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1. Behavioral and Transcriptomic Changes Following Brain-Specific Loss of Noradrenergic Transmission

Author

Elsa Isingrini, Chloé Guinaudie, Léa Perret, Elisa Guma, Victor Gorgievski, Ian D. Blum, Jessica Colby-Milley, Maryia Bairachnaya, Sébastien Mella, Antoine Adamantidis, Kai-Florian Storch, and Bruno Giros

Subjects
noradrenaline, depression, anxiety, cocaine sensitization, circadian rhythms, sleep, Microbiology, QR1-502
Abstract

Noradrenaline (NE) plays an integral role in shaping behavioral outcomes including anxiety/depression, fear, learning and memory, attention and shifting behavior, sleep-wake state, pain, and addiction. However, it is unclear whether dysregulation of NE release is a cause or a consequence of maladaptive orientations of these behaviors, many of which associated with psychiatric disorders. To address this question, we used a unique genetic model in which the brain-specific vesicular monoamine transporter-2 (VMAT2) gene expression was removed in NE-positive neurons disabling NE release in the entire brain. We engineered VMAT2 gene splicing and NE depletion by crossing floxed VMAT2 mice with mice expressing the Cre-recombinase under the dopamine β-hydroxylase (DBH) gene promotor. In this study, we performed a comprehensive behavioral and transcriptomic characterization of the VMAT2DBHcre KO mice to evaluate the role of central NE in behavioral modulations. We demonstrated that NE depletion induces anxiolytic and antidepressant-like effects, improves contextual fear memory, alters shifting behavior, decreases the locomotor response to amphetamine, and induces deeper sleep during the non-rapid eye movement (NREM) phase. In contrast, NE depletion did not affect spatial learning and memory, working memory, response to cocaine, and the architecture of the sleep-wake cycle. Finally, we used this model to identify genes that could be up- or down-regulated in the absence of NE release. We found an up-regulation of the synaptic vesicle glycoprotein 2c (SV2c) gene expression in several brain regions, including the locus coeruleus (LC), and were able to validate this up-regulation as a marker of vulnerability to chronic social defeat. The NE system is a complex and challenging system involved in many behavioral orientations given it brain wide distribution. In our study, we unraveled specific role of NE neurotransmission in multiple behavior and link it to molecular underpinning, opening future direction to understand NE role in health and disease.

Published
2023
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2. Association between repeated unpredictable chronic mild stress (UCMS) procedures with a high fat diet: a model of fluoxetine resistance in mice.

Author

Elsa Isingrini, Vincent Camus, Anne-Marie Le Guisquet, Maryse Pingaud, Séverine Devers, and Catherine Belzung

Subjects
Medicine, Science
Abstract

Major depressive disorder is a debilitating disease. Unfortunately, treatment with antidepressants (ADs) has limited therapeutic efficacy since resistance to AD is common. Research in this field is hampered by the lack of a reliable natural animal model of AD resistance. Depression resistance is related to various factors, including the attendance of cardiovascular risk factors and past depressive episodes. We aimed to design a rodent model of depression resistance to ADs, associating cardiovascular risk factors with repeated unpredicted chronic mild stress (UCMS). Male BALB/c mice were given either a regular (4% fat) or a high fat diet (45% fat) and subjected to two 7-week periods of UCMS separated by 6 weeks. From the second week of each UCMS procedure, vehicle or fluoxetine (10 mg/kg, i.p.) was administrated daily. The effects of the UCMS and fluoxetine in both diet conditions were assessed using physical (coat state and body weight) and behavioural tests (the reward maze test and the splash test). The results demonstrate that during the second procedure, UCMS induced behavioural changes, including coat state degradation, disturbances in self-care behaviour (splash test) and anhedonia (reward maze test) and these were reversed by fluoxetine in the regular diet condition. In contrast, the high-fat diet regimen prevented the AD fluoxetine from abolishing the UCMS-induced changes. In conclusion, by associating UCMS-an already validated animal model of depression-with high-fat diet regimen, we designed a naturalistic animal model of AD resistance related to a sub-nosographic clinical entity of depression.

Published
2010
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3. Regulation of GluA1 Phosphorylation by D-amphetamine and Methylphenidate in the Cerebellum

Author

Christian Lüscher, Alban de Kerchove d'Exaerde, Elsa Isingrini, Emma Puighermanal, Laura Cutando, Vincent Pascoli, Patricia Bonnavion, Laia Castell, Federica Bertaso, Micaela Galante, Pauline Tarot, Bruno Giros, Glenn Dallérac, Emmanuel Valjent, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Universitat Autònoma de Barcelona (UAB), ULB Neuroscience Institute [Brussels] (UNI), Université libre de Bruxelles (ULB), Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), McGill University = Université McGill [Montréal, Canada], Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), University of Geneva [Switzerland], University of Barcelona, Autonomous University of Barcelona, and Douglas Hospital Research Center, Department of Psychiatry, Faculty of Medicine

Subjects
Male, medicine.medical_specialty, Génétique moléculaire, Dextroamphetamine, Monoaminergic system, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), AMPA receptor, 03 medical and health sciences, Norepinephrine, Mice, Cerebellar Cortex, 0302 clinical medicine, Dopamine receptor D1, Dopamine, Internal medicine, Cerebellum, medicine, Bergmann Glia Cells, Animals, Phosphorylation, Prescription stimulants, Amphetamine, Pharmacology, Neurophysiologie, Methylphenidate, Chemistry, Receptors, Dopamine D1, Phosphotransferases, Biologie moléculaire, monoaminergic system, 3. Good health, 030227 psychiatry, ddc:616.8, Psychiatry and Mental health, Endocrinology, nervous system, prescription stimulants, Cerebellar cortex, Central Nervous System Stimulants, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], cerebellar cortex, 030217 neurology & neurosurgery, Bergmann glial cells, GluA1, medicine.drug
Abstract

Prescription stimulants, such as d-amphetamine or methylphenidate are used to treat suffering from attention-deficit hyperactivity disorder (ADHD). They potently release dopamine (DA) and norepinephrine (NE) and cause phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 in the striatum. Whether other brain regions are also affected remains elusive. Here, we demonstrate that d-amphetamine and methylphenidate increase phosphorylation at Ser845 (pS845-GluA1) in the membrane fraction of mouse cerebellum homogenate. We identify Bergmann glial cells as the source of pS845-GluA1 and demonstrate a requirement for intact NE release. Consequently, d-amphetamine-induced pS845-GluA1 was prevented by β1-adenoreceptor antagonist, whereas the blockade of DA D1 receptor had no effect. Together, these results indicate that NE regulates GluA1 phosphorylation in Bergmann glial cells in response to prescription stimulants., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2021

4. Regulation of GluA1 Phosphorylation by D-amphetamine and Methylphenidate in the Cerebellum

Author

Elsa Isingrini, Micaela Galante, Patricia Bonnavion, Federica Bertaso, Glenn Dallérac, Alban de Kerchove d'Exaerde, Pauline Tarot, Vincent Pascoli, Emma Puighermanal, Emmanuel Valjent, Bruno Giros, Laura Cutando, Laia Castell, and Christian Lüscher

