41 results on '"Benchenane K"'
Search Results
2. Tissue type plasminogen activator (tPA), a key partner for the working brain
- Author
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Vivien, D., Monreal, M. Fernandez, Atalaya, J. Lopez, Benchenane, K., Ali, C., and Touzani, O.
- Published
- 2004
3. Rat anterior cingulate neurons responsive to rule or strategy changes are modulated by the hippocampal theta rhythm and sharp‐wave ripples.
- Author
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Khamassi, M., Peyrache, A., Benchenane, K., Hopkins, D. A., Lebas, N., Douchamps, V., Droulez, J., Battaglia, F. P., and Wiener, S. I.
- Subjects
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COGNITIVE flexibility , *PREFRONTAL cortex , *HIPPOCAMPUS (Brain) , *NEURONS , *THETA rhythm , *SYNCHRONIC order , *VISUAL discrimination - Abstract
To better understand neural processing during adaptive learning of stimulus‐response‐reward contingencies, we recorded synchrony of neuronal activity in anterior cingulate cortex (ACC) and hippocampal rhythms in male rats acquiring and switching between spatial and visual discrimination tasks in a Y‐maze. ACC population activity as well as single unit activity shifted shortly after task rule changes or just before the rats adopted different task strategies. Hippocampal theta oscillations (associated with memory encoding) modulated an elevated proportion of rule‐change responsive neurons (70%), but other neurons that were correlated with strategy‐change, strategy value and reward‐rate were not. However, hippocampal sharp wave‐ripples modulated significantly higher proportions of rule‐change, strategy‐change and reward‐rate responsive cells during post‐session sleep but not pre‐session sleep. This suggests an underestimated mechanism for hippocampal mismatch and contextual signals to facilitate ACC to detect contingency changes for cognitive flexibility, a function that is attenuated after it is damaged. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Fabrication technology for silicon-based microprobe arrays used in acute and sub-chronic neural recording
- Author
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Herwik, S, primary, Kisban, S, additional, Aarts, A A A, additional, Seidl, K, additional, Girardeau, G, additional, Benchenane, K, additional, Zugaro, M B, additional, Wiener, S I, additional, Paul, O, additional, Neves, H P, additional, and Ruther, P, additional
- Published
- 2009
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5. ID: 96 Molecular requirements for modulation of NMDA receptor signaling by tissue-type plasminogen activator
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López-Atalaya, J., primary, Roussel, B., additional, Levrat, D., additional, Nicole, O., additional, Benchenane, K., additional, Rault, S., additional, Vaudry, H., additional, Petersen, K., additional, Ali, C., additional, and Vivien, D., additional
- Published
- 2006
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6. Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis.
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Benchenane K, Berezowski V, Ali C, Fernández-Monreal M, López-Atalaya JP, Brillault J, Chuquet J, Nouvelot A, MacKenzie ET, Bu G, Cecchelli R, Touzani O, and Vivien D
- Published
- 2005
7. Coherent oscillations and learning-related reorganization of spike timing
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Benchenane, K., Adrien Peyrache, Khamassi, M., Tierney, P. L., Douchamps, V., Battaglia, F. P., and Wiener, S. I.
8. Astroglial hemichannels modulate UP and DOWN states in the olfactory bulb.
- Author
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Roux, L., Madar, A., Lacroix, M., Benchenane, K., and Giaume, C.
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ASTROCYTES ,CONNEXINS ,GAP junctions (Cell biology) - Abstract
While the role played by astrocytes in synaptic transmission has now largely been documented, their contribution to network activities only starts to be appreciated. A typical feature of astrocytes is their high rate of connexin expression (Cx43 and Cx30), the molecular basis for gap junctional communication and hemichannel (HC) formation. Even though connexin-formed HCs have been shown to be permeable to several neuroactive compounds, their role in physiological conditions has largely been unexplored. We thus question whether the function of Cx-based HCs in astrocytes has an impact on neuronal network behaviors in the mouse olfactory bulb (OB). In OB acute slices, we observed that the membrane potential of mitral cells (MCs) alternates between a DOWN (hyperpolarized, silent) and an UP (depolarized, spiking) state at a slow frequency (~0.2Hz), resembling slow oscillations observed in cortical neurons during slow-wave sleep. Such alternations were inhibited by a pharmalogical blockage of glutamatergic transmission and correlated with the local field potential monitored within the corresponding glomerulus, highlighting a network effect. Interestingly, this spontaneous neuronal activity induced the opening of Cx HCs in astrocytes as shown by ethidium bromide uptake assays. We then asked whether such astroglial HC activity can in turn impact on the slow network activity, using knock-out (KO) mice for astroglial Cxs. In absence of Cx43, but not Cx30, MCs showed significant decrease in UP state amplitude compared to control. This alteration was mimicked by a blockage of Cx43 HCs, pointing out the role played by Cx43 HC function in the modulation of MC UP and DOWN states. Importantly, we found that this effect requires the activation of adenosine A1 receptors, likely via ATP release by astrocytes through Cx43 HCs. These results suggest that Cx43 HC function in astrocytes is promoted by neuronal activity, and in turn modulates neuronal network activity. Such bidirectional neuroglial interactions could play an important role in olfactory information processing. [ABSTRACT FROM AUTHOR]
- Published
- 2013
9. [Animal models of trauma and post-traumatic stress disorder].
