Preclinical imaging studies offer a unique access to the rat brain, allowing investigations that go beyond what is possible in human studies. Unfortunately, these techniques still suffer from a lack of dedicated and standardized... more
Preclinical imaging studies offer a unique access to the rat brain, allowing investigations that go beyond what is possible in human studies. Unfortunately, these techniques still suffer from a lack of dedicated and standardized neuroimaging tools, namely brain templates and descriptive atlases. Here, we present two rat brain MRI templates and their associated gray matter, white matter and cerebrospinal fluid probability maps, generated from ex vivo $${\mathrm{T}}_2^ \ast$$ T 2 * -weighted images (90 µm isotropic resolution) and in vivo T2-weighted images (150 µm isotropic resolution). In association with these templates, we also provide both anatomical and functional 3D brain atlases, respectively derived from the merging of the Waxholm and Tohoku atlases, and analysis of resting-state functional MRI data. Finally, we propose a complete set of preclinical MRI reference resources, compatible with common neuroimaging software, for the investigation of rat brain structures and functions.
Research Interests: Computer Science, Artificial Intelligence, Neuroimaging, Magnetic Resonance Imaging, Medicine, and 14 moreMultidisciplinary, Brain Mapping, Software, Cerebrospinal Fluid, Animals, Male, Three Dimensional Imaging, Behavioral Animal Models, White matter, Rats, Science Technology, Wistar Rats, Gray Matter, and Nature Communications
Stress is a well-established trigger for a number of neuropsychiatric disorders, as it alters both structure and function of several brain regions and its networks. Herein, we conduct a longitudinal neuroimaging study to assess how a... more
Stress is a well-established trigger for a number of neuropsychiatric disorders, as it alters both structure and function of several brain regions and its networks. Herein, we conduct a longitudinal neuroimaging study to assess how a chronic unpredictable stress protocol impacts the structure of the rat brain and its functional connectome in both high and low responders to stress. Our results reveal the changes that stress triggers in the brain, with structural atrophy affecting key regions such as the prelimbic, cingulate, insular and retrosplenial, somatosensory, motor, auditory and perirhinal/entorhinal cortices, the hippocampus, the dorsomedial striatum, nucleus accumbens, the septum, the bed nucleus of the stria terminalis, the thalamus and several brain stem nuclei. These structural changes are associated with increasing functional connectivity within a network composed by these regions. Moreover, using a clustering based on endocrine and behavioural outcomes, animals were cla...
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In today’s society, every individual is subjected to stressful stimuli with different intensities and duration. This exposure can be a key trigger in several mental illnesses greatly affecting one’s quality of life. Yet not all subjects... more
In today’s society, every individual is subjected to stressful stimuli with different intensities and duration. This exposure can be a key trigger in several mental illnesses greatly affecting one’s quality of life. Yet not all subjects respond equally to the same stimulus and some are able to better adapt to them delaying the onset of its negative consequences. The neural specificities of this adaptation can be essential to understand the true dynamics of stress as well as to design new approaches to reduce its consequences. In the current work, we employed ex vivo high field diffusion magnetic resonance imaging (MRI) to uncover the differences in white matter properties in the entire brain between Fisher 344 (F344) and Sprague–Dawley (SD) rats, known to present different responses to stress, and to examine the effects of a 2-week repeated inescapable stress paradigm. We applied a tract-based spatial statistics (TBSS) analysis approach to a total of 25 animals. After exposure to st...