Subjects
medicine.medical_specialty, Cerebellum, Methylphenidate, Chemistry, AMPA receptor, Norepinephrine, Monoamine neurotransmitter, Endocrinology, medicine.anatomical_structure, Dopamine receptor D1, nervous system, Dopamine, Internal medicine, medicine, Amphetamine, medicine.drug
Abstract

Prescription stimulants, such as d-amphetamine or methylphenidate, are potent dopamine (DA) and norepinephrine (NE) releasers used to treat children and adults diagnosed for attention-deficit/hyperactivity disorder (ADHD). Although increased phosphorylation of the AMPA receptor subunit GluA1 at Ser845 (pS845-GluA1) in the striatum has been identified as an important cellular effector for the actions of these drugs, regulation of this posttranslational modification in the cerebellum has never been recognized. Here, we demonstrate that d-amphetamine and methylphenidate increase pS845-GluA1 in the membrane fraction in both vermis and lateral hemispheres of the mouse cerebellum. This regulation occurs selectively in Bergmann Glia Cells and requires intact norepinephrine release since the effects were abolished in mice lacking the vesicular monoamine transporter-2 selectively in NE neurons. Moreover, d-amphetamine-induced pS845-GluA1 was prevented by β1-adenoreceptor antagonist, whereas the blockade of dopamine D1 receptor had no effect. Additionally, we identified transcriptional alterations of several regulators of the cAMP/PKA pathway, which might account for the absence of pS845-GluA1 desensitization in mice repeatedly exposed to d-amphetamine or methylphenidate. Together, these results point to norepinephrine transmission as a key regulator of GluA1 phosphorylation in Bergmann Glial Cells, which may represent a new target for the treatment of ADHD.

Published
2020

5. Genetic elimination of dopamine vesicular stocks in the nigrostriatal pathway replicates Parkinson’s disease motor symptoms without neuronal degeneration in adult mice

Author

Chloé Guinaudie, Léa C. Perret, Quentin Rainer, Bruno Giros, Alain Gratton, Luc Moquin, Elsa Isingrini, Research Center of the Douglas Mental Health University Institute, Physiopathologie des maladies psychiatriques = Pathophysiology of Psychiatric Disorders (NPS-07), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Psychiatry [Montreal, Quebec, Canada], McGill University- Douglas Mental Health Research Center [Montréal Quebec, Canada], Neuroscience Paris Seine ( NPS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), HAL-UPMC, Gestionnaire, and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS)

Subjects
Male, 0301 basic medicine, Pathology, MESH: Integrases, Parkinson's disease, Dopamine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Gene Expression, Nigrostriatal pathway, lcsh:Medicine, MESH: Vesicular Monoamine Transport Proteins, MESH: Dependovirus, MESH: Eating, MESH: Corpus Striatum, Eating, Mice, 0302 clinical medicine, MESH: Dopaminergic Neurons, Monoaminergic, MESH: Animals, lcsh:Science, Multidisciplinary, Neurodegeneration, Dependovirus, 3. Good health, Substantia Nigra, medicine.anatomical_structure, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Synaptic Vesicles, MESH: Injections, Intraventricular, MESH: Parkinson Disease, Secondary, MESH: Drinking, medicine.drug, medicine.medical_specialty, MESH: Gene Expression, MESH: Mice, Transgenic, Drinking, MESH: Substantia Nigra, Mice, Transgenic, MESH: Dopamine, Biology, Article, MESH: Weight Loss, 03 medical and health sciences, Weight Loss, Genetic model, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Parkinson Disease, Secondary, MESH: Mice, Injections, Intraventricular, Integrases, Dopaminergic Neurons, lcsh:R, MESH: Synaptic Vesicles, medicine.disease, Corpus Striatum, MESH: Male, Vesicular monoamine transporter, 030104 developmental biology, Monoamine neurotransmitter, MESH: Gene Deletion, Vesicular Monoamine Transport Proteins, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], lcsh:Q, Neuroscience, Gene Deletion, 030217 neurology & neurosurgery
Abstract

International audience; The type 2 vesicular monoamine transporter (VMAT2), by regulating the storage of monoamines transmitters into synaptic vesicles, has a protective role against their cytoplasmic toxicity. Increasing evidence suggests that impairment of VMAT2 neuroprotection contributes to the pathogenesis of Parkinson's disease (PD). Several transgenic VMAT2 mice models have been developed, however these models lack specificity regarding the monoaminergic system targeting. To circumvent this limitation, we created VMAT2-KO mice specific to the dopamine (DA) nigrostriatal pathway to analyze VMAT2's involvement in DA depletion-induced motor features associated to PD and examine the relevance of DA toxicity in the pathogenesis of neurodegeneration. Adult VMAT2 floxed mice were injected in the substancia nigra (SN) with an adeno-associated virus (AAV) expressing the Cre-recombinase allowing VMAT2 removal in DA neurons of the nigrostriatal pathway solely. VMAT2 deletion in the SN induced both DA depletion exclusively in the dorsal striatum and motor dysfunction. At 16 weeks post-injection, motor symptoms were accompanied with a decreased in food and water consumption and weight loss. However, despite an accelerating death, degeneration of nigrostriatal neurons was not observed in this model during this time frame. This study highlights a non-cytotoxic role of DA in our genetic model of VMAT2 deletion exclusively in nigrostriatal neurons. Parkinson's disease (PD), is one of the most common neurodegenerative disorders affecting 1–2% of individuals older than 65 years old worldwide 1. PD is a progressive disorder clinically characterized by a large number of motor features in particular rest tremor, bradykinesia, rigidity and loss of postural reflexes 2,3. At the pathological level, processes leading to PD begin before the appearance of the typical motor symptoms, and by the time the disease is diagnosed about 70–80% of striatal dopamine (DA) is depleted and one third of substantia nigra (SN) DA neurons and striatal DA fibers are already lost 2,4–7. Understanding the biochemical markers relevant to the pathogenesis of neurodegeneration in PD remain essential. Oxidative stress contribution to PD neurodegeneration is currently well established 8. Post-mortem studies have shown an imbalance between reactive oxygen species (ROS) production and the antioxidant protective system resulting in oxidative stress in the SN of PD patients 9,10. Superoxide (O 2−), hydrogen peroxide (H 2 O 2), and the hydroxyl radical (OH •), three important ROS in mammalian cells, can damage macromolecules including nucleic acids, lipids and proteins, leading to DA neuron degeneration, and neuron network dysfunction, ultimately progressing to PD 11. For a better understanding of the oxidative stress mechanisms in PD, the MPTP

