodevelopmental etiologies. Whilst there is increasing evidence for significant health consequences, the effects of MIA on the offspring appear to be variable. Here, we aimed to identify and characterize subgroups of isogenic mouse offspring exposed to identical MIA, which was induced in C57BL6/N mice by administration of the viral mimetic, poly(I:C), on gestation day 12. Cluster analysis of behavioral data obtained from a first cohort containing >150 MIA and control offspring revealed that MIA offspring could be stratified into distinct subgroups that were characterized by the presence or absence of multiple behavioral dysfunctions. The two subgroups also differed in terms of their transcriptional profiles in cortical and subcortical brain regions and brain networks of structural covariance, as measured by ex vivo structural magnetic resonance imaging (MRI). In a second, independent cohort containing 50 MIA and control offspring, we identified a subgroup of MIA offspring that displayed elevated peripheral production of innate inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in adulthood. This subgroup also showed significant impairments in social approach behavior and sensorimotor gating, whereas MIA offspring with a low inflammatory cytokine status did not. Taken together, our results highlight the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network, and immunological profiles even under conditions of genetic homogeneity. These data have relevance for advancing our understanding of the variable neurodevelopmental effects induced by MIA and for biomarker-guided approaches in preclinical psychiatric research.
- Published
- 2021
- Full Text
- View/download PDF
23. Transgenerational modification of dopaminergic dysfunctions induced by maternal immune activation.
- Author
-
Weber-Stadlbauer U, Richetto J, Zwamborn RAJ, Slieker RC, and Meyer U
- Subjects
- Animals, Disease Models, Animal, Dopamine, Female, Poly I-C, Pregnancy, Behavior, Animal, Prenatal Exposure Delayed Effects chemically induced
- Abstract
Prenatal exposure to infectious and/or inflammatory insults is increasingly recognized to contribute to the etiology of psychiatric disorders with neurodevelopmental components. Recent research using animal models suggests that maternal immune activation (MIA) can induce transgenerational effects on brain and behavior, possibly through epigenetic mechanisms. Using a mouse model of MIA that is based on gestational treatment with the viral mimeticpoly(I:C) (= polyriboinosinic-polyribocytidilic acid), the present study explored whether the transgenerational effects of MIA are extendable to dopaminergic dysfunctions. We show that the direct descendants born to poly(I:C)-treated mothers display signs of hyperdopaminergia, as manifested by a potentiated sensitivity to the locomotor-stimulating effects of amphetamine (Amph) and increased expression of tyrosine hydroxylase (Th) in the adult ventral midbrain. In stark contrast, second- and third-generation offspring of MIA-exposed ancestors displayed blunted locomotor responses to Amph and reduced expression of Th. Furthermore, we found increased DNA methylation at the promoter region of the dopamine-specifying factor, nuclear receptor-related 1 protein (Nurr1), in the sperm of first-generation MIA offspring and in the ventral midbrain of second-generation offspring of MIA-exposed ancestors. The latter effect was further accompanied by reduced mRNA levels of Nurr1 in this brain region. Together, our results suggest that MIA has the potential to modify dopaminergic functions across multiple generations with opposite effects in the direct descendants and their progeny. The presence of altered DNA methylation in the sperm of MIA-exposed offspring highlights the possibility that epigenetic processes in the male germline play a role in the transgenerational effects of MIA.
- Published
- 2021
- Full Text
- View/download PDF
24. Enzymatic Dissociation Induces Transcriptional and Proteotype Bias in Brain Cell Populations.
- Author
-
Mattei D, Ivanov A, van Oostrum M, Pantelyushin S, Richetto J, Mueller F, Beffinger M, Schellhammer L, Vom Berg J, Wollscheid B, Beule D, Paolicelli RC, and Meyer U
- Subjects
- Animals, Brain Neoplasms genetics, Cell Line, Tumor, Cell Separation methods, Chromatography, Liquid, Glioma genetics, Humans, Male, Mice, Neoplasm Transplantation, Proteomics methods, Sequence Analysis, RNA, Single-Cell Analysis, Tandem Mass Spectrometry, Astrocytes chemistry, Brain Neoplasms metabolism, Enzymes metabolism, Flow Cytometry methods, Gene Expression Profiling methods, Glioma metabolism, Microglia chemistry
- Abstract
Different cell isolation techniques exist for transcriptomic and proteotype profiling of brain cells. Here, we provide a systematic investigation of the influence of different cell isolation protocols on transcriptional and proteotype profiles in mouse brain tissue by taking into account single-cell transcriptomics of brain cells, proteotypes of microglia and astrocytes, and flow cytometric analysis of microglia. We show that standard enzymatic digestion of brain tissue at 37 °C induces profound and consistent alterations in the transcriptome and proteotype of neuronal and glial cells, as compared to an optimized mechanical dissociation protocol at 4 °C. These findings emphasize the risk of introducing technical biases and biological artifacts when implementing enzymatic digestion-based isolation methods for brain cell analyses.
- Published
- 2020
- Full Text
- View/download PDF
25. Prenatal exposure to environmental insults and enhanced risk of developing Schizophrenia and Autism Spectrum Disorder: focus on biological pathways and epigenetic mechanisms.