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Research Interests: Neuroscience, Psychology, Fear, Medicine, Molecular Psychiatry, and 14 moreBiological Sciences, Antidepressant, Animals, Male, Amygdala, Neurons, Rats, Analysis of Variance, Time Factors, Tianeptine, Gene Expression Regulation, Acoustic Stimulation, Psychology and Cognitive Sciences, and Medical and Health Sciences
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Dopamine: a potential substrate for synaptic plasticity and memory mechanisms
La consommation de cannabis chez les adolescents et les jeunes adultes constitue un facteur de risque de developpement de symptomes psychotiques. L’objectif de cette these etait d’etudier les consequences a l’âge adulte d’une exposition... more
La consommation de cannabis chez les adolescents et les jeunes adultes constitue un facteur de risque de developpement de symptomes psychotiques. L’objectif de cette these etait d’etudier les consequences a l’âge adulte d’une exposition chronique aux cannabinoides pendant l’adolescence. Nous avons realise ces etudes chez le Rat et demontre que l’administration chronique d’un agoniste des recepteurs cannabinoides, le CP55, 940, durant l’adolescence (JPN 29 a 50) entraine a l’âge adulte des deficits significatifs et durables de la memoire a court terme et de la memoire de travail spatiale. Le meme traitement administre a l’âge adulte (JPN 70 a 91) n’entraine pas de deficits cognitifs a long terme. L’apport de ces travaux et leur originalite a ete de contribuer a la comprehension des mecanismes sous-jacents au developpement de ces deficits cognitifs. Nous avons mis en evidence, chez ces rats a l’âge adulte, une diminution significative de l’amplitude de la PLT induite sur le circuit re...
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During mobile phone conversations, the temporal lobe neural networks involved in processing auditory information are exposed to electromagnetic fields (EMF) such as pulse-modulated GSM-1800 MHz radiofrequencies that convey wireless... more
During mobile phone conversations, the temporal lobe neural networks involved in processing auditory information are exposed to electromagnetic fields (EMF) such as pulse-modulated GSM-1800 MHz radiofrequencies that convey wireless communications. The effects of these EMF on the brain affected by a pathological condition remain little investigated. In this study, rats injected with lipopolysaccharide (LPS) to induce neuroinflammation were exposed "head-only" to GSM-1800 MHz signals for two hours at a specific absorption rate (SAR) that reached an average value of 1.55 W/kg in the auditory cortex (ACx). Immunodetection of Iba1, a microglial marker, and electrophysiological recordings in the ACx three to six hours after global system for communication (GSM) exposure, or sham-exposure, showed that exposure to GSM-1800 MHz resulted in a growth of microglial processes and a reduction in spontaneous firing rate. More importantly, there was a significant reduction in evoked respo...
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Despite consistent evidence of an association between depression and impaired memory performance, only a few studies have investigated memory processes in animal models of depression. The aim of the present study was to determine if rats... more
Despite consistent evidence of an association between depression and impaired memory performance, only a few studies have investigated memory processes in animal models of depression. The aim of the present study was to determine if rats selected for marked differences in their immobility response in the forced swimming test (FST, i.e. high-immobility, [HI] and low-immobility [LI] rats) exhibit differences in spatial and non-spatial memory performances. In a classic radial maze elimination task, we observed that HI rats made significantly more errors than LI rats, and their first error appeared significantly earlier. In a delayed spatial win-shift procedure where rats have to hold spatially relevant information in working memory across a 30 min delay, HI rats tended initially to perform more poorly than LI rats. HI rats made more across-phase errors, the occurrence of the first error was earlier and by the end of the experiment the differences between the two groups disappeared. Thu...
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High-frequency deep brain stimulation (DBS) represents a major stake for treatment for treatment-resistant depression (TRD). We describe a preliminary trial of DBS of two potential brain targets in chronic TRD: the nucleus accumbens (Acb)... more
High-frequency deep brain stimulation (DBS) represents a major stake for treatment for treatment-resistant depression (TRD). We describe a preliminary trial of DBS of two potential brain targets in chronic TRD: the nucleus accumbens (Acb) and, in the event of failure, the caudate nucleus. Patients were followed for 6 months before surgery (M0). From M1 to M5, they underwent stimulation of the Acb target. PET scans allowed us to track metabolic modifications resulting from this stimulation. The caudate target of nonresponders was stimulated between M5 and M9. Patients then entered an extension phase, in which it was possible to adapt stimulation parameters and treatments. Six patients were included and four were operated on. At M5, none of the patients were either responders or remitters, but we did observe a decrease in Hamilton Depression Rating Scale (HDRS) scores. Three patients were switched to caudate stimulation, but no improvement was observed. During the extension phase, the...