Published
2017

6. Resilience to chronic stress is mediated by noradrenergic regulation of dopamine neurons

Author

Bénédicte Amilhon, Fabio Marti, Léa C. Perret, Naguib Mechawar, Elsa Isingrini, Jennifer Robinson, Luc Moquin, Bruno Giros, Quentin Rainer, Elisa Guma, Alain Gratton, Garance Martin, Sylvain Williams, Arnaud Tanti, Neurophysiologie et comportements = Neurophysiology and Behavior (NPS-06), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Canadian Research Chair in the Neurobiology of Mental Disorders, Fonds de Recherche du Quebec - Sante, Canada Research Chairs program, Graham Boeckh Foundation for Schizophrenia Research, Natural and Engineering Research Council of Canada [RGPIN 385732-2012], Neuroscience Paris Seine (NPS), Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Research Center of the Douglas Mental Health University Institute, Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adrenergic Neurons, Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Mice, Transgenic, Social defeat, Mice, Norepinephrine, 03 medical and health sciences, 0302 clinical medicine, Dopamine, mental disorders, medicine, Biological neural network, Animals, Chronic stress, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Dopaminergic Neurons, musculoskeletal, neural, and ocular physiology, General Neuroscience, Ventral Tegmental Area, Neural Inhibition, Resilience, Psychological, Mice, Inbred C57BL, Ventral tegmental area, 030104 developmental biology, medicine.anatomical_structure, nervous system, Vesicular Monoamine Transport Proteins, Chronic Disease, Locus coeruleus, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Psychology, Neuroscience, Stress, Psychological, psychological phenomena and processes, 030217 neurology & neurosurgery, medicine.drug
Abstract

International audience; Dopamine (DA) neurons in the ventral tegmental area (VTA) help mediate stress susceptibility and resilience. However, upstream mechanisms controlling these neurons remain unknown. Noradrenergic (NE) neurons in the locus coeruleus, implicated in the pathophysiology of depression, have direct connections within the VTA. Here we demonstrate that NE neurons regulate vulnerability to social defeat through inhibitory control of VTA DA neurons.

Published
2016

8. Antidepressive effects of targeting ELK-1 signal transduction

Author

Juan Pablo Lopez, Elsa Isingrini, Marie-Anne El Khoury, Naguib Mechawar, Chloé Guinaudie, Alejandro Orrico, Raphaele Mongredien, Jocelyne Caboche, Carlos Eduardo Macedo, Fabio Marti, Yiu C. Tse, Wojciech Jaworski, Bruno Giros, Severine Farley, Tak Pan Wong, Gustavo Turecki, Vincent Vialou, Kallia Apazoglou, Elise Morice, Ferah Yildirim, Franck Louis, Julien Grenier, Sophie Gautron, Laurent Groc, Ariane Bochereau, Sylvie Dumas, El Chérif Ibrahim, Raoul Belzeaux, Lenka Mikasova, Victor Gorgievski, Alexandre Barbé, Charbel Massaad, Eleni T. Tzavara, Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Département Universitaire de Psychiatrie - [Hôpital Sainte Marguerite - APHM] (Hôpitaux Sud), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), McGill University = Université McGill [Montréal, Canada], FondaMental Foundation, Fondation de Coopération Scientifique Hôpital, A. Chenevier, Douglas Mental Health University Institute [Montréal], Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroplasticité et thérapie des addictions (ERL 3649), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Oramacell [Paris, France], Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des maladies psychiatriques = Pathophysiology of Psychiatric Disorders (NPS-07), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Pôle de Psychiatrie Universitaire Solaris, Marseille, Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Research Center of the Douglas Mental Health University Institute, PMSNC, Interdisciplinary Institute for Neuroscience, Régulation de la transcription et maladies génétiques (RTMG), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Neurophysiologie et comportements = Neurophysiology and Behavior (NPS-06), Neurobiologie des processus adaptatifs (NPA), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), McGill University, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Pôle de Psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-CHU Marseille, Fondation FondaMental [Créteil], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and caboche, jocelyne

Subjects
Adult, Male, 0301 basic medicine, MAPK/ERK pathway, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], Druggability, Hippocampus, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, Elk-1, 0302 clinical medicine, Downregulation and upregulation, ELK1, Animals, Humans, Medicine, RNA, Messenger, dentate gyrus, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Transcription factor, ets-Domain Protein Elk-1, chronic stress, Neuronal Plasticity, Behavior, Animal, Depression, General Commentary, business.industry, Kinase, General Medicine, Middle Aged, Antidepressive Agents, adult neurogenesis, [SDV] Life Sciences [q-bio], 030104 developmental biology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Synaptic plasticity, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Signal transduction, business, Neuroscience, Stress, Psychological, 030217 neurology & neurosurgery, Signal Transduction
Abstract

International audience; Depression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement 1 . In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted2-4. The extracellular signal-regulated kinase (ERK) pathway is implicated in mood regulation5-7, but its pleiotropic functions and lack of target specificity prohibit optimal drug development. Here, we identified the transcription factor ELK-1, an ERK downstream partner 8 , as a specific signaling module in the pathophysiology and treatment of depression that can be targeted independently of ERK. ELK1 mRNA was upregulated in postmortem hippocampal tissues from depressed suicides; in blood samples from depressed individuals, failure to reduce ELK1 expression was associated with resistance to treatment. In mice, hippocampal ELK-1 overexpression per se produced depressive behaviors; conversely, the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states induced by stress. Our work stresses the importance of target selectivity for a successful approach for signal-transduction-based antidepressants, singles out ELK-1 as a depression-relevant transducer downstream of ERK and brings proof-of-concept evidence for the druggability of ELK-1.

Published
2018

9. VMAT2-Mediated Neurotransmission from Midbrain Leptin Receptor Neurons in Feeding Regulation

Author

Bruno Giros, Yungang Lu, Elsa Isingrini, Pingwen Xu, Yong Xu, Qingchun Tong, Yuanzhong Xu, Leandra R. Mangieri, The University of Texas Health Science Center at Houston (UTHealth), Baylor College of Medicine (BCM), Baylor University, McGill University = Université McGill [Montréal, Canada], and Isingrini, Elsa

Subjects
Male, obesity, HFD feeding, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Vesicular monoamine transporter 2, Synaptic Transmission, Tissue Culture Techniques, chemistry.chemical_compound, 0302 clinical medicine, Mesencephalon, Bulimia, Neurotransmitter, gamma-Aminobutyric Acid, Neurons, 0303 health sciences, General Neuroscience, Dopaminergic, digestive, oral, and skin physiology, Glutamate receptor, food and beverages, 3.1, General Medicine, New Research, Receptors, Leptin, GABAergic, Female, Disease Susceptibility, dopamine, hormones, hormone substitutes, and hormone antagonists, medicine.drug, medicine.medical_specialty, Glutamic Acid, Mice, Transgenic, Biology, Neurotransmission, Diet, High-Fat, leptin, 03 medical and health sciences, VMAT2, Dopamine, Internal medicine, medicine, Animals, 030304 developmental biology, Leptin receptor, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, nutritional and metabolic diseases, Feeding Behavior, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Disease Models, Animal, Endocrinology, chemistry, nervous system, Vesicular Monoamine Transport Proteins, biology.protein, Disorders of the Nervous System, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery
Abstract