- Author
-
Cattane N, Richetto J, and Cattaneo A
- Subjects
- Epigenesis, Genetic, Female, Genome-Wide Association Study, Humans, Pregnancy, Autism Spectrum Disorder genetics, Prenatal Exposure Delayed Effects genetics, Schizophrenia genetics
- Abstract
When considering neurodevelopmental disorders (NDDs), Schizophrenia (SZ) and Autism Spectrum Disorder (ASD) are considered to be among the most severe in term of prevalence, morbidity and impact on the society. Similar features and overlapping symptoms have been observed at multiple levels, suggesting common pathophysiological bases. Indeed, recent genome-wide association studies (GWAS) and epidemiological data report shared vulnerability genes and environmental triggers across the two disorders. In this review, we will discuss the possible biological mechanisms, including glutamatergic and GABAergic neurotransmissions, inflammatory signals and oxidative stress related systems, which are targeted by adverse environmental exposures and that have been associated with the development of SZ and ASD. We will also discuss the emerging role of the gut microbiome as possible interplay between environment, immune system and brain development. Finally, we will describe the involvement of epigenetic mechanisms in the maintenance of long-lasting effects of adverse environments early in life. This will allow us to better understand the pathophysiology of these NDDs, and also to identify novel targets for future treatment strategies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
26. Preclinical validation of the micropipette-guided drug administration (MDA) method in the maternal immune activation model of neurodevelopmental disorders.
- Author
-
Scarborough J, Mueller F, Arban R, Dorner-Ciossek C, Weber-Stadlbauer U, Rosenbrock H, Meyer U, and Richetto J
- Subjects
- Administration, Oral, Animals, Mice, Risperidone, Antipsychotic Agents, Neurodevelopmental Disorders, Pharmaceutical Preparations
- Abstract
Pharmacological treatments in laboratory rodents remain a cornerstone of preclinical psychopharmacological research and drug development. There are numerous ways in which acute or chronic pharmacological treatments can be implemented, with each method having certain advantages and drawbacks. Here, we describe and validate a novel treatment method in mice, which we refer to as the micropipette-guided drug administration (MDA) procedure. This administration method is based on a sweetened condensed milk solution as a vehicle for pharmacological substances, which motivates the animals to consume vehicle and/or drug solutions voluntarily in the presence of the experimenter. In a proof-of-concept study, we show that the pharmacokinetic profiles of the atypical antipsychotic drug, risperidone, were similar whether administered via the MDA procedure or via the conventional oral gavage method. Unlike the latter, however, MDA did not induce the stress hormone, corticosterone. Furthermore, we assessed the suitability and validity of the MDA method in a mouse model of maternal immune activation, which is frequently used as a model of immune-mediated neurodevelopmental disorders. Using this model, we found that chronic treatment (>4 weeks, once per day) with risperidone via MDA led to a dose-dependent mitigation of MIA-induced social interaction deficits and amphetamine hypersensitivity. Taken together, the MDA procedure described herein represents a novel pharmacological administration method for per os treatments in mice that is easy to implement, cost effective, non-invasive, and less stressful for the animals than conventional oral gavage methods., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
27. Influence of poly(I:C) variability on thermoregulation, immune responses and pregnancy outcomes in mouse models of maternal immune activation.
- Author
-
Mueller FS, Richetto J, Hayes LN, Zambon A, Pollak DD, Sawa A, Meyer U, and Weber-Stadlbauer U
- Subjects
- Animals, Cytokines immunology, Disease Models, Animal, Female, Fetus immunology, Lipopolysaccharides analysis, Lipopolysaccharides pharmacology, Mice, Inbred C57BL, Placenta immunology, Poly I-C analysis, Pregnancy, Pregnancy Complications, Infectious etiology, RNA analysis, Body Temperature Regulation drug effects, Poly I-C pharmacology, Pregnancy Complications, Infectious immunology, Pregnancy Outcome
- Abstract
Maternal immune activation (MIA) models that are based on administration of the viral mimetic, poly(I:C), are widely used as experimental tools to study neuronal and behavioral dysfunctions in relation to immune-mediated neurodevelopmental disorders and mental illnesses. Evidence from investigations in non-pregnant rodents suggests that different poly(I:C) products can vary in terms of their immunogenicity, even if they are obtained from the same vendor. The present study aimed at extending these findings to pregnant mice, while also controlling various poly(I:C) products for potential contamination with lipopolysaccharide (LPS). We found significant variability between different batches of poly(I:C) potassium salt obtained from the same vendor (Sigma-Aldrich) in terms of the relative amount of dsRNA fragments in the high molecular weight range (1000-6000 nucleotides long) and with regards to their effects on maternal thermoregulation and immune responses in maternal plasma, placenta and fetal brain. Batches of poly(I:C) potassium salt containing larger amounts of high molecular weight fragments induced more extensive effects on thermoregulation and immune responses compared to batches with minimal amounts of high molecular weight fragments. Consistent with these findings, poly(I:C) enriched for high molecular weight dsRNA (HMW) caused larger maternal and placental immune responses compared to low molecular weight (LMW) poly(I:C). These variable effects were unrelated to possible LPS contamination. Finally, we found marked variability between different batches of the poly(I:C) potassium salt in terms of their effects on spontaneous abortion rates. This batch-to-batch variability was confirmed by three independent research groups using distinct poly(I:C) administration protocols in mice. Taken together, the present data confirm that different poly(I:C) products can induce varying immune responses and can differentially affect maternal physiology and pregnancy outcomes. It is therefore pivotal that researchers working with poly(I:C)-based MIA models ascertain and consider the precise molecular composition and immunogenicity of the product in use. We recommend the establishment of reference databases that combine phenotype data with empirically acquired quality information, which can aid the design, implementation and interpretation of poly(I:C)-based MIA models., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