Research Interests: Neuroscience, Biophysics, Deep Brain Stimulation, Depression, Cognition, and 15 moreMagnetic Resonance Imaging, Positron Emission Tomography, Medicine, Nucleus Accumbens, Humans, Caudate Nucleus, Female, Male, Middle Aged, Brain Stimulation, Adult, Accumbens, Neuropsychological Tests, Limbic Lobe, and Medical and Health Sciences
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Research Interests: Neuroscience, Chemistry, Long Term Potentiation, Neuropsychopharmacology, Medicine, and 14 morePrefrontal Cortex, Synaptic Plasticity, Serotonin, Dopamine, Hippocampus, Animals, Male, Norepinephrine, Rats, Stimulation, Locus coeruleus, Clonidine, Psychology and Cognitive Sciences, and Medical and Health Sciences
While functional imaging and deep brain stimulation studies point to a pivotal role of the hypothalamus in the pathophysiology of migraine and trigeminal autonomic cephalalgias, the circuitry and the mechanisms underlying the modulation... more
While functional imaging and deep brain stimulation studies point to a pivotal role of the hypothalamus in the pathophysiology of migraine and trigeminal autonomic cephalalgias, the circuitry and the mechanisms underlying the modulation of medullary trigeminovascular (Sp5C) neurons have not been fully identified. We investigated the existence of a direct anatomo-functional relationship between hypothalamic excitability disturbances and modifications of the activities of Sp5C neurons in the rat. Anterograde and retrograde neuronal anatomical tracing, intrahypothalamic microinjections, extracellular single-unit recordings of Sp5C neurons, and behavioral trials were used in this study. We found that neurons of the paraventricular nucleus of the hypothalamus (PVN) send descending projections to the superior salivatory nucleus, a region that gives rise to parasympathetic outflow to cephalic and ocular/nasal structures. PVN cells project also to laminae I and outer II of the Sp5C. Microin...
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Research on the detrimental effects of stress in the brain has mainly focused on the hippocampus. Because prefrontal cortex (PFC) dysfunction characterizes many stress-related disorders, we here analyzed the impact of chronic stress in... more
Research on the detrimental effects of stress in the brain has mainly focused on the hippocampus. Because prefrontal cortex (PFC) dysfunction characterizes many stress-related disorders, we here analyzed the impact of chronic stress in rats on the integrity of the hippocampal–PFC pathway, monitored by behavioral and electrophysiological function and morphological assessment. We show that chronic stress impairs synaptic plasticity by reducing LTP induction in the hippocampal–PFC connection; in addition, it induces selective atrophy within the PFC and severely disrupts working memory and behavioral flexibility, two functions that depend on PFC integrity. We also demonstrate that short periods of stress exposure induce spatial reference memory deficits before affecting PFC-dependent tasks, thus suggesting that the impairment of synaptic plasticity within the hippocampus-to-PFC connection is of relevance to the stress-induced PFC dysfunction. These findings evidence a fundamental role o...
Research Interests: Neuroscience, Psychology, Plasticity, Long Term Potentiation, Medicine, and 15 morePrefrontal Cortex, Memory, Hippocampus, Animals, Male, Neuronal Plasticity, Rat, LTP, Chronic Stress, Neural pathways, Physiological Stress Markers, Memory Disorders, Hippocampal formation, Psychology and Cognitive Sciences, and Medical and Health Sciences
Specific patterns of stimulation applied in the ventral hippocampus produce long-term potentiation (LTP) of postsynaptic synapses in the prefrontal cortex in vivo. The induction of LTP is dependent on NMDA receptors and cAMP-dependant... more
Specific patterns of stimulation applied in the ventral hippocampus produce long-term potentiation (LTP) of postsynaptic synapses in the prefrontal cortex in vivo. The induction of LTP is dependent on NMDA receptors and cAMP-dependant kinase (PKA) activation. Yet little is known concerning the cellular mechanisms underlying the expression of this neocortical form of LTP. In the present study, we tested whether LTP at hippocampal to prefrontal cortex synapses leads to activation of DARPP-32 and CREB as well as defined the temporal regulation of the phosphorylation states of both proteins. Our data indicate a peak in CREB and DARPP-32 phosphorylation during the late phase of prefrontal LTP (2 h posttetanus). These findings support the hypothesis that prolonged expression of hippocampal-prefrontal cortex LTP depends on a synergistic mechanism involving phosphorylation of both CREB and DARPP-32 via activation of the cAMP/PKA-dependent pathway.
