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1. SCO-spondin knockout mice exhibit small brain ventricles and mild spine deformation

Author

Huixin Xu, Guillaume P. Dugué, Yasmine Cantaut-Belarif, François-Xavier Lejeune, Suhasini Gupta, Claire Wyart, and Maria K. Lehtinen

Subjects
SCO-spondin/SSPO, Subcommissural organ (SCO), Reissner’s fiber, Cerebrospinal fluid, Spinal cord, Ventricular volume, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Reissner’s fiber (RF) is an extracellular polymer comprising the large monomeric protein SCO-spondin (SSPO) secreted by the subcommissural organ (SCO) that extends through cerebrospinal fluid (CSF)-filled ventricles into the central canal of the spinal cord. In zebrafish, RF and CSF-contacting neurons (CSF-cNs) form an axial sensory system that detects spinal curvature, instructs morphogenesis of the body axis, and enables proper alignment of the spine. In mammalian models, RF has been implicated in CSF circulation. However, challenges in manipulating Sspo, an exceptionally large gene of 15,719 nucleotides, with traditional approaches has limited progress. Here, we generated a Sspo knockout mouse model using CRISPR/Cas9-mediated genome-editing. Sspo knockout mice lacked RF-positive material in the SCO and fibrillar condensates in the brain ventricles. Remarkably, Sspo knockout brain ventricle sizes were reduced compared to littermate controls. Minor defects in thoracic spine curvature were detected in Sspo knockouts, which did not alter basic motor behaviors tested. Altogether, our work in mouse demonstrates that SSPO and RF regulate ventricle size during development but only moderately impact spine geometry.

Published
2023
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2. Inertial Measurement of Head Tilt in Rodents: Principles and Applications to Vestibular Research

Author

Romain Fayat, Viviana Delgado Betancourt, Thibault Goyallon, Mathieu Petremann, Pauline Liaudet, Vincent Descossy, Lionel Reveret, and Guillaume P. Dugué

Subjects
inertial sensors, rodents, head tilt, attitude estimation, orientation filters, vestibular system, Chemical technology, TP1-1185
Abstract

Inertial sensors are increasingly used in rodent research, in particular for estimating head orientation relative to gravity, or head tilt. Despite this growing interest, the accuracy of tilt estimates computed from rodent head inertial data has never been assessed. Using readily available inertial measurement units mounted onto the head of freely moving rats, we benchmarked a set of tilt estimation methods against concurrent 3D optical motion capture. We show that, while low-pass filtered head acceleration signals only provided reliable tilt estimates in static conditions, sensor calibration combined with an appropriate choice of orientation filter and parameters could yield average tilt estimation errors below 1.5∘ during movement. We then illustrate an application of inertial head tilt measurements in a preclinical rat model of unilateral vestibular lesion and propose a set of metrics describing the severity of associated postural and motor symptoms and the time course of recovery. We conclude that headborne inertial sensors are an attractive tool for quantitative rodent behavioral analysis in general and for the study of vestibulo-postural functions in particular.

Published
2021
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3. Functional Principles of Posterior Septal Inputs to the Medial Habenula

Author

Yo Otsu, Salvatore Lecca, Katarzyna Pietrajtis, Charly Vincent Rousseau, Païkan Marcaggi, Guillaume Pierre Dugué, Caroline Mailhes-Hamon, Manuel Mameli, and Marco Alberto Diana

Subjects
posterior septum, medial habenula, glutamatergic transmission, calcium-permeable AMPA receptors, heterotrimeric NMDA receptors, locomotion, anxiety, Biology (General), QH301-705.5
Abstract

The medial habenula (MHb) is an epithalamic hub contributing to expression and extinction of aversive states by bridging forebrain areas and midbrain monoaminergic centers. Although contradictory information exists regarding their synaptic properties, the physiology of the excitatory inputs to the MHb from the posterior septum remains elusive. Here, combining optogenetics-based mapping with ex vivo and in vivo physiology, we examine the synaptic properties of posterior septal afferents to the MHb and how they influence behavior. We demonstrate that MHb cells receive sparse inputs producing purely glutamatergic responses via calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), heterotrimeric GluN2A-GluN2B-GluN1 N-methyl-D-aspartate (NMDA) receptors, and inhibitory group II metabotropic glutamate receptors. We describe the complex integration dynamics of these components by MHb cells. Finally, we combine ex vivo data with realistic afferent firing patterns recorded in vivo to demonstrate that efficient optogenetic septal stimulation in the MHb induces anxiolysis and promotes locomotion, contributing long-awaited evidence in favor of the importance of this septo-habenular pathway.