Leptin receptors (LepRs) expressed in the midbrain contribute to the action of leptin on feeding regulation. The midbrain neurons release a variety of neurotransmitters including dopamine (DA), glutamate and GABA. However, which neurotransmitter mediates midbrain leptin action on feeding remains unclear. Here, we showed that midbrain LepR neurons overlap with a subset of dopaminergic, GABAergic and glutamatergic neurons. Specific removal of vesicular monoamine transporter 2 (VMAT2) in midbrain LepR neurons (KO mice) disrupted DA accumulation in vesicles, but failed to cause a significant change in the evoked release of either glutamate or GABA to downstream neurons. While KO mice showed no differences on chow, they presented a reduced high-fat diet (HFD) intake and resisted to HFD-induced obesity. Specific activation of midbrain LepR neurons promoted VMAT2-dependent feeding on chow and HFD. When tested with an intermittent access to HFD where first 2.5-h HFD eating (binge-like) and 24-h HFD feeding were measured, KO mice exhibited more binge-like, but less 24-h HFD feeding. Interestingly, leptin inhibited 24-h HFD feeding in controls but not in KO mice. Thus, VMAT2-mediated neurotransmission from midbrain LepR neurons contributes to both binge-like eating and HFD feeding regulation.

Published
2017

10. Disrupted hippocampal neuregulin-1/ErbB3 signaling and dentate gyrus granule cell alterations in suicide

Author

Léa C. Perret, Ian Mahar, Naguib Mechawar, Maria Antonietta Davoli, Benoit Labonté, S Yogendran, Bruno Giros, Elsa Isingrini, Gustavo Turecki, Adeline Rachalski, Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique (LHEEA), École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), McGill University = Université McGill [Montréal, Canada], and Department of Psychiatry [Montréal]

Subjects
0301 basic medicine, Adult, Male, Receptor, ErbB-3, [SDV]Life Sciences [q-bio], Neuregulin-1, Stereology, Hippocampal formation, Epigenesis, Genetic, Social defeat, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cresyl violet, chemistry.chemical_compound, 0302 clinical medicine, medicine, Animals, Humans, Neuregulin 1, Biological Psychiatry, ComputingMilieux_MISCELLANEOUS, Neurons, biology, Dentate gyrus, Neurogenesis, DNA Methylation, Granule cell, 3. Good health, Mice, Inbred C57BL, Psychiatry and Mental health, Suicide, 030104 developmental biology, medicine.anatomical_structure, chemistry, Dentate Gyrus, biology.protein, Original Article, Female, Erratum, Psychology, Neuroscience, Neuroglia, 030217 neurology & neurosurgery, Stress, Psychological
Abstract

Neuregulin-1 (NRG1) and ErbB receptors have been associated with psychopathology, and NRG1-ErbB3 signaling has been shown to increase hippocampal neurogenesis and induce antidepressant-like effects. In this study, we aimed to determine whether deficits in NRG1 or ErbBs might be present in the hippocampus of suicide completers. In well-characterized postmortem hippocampal samples from suicides and matched sudden-death controls, we assessed gene expression and methylation using qRT-PCR and EpiTYPER, respectively. Moreover, in hippocampal tissues stained with cresyl violet, stereology was used to quantify numbers of granule cells and of glia. Granule cell body size was examined with a nucleator probe, and granule cell layer volume with a Cavalieri probe. Unmedicated suicides showed sharply decreased hippocampal ErbB3 expression and decreased numbers of ErbB3-expressing granule cell neurons in the anterior dentate gyrus; a phenomenon seemingly reversed by antidepressant treatment. Furthermore, we found ErbB3 expression to be significantly decreased in the dentate gyrus of adult mice exposed to chronic social defeat stress. Taken together, these results reveal novel suicidal endophenotypes in the hippocampus, as well as a putative etiological mechanism underlying suicidality, and suggest that antidepressant or NRG1 treatment may reverse a potential deficit in anterior dentate gyrus granule cell neurons in individuals at risk of dying by suicide.

Published
2016

11. Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

Author

Elsa Isingrini, Alain Gratton, Quentin Rainer, Bruno Giros, Léa C. Perret, Luc Moquin, Sara Sagueby, Physiopathologie des maladies psychiatriques = Pathophysiology of Psychiatric Disorders (NPS-07), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Canada Research Chairs program, Canadian Foundation for Innovation, Graham Boeckh Foundation for Schizophrenia Research, NSERC [RGPIN 385732-2012], Fonds de recherche du Quebec - Sante, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Research Center of the Douglas Mental Health University Institute, Université Pierre et Marie Curie - Paris 6 (UPMC), and Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
0301 basic medicine, Serotonin, Cell Survival, [SDV]Life Sciences [q-bio], Dopamine, Emotions, Dopamine beta-Hydroxylase, Motor Activity, Serotonergic, Synaptic Transmission, 03 medical and health sciences, Norepinephrine, 0302 clinical medicine, Neurochemical, Reward, Monoaminergic, medicine, Animals, Pharmacology (medical), Amphetamine, Biological Psychiatry, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Neurons, Serotonin Plasma Membrane Transport Proteins, Dopamine Plasma Membrane Transport Proteins, Depression, Dopaminergic, Behavior, Addictive, Psychiatry and Mental health, 030104 developmental biology, Monoamine neurotransmitter, Phenotype, Vesicular Monoamine Transport Proteins, Central Nervous System Stimulants, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Psychology, Neuroscience, 030217 neurology & neurosurgery, medicine.drug, Research Paper
Abstract

International audience; Background The monoaminergic transmitters dopamine (DA), noradrenaline (NE) and serotonin (5-HT) modulate cerebral functions via their extensive effects in the brain. Investigating their roles has led to the creation of vesicular monoaminergic transporter-2 (VMAT2) knockout (KO) mice. While this mutation results in postnatal death, VMAT2-heterozygous (HET) mice are viable and show a complex behavioural phenotype. However, the simultaneous alteration of the 3 systems prevents investigations into their individual functions. Methods To assess the specific role of NE, 5-HT and DA, we genetically disrupted their neurotransmission by creating conditional VMAT2-KO mice with targeted recombination. These specific recombinations were obtained by breeding VMAT2(lox/lox) mice with DBHcre, SERTcre and DATcre mice, respectively. We conducted a complete neurochemical and behavioural characterization of VMAT2-HET animals in each system. Results Conditional VMAT2-KO mice revealed an absence of VMAT2 expression, and a specific decrease in the whole brain levels of each monoamine. Although NE- and 5-HT-depleted mice are viable into adulthood, DA depletion results in postnatal death before weaning. Interestingly, alteration of the DA transmission fully accounted for the increased amphetamine response formerly observed in the VMAT2-HET mice, whereas alteration of the 5-HT system was solely responsible for the increase in cocaine response. Limitations We used VMAT2-HET mice that displayed a mild phenotype. Because the VMAT2-KO in DA neurons is lethal, it precluded a straightforward comparison of the full KOs in the 3 systems. Conclusion Given the intermingled functions of NE, 5-HT and DA in regulating cognitive and affective functions, this model will enhance understanding of their respective roles in the pathophysiology of psychiatric disorders.