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Research Interests: Psychology, Psychopharmacology, Cognition, Performance, Comparative Study, and 15 moreMedicine, Prefrontal Cortex, Memory, Learning and Memory, Antidepressant, Animals, Male, Cognitive Performance, Cognitive impairment, Analysis of Variance, Maze Learning, Imipramine, Paroxetine, Psychology and Cognitive Sciences, and Medical and Health Sciences
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Research Interests: Neuroscience, Biology, Medicine, Multidisciplinary, Prefrontal Cortex, and 15 moreBrain Mapping, Hippocampus, Humans, Methylation, Animals, Mental Disorders, Neurons, PLoS one, Entorhinal Cortex, Embryonic Development, Rats, Mechanism of action, DAB, Extracellular Matrix Proteins, and Hippocampal formation
Exposure to stress causes dysfunctions in circuits connecting hippocampus and prefrontal cortex (H-PFC). Long term potentiation (LTP) induced in vivo in rats at H-PFC synapses is impaired by acute elevated platform stress in a manner that... more
Exposure to stress causes dysfunctions in circuits connecting hippocampus and prefrontal cortex (H-PFC). Long term potentiation (LTP) induced in vivo in rats at H-PFC synapses is impaired by acute elevated platform stress in a manner that can be restored by treatment with certain antidepressants. To identify biochemical pathways in rat frontal cortex underlying this stress-mediated impairment of synaptic plasticity, we examined the phosphorylation state of receptors, signaling proteins and transcription factors implicated in neuronal plasticity. Transient changes in the phosphorylation states of Ser217/221-MEK, Thr183/Tyr185-p42MAPK, Thr202/Tyr204-p44MAPK, Thr180/Tyr182-p38MAPK, Thr218/Tyr220-ERK5, Thr308-Akt, Ser63-ATF-1, Ser1303-GluN2B, Tyr490/515-TrkA/B were found. BDNF was down-regulated after elevated platform stress suggesting that it could regulate the MEK/MAPK signaling cascade. Acute treatment with the antidepressants tianeptine and imipramine reversed the stress-induced down-regulation of P-Ser217/221-MEK. However, stress-induced impairment of H-PFC LTP was only restored by acute treatment with tianeptine and not by imipramine. Tianeptine, but not imipramine, increased the phosphorylation of Ser831-GluA1. Altogether, these results indicate that acute elevated platform stress down-regulates a putative BDNF/MEK/MAPK signaling cascade in the frontal cortex in a manner that is reversible by the antidepressants tianeptine and imipramine. Moreover, changes in LTP may be associated with phosphorylation of AMPA receptors and with some specificity for certain antidepressants. Indeed, stress-induced impairment of H-PFC LTP was only restored by acute treatment with tianeptine and not by imipramine. Tianeptine, but not imipramine, increased the phosphorylation of Ser831-GluA1, indicating a potential effect on AMPA receptor phosphorylation being involved in the reversal of LTP.
Research Interests: Psychology, Chemistry, Depression, Long Term Potentiation, Neuropharmacology, and 15 moreMedicine, Prefrontal Cortex, Glutamate, Animals, Male, Neuronal Plasticity, Frontal Cortex, Phosphorylation, Intracellular Signaling, Neurosciences, Enzyme Linked Immunosorbent Assay, Imipramine, Pharmacology and pharmaceutical sciences, Antidepressive agents, and Electric stimulation
Despite enormous progress in fundamental knowledge in neuroscience, no revolutionary therapies in psychiatry (and neurology) have emerged in the past ten years. Most drugs alleviate symptoms, rather than restoring the... more
Despite enormous progress in fundamental knowledge in neuroscience, no revolutionary therapies in psychiatry (and neurology) have emerged in the past ten years. Most drugs alleviate symptoms, rather than restoring the 'set point' of brain function from a pathological position to a more normal one. We propose a hypothesis-driven, systems-level approach to drug discovery and development that is based on pathophysiology and which uses new animal models.