Published
2018
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4. Optogenetic recruitment of dorsal raphe serotonergic neurons acutely decreases mechanosensory responsivity in behaving mice.

Author

Guillaume P Dugué, Magor L Lörincz, Eran Lottem, Enrica Audero, Sara Matias, Patricia A Correia, Clément Léna, and Zachary F Mainen

Subjects
Medicine, Science
Abstract

The inhibition of sensory responsivity is considered a core serotonin function, yet this hypothesis lacks direct support due to methodological obstacles. We adapted an optogenetic approach to induce acute, robust and specific firing of dorsal raphe serotonergic neurons. In vitro, the responsiveness of individual dorsal raphe serotonergic neurons to trains of light pulses varied with frequency and intensity as well as between cells, and the photostimulation protocol was therefore adjusted to maximize their overall output rate. In vivo, the photoactivation of dorsal raphe serotonergic neurons gave rise to a prominent light-evoked field response that displayed some sensitivity to a 5-HT1A agonist, consistent with autoreceptor inhibition of raphe neurons. In behaving mice, the photostimulation of dorsal raphe serotonergic neurons produced a rapid and reversible decrease in the animals' responses to plantar stimulation, providing a new level of evidence that serotonin gates sensory-driven responses.

Published
2014
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5. Inertial Measurement of Head Tilt in Rodents: Principles and Applications to Vestibular Research

Author

Pauline Liaudet, Lionel Reveret, Mathieu Petremann, Romain Fayat, Guillaume P. Dugué, Vincent Descossy, Viviana Delgado Betancourt, Thibault Goyallon, Dugué, Guillaume, Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Sensorion [Montpellier], Calcul des Variations, Géométrie, Image (CVGI), Laboratoire Jean Kuntzmann (LJK), Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), ANR-20-CE37-0016,InVest,Circuits vestibulo-cérébelleux impliqués dans la cognition spatiale(2020), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris

Subjects
Inertial frame of reference, Computer science, Movement, Acceleration, ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION, [SDV.NEU.PC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, unilateral vestibular lesion, Rodentia, TP1-1185, Biochemistry, Motion capture, Article, Analytical Chemistry, 03 medical and health sciences, 0302 clinical medicine, Inertial measurement unit, [SPI.MECA.BIOM] Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph], Animals, Computer vision, Electrical and Electronic Engineering, orientation filters, Instrumentation, 030304 developmental biology, Vestibular system, 0303 health sciences, Quantitative Biology::Neurons and Cognition, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Orientation (computer vision), business.industry, Chemical technology, head tilt, vestibular system, [SPI.MECA.BIOM]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph], inertial sensors, attitude estimation, Atomic and Molecular Physics, and Optics, Rats, Tilt (optics), rodents, Computer Science::Programming Languages, Head (vessel), Vestibule, Labyrinth, Artificial intelligence, business, 030217 neurology & neurosurgery, Gravitation
Abstract

Inertial sensors are increasingly used in rodent research, in particular for estimating head orientation relative to gravity, or head tilt. Despite this growing interest, the accuracy of tilt estimates computed from rodent head inertial data has never been assessed. Using readily available inertial measurement units mounted onto the head of freely moving rats, we benchmarked a set of tilt estimation methods against concurrent 3D optical motion capture. We show that, while low-pass filtered head acceleration signals only provided reliable tilt estimates in static conditions, sensor calibration combined with an appropriate choice of orientation filter and parameters could yield average tilt estimation errors below 1.5∘ during movement. We then illustrate an application of inertial head tilt measurements in a preclinical rat model of unilateral vestibular lesion and propose a set of metrics describing the severity of associated postural and motor symptoms and the time course of recovery. We conclude that headborne inertial sensors are an attractive tool for quantitative rodent behavioral analysis in general and for the study of vestibulo-postural functions in particular.