Published
2016

12. Altered aortic vascular reactivity in the unpredictable chronic mild stress model of depression in mice

Author

Vincent Camus, Alexandre Surget, Elsa Isingrini, James M. O'Donnell, Jefferson C. Frisbee, Catherine Belzung, Alexandre d'Audiffret, Jean-Louis Freslon, Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Edinburgh, Ecole Polytechnique Fédérale de Lausanne (EPFL), and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Phenylephrine, medicine.medical_specialty, MESH: Depression, [SDV]Life Sciences [q-bio], MESH: Mice, Inbred BALB C, Experimental and Cognitive Psychology, Disease, 030204 cardiovascular system & hematology, MESH: Dose-Response Relationship, Drug, MESH: Vasodilation, 03 medical and health sciences, Behavioral Neuroscience, Vascular reactivity, 0302 clinical medicine, Mild stress, Internal medicine, MESH: Behavior, Animal, medicine, MESH: Animals, Risk factor, Endothelial dysfunction, MESH: Mice, Depression (differential diagnoses), Relaxation (psychology), MESH: Acetylcholine, MESH: Stress, Psychological, MESH: Aorta, medicine.disease, MESH: Male, 3. Good health, Anesthesia, Cardiology, MESH: Vasoconstriction, MESH: Corticosterone, MESH: Disease Models, Animal, medicine.symptom, Psychology, 030217 neurology & neurosurgery, Vasoconstriction
Abstract

International audience; Major depression is an independent risk factor for the development of cardiovascular disease. This impact of depression on vascular function seems to be mediated by the endothelial dysfunction, defined as an impairment of endothelium-dependent vasorelaxation, which represents a reliable predictor of atherosclerosis and has been regularly found to be associated with depression. This study aimed at investigating aortic vascular reactivity in mice submitted to the unpredictable chronic mild stress (UCMS) procedure, a reliable model of depression. The results confirm the effectiveness of the UCMS procedure to induce neuroendocrine, physical and behavioral depression-like alterations as well as a significant decrease of acetylcholine-induced vasorelaxation without any effect on phenylephrine-induced vasoconstriction. In this study, we reveal an altered vascular reactivity in an animal model of depression, demonstrating an endothelial dysfunction reminiscent to the one found in depressed patients.

Published
2011

13. Presynaptic D-2 Dopamine Receptors Control Long-Term Depression Expression and Memory Processes in the Temporal Hippocampus

Author

Gregory Dal Bo, Elsa Isingrini, Aurore Menegaux, Alain Gratton, Marcelo Rubinstein, Luc Moquin, Sara Sagheby, Tak Pan Wong, François Tronche, Daniel Lévesque, Bruno Giros, Jill Rocchetti, Physiopathologie des maladies psychiatriques = Pathophysiology of Psychiatric Disorders (NPS-07), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Canada Research Chairs program, Canadian Foundation for Innovation, Graham Boeckh Foundation for Schizophrenia Research, Fond de Recherche du Quebec-Sante, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Neurosciences Paris Seine (NPS)

Subjects
Male, CIENCIAS MÉDICAS Y DE LA SALUD, medicine.medical_treatment, Long-Term Potentiation, Hippocampus, Dopamina, Mice, Transgenic, Medicina Clínica, Ratones transgénicos, Neurochemical, Dopamine, Memory, Neural Pathways, Neuroplasticity, Hipocampo, medicine, Animals, Learning, Antipsychotics, RNA, Messenger, Antipsychotic, Long-term depression, Biological Psychiatry, Receptors, Dopamine D2, Long-Term Synaptic Depression, Ventral Tegmental Area, Excitatory Postsynaptic Potentials, Long-term potentiation, humanities, 3. Good health, Mice, Inbred C57BL, Dopamine D2 Receptor Antagonists, Receptor D2, Dopamine receptor, Neuronal plasticity, Space Perception, LTD, Temporal hippocampus, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Medicina Critica y de Emergencia, D-2 dopamine receptors, Psychology, Neuroscience, medicine.drug
Abstract

BACKGROUND: Dysfunctional mesocorticolimbic dopamine signaling has been linked to alterations in motor and reward-based functions associated with psychiatric disorders. Converging evidence from patients with psychiatric disorders and use of antipsychotics suggests that imbalance of dopamine signaling deeply alters hippocampal functions. However, given the lack of full characterization of a functional mesohippocampal pathway, the precise role of dopamine transmission in memory deficits associated with these disorders and their dedicated therapies is unknown. In particular, the positive outcome of antipsychotic treatments, commonly antagonizing D2 dopamine receptors (D2Rs), on cognitive deficits and memory impairments remains questionable. METHODS: Following pharmacologic and genetic manipulation of dopamine transmission, we performed anatomic, neurochemical, electrophysiologic, and behavioral investigations to uncover the role of D2Rs in hippocampal-dependent plasticity and learning. Naïve mice (n = 4-21) were used in the different procedures. RESULTS: Dopamine modulated both long-term potentiation and long-term depression in the temporal hippocampus as well as spatial and recognition learning and memory in mice through D2Rs. Although genetic deletion or pharmacologic blockade of D2Rs led to the loss of long-term potentiation expression, the specific genetic removal of presynaptic D2Rs impaired long-term depression and performances on spatial memory tasks. CONCLUSIONS: Presynaptic D2Rs in dopamine fibers of the temporal hippocampus tightly modulate long-term depression expression and play a major role in the regulation of hippocampal learning and memory. This direct role of mesohippocampal dopamine input as uncovered here adds a new dimension to dopamine involvement in the physiology underlying deficits associated with neuropsychiatric disorders. Fil: Rocchett, Jill. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Isingrini, Elsa. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Dal Bo, Gregory. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Sagheby, Sara. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Menegaux, Aurore. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Tronche, François. Centre National de la Recherche Scientifique; Francia. Institut National de la Santé et de la Recherche Médicale; Francia Fil: Levesque, Daniel. Université de Montréal. Département de Pharmacie; Canadá Fil: Moquin, Luc. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Gratton, Alain. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Wong, Tak Pan. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina Fil: Giros, Bruno. McGill University. Douglas Mental Health University Institute. Department of Psychiatry; Canadá. Centre National de la Recherche Scientifique; Francia. Institut National de la Santé et de la Recherche Médicale; Francia

Published
2015

14. 695. Resilience against Chronic Stress is Mediated by Noradrenergic Regulation of the Ventral Tegmental Area