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Research Interests: Neuroscience, Depression, Medicine, Molecular Psychiatry, Anxiety, and 15 moreBiological Sciences, Molecular, Glutamate, Brain, Humans, Antidepressant, Animals, Neuronal Plasticity, Depressive Disorder, ANXIETY, Mechanism of action, Glutamic Acid, Psychiatry and Psychology, Cognition disorders, and Medical and Health Sciences
A translocase to transport hexose phosphate formed in the cytosol into the cisterns of the endoplasmic reticulum, where the phosphatase resides, is absent in brain (Fishman and Karnovsky, 1986). 2-Deoxyglucose-6-phosphate (DG-6-P) may... more
A translocase to transport hexose phosphate formed in the cytosol into the cisterns of the endoplasmic reticulum, where the phosphatase resides, is absent in brain (Fishman and Karnovsky, 1986). 2-Deoxyglucose-6-phosphate (DG-6-P) may therefore have limited access to glucose-6-phosphatase (G-6-Pase), and transport of the DG-6-P across the endoplasmic reticular membrane may be rate limiting to its dephosphorylation. To take this compartmentation into account, a five-rate constant (5K) model was developed to describe the kinetic behavior of 2-deoxyglucose (DG) and its phosphorylated product in brain. Loss of DG-6-P was modeled as a two-step process: (a) transfer of DG-6-P from the cytosol into the cisterns of the endoplasmic reticulum; (b) hydrolysis of DG-6-P by G-6-Pase and subsequent return of the free DG to the precursor pool. Local CMRglc(LCMRglc) was calculated in the rat on the basis of this model and compared with values calculated on the basis of the three-rate constant (3K) ...
Research Interests: Neuroscience, Mathematics, Chemistry, Neurology, Metabolism, and 15 moreKinetics, Medicine, Brain, Models, Brain Circulation, Animals, Male, Endoplasmic Reticulum, Clinical Sciences, Lumping Kinetic Model, Hydrolysis, Neurosciences, Dephosphorylation, Cardiovascular medicine and haematology, and Kinetic model
Exposure to stress causes differential neural modifications in various limbic regions, namely the prefrontal cortex, hippocampus and amygdala. We investigated whether α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)... more
Exposure to stress causes differential neural modifications in various limbic regions, namely the prefrontal cortex, hippocampus and amygdala. We investigated whether α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) phosphorylation is involved with these stress effects. Using an acute inescapable stress protocol with rats, we found opposite effects on AMPA receptor phosphorylation in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DH) compared to the amygdala and ventral hippocampus (VH). After stress, the phosphorylation of Ser831-GluA1 was markedly decreased in the mPFC and DH, whereas the phosphorylation of Ser845-GluA1 was increased in the amygdala and VH. Stress also modulated the GluA2 subunit with a decrease in the phosphorylation of both Tyr876-GluA2 and Ser880-GluA2 residues in the amygdala, and an increase in the phosphorylation of Ser880-GluA2 in the mPFC. These results demonstrate that exposure to acute stress causes subunit-specific and ...
Research Interests: Neuroscience, Chemistry, Long Term Potentiation, Medicine, Multidisciplinary, and 15 moreBrain Mapping, Hippocampus, Animals, Corticosterone, Male, Amygdala, Phosphorylation, Immunoassay, Frontal Lobe, Glutamic Acid, Medial Prefrontal Cortex, Cognition disorders, Dorsal hippocampus, Glutamate Receptor, and Acute stress
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Research Interests: Neuroscience, Plasticity, Long Term Potentiation, Biology, Oxidative Stress, and 15 moreMedicine, Hippocampus, Animals, Male, Mitogen Activated Protein Kinase, Clinical Sciences, Experimental, Chronic Stress, Experimental Neurology, Neural pathways, Neurosciences, Blockade, Acute stress, Hippocampal formation, and Mifepristone
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The purpose of the present study was to examine whether cAMP-dependent protein kinase (PKA) was implicated in the process of long-term potentiation (LTP) in the hippocampal afferent fibre system to the prefrontal cortex in vivo. Using a... more
The purpose of the present study was to examine whether cAMP-dependent protein kinase (PKA) was implicated in the process of long-term potentiation (LTP) in the hippocampal afferent fibre system to the prefrontal cortex in vivo. Using a biochemical approach, we measured PKA activity at different times after induction of LTP. We show that there is an NMDA receptor-dependent increase in PKA activity in the prefrontal cortex, only at five minutes after LTP induction. These data demonstrate a role of PKA in the induction and not the expression of cortical LTP and suggest that if PKA is involved in the late phase of LTP, it does not appear to be a persistent activation.