Published
2021
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6. Optogenetic Tractography for anatomo-functional characterization of cortico-subcortical neural circuits in non-human primates

Author

Caroline Jan, Koichi Hosomi, Emmanuel Brouillet, Christophe Pouzat, Kyriacos A. Mitrophanous, Edward S. Boyden, Xavier Drouot, Philippe Hantraye, J. F. Mangin, Romina Aron-Badin, J. Dauguet, Stéphane Palfi, S Senova, Isabelle Doignon, G. S. Ralph, L. Barnes, Frédéric Pain, Guillaume P. Dugué, C. Poupon, Hannah J Stewart, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC (UMR_8165)), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Massachusetts Institute of Technology. Media Laboratory, Program in Media Arts and Sciences (Massachusetts Institute of Technology), and Boyden, Edward

Subjects
0301 basic medicine, Male, Deep brain stimulation, medicine.medical_treatment, Genetic Vectors, lcsh:Medicine, Action Potentials, Biology, Optogenetics, Article, 03 medical and health sciences, 0302 clinical medicine, Genes, Reporter, Subthalamic Nucleus, Transduction, Genetic, Biological neural network, medicine, Connectome, Animals, lcsh:Science, [PHYS]Physics [physics], Multidisciplinary, Opsins, lcsh:R, Lentivirus, Motor Cortex, Macaca mulatta, Magnetic Resonance Imaging, Neuromodulation (medicine), Transcranial magnetic stimulation, Subthalamic nucleus, 030104 developmental biology, nervous system, lcsh:Q, Nerve Net, Neuroscience, 030217 neurology & neurosurgery, Tractography
Abstract

Dissecting neural circuitry in non-human primates (NHP) is crucial to identify potential neuromodulation anatomical targets for the treatment of pharmacoresistant neuropsychiatric diseases by electrical neuromodulation. How targets of deep brain stimulation (DBS) and cortical targets of transcranial magnetic stimulation (TMS) compare and might complement one another is an important question. Combining optogenetics and tractography may enable anatomo-functional characterization of large brain cortico-subcortical neural pathways. For the proof-of-concept this approach was used in the NHP brain to characterize the motor cortico-subthalamic pathway (m_CSP) which might be involved in DBS action mechanism in Parkinson’s disease (PD). Rabies-G-pseudotyped and Rabies-G-VSVg-pseudotyped EIAV lentiviral vectors encoding the opsin ChR2 gene were stereotaxically injected into the subthalamic nucleus (STN) and were retrogradely transported to the layer of the motor cortex projecting to STN. A precise anatomical mapping of this pathway was then performed using histology-guided high angular resolution MRI tractography guiding accurately cortical photostimulation of m_CSP origins. Photoexcitation of m_CSP axon terminals or m_CSP cortical origins modified the spikes distribution for photosensitive STN neurons firing rate in non-equivalent ways. Optogenetic tractography might help design preclinical neuromodulation studies in NHP models of neuropsychiatric disease choosing the most appropriate target for the tested hypothesis.

Published
2018
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7. Activity patterns of serotonin neurons underlying cognitive flexibility

Author

Sara Matias, Eran Lottem, Zachary F. Mainen, and Guillaume P. Dugué

Subjects
Dorsal Raphe Nucleus, 0301 basic medicine, Serotonin, Surprise, Mouse, QH301-705.5, media_common.quotation_subject, Perseveration, Science, Reversal Learning, perseveration, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Dopamine, medicine, Animals, Closure (psychology), Biology (General), media_common, General Immunology and Microbiology, General Neuroscience, Cognitive flexibility, Flexibility (personality), Serotonin-dopamine opponency, General Medicine, 030104 developmental biology, Mood, reversal learning, Medicine, medicine.symptom, Psychology, Neuroscience, 030217 neurology & neurosurgery, Serotonergic Neurons, Research Article, medicine.drug
Abstract