Author

Fabio Marti, Elisa Guma, Garance Martin, Naguib Mechawar, Arnaud Tanti, Jennifer Robinson, Luc Moquin, Sylvain Williams, Elsa Isingrini, Quentin Rainer, Alain Gratton, Bruno Giros, Léa C. Perret, and Bénédicte Amilhon

Subjects
Ventral tegmental area, medicine.anatomical_structure, medicine, Chronic stress, Biology, Resilience (network), Neuroscience, Biological Psychiatry
Published
2017

15. Is unpredictable chronic mild stress (UCMS) a reliable model to study depression-induced neuroinflammation?

Author

Elsa Isingrini, Frédéric Minier, Sylvie Chalon, Samuel Leman, Catherine Belzung, Arnaud Tanti, Vincent Camus, Rai Khalid Farooq, Nicolas Arlicot, Anne-Marie Le Guisquet, Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), McGill University = Université McGill [Montréal, Canada], Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), U930, Institut National de la Santé et de la Recherche Médicale (INSERM), Unité informatique du magneraud UIM, Institut National de la Recherche Agronomique (INRA), Université Francois Rabelais [Tours], Ecole Polytechnique Fédérale de Lausanne (EPFL), and Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, MESH: Depression, [SDV]Life Sciences [q-bio], Hippocampus, Nucleus accumbens, Amygdala, 03 medical and health sciences, Behavioral Neuroscience, MESH: Brain, Mice, 0302 clinical medicine, Stress, Physiological, Animal models of depression, MESH: Behavior, Animal, medicine, Animals, MESH: Animals, MESH: Stress, Physiological, MESH: Mice, Depression (differential diagnoses), Neuroinflammation, 030304 developmental biology, 0303 health sciences, MESH: Cytokines, Behavior, Animal, Depression, Brain, MESH: Stress, Psychological, MESH: Male, Stria terminalis, Disease Models, Animal, medicine.anatomical_structure, Cerebral cortex, MESH: Encephalitis, Cytokines, Encephalitis, MESH: Disease Models, Animal, Psychology, Neuroscience, 030217 neurology & neurosurgery, Stress, Psychological
Abstract

International audience; Unipolar depression is one of the leading causes of disability. The pathophysiology of depression is poorly understood. Evidence suggests that inflammation is associated with depression. For instance, pro-inflammatory cytokines are found to be elevated in the peripheral blood of depressed subjects. Cytokine immunotherapy itself is known to induce depressive symptoms. While the epidemiological and biochemical relationship between inflammation and depression is strong, little is known about the possible existence of neuroinflammation in depression. The use of animal models of depression such as the Unpredictable Chronic Mild Stress (UCMS) has already contributed to the elucidation of the pathophysiological mechanisms of depression such as decreased neurogenesis and HPA axis alterations. We used this model to explore the association of depressive-like behavior in mice with changes in peripheral pro-inflammatory cytokines IL-1β, TNFα and IL-6 level as well as the neuroinflammation by quantifying CD11b expression in brain areas known to be involved in the pathophysiology of depression. These areas include the cerebral cortex, the nucleus accumbens, the bed nucleus of the stria terminalis, the caudate putamen, the amygdala and the hippocampus. The results indicate that microglial activation is significantly increased in the infralimbic, cingulate and medial orbital cortices, nucleus accumbens, caudate putamen, amygdala and hippocampus of the mouse brain as a function of UCMS, while levels of pro-inflammatory cytokines did not differ among the groups. This finding suggests that neuroinflammation occurs in depression and may be implicated in the subject's behavioral response. They also suggest that UCMS could be a potentially reliable model to study depression-induced neuroinflammation.

Published
2012

16. Fluoxetine Effect on Aortic Nitric Oxide-Dependent Vasorelaxation in the Unpredictable Chronic Mild Stress Model of Depression in Mice

Author

Catherine Belzung, Marie-Christine Machet, Elsa Isingrini, Jean-Louis Freslon, Vincent Camus, Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomopathologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Ecole Polytechnique Fédérale de Lausanne (EPFL), and Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Random Allocation, [SDV]Life Sciences [q-bio], Prostacyclin, MESH: Logistic Models, 030204 cardiovascular system & hematology, MESH: Atherosclerosis, MESH: Dose-Response Relationship, Drug, chemistry.chemical_compound, Biological Factors, Mice, Random Allocation, 0302 clinical medicine, MESH: Animals, MESH: Endothelium-Dependent Relaxing Factors, Endothelial dysfunction, Applied Psychology, Depression (differential diagnoses), Aorta, Mice, Inbred BALB C, Relaxation (psychology), MESH: Stress, Psychological, MESH: Aorta, 3. Good health, Vasodilation, MESH: Serotonin Uptake Inhibitors, Psychiatry and Mental health, Anesthesia, cardiovascular system, MESH: Endothelium, Vascular, medicine.symptom, Selective Serotonin Reuptake Inhibitors, medicine.drug, medicine.medical_specialty, MESH: Mice, Inbred BALB C, MESH: Depressive Disorder, Major, MESH: Epoprostenol, Nitric Oxide, Nitric oxide, Lesion, MESH: Vasodilation, 03 medical and health sciences, Internal medicine, medicine.artery, Fluoxetine, medicine, Animals, MESH: Fluoxetine, MESH: Mice, Endothelium-Dependent Relaxing Factors, Depressive Disorder, Major, Dose-Response Relationship, Drug, business.industry, MESH: Acetylcholine, medicine.disease, Atherosclerosis, Epoprostenol, Acetylcholine, Disease Models, Animal, Endocrinology, Logistic Models, chemistry, MESH: Nitric Oxide, MESH: Biological Factors, Endothelium, Vascular, MESH: Disease Models, Animal, business, 030217 neurology & neurosurgery, Stress, Psychological
Abstract

OBJECTIVE Major depression is an independent risk factor for the development of cardiovascular diseases. However, the exact mechanism by which depression may induce cardiovascular events is unclear. Endothelial dysfunction has been reported as a possible link between depression and subsequent cardiovascular events as described in depressed subjects. The purpose of this study was to investigate endothelial dysfunction and atherosclerosis formation in the aorta of mice exposed to the unpredictable chronic mild stress (UCMS) procedure. METHODS BALB/c mice were exposed to two 7-week UCMS procedures separated by 6 weeks. Treatments (fluoxetine 10 mg/kg; NaCl 0.9%) started at the third week until the end of the seventh week of each procedure. Endothelial function was evaluated by in vitro assessment of acetylcholine-induced vasorelaxation in aortic rings. By using specific inhibitors for nitric oxide (NO)- and prostacyclin-dependent relaxation, we assessed the part played by NO, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF)-like mediators in endothelium-dependent relaxation. Atherosclerosis was evaluated by histological examination. RESULTS Depression-like behavior was increased in the UCMS versus unstressed group and was reversed by chronic fluoxetine treatment. Vascular reactivity study indicated that UCMS induced a decrease in the NO-dependent relaxation that was partially compensated by an EDHF-like dependent relaxation. Because fluoxetine per se increased the NO-dependent relaxation, fluoxetine was able to reverse UCMS effect on the NO component and abolished the EDHF-like component. Atherosclerotic lesion was found in aorta of UCMS and nonstressed animals. CONCLUSIONS As an independent risk factor, UCMS reproduced the endothelial alterations observed in depression but was not sufficient to provoke morphological alterations.