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Research Interests: Neuroscience, Psychology, Cognitive Science, Long Term Potentiation, Medicine, and 14 morePrefrontal Cortex, Synaptic Plasticity, Hippocampus, Cerebral Cortex, Animals, Male, Rats, FLUOXETINE, Neural pathways, Neurosciences, Acute stress, Hippocampal formation, Acute Disease, and Stress Physiological
There is considerable physiological evidence indicating that the medial preoptic area plays an important role in neural circuits mediating ingestive, thermoregulatory, and reproductive behaviors, all of which involve foraging. The current... more
There is considerable physiological evidence indicating that the medial preoptic area plays an important role in neural circuits mediating ingestive, thermoregulatory, and reproductive behaviors, all of which involve foraging. The current series of anatomical and electrophysiological experiments was therefore designed to characterize a direct projection from the medial preoptic area to a region in the zona incerta just dorsal to the subthalamic nucleus, which appears to lie within the 'subthalamic locomotor region', and to the pedunculopontine nucleus, which lies within the 'mesencephalic locomotor region'. First, implants of the fluorescent tracer True blue were placed in the pedunculopontine nucleus, and retrogradely labeled neurons were consistently found in dorsal regions of the medial preoptic nucleus, anteroventral preoptic nucleus, rostral tip of the medial preoptic area, lateral parts of the medial preoptic area, and median preoptic nucleus. Second, combined retrograde-immunostaining experiments indicated that a small number of galanin-stained neurons in the rostral tip of the medial preoptic area project to the pedunculopontine nucleus, whereas in nearby regions some galanin- or neurotensin-stained neurons in the lateral preoptic area, and some neurotensin-stained neurons in the substriatal gray appear to project to the pedunculopontine nucleus, as do some neurotensin- or corticotropin releasing factor (CRF)-stained cells in the bed nucleus of the stria terminalis. Third, injections of the anterograde tracer Phaseolus vulgaris leukoagglutinin (PHA-L) into various parts of the medial preoptic area all labeled axons with terminal boutons in the caudal zona incerta and pedunculopontine nucleus. Fourth, single-pulse stimuli were delivered to the zona incerta and pedunculopontine nucleus and the location of antidromically activated neurons in the medial preoptic area was mapped using extracellular recordings. Somewhat less than one-third of the cells recorded from in the medial preoptic area were antidromically activated from either site and some 14% were influenced from both sites. The application of a reciprocal collision test to a small number of neurons suggested that at least some neurons in the medial preoptic area may send collaterals to both sites. And fifth, injections of procaine into the zona incerta were shown to block the antidromic activation of medial preoptic neurons by single-pulse stimulation of the pedunculopontine nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)
Research Interests: Neuroscience, Cognitive Science, Biology, Locomotion, Medicine, and 15 moreBrain Mapping, Hippocampus, Brain, Evoked Potentials, Cerebral Cortex, Animals, Male, Neural pathways, Preoptic Area, Neurosciences, Diencephalon, Medial Preoptic Area, Mesencephalon, Medical and Health Sciences, and Electric stimulation
The role of low-voltage-activated (LVA) calcium channels in the expression of long-term potentiation (LTP) was examined by intracellular recording in slices from cat agranular cortex. In the normal solution, LTP was induced, and the... more
The role of low-voltage-activated (LVA) calcium channels in the expression of long-term potentiation (LTP) was examined by intracellular recording in slices from cat agranular cortex. In the normal solution, LTP was induced, and the potentiation of low-threshold rebound potential was evoked by negative current injection. In the cells, in which resting membrane potential was depolarized, the incidence of LTP was
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Research Interests: Neuroscience, Psychology, Depression, Evidence Based Medicine, Fear, and 15 moreMedicine, Prefrontal Cortex, Pathophysiology, Learning, Hippocampus, Humans, Major Depressive Disorder, Animals, Neuronal Plasticity, Mental Disorders, Neurons, Limbic System, Hippocampal formation, Psychology and Cognitive Sciences, and Medical and Health Sciences
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The multiple brain circuits involved in psychiatric diseases may appear daunting, but we prefer to concentrate on a select few, with a particular sensitivity to stress and neurodevelopmental issues, with a clear pharmacotherapy. This... more
The multiple brain circuits involved in psychiatric diseases may appear daunting, but we prefer to concentrate on a select few, with a particular sensitivity to stress and neurodevelopmental issues, with a clear pharmacotherapy. This review is structured around 1. the key circuits, their role in health and disease, and the neurotransmitters maintaining them, 2. The influence of upbringing, stress, chronobiology, inflammation and infection, 3. The genetic and epigenetic influence on these circuits, particularly regarding copy number variants and neuronal plasticity, 4. The use and abuse of pharmacological agents with the particular risks of stress and chronobiology at critical periods. A major emphasis is placed on the links between hippocampus, prefrontal cortex and amygdala/periaqueductal grey which control specific aspects of cognition, mood, pain and even violence. Some of the research findings were from the innovative medicine initiative (IMI) NEWMEDS, a 22M€ academic/industrial...