Serotonin is implicated in mood and affective disorders. However, growing evidence suggests that a core endogenous role is to promote flexible adaptation to changes in the causal structure of the environment, through behavioral inhibition and enhanced plasticity. We used long-term photometric recordings in mice to study a population of dorsal raphe serotonin neurons, whose activity we could link to normal reversal learning using pharmacogenetics. We found that these neurons are activated by both positive and negative prediction errors, and thus report signals similar to those proposed to promote learning in conditions of uncertainty. Furthermore, by comparing the cue responses of serotonin and dopamine neurons, we found differences in learning rates that could explain the importance of serotonin in inhibiting perseverative responding. Our findings show how the activity patterns of serotonin neurons support a role in cognitive flexibility, and suggest a revised model of dopamine–serotonin opponency with potential clinical implications. DOI: http://dx.doi.org/10.7554/eLife.20552.001, eLife digest Serotonin is a molecule that plays various roles in the human body. In the brain, it is involved in regulating mood and emotions. Growing evidence suggests that serotonin also helps animals – including humans – adapt their behavior to changes in their environment. To allow for such behavioral flexibility, serotonin might promote changes in the underlying brain structures and activity. In a type of learning known as ‘reversal learning’, for instance, it is necessary to adapt to a sudden change in a previously familiar environment. For example, if there were a road closure on a person’s way to work, they might want to learn to stop following their usual route and learn a new and better one. Previous research has shown that when serotonin signaling is reduced, people persevere. That is, they will keep following the old route even if it is no longer the best choice. How this process works is still largely unknown. To start unraveling these mechanisms, Matias et al. trained mice in a reversal learning task while manipulating and recording the activity of the neurons that produce serotonin. The results showed that when the activity in serotonin neurons was experimentally blocked, the mice tended to keep looking for a reward that was no longer available. Then, by recording the activity of serotonin neurons, Matias et al. found that it was the surprise of discovering a change in a previously familiar environment that activates serotonin neurons. It did not matter whether the change was better or worse than expected. The findings suggest that together with dopamine, another molecule involved in learning from rewards, serotonin could play an important role during reversal learning. One next step will be to determine if serotonin mainly stops perseverance in its tracks, or whether it works by helping to unlearn the old behavior, or a combination of both. In the future, this could further our understanding of depression, which can be viewed as a disorder characterized by patients being unable to adapt to adverse situations, leaving them trapped to repeat behaviors and thoughts that are not beneficial. Future studies could also build on these findings to guide the development of new treatments for depression that involve serotonin. DOI: http://dx.doi.org/10.7554/eLife.20552.002