Published
2012

17. Early and late-onset effect of chronic stress on vascular function in mice: a possible model of the impact of depression on vascular disease in aging

Author

Elsa Isingrini, Vincent Camus, Catherine Belzung, Alexandre d'Audiffret, Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique Psychiatrique Universitaire [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, medicine.medical_specialty, Aging, Heart disease, [SDV]Life Sciences [q-bio], Vascular Cell Adhesion Molecule-1, 030204 cardiovascular system & hematology, Motor Activity, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Internal medicine, Fluoxetine, Plasminogen Activator Inhibitor 1, medicine, Animals, Humans, Chronic stress, Platelet activation, Vascular Diseases, Endothelial dysfunction, ComputingMilieux_MISCELLANEOUS, Vascular disease, Depression, Body Weight, medicine.disease, Intercellular Adhesion Molecule-1, Grooming, Psychiatry and Mental health, Disease Models, Animal, Endocrinology, chemistry, Matrix Metalloproteinase 9, Mice, Inbred DBA, Plasminogen activator inhibitor-1, Geriatrics and Gerontology, Psychology, Plasminogen activator, 030217 neurology & neurosurgery, Biomarkers, Stress, Psychological, medicine.drug
Abstract

Depression is recognized as a predictor of increased cardiac morbidity and mortality. In addition, depressed patients exhibit an increase in the serum markers of endothelial dysfunction and platelet activation involved in the cascade of events leading to atherosclerosis. The purpose of this study was to determine the early and late-onset expression of various vascular markers in a rodent model of depression. Male DBA (an inbred strain of mice)/2J mice were exposed to either 7 weeks of controlled living conditions or unpredictable chronic mild stress (UCMS), and subsequently given daily fluoxetine (10 mg/kg) or NaCl (9%) during the last 5 weeks of the experiment. Depressive-like behavior was evaluated by using motivational and self-care behavior, including the assessment of the animal's coat state and grooming behavior. Enzyme-linked immunoassay was used to quantify matrix metalloproteinase-9 (MMP-9), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and plasminogen activator inhibitor-1 (PAI-1) expression either immediately after the end of the UCMS procedure (short term condition) or 10 months later (long-term condition). Results indicate that 1) UCMS procedure induces a short-term depressive-like behavior in mice, defined as coat state deterioration, an effect that is prevented by fluoxetine treatment; 2) UCMS procedure has no effect on the short-term expression of the studied markers; however, UCMS increases expression of plasminogen activator inhibitor-1 only in the long-term group; 3) fluoxetine treatment is unable to counteract this UCMS-induced change; 4) aging induces behavioral perturbation, defined as a decrease in grooming motivation, and an increase of all the vascular markers in both control and UCMS groups and 5) pretreatment with fluoxetine has no protective effects on aging-induced behavioral and vascular alterations. Thus, in this model of depression-like behavior, UCMS appears to induce late-onset physiological changes, which are consistent with human studies indicating that depression is a risk factor for the development of heart disease.

Published
2011

18. Altered aortic vascular reactivity in the unpredictable chronic mild stress model of depression in mice: UCMS causes relaxation impairment to ACh

Author

Elsa, Isingrini, Alexandre, Surget, Catherine, Belzung, Jean-Louis, Freslon, Jefferson, Frisbee, James, O'Donnell, Vincent, Camus, and Alexandre, d'Audiffret

Subjects
Male, Mice, Inbred BALB C, Behavior, Animal, Dose-Response Relationship, Drug, Depression, Acetylcholine, Vasodilation, Disease Models, Animal, Mice, Phenylephrine, Vasoconstriction, Animals, Corticosterone, Aorta, Stress, Psychological
Abstract

Major depression is an independent risk factor for the development of cardiovascular disease. This impact of depression on vascular function seems to be mediated by the endothelial dysfunction, defined as an impairment of endothelium-dependent vasorelaxation, which represents a reliable predictor of atherosclerosis and has been regularly found to be associated with depression. This study aimed at investigating aortic vascular reactivity in mice submitted to the unpredictable chronic mild stress (UCMS) procedure, a reliable model of depression. The results confirm the effectiveness of the UCMS procedure to induce neuroendocrine, physical and behavioral depression-like alterations as well as a significant decrease of acetylcholine-induced vasorelaxation without any effect on phenylephrine-induced vasoconstriction. In this study, we reveal an altered vascular reactivity in an animal model of depression, demonstrating an endothelial dysfunction reminiscent to the one found in depressed patients.

Published
2010

19. Depressive behavior and vascular dysfunction: a link between clinical depression and vascular disease?

Author

Stephanie J. Frisbee, Elsa Isingrini, Phoebe A. Stapleton, Adam G. Goodwill, Alexandre d'Audiffret, Jefferson C. Frisbee, Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), and Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Male, MESH: Inflammation, Time Factors, Physiology, Vasodilator Agents, [SDV]Life Sciences [q-bio], Vasodilation, Severity of Illness Index, MESH: Hypertension, MESH: Dose-Response Relationship, Drug, Mice, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, MESH: Behavior, Animal, Medicine, Vasoconstrictor Agents, Chronic stress, MESH: Animals, Depression (differential diagnoses), Aorta, 0303 health sciences, Mice, Inbred BALB C, Behavior, Animal, Depression, MESH: Aorta, MESH: Stress, Psychological, Articles, Peripheral, MESH: Insulin Resistance, Anesthesia, Hypertension, Cardiology, MESH: Vascular Diseases, MESH: Hydrogen Peroxide, MESH: Vasoconstriction, Inflammation Mediators, MESH: Nitric Oxide Synthase Type III, medicine.medical_specialty, Nitric Oxide Synthase Type III, MESH: Depression, MESH: Inflammation Mediators, MESH: Mice, Inbred BALB C, Nitric Oxide, MESH: Vasodilation, 03 medical and health sciences, MESH: Vasoconstrictor Agents, MESH: Cyclooxygenase Inhibitors, Insulin resistance, Physiology (medical), Internal medicine, MESH: Severity of Illness Index, Severity of illness, Animals, In patient, Cyclooxygenase Inhibitors, Vascular Diseases, MESH: Mice, 030304 developmental biology, Inflammation, Dose-Response Relationship, Drug, business.industry, Vascular disease, MESH: Chronic Disease, MESH: Time Factors, Hydrogen Peroxide, medicine.disease, MESH: Male, MESH: Vasodilator Agents, Disease Models, Animal, Vasoconstriction, MESH: Nitric Oxide, Chronic Disease, MESH: Biomarkers, Insulin Resistance, MESH: Disease Models, Animal, business, 030217 neurology & neurosurgery, Biomarkers, Stress, Psychological
Abstract