28. Ossified blood vessels in primary familial brain calcification elicit a neurotoxic astrocyte response.
- Author
-
Zarb Y, Weber-Stadlbauer U, Kirschenbaum D, Kindler DR, Richetto J, Keller D, Rademakers R, Dickson DW, Pasch A, Byzova T, Nahar K, Voigt FF, Helmchen F, Boss A, Aguzzi A, Klohs J, and Keller A
- Subjects
- Aged, Animals, Brain pathology, Brain Diseases genetics, Calcinosis pathology, Female, Humans, Male, Mice, Mutation, Osteogenesis physiology, Oxidative Stress, Pedigree, Proto-Oncogene Proteins c-sis genetics, Proto-Oncogene Proteins c-sis physiology, Receptor, Platelet-Derived Growth Factor beta genetics, Sodium-Phosphate Cotransporter Proteins, Type III genetics, Xenotropic and Polytropic Retrovirus Receptor, Astrocytes metabolism, Ossification, Heterotopic pathology, Proto-Oncogene Proteins c-sis metabolism
- Abstract
Brain calcifications are commonly detected in aged individuals and accompany numerous brain diseases, but their functional importance is not understood. In cases of primary familial brain calcification, an autosomally inherited neuropsychiatric disorder, the presence of bilateral brain calcifications in the absence of secondary causes of brain calcification is a diagnostic criterion. To date, mutations in five genes including solute carrier 20 member 2 (SLC20A2), xenotropic and polytropic retrovirus receptor 1 (XPR1), myogenesis regulating glycosidase (MYORG), platelet-derived growth factor B (PDGFB) and platelet-derived growth factor receptor β (PDGFRB), are considered causal. Previously, we have reported that mutations in PDGFB in humans are associated with primary familial brain calcification, and mice hypomorphic for PDGFB (Pdgfbret/ret) present with brain vessel calcifications in the deep regions of the brain that increase with age, mimicking the pathology observed in human mutation carriers. In this study, we characterize the cellular environment surrounding calcifications in Pdgfbret/ret animals and show that cells around vessel-associated calcifications express markers for osteoblasts, osteoclasts and osteocytes, and that bone matrix proteins are present in vessel-associated calcifications. Additionally, we also demonstrate the osteogenic environment around brain calcifications in genetically confirmed primary familial brain calcification cases. We show that calcifications cause oxidative stress in astrocytes and evoke expression of neurotoxic astrocyte markers. Similar to previously reported human primary familial brain calcification cases, we describe high interindividual variation in calcification load in Pdgfbret/ret animals, as assessed by ex vivo and in vivo quantification of calcifications. We also report that serum of Pdgfbret/ret animals does not differ in calcification propensity from control animals and that vessel calcification occurs only in the brains of Pdgfbret/ret animals. Notably, ossification of vessels and astrocytic neurotoxic response is associated with specific behavioural and cognitive alterations, some of which are associated with primary familial brain calcification in a subset of patients., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2019
- Full Text
- View/download PDF
29. Dependency of prepulse inhibition deficits on baseline startle reactivity in a mouse model of the human 22q11.2 microdeletion syndrome.
- Author
-
Scarborough J, Mueller F, Weber-Stadlbauer U, Richetto J, and Meyer U
- Subjects
- Animals, Chromosome Duplication, Chromosomes, Human, Pair 22, Male, Mice, Mice, Inbred C57BL, Reaction Time, Abnormalities, Multiple physiopathology, DiGeorge Syndrome physiopathology, Neural Inhibition, Reflex, Startle
- Abstract
Hemizygous microdeletion at the chromosomal locus 22q11.2 is a copy number variation with strong genetic linkage to schizophrenia and related disorders. This association, along with its phenotypic overlap with the 22q11.2 microdeletion syndrome, has motivated the establishment of Df[h22q11]/+ mice, in which the human 22q11.2 orthologous region is deleted. Previous investigations using this model showed the presence of reduced prepulse inhibition (PPI) of the acoustic startle reflex, a form of sensorimotor gating known to be impaired in a number of psychiatric disorders. Concomitantly to reduced PPI, however, Df[h22q11]/+ mice are also characterized by a robust increase in baseline startle reactivity, which may complicate or confound the interpretation of PPI. Therefore, the present study re-examined the relationship between acoustic startle reactivity and PPI in this mouse model. We found that while PPI is reduced in Df[h22q11]/+ mice when using its relative indexation (ie, % PPI), this deficit is no longer apparent when using the absolute quantification, that is, the direct comparison between pulse-alone and prepulse-plus-pulse conditions with successively increasing prepulse intensities. We further identified marked negative correlations between % PPI and startle reactivity in Df[h22q11]/+ mice. Moreover, when stratifying Df[h22q11]/+ mice into subgroups displaying low- and high-startle reactivity, only the latter subgroup displayed a significant reduction in % PPI. Collectively, our data suggest that alterations in baseline startle reactivity can confound the outcomes and interpretation of PPI in this mouse model of the human 22q11.2 microdeletion syndrome., (© 2018 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)
- Published
- 2019
- Full Text
- View/download PDF
30. Effects of light and dark phase testing on the investigation of behavioural paradigms in mice: Relevance for behavioural neuroscience.