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The long lapse between the presumptive origin of schizophrenia (SCZ) during early development and its diagnosis in late adolescence has hindered the study of crucial neurodevelopmental processes directly in living patients. Dopamine, a... more
The long lapse between the presumptive origin of schizophrenia (SCZ) during early development and its diagnosis in late adolescence has hindered the study of crucial neurodevelopmental processes directly in living patients. Dopamine, a neurotransmitter consistently associated with the pathophysiology of SCZ, participates in several aspects of brain development including pruning of neuronal extensions. Excessive pruning is considered the cause of the most consistent finding in SCZ, namely decreased brain volume. It is therefore possible that patients with SCZ carry an increased susceptibility to dopamine’s pruning effects and that this susceptibility would be more obvious in the early stages of neuronal development when dopamine pruning effects appear to be more prominent. Obtaining developing neurons from living patients is not feasible. Instead, we used Monocyte-Derived-Neuronal-like Cells (MDNCs) as these cells can be generated in only 20 days and deliver reproducible results. In ...
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Background Memantine, a noncompetitive N-methyl-D-aspartate receptor antagonist, has been approved for use in Alzheimer’s disease, but an increasing number of studies have investigated its utility for neuropsychiatric disorders. Here, we... more
Background Memantine, a noncompetitive N-methyl-D-aspartate receptor antagonist, has been approved for use in Alzheimer’s disease, but an increasing number of studies have investigated its utility for neuropsychiatric disorders. Here, we characterized a novel compound, fluoroethylnormemtantine (FENM), which was derived from memantine with an extra Fluor in an optimized position for in vivo biomarker labeling. We sought to determine if FENM produced similar behavioral effects as memantine and/or if FENM has beneficial effects against fear, avoidance, and behavioral despair. Methods We administered saline, FENM, or memantine prior to a number of behavioral assays, including paired-pulse inhibition, open field, light dark test, forced swim test, and cued fear conditioning in male Wistar rats. Results Unlike memantine, FENM did not produce nonspecific side effects and did not alter sensorimotor gating or locomotion. FENM decreased immobility in the forced swim test. Moreover, FENM robus...
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Genetic microdeletion at the 22q11 locus is associated with very high risk for schizophrenia. The 22q11.2 microdeletion (Df(h22q11)/+) mouse model shows cognitive deficits observed in this disorder, some of which can be linked to... more
Genetic microdeletion at the 22q11 locus is associated with very high risk for schizophrenia. The 22q11.2 microdeletion (Df(h22q11)/+) mouse model shows cognitive deficits observed in this disorder, some of which can be linked to dysfunction of the prefrontal cortex (PFC). We used behavioral (n = 10 per genotype), electrophysiological (n = 7 per genotype per group), and neuroanatomical (n = 5 per genotype) techniques to investigate schizophrenia-related pathology of Df(h22q11)/+ mice, which showed a significant decrease in the total number of parvalbumin positive interneurons in the medial PFC. The Df(h22q11)/+ mice when tested on PFC-dependent behavioral tasks, including gambling tasks, perform significantly worse than control animals while exhibiting normal behavior on hippocampus-dependent tasks. They also show a significant decrease in hippocampus-medial Prefrontal cortex (H-PFC) synaptic plasticity (long-term potentiation, LTP). Acute platform stress almost abolished H-PFC LTP ...