As chronic stress and depression have become recognized as significant risk factors for peripheral vascular disease in patients with no prior history of vasculopathy, we interrogated this relationship utilizing an established mouse model of chronic stress/depressive symptoms from behavioral research. Male mice were exposed to 8 wk of unpredictable chronic mild stress (UCMS; e.g., wet bedding, predator sound/smell, random disruption of light/dark cycle), with indexes of depressive behavior (coat status, grooming, and mobility) becoming exacerbated vs. controls. In vascular rings, constrictor (phenylephrine) and endothelium-independent dilator (sodium nitroprusside) responses were not different between groups, although endothelium-dependent dilation (methacholine) was attenuated with UCMS. Nitric oxide synthase (NOS) inhibition was without effect in UCMS but nearly abolished reactivity in controls, while cyclooxygenase inhibition blunted dilation in both. Combined blockade abolished reactivity in controls, although a significant dilation remained in UCMS that was abolished by catalase. Arterial NO production was attenuated by UCMS, although H2O2 production was increased. UCMS mice demonstrated an increased, although variable, insulin resistance and inflammation. However, while UCMS-induced vascular impairments were consistent, the predictive power of aggregate plasma levels of insulin, TNF-α, IL-1β, and C-reactive peptide were limited. However, when separated into tertiles with regard to vascular outcomes, insulin resistance and hypertension were predictive of the most severe vascular impairments. Taken together, these data suggest that aggregate insulin resistance, inflammation, and hypertension in UCMS mice are not robust predictors of vascular dysfunction, suggesting that unidentified mechanisms may be superior predictors of poor vascular outcomes in this model.

Published
2010

20. Endothelial dysfunction: A potential therapeutic target for geriatric depression and brain amyloid deposition in Alzheimer's disease?

Author

Elsa, Isingrini, Thomas, Desmidt, Catherine, Belzung, Vincent, Camus, Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Isingrini, Elsa, and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Aged, Amyloid, MESH: Amyloid, MESH: Humans, MESH: Depression, Depression, [SDV]Life Sciences [q-bio], Brain, MESH: Drug Design, [SDV] Life Sciences [q-bio], MESH: Brain, Alzheimer Disease, Drug Design, MESH: Vascular Diseases, Animals, Humans, MESH: Animals, Endothelium, Vascular, Vascular Diseases, MESH: Endothelium, Vascular, MESH: Alzheimer Disease, Aged
Abstract

International audience; Depression and Alzheimer's disease (AD) are among the most prevalent mental disorders in the elderly. Strong evidence suggests that vascular diseases and vascular risk factors are associated with both depression and AD, and could partially explain the coexistence or the concurrent onset of these two diseases. In particular, endothelial dysfunction appears to play a critical role in the neurobiology of depression and amyloid deposition in the brains of patients with AD. Antidepressants have a significant impact on endothelial function. In addition, several drugs used to treat vascular disease or vascular risk factors, such as calcium-channel blockers, angiotensin-converting enzyme inhibitors and statins, have, to variable extents, significant clinical effects on depressive symptomatology or amyloid deposition in AD. Furthermore, preclinical and clinical data suggest that the nitric oxide and VEGF signaling pathways may be of value for the treatment of depression and AD.

Published
2009

21. Cocaine-induced reinstatement in rats: evidence for a critical role of cocaine stimulus properties

Author

Martine Cador, Ronald Keiflin, Elsa Isingrini, Centre Neurosciences intégratives et Cognition (INCC - UMR 8002), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Aquitaine Institute of Cognitive and Integrative Neurosciences, and Université de Bordeaux (UB)

Subjects
Male, [SDV]Life Sciences [q-bio], MESH: Mental Recall, Pharmacology, Stimulus Salience, MESH: Association Learning, Extinction, Psychological, MESH: Appetitive Behavior, MESH: Dose-Response Relationship, Drug, Discrimination Learning, 0302 clinical medicine, Cocaine, Operant response, MESH: Animals, Food pellet, Discrimination learning, Sensitization, 2. Zero hunger, Appetitive Behavior, digestive, oral, and skin physiology, food and beverages, MESH: Motor Activity, medicine.anatomical_structure, Anesthesia, Incentive salience, Psychology, Injections, Intraperitoneal, MESH: Injections, Intraperitoneal, MESH: Rats, MESH: Motivation, Motor Activity, Stimulus (physiology), MESH: Central Nervous System Stimulants, 03 medical and health sciences, MESH: Cocaine, medicine, Animals, Rats, Wistar, Motivation, Dose-Response Relationship, Drug, fungi, Association Learning, MESH: Rats, Wistar, MESH: Extinction, Psychological, MESH: Discrimination Learning, MESH: Male, Rats, 030227 psychiatry, Locomotor sensitization, Mental Recall, Central Nervous System Stimulants, 030217 neurology & neurosurgery
Abstract

The exact behavioral nature of drug-induced reinstatement of drug seeking is still debated. As an incentive, the drug can have general facilitatory influences on appetitive behaviors. As an interoceptive stimulus, the drug can acquire discriminative properties and control behavior. This study assessed the relative contribution of the incentive versus discriminative properties of cocaine in food-seeking reinstatement. In Experiment 1, eight groups of rats were trained to press a lever for food pellets and experienced cocaine (0, 5, 10, or 15 mg/kg; i.p.), either during the operant conditioning sessions or 4 h after, in another environment without food access. In Experiment 2, to dissociate the role of the operant response per se from the consummatory response, two groups of rats experienced food consumption under cocaine (10 mg/kg; i.p.) either during operant conditioning sessions or during alternate sessions of free access to the food. Then, for both experiments, food pellets were withheld and cocaine injections ceased (extinction). The reinstating effects of noncontingent cocaine (10 mg/kg; i.p.) and food pellet delivery were assessed. Locomotor activity was recorded to probe expression of behavioral sensitization. Cocaine reinstated lever pressing only in rats having previously performed the operant responses under cocaine. In contrast, food pellet delivery reinstated lever pressing independently of rats’ history with cocaine. Locomotor sensitization was evidenced for all cocaine-pre-exposed rats, dissociating sensitization from reinstatement. When present during operant conditioning, the stimulus “cocaine” acquires conditioned properties which can then promote reinstatement of the extinguished behavior.

Published
2008

22. P.2.b.003 Endothelial dysfunction in a rodent model of depression may underlie atherosclerosis formation

Author

Elsa Isingrini, Jean-Louis Freslon, Catherine Belzung, Vincent Camus, and M.C. Machet

Subjects
Pharmacology, medicine.medical_specialty, business.industry, Rodent model, medicine.disease, Psychiatry and Mental health, Endocrinology, Neurology, Internal medicine, Medicine, Pharmacology (medical), Neurology (clinical), Endothelial dysfunction, business, Biological Psychiatry, Depression (differential diagnoses)
Published
2009

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