- Author
-
Richetto J, Polesel M, and Weber-Stadlbauer U
- Subjects
- Amphetamine administration & dosage, Amphetamine pharmacology, Animals, Anxiety psychology, Cohort Studies, Dopamine Plasma Membrane Transport Proteins genetics, Female, Gene Expression drug effects, Locomotion drug effects, Male, Memory, Short-Term, Mesencephalon drug effects, Mesencephalon metabolism, Mice, Mice, Inbred C57BL, Nucleus Accumbens drug effects, Nucleus Accumbens metabolism, Proto-Oncogene Proteins c-fos genetics, Reflex, Startle, Social Behavior, Tyrosine 3-Monooxygenase genetics, Behavior, Animal physiology, Circadian Rhythm physiology, Photoperiod
- Abstract
Different timing and light phases are critical factors in behavioural neuroscience, which can greatly affect the experimental outcomes of the performed tests. Despite the fact that time of testing is one of the most common factors that varies across behavioural laboratories, knowledge about the consequences of testing time on behavioural readouts is limited. Thus, in this study we systematically assessed the effect of this factor on the readout of a variety of elementary and recurrent behavioural paradigms in C57Bl/6 mice. Furthermore, we investigated potential neuronal correlates of this phenomenon by analysing how testing time influences the expression pattern of genes relevant for neuronal activation functions and the control of brain circadian rhythms. We show that animals tested in the light phase display reduced social approach behaviour and sensorimotor gating and increased locomotor activity, whereas anxiety-related behaviour and working memory are not affected. In addition, animals tested in the light phase also exhibit increased locomotor response to systemic amphetamine treatment, which is paralleled by alterations in the expression patterns of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the Nucleus Accumbens (NAc) and/or Midbrain (Mid). Lastly, we observed that neuronal activation, indexed by the gene expression levels of cFos, was increased in the NAc and Mid of animals tested during the light phase. Our data thus suggest that daily alterations in gene expression in mesolimbic brain structures might be involved in the different behavioural responses of mice tested in the light- versus the dark-phase. At the same time, our study adds further weight to the notion that the specific timing of testing can indeed strongly affect the readout of a given test. As comparison and reproducibility of findings is pivotal in science, experimental protocols should be clarified in detail to allow appropriate data comparison across different laboratories., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
31. Mouse models of maternal immune activation: Mind your caging system!
- Author
-
Mueller FS, Polesel M, Richetto J, Meyer U, and Weber-Stadlbauer U
- Subjects
- Animals, Behavior, Animal physiology, Chemokines analysis, Cytokines analysis, Disease Models, Animal, Female, Mice, Mice, Inbred C57BL, Mothers, Poly I-C pharmacology, Pregnancy, Housing, Animal standards, Immune System Phenomena physiology, Prenatal Exposure Delayed Effects immunology
- Abstract
Rodent models of maternal immune activation (MIA) are increasingly used as experimental tools to study neuronal and behavioral dysfunctions in relation to infection-mediated neurodevelopmental disorders. One of the most widely used MIA models is based on gestational administration of poly(I:C) (= polyriboinosinic-polyribocytdilic acid), a synthetic analog of double-stranded RNA that induces a cytokine-associated viral-like acute phase response. The effects of poly(I:C)-induced MIA on phenotypic changes in the offspring are known to be influenced by various factors, including the precise prenatal timing, genetic background, and immune stimulus intensity. Thus far, however, it has been largely ignored whether differences in the basic type of laboratory housing can similarly affect the outcomes of MIA models. Here, we examined this possibility by comparing the poly(I:C)-based MIA model in two housing systems that are commonly used in preclinical mouse research, namely the open cage (OC) and individually ventilated cage (IVC) systems. Pregnant C57BL6/N mice were kept in OCs or IVCs and treated with a low (1 mg/kg, i.v.) or high (5 mg/kg, i.v.) dose of poly(I:C), or with control vehicle solution. MIA or control treatment was induced on gestation day (GD) 9 or 12, and the resulting offspring were raised and maintained in OCs or IVCs until adulthood for behavioral testing. An additional cohort of dams was used to assess the influence of the different caging systems on poly(I:C)-induced cytokine and stress responses in the maternal plasma. Maternal poly(I:C) administration on GD9 caused a dose-dependent increase in spontaneous abortion in IVCs but not in OCs, whereas MIA in IVC systems during a later gestational time-point (GD12) did not affect pregnancy outcomes. Moreover, the precise type of caging system markedly affected maternal cytokines and chemokines at basal states and in response to poly(I:C) and further influenced the maternal levels of the stress hormone, corticosterone. The efficacy of MIA to induce deficits in working memory, social interaction, and sensorimotor gating in the adult offspring was influenced by the different housing conditions, the dosing of poly(I:C), and the precise prenatal timing. Taken together, the present study identifies the basic type of caging system as a novel factor that can confound the outcomes of MIA in mice. Our findings thus urge the need to consider and report the kind of laboratory housing systems used to implement MIA models. Providing this information seems pivotal to yield reproducible results in these models., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
32. MicroRNA Expression Profiling in the Prefrontal Cortex: Putative Mechanisms for the Cognitive Effects of Adolescent High Fat Feeding.