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Research Interests: Neuroscience, Chemistry, Long Term Potentiation, Enzyme Inhibitors, Medicine, and 14 morePrefrontal Cortex, Dopamine, Hippocampus, Animals, Male, Neuronal Plasticity, Long Term Depression, Rats, SYNAPSES, Extracellular Space, Dopamine antagonists, NMDA receptor, Psychology and Cognitive Sciences, and Medical and Health Sciences
Une voie monosynaptique glutamatergique relie l'hippocampe au cortex prefrontal (cpf) et une potentialisation a long terme (plt) dependante des recepteurs nmda peut etre induite in vivo dans le cpf apres stimulation de... more
Une voie monosynaptique glutamatergique relie l'hippocampe au cortex prefrontal (cpf) et une potentialisation a long terme (plt) dependante des recepteurs nmda peut etre induite in vivo dans le cpf apres stimulation de l'hippocampe. Une autre afference necessaire a l'activite du cpf est la voie mesocorticale dopaminergique (da). Compte tenue de la proximite des afferences hippocampiques et des fibres da issues de l'aire tegmentale ventrale (atv) dans le cpf chez le rat, l'objectif de cette these etait d'examiner le role de la da dans la plasticite synaptique hippocampo-prefrontale in vivo. (i) la stimulation de l'atv diminue transitoirement la transmission synaptique, tandis qu'elle induit une augmentation de l'amplitude de la plt. A l'inverse, l'amplitude de la plt est diminuee chez des rats porteurs d'une lesion de l'atv et deficients en da corticale. L'existence d'une correlation entre taux de da et amplitude de la plt montre qu'un taux minimum de da est necessaire a l'induction de la plt dans le cpf. (ii) l'infusion d'un antagoniste des recepteurs d1 (sch 23390) dans le cpf bloque l'induction de la plt alors que l'agoniste d1 (skf 81297) augmente durablement la plt. L'infusion d'un antagoniste des recepteurs d2 (sulpiride) n'a aucun effet. Enfin, une liberation accrue de da a ete mesuree dans le cpf pendant l'induction de la plt. (iii) l'activation de la proteine kinase a (pka) dans le cpf est dependante des recepteurs nmda et a lieu pendant l'induction de la plt. La cascade adenylyl cyclase-pka etant liee aux recepteurs d1, nous avons explore son role dans la plt : l'induction de la plt est facilitee par la forskoline (activateur d'adenylyl cyclase) et bloquee par le rp-camps (inhibiteur pka). Les recepteurs d1, probablement via la pka, sont donc responsables du controle de l'induction nmda-dependente de la plt hippocampo-prefrontale. Ces resultats demontrent que la da a un role permissif sur le renforcement de l'efficacite des synapses hippocampo-prefrontales.
Research Interests: Chemistry, Biology, Prefrontal Cortex, Dopamine, Glutamate, and 5 morePsychologie, Paris, Biologie, Rat, and Protein Kinase
Extensive evidence on rapid and long-lasting antidepressant effects of intravenous ketamine motivated efforts to identify underlying mechanisms that would enable development of novel drugs with similar efficacy, but improved safety and... more
Extensive evidence on rapid and long-lasting antidepressant effects of intravenous ketamine motivated efforts to identify underlying mechanisms that would enable development of novel drugs with similar efficacy, but improved safety and pharmacokinetic profiles. It has been suggested that the antidepressant-like action of ketamine may be mediated by the activation of mTOR-dependent intracellular cascades. Therefore, without any coordination or pre-existing agreement, research labs at AbbVie, Servier, Pfizer and Alkermes started independent experiments aiming to reproduce and extend published evidence. More than a dozen experiments conducted by these four independent teams failed to detect robust effects of ketamine on markers reported to be affected in the original study by Li et al. (2010). Thus, detection of the effects of ketamine on mTOR seem to require special conditions that are difficult to identify and establish, at least in some labs. Present results emphasize the importance...