Published
2017

8. A subcortical inhibitory signal for behavioral arrest in the thalamus

Author

Charly V. Rousseau, Marco A. Diana, Stéphane Dieudonné, Viktor M. Plattner, Balázs Hangya, Hanns Ulrich Zeilhofer, Guillaume P. Dugué, Kristóf Giber, Hajnalka Bokor, László Havas, László Acsády, Hendrik Wildner, Zsófia Maglóczky, Réseaux de neurones et rythmes physiopathologiques = Neuronal Networks and Physiopathological Rhythms (NPS-09), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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)-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)-Centre National de la Recherche Scientifique (CNRS), Hungarian Scientific Research Fund (OTKA) [T109754, T75676], National Office for Research and Technology [NKTH-ANR-09-BLAN-0401], Research University, Swartz Foundation, EU, Hungarian Korean Joint Laboratory Program, Hungarian Brain Research Program [KTIA\₁3_NAP-A-I/1], Wellcome Trust [fWT094513], Advanced Investigator ERC [DHISP 250128], CNRS, INSERM, Ecole Normale Superieure, French Government and implemented by the ANR [ANR-10LABX-54 MEMO LIFE, ANR-11-IDEX-0001-02 PSL], 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), University of Zurich, Acsády, László, 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
Male, Patch-Clamp Techniques, Thalamus, Glycine, Pontine Tegmentum, 10050 Institute of Pharmacology and Toxicology, 610 Medicine & health, Biology, Inhibitory postsynaptic potential, Article, Mice, 03 medical and health sciences, Nerve Fibers, Receptors, Glycine, 0302 clinical medicine, Receptors, GABA, medicine, Biological neural network, Tegmentum, Animals, GABAergic Neurons, 030304 developmental biology, Afferent Pathways, 0303 health sciences, Behavior, Animal, Intralaminar Thalamic Nuclei, General Neuroscience, 2800 General Neuroscience, Neural Inhibition, Paramedian pontine reticular formation, Optogenetics, medicine.anatomical_structure, nervous system, Forebrain, GABAergic, 570 Life sciences, biology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Brainstem, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; Organization of behavior requires rapid coordination of brainstem and forebrain activity. The exact mechanisms of effective communication between these regions are presently unclear. The intralaminar thalamic nuclei (IL) probably serves as a central hub in this circuit by connecting the critical brainstem and forebrain areas. We found that GABAergic and glycinergic fibers ascending from the pontine reticular formation (PRF) of the brainstem evoked fast and reliable inhibition in the IL via large, multisynaptic terminals. This inhibition was fine-tuned through heterogeneous GABAergic and glycinergic receptor ratios expressed at individual synapses. Optogenetic activation of PRF axons in the IL of freely moving mice led to behavioral arrest and transient interruption of awake cortical activity. An afferent system with comparable morphological features was also found in the human IL. These data reveal an evolutionarily conserved ascending system that gates forebrain activity through fast and powerful synaptic inhibition of the IL.

Published
2015
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9. Optogenetic Recruitment of Dorsal Raphe Serotonergic Neurons Acutely Decreases Mechanosensory Responsivity in Behaving Mice

Author

Eran Lottem, Magor L. Lorincz, Sara Matias, Zachary F. Mainen, Enrica Audero, Guillaume P. Dugué, Patrícia A. Correia, and Clément Léna

Subjects
Dorsal Raphe Nucleus, Serotonin, Neurophysiology, lcsh:Medicine, Stimulation, Mice, Transgenic, Biology, Optogenetics, Serotonergic, Mechanotransduction, Cellular, Biochemistry, Photostimulation, 03 medical and health sciences, Mice, 0302 clinical medicine, Dorsal raphe nucleus, Organ Culture Techniques, Animals, Tactile Sensation, lcsh:Science, 030304 developmental biology, Neurons, 0303 health sciences, 8-Hydroxy-2-(di-n-propylamino)tetralin, Multidisciplinary, Raphe, Behavior, Animal, Neuromodulation, lcsh:R, Biology and Life Sciences, Pain Sensation, Neurochemistry, Anatomy, Serotonin 5-HT1 Receptor Agonists, Sensory Systems, Somatosensory System, nervous system, Autoreceptor, lcsh:Q, Neuroscience, 030217 neurology & neurosurgery, Photic Stimulation, Research Article
Abstract

The inhibition of sensory responsivity is considered a core serotonin function, yet this hypothesis lacks direct support due to methodological obstacles. We adapted an optogenetic approach to induce acute, robust and specific firing of dorsal raphe serotonergic neurons. In vitro, the responsiveness of individual dorsal raphe serotonergic neurons to trains of light pulses varied with frequency and intensity as well as between cells, and the photostimulation protocol was therefore adjusted to maximize their overall output rate. In vivo, the photoactivation of dorsal raphe serotonergic neurons gave rise to a prominent light-evoked field response that displayed some sensitivity to a 5-HT1A agonist, consistent with autoreceptor inhibition of raphe neurons. In behaving mice, the photostimulation of dorsal raphe serotonergic neurons produced a rapid and reversible decrease in the animals' responses to plantar stimulation, providing a new level of evidence that serotonin gates sensory-driven responses. ERC 250334, 5-HT Optogenetic MSCA 220098 info:eu-repo/semantics/publishedVersion

Published
2014

10. Mixed Inhibitory Synaptic Balance Correlates with Glutamatergic Synaptic Phenotype in Cerebellar Unipolar Brush Cells