- Author
-
Labouesse MA, Polesel M, Clementi E, Müller F, Markkanen E, Mouttet F, Cattaneo A, and Richetto J
- Subjects
- Age Factors, Animals, Cognition physiology, Cognitive Dysfunction metabolism, Diet, High-Fat adverse effects, Male, Mice, Mice, Inbred C57BL, MicroRNAs metabolism, Prefrontal Cortex metabolism, Prefrontal Cortex physiology, Transcriptome genetics, Gene Expression Profiling methods, MicroRNAs genetics
- Abstract
The medial prefrontal cortex (mPFC), master regulator of higher-order cognitive functions, is the only brain region that matures until late adolescence. During this period, the mPFC is sensitive to stressful events or suboptimal nutrition. For instance, high-fat diet (HFD) feeding during adolescence markedly impairs prefrontal-dependent cognition. It also provokes multiple changes at the cellular and synaptic scales within the mPFC, suggesting that major transcriptional events are elicited by HFD during this maturational period. The nature of this transcriptional reprogramming remains unknown, but may include epigenetic processes, in particular microRNAs, known to directly regulate synaptic functions. We used high-throughput screening in the adolescent mouse mPFC and identified 38 microRNAs differentially regulated by HFD, in particular mir-30e-5p. We used a luciferase assay to confirm the functional effect of mir-30e-5p on a chosen target: Ephrin-A3. Using global pathway analyses of predicted microRNA targets, we identified biological pathways putatively affected by HFD. Axon guidance was the top-1 pathway, validated by identifying gene expression changes of axon guidance molecules following HFD. Our findings delineate major microRNA transcriptional reprogramming within the mPFC induced by adolescent HFD. These results will help understanding the contribution of microRNAs in the emergence of cognitive deficits following early-life environmental events.
- Published
- 2018
- Full Text
- View/download PDF
33. Abdominal Vagal Afferents Modulate the Brain Transcriptome and Behaviors Relevant to Schizophrenia.
- Author
-
Klarer M, Krieger JP, Richetto J, Weber-Stadlbauer U, Günther L, Winter C, Arnold M, Langhans W, and Meyer U
- Subjects
- Amphetamine pharmacology, Animals, Association Learning, Attention drug effects, Denervation, Dopamine metabolism, Dopamine Agents pharmacology, Male, RNA, Messenger genetics, Rats, Rats, Sprague-Dawley, Reflex, Startle, Sensory Gating, Abdomen innervation, Brain Chemistry genetics, Neurons, Afferent physiology, Schizophrenia genetics, Transcriptome, Vagus Nerve physiology
- Abstract
Reduced activity of vagal efferents has long been implicated in schizophrenia and appears to be responsible for diminished parasympathetic activity and associated peripheral symptoms such as low heart rate variability and cardiovascular complications in affected individuals. In contrast, only little attention has been paid to the possibility that impaired afferent vagal signaling may be relevant for the disorder's pathophysiology as well. The present study explored this hypothesis using a model of subdiaphragmatic vagal deafferentation (SDA) in male rats. SDA represents the most complete and selective vagal deafferentation method existing to date as it leads to complete disconnection of all abdominal vagal afferents while sparing half of the abdominal vagal efferents. Using next-generation mRNA sequencing, we show that SDA leads to brain transcriptional changes in functional networks annotating with schizophrenia. We further demonstrate that SDA induces a hyperdopaminergic state, which manifests itself as increased sensitivity to acute amphetamine treatment and elevated accumbal levels of dopamine and its major metabolite, 3,4-dihydroxyphenylacetic acid. Our study also shows that SDA impairs sensorimotor gating and the attentional control of associative learning, which were assessed using the paradigms of prepulse inhibition and latent inhibition, respectively. These data provide converging evidence suggesting that the brain transcriptome, dopamine neurochemistry, and behavioral functions implicated in schizophrenia are subject to visceral modulation through abdominal vagal afferents. Our findings may encourage the further establishment and use of therapies for schizophrenia that are based on vagal interventions. SIGNIFICANCE STATEMENT The present work provides a better understanding of how disrupted vagal afferent signaling can contribute to schizophrenia-related brain and behavioral abnormalities. More specifically, it shows that subdiaphragmatic vagal deafferentation (SDA) in rats leads to (1) brain transcriptional changes in functional networks related to schizophrenia, (2) increased sensitivity to dopamine-stimulating drugs and elevated dopamine levels in the nucleus accumbens, and (3) impairments in sensorimotor gating and the attentional control of associative learning. These findings may encourage the further establishment of novel therapies for schizophrenia that are based on vagal interventions., (Copyright © 2018 the authors 0270-6474/18/381634-14$15.00/0.)
- Published
- 2018
- Full Text
- View/download PDF
34. Genome-Wide Transcriptional Profiling and Structural Magnetic Resonance Imaging in the Maternal Immune Activation Model of Neurodevelopmental Disorders.
- Author
-
Richetto J, Chesters R, Cattaneo A, Labouesse MA, Gutierrez AMC, Wood TC, Luoni A, Meyer U, Vernon A, and Riva MA
- Subjects
- Animals, Brain drug effects, Brain growth & development, Cohort Studies, DNA Methylation drug effects, Disease Models, Animal, Female, Gene Expression Regulation drug effects, Gestational Age, Interferon Inducers toxicity, Male, Memory, Short-Term drug effects, Memory, Short-Term physiology, Mice, Mice, Inbred C57BL, Myelin Basic Protein metabolism, Myelin Proteins metabolism, Poly I-C toxicity, Pregnancy, Prenatal Exposure Delayed Effects chemically induced, Recognition, Psychology drug effects, Recognition, Psychology physiology, Brain diagnostic imaging, Brain metabolism, Gene Expression Regulation physiology, Magnetic Resonance Imaging, Neurodevelopmental Disorders diagnostic imaging, Neurodevelopmental Disorders etiology, Neurodevelopmental Disorders metabolism, Prenatal Exposure Delayed Effects physiopathology
- Abstract
Prenatal exposure to maternal infection increases the risk of neurodevelopmental disorders, including schizophrenia and autism. The molecular processes underlying this pathological association, however, are only partially understood. Here, we combined unbiased genome-wide transcriptional profiling with follow-up epigenetic analyses and structural magnetic resonance imaging to explore convergent molecular and neuromorphological alterations in corticostriatal areas of adult offspring exposed to prenatal immune activation. Genome-wide transcriptional profiling revealed that prenatal immune activation caused a differential expression of 116 and 251 genes in the medial prefrontal cortex and nucleus accumbens, respectively. A large part of genes that were commonly affected in both brain areas were related to myelin functionality and stability. Subsequent epigenetic analyses indicated that altered DNA methylation of promoter regions might contribute to the differential expression of myelin-related genes. Quantitative relaxometry comparing T1, T2, and myelin water fraction revealed sparse increases in T1 relaxation times and consistent reductions in T2 relaxation times. Together, our multi-system approach demonstrates that prenatal viral-like immune activation causes myelin-related transcriptional and epigenetic changes in corticostriatal areas. Even though these abnormalities do not seem to be associated with overt white matter reduction, they may provide a molecular mechanism whereby prenatal infection can impair myelin functionality and stability., (© The Author 2017. Published by Oxford University Press.)
- Published
- 2017
- Full Text
- View/download PDF
35. Genome-wide DNA Methylation Changes in a Mouse Model of Infection-Mediated Neurodevelopmental Disorders.
- Author
-
Richetto J, Massart R, Weber-Stadlbauer U, Szyf M, Riva MA, and Meyer U
- Subjects
- Animals, Behavior, Animal physiology, CpG Islands, Disease Models, Animal, Epigenesis, Genetic, Female, GABAergic Neurons metabolism, Genome, Interpersonal Relations, Male, Maze Learning drug effects, Maze Learning physiology, Mice, Mice, Inbred C57BL, Neurodevelopmental Disorders chemically induced, Neurodevelopmental Disorders immunology, Poly I-C, Pregnancy, Prenatal Exposure Delayed Effects immunology, Prepulse Inhibition drug effects, Prepulse Inhibition physiology, Wnt Signaling Pathway, DNA Methylation, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders metabolism, Prefrontal Cortex metabolism, Prenatal Exposure Delayed Effects genetics, Prenatal Exposure Delayed Effects metabolism
- Abstract
Background: Prenatal exposure to infectious or inflammatory insults increases the risk of neurodevelopmental disorders. Using a well-established mouse model of prenatal viral-like immune activation, we examined whether this pathological association involves genome-wide DNA methylation differences at single nucleotide resolution., Methods: Prenatal immune activation was induced by maternal treatment with the viral mimetic polyriboinosinic-polyribocytidylic acid in middle or late gestation. Following behavioral and cognitive characterization of the adult offspring (n = 12 per group), unbiased capture array bisulfite sequencing was combined with subsequent matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and quantitative real-time polymerase chain reaction analyses to quantify DNA methylation changes and transcriptional abnormalities in the medial prefrontal cortex of immune-challenged and control offspring. Gene ontology term enrichment analysis was used to explore shared functional pathways of genes with differential DNA methylation., Results: Adult offspring of immune-challenged mothers displayed hyper- and hypomethylated CpGs at numerous loci and at distinct genomic regions, including genes relevant for gamma-aminobutyric acidergic differentiation and signaling (e.g., Dlx1, Lhx5, Lhx8), Wnt signaling (Wnt3, Wnt8a, Wnt7b), and neural development (e.g., Efnb3, Mid1, Nlgn1, Nrxn2). Altered DNA methylation was associated with transcriptional changes of the corresponding genes. The epigenetic and transcriptional effects were dependent on the offspring's age and were markedly influenced by the precise timing of prenatal immune activation., Conclusions: Prenatal viral-like immune activation is capable of inducing stable DNA methylation changes in the medial prefrontal cortex. These long-term epigenetic modifications are a plausible mechanism underlying the disruption of prefrontal gene transcription and behavioral functions in subjects with prenatal infectious histories., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
36. Daily exposure to a touchscreen-paradigm and associated food restriction evokes an increase in adrenocortical and neural activity in mice.