Author

Marco Diana, Stéphane Dieudonné, Enrico Mugnaini, Charly V. Rousseau, Andréa Dumoulin, Guillaume P. Dugué, Réseaux de neurones et rythmes physiopathologiques = Neuronal Networks and Physiopathological Rhythms (NPS-09), 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), Region iie de France and Fondation pour la Recherche Medicale fellowships, French Research Ministry, and Agence Nationale de la Recherche Grant Vesticode [07BSYS010], Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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)-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)-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)-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
Male, Mossy fiber (hippocampus), Glycine, Glutamic Acid, In Vitro Techniques, Biology, Receptors, Metabotropic Glutamate, Inhibitory postsynaptic potential, Synaptic Transmission, GABA Antagonists, 03 medical and health sciences, Glutamatergic, Nerve Fibers, Receptors, Glycine, 0302 clinical medicine, Interneurons, Postsynaptic potential, Cerebellum, Excitatory Amino Acid Agonists, Animals, Rats, Wistar, GABA Agonists, gamma-Aminobutyric Acid, 030304 developmental biology, Neurons, 0303 health sciences, Kainic Acid, General Neuroscience, fungi, Glycine Agents, Neural Inhibition, Articles, Rats, Inhibitory Postsynaptic Potentials, Metabotropic glutamate receptor, Excitatory postsynaptic potential, GABAergic, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Glutamatergic synapse, Excitatory Amino Acid Antagonists, Neuroscience, 030217 neurology & neurosurgery
Abstract

Inhibitory synapses display a great diversity through varying combinations of presynaptic GABA and glycine release and postsynaptic expression of GABA and glycine receptor subtypes. We hypothesized that increased flexibility offered by this dual transmitter system might serve to tune the inhibitory phenotype to the properties of afferent excitatory synaptic inputs in individual cells. Vestibulocerebellar unipolar brush cells (UBC) receive a single glutamatergic synapse from a mossy fiber (MF), which makes them an ideal model to study excitatory–inhibitory interactions. We examined the functional phenotypes of mixed inhibitory synapses formed by Golgi interneurons onto UBCs in rat slices. We show that glycinergic IPSCs are present in all cells. An additional GABAergic component of large amplitude is only detected in a subpopulation of UBCs. This GABAergic phenotype is strictly anti-correlated with the expression of type II, but not type I, metabotropic glutamate receptors (mGluRs) at the MF synapse. Immunohistochemical stainings and agonist applications show that global UBC expression of glycine and GABAAreceptors matches the pharmacological profile of IPSCs. Paired recordings of Golgi cells and UBCs confirm the postsynaptic origin of the inhibitory phenotype, including the slow kinetics of glycinergic components. These results strongly suggest the presence of a functional coregulation of excitatory and inhibitory phenotypes at the single-cell level. We propose that slow glycinergic IPSCs may provide an inhibitory tone, setting the gain of the MF to UBC relay, whereas large and fast GABAergic IPSCs may in addition control spike timing in mGluRII-negative UBCs.

Published
2012
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11. Cerebellar re-encoding of self-generated head movements

Author

Guillaume P Dugué, Matthieu Tihy, Boris Gourévitch, and Clément Léna

Subjects
cerebellum, vestibular system, Purkinje cells, self-motion, head direction, gravity, Medicine, Science, Biology (General), QH301-705.5
Abstract

Head movements are primarily sensed in a reference frame tied to the head, yet they are used to calculate self-orientation relative to the world. This requires to re-encode head kinematic signals into a reference frame anchored to earth-centered landmarks such as gravity, through computations whose neuronal substrate remains to be determined. Here, we studied the encoding of self-generated head movements in the rat caudal cerebellar vermis, an area essential for graviceptive functions. We found that, contrarily to peripheral vestibular inputs, most Purkinje cells exhibited a mixed sensitivity to head rotational and gravitational information and were differentially modulated by active and passive movements. In a subpopulation of cells, this mixed sensitivity underlay a tuning to rotations about an axis defined relative to gravity. Therefore, we show that the caudal vermis hosts a re-encoded, gravitationally polarized representation of self-generated head kinematics in freely moving rats.

Published
2017
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