- Author
-
Mallien AS, Palme R, Richetto J, Muzzillo C, Richter SH, Vogt MA, Inta D, Riva MA, Vollmayr B, and Gass P
- Subjects
- Adaptation, Psychological physiology, Animals, Caloric Restriction veterinary, Corticosterone metabolism, Environmental Exposure, Hippocampus metabolism, Male, Maze Learning physiology, Mice, Mice, Inbred C57BL, Physical Conditioning, Animal physiology, Physical Conditioning, Animal psychology, RNA, Messenger metabolism, Adrenal Glands metabolism, Caloric Restriction psychology, Conditioning, Psychological physiology, Neurons metabolism, Reward, Touch
- Abstract
The translational assessment of mechanisms underlying cognitive functions using touchscreen-based approaches for rodents is growing in popularity. In these paradigms, daily training is usually accompanied by extended food restriction to maintain animals' motivation to respond for rewards. Here, we show a transient elevation in stress hormone levels due to food restriction and touchscreen training, with subsequent adaptation effects, in fecal corticosterone metabolite concentrations, indicating effective coping in response to physical and psychological stressors. Corticosterone concentrations of experienced but training-deprived mice revealed a potential anticipation of task exposure, indicating a possible temporary environmental enrichment-like effect caused by cognitive challenge. Furthermore, the analyses of immediate early gene (IEG) immunoreactivity in the hippocampus revealed alterations in Arc, c-Fos and zif268 expression immediately following training. In addition, BDNF expression was altered as a function of satiation state during food restriction. These findings suggest that standard protocols for touchscreen-based training induce changes in hippocampal neuronal activity related to satiation and learning that should be considered when using this paradigm., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
37. Late prenatal immune activation causes hippocampal deficits in the absence of persistent inflammation across aging.
- Author
-
Giovanoli S, Notter T, Richetto J, Labouesse MA, Vuillermot S, Riva MA, and Meyer U
- Subjects
- Aging metabolism, Animals, Female, Hippocampus metabolism, Inflammation immunology, Inflammation metabolism, Inflammation pathology, Inflammation Mediators metabolism, Male, Mice, Mice, Inbred C57BL, Pregnancy, Prenatal Exposure Delayed Effects metabolism, Aging immunology, Aging pathology, Hippocampus pathology, Inflammation Mediators immunology, Prenatal Exposure Delayed Effects immunology, Prenatal Exposure Delayed Effects pathology
- Abstract
Background: Prenatal exposure to infection and/or inflammation is increasingly recognized to play an important role in neurodevelopmental brain disorders. It has recently been postulated that prenatal immune activation, especially when occurring during late gestational stages, may also induce pathological brain aging via sustained effects on systemic and central inflammation. Here, we tested this hypothesis using an established mouse model of exposure to viral-like immune activation in late pregnancy., Methods: Pregnant C57BL6/J mice on gestation day 17 were treated with the viral mimetic polyriboinosinic-polyribocytidilic acid (poly(I:C)) or control vehicle solution. The resulting offspring were first tested using cognitive and behavioral paradigms known to be sensitive to hippocampal damage, after which they were assigned to quantitative analyses of inflammatory cytokines, microglia density and morphology, astrocyte density, presynaptic markers, and neurotrophin expression in the hippocampus throughout aging (1, 5, and 22 months of age)., Results: Maternal poly(I:C) treatment led to a robust increase in inflammatory cytokine levels in late gestation but did not cause persistent systemic or hippocampal inflammation in the offspring. The late prenatal manipulation also failed to cause long-term changes in microglia density, morphology, or activation, and did not induce signs of astrogliosis in pubescent, adult, or aged offspring. Despite the lack of persistent inflammatory or glial anomalies, offspring of poly(I:C)-exposed mothers showed marked and partly age-dependent deficits in hippocampus-regulated cognitive functions as well as impaired hippocampal synaptophysin and brain-derived neurotrophic factor (BDNF) expression., Conclusions: Late prenatal exposure to viral-like immune activation in mice causes hippocampus-related cognitive and synaptic deficits in the absence of chronic inflammation across aging. These findings do not support the hypothesis that this form of prenatal immune activation may induce pathological brain aging via sustained effects on systemic and central inflammation. We further conclude that poly(I:C)-based prenatal immune activation models are reliable in their effectiveness to induce (hippocampal) neuropathology across aging, but they appear unsuited for studying the role of chronic systemic or central inflammation in brain aging.
- Published
- 2015
- Full Text
- View/download PDF
38. Behavioral effects of the benzodiazepine-positive allosteric modulator SH-053-2'F-S-CH₃ in an immune-mediated neurodevelopmental disruption model.
- Author
-
Richetto J, Labouesse MA, Poe MM, Cook JM, Grace AA, Riva MA, and Meyer U
- Subjects
- Amphetamine pharmacology, Animals, Central Nervous System Stimulants pharmacology, Cognition Disorders physiopathology, Disease Models, Animal, Female, Hippocampus drug effects, Hippocampus physiopathology, Male, Memory, Short-Term drug effects, Memory, Short-Term physiology, Mice, Inbred C57BL, Motor Activity drug effects, Motor Activity physiology, Polynucleotides, Prefrontal Cortex drug effects, Prefrontal Cortex physiopathology, Pregnancy, Prenatal Exposure Delayed Effects, Receptors, GABA-A metabolism, Social Behavior, Benzodiazepines pharmacology, Cognition Disorders drug therapy, GABA Agents pharmacology, Psychotropic Drugs pharmacology
- Abstract
Background: Impaired γ-aminobutyric acid (GABA) signaling may contribute to the emergence of cognitive deficits and subcortical dopaminergic hyperactivity in patients with schizophrenia and related psychotic disorders. Against this background, it has been proposed that pharmacological interventions targeting GABAergic dysfunctions may prove useful in correcting such cognitive impairments and dopaminergic imbalances., Methods: Here, we explored possible beneficial effects of the benzodiazepine-positive allosteric modulator SH-053-2'F-S-CH₃, with partial selectivity at the α2, α3, and α5 subunits of the GABAA receptor in an immune-mediated neurodevelopmental disruption model. The model is based on prenatal administration of the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)] in mice, which is known to capture various GABAergic, dopamine-related, and cognitive abnormalities implicated in schizophrenia and related disorders., Results: Real-time polymerase chain reaction analyses confirmed the expected alterations in GABAA receptor α subunit gene expression in the medial prefrontal cortices and ventral hippocampi of adult poly(I:C) offspring relative to control offspring. Systemic administration of SH-053-2'F-S-CH₃ failed to normalize the poly(I:C)-induced deficits in working memory and social interaction, but instead impaired performance in these cognitive and behavioral domains both in control and poly(I:C) offspring. In contrast, SH-053-2'F-S-CH₃ was highly effective in mitigating the poly(I:C)-induced amphetamine hypersensitivity phenotype without causing side effects in control offspring., Conclusions: Our preclinical data suggest that benzodiazepine-like positive allosteric modulators with activity at the α2, α3, and α5 subunits of the GABAA receptor may be particularly useful in correcting pathological overactivity of the dopaminergic system, but they may be ineffective in targeting multiple pathological domains that involve the co-existence of psychotic, social, and cognitive dysfunctions., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)
- Published
- 2015
- Full Text
- View/download PDF
39. The long-term impact of early adversities on psychiatric disorders: focus on neuronal plasticity.
- Author
-
Luoni A, Richetto J, Racagni G, and Molteni R
- Subjects
- Animals, Disease Models, Animal, Female, Humans, Mental Disorders epidemiology, Mental Disorders physiopathology, Pregnancy, Pregnancy Complications epidemiology, Prenatal Exposure Delayed Effects epidemiology, Time Factors, Mental Disorders etiology, Neuronal Plasticity physiology, Stress, Psychological complications
- Abstract
The impact of early physical and social environments on life-long pathological phenotypes is well known and there is now compelling evidence that stressful experiences during gestation or early in life can lead to enhanced susceptibility to mental illness. Here, we discuss the data from preclinical studies aimed at investigating the molecular consequences of the exposure to stressful events during prenatal or early postnatal life that might contribute to later psychopathology. Particularly, we will discuss the existence of age windows of vulnerability to environmental conditions during brain maturation using as examples several studies performed with different animal models. Specifically, major deviations from normative neurobehavioural trajectories have been reported in animal models obtained following exposure to severe stress (maternal separation) ea rly in infancy or with rodent models of difficult and/or stressful pregnancies, including obstetric complications (e.g. prenatal restrain stress) and gestational exposure to infection (e.g prenatal immune challenge). These models have been associated with profound long-lasting deficits in the offspring's emotional and social behaviour, and with molecular changes associated with neuroplasticity.
- Published
- 2015
- Full Text
- View/download PDF
40. Prenatal maternal factors in the development of cognitive impairments in the offspring.
- Author
-
Richetto J and Riva MA
- Subjects
- Female, Humans, Pregnancy, Prenatal Exposure Delayed Effects prevention & control, Hippocampus embryology, Hippocampus immunology, Maternal Exposure adverse effects, Memory, Mental Disorders congenital, Mental Disorders immunology, Mental Disorders therapy, Prenatal Exposure Delayed Effects immunology
- Abstract
Different environmental factors acting during sensitive prenatal periods can have a negative impact on neurodevelopment and predispose the individual to the development of various psychiatric conditions that often share cognitive impairments as a common component. As cognitive symptoms remain one of the most challenging and resistant aspects of mental illness to be treated pharmacologically, it is important to investigate the mechanisms underlying such cognitive deficits, with particular focus on the impact of early life adverse events that predispose the individual to mental disorders. Multiple clinical studies have, in fact, repeatedly confirmed that prenatal maternal factors, such as infection, stress or malnutrition, are pivotal in shaping behavioral and cognitive functions of the offspring, and in the past decade many preclinical studies have investigated this hypothesis. The purpose of this review is to describe recent preclinical studies aimed at dissecting the relative impact of various prenatal maternal factors on the development of cognitive impairments in offspring, focusing on animal models of prenatal stress and prenatal infection. These recent studies point to the pivotal role of prenatal stressful experiences in shaping memory and learning functions associated with specific brain structures, such as the hippocampus and the prefrontal cortex. More importantly, such experimental evidence suggests that different insults converge on similar downstream functional targets, such as cognition, which may therefore represent an endophenotype for several pathological conditions. Future studies should thus focus on investigating the mechanisms contributing to the convergent action of different prenatal insults in order to identify targets for novel therapeutic intervention., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.