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Benchenane K
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- Animals, Humans, Fear physiology, Fear psychology, Conditioning, Classical physiology, Models, Animal, Stress Disorders, Post-Traumatic diagnosis, Stress Disorders, Post-Traumatic psychology
- Abstract
Initially believed to be specific to humans emerging from life-threatening events, Post-traumatic stress disorder (PTSD) has been found to occur in wild animals and can also be experimentally induced in laboratory rodents. This article aims to highlight and discuss the evolution and relevance of animal models in PTSD research. Studies by LeDoux, Davis, and McGaugh have made significant contributions to our understanding of PTSD. By focusing on fear responses in rodents and aversive Pavlovian conditioning, they suggested that PTSD could result from excessively efficient aversive learning processes, with a significant role played by amygdala. However, numerous studies have shown that this explanation fails to account for the complexity of processes involved in PTSD. Current hypotheses focus on deficits in extinction retention, perception of safety signals, or emotional regulation. This review will specifically address the animal models that closely resemble human PTSD and explore reasons for their limited utilization, as a majority of animal studies continues to employ classical Pavlovian conditioning protocols. Furthermore, this review will present cutting-edge experimental studies that tackle previously challenging questions in animal research. Specifically, we will examine the relationship between respiration and the maintenance of fear states, offering a potential explanation for the efficacy of meditation and breath control techniques in emotion regulation. We will also shed light on recent findings on decoding neural activity related to internal representations in animals, thus enabling now the exploration of rumination, a characteristic symptom of PTSD previously inaccessible to animal studies., (© Société de Biologie, 2023.)
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- 2023
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10. Breathing-driven prefrontal oscillations regulate maintenance of conditioned-fear evoked freezing independently of initiation.
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Bagur S, Lefort JM, Lacroix MM, de Lavilléon G, Herry C, Chouvaeff M, Billand C, Geoffroy H, and Benchenane K
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- Action Potentials physiology, Animals, Antithyroid Agents administration & dosage, Antithyroid Agents pharmacology, Electrophysiology, Interneurons cytology, Interneurons physiology, Male, Markov Chains, Methimazole administration & dosage, Methimazole pharmacology, Mice, Mice, Inbred C57BL, Models, Psychological, Optogenetics, Periodicity, Pyramidal Cells cytology, Pyramidal Cells physiology, Fear physiology, Olfactory Bulb physiology, Prefrontal Cortex physiology, Respiration drug effects
- Abstract
Brain-body interactions are thought to be essential in emotions but their physiological basis remains poorly understood. In mice, regular 4 Hz breathing appears during freezing after cue-fear conditioning. Here we show that the olfactory bulb (OB) transmits this rhythm to the dorsomedial prefrontal cortex (dmPFC) where it organizes neural activity. Reduction of the respiratory-related 4 Hz oscillation, via bulbectomy or optogenetic perturbation of the OB, reduces freezing. Behavioural modelling shows that this is due to a specific reduction in freezing maintenance without impacting its initiation, thus dissociating these two phenomena. dmPFC LFP and firing patterns support the region's specific function in freezing maintenance. In particular, population analysis reveals that network activity tracks 4 Hz power dynamics during freezing and reaches a stable state at 4 Hz peak that lasts until freezing termination. These results provide a potential mechanism and a functional role for bodily feedback in emotions and therefore shed light on the historical James-Cannon debate.
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- 2021
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11. Validating the theoretical bases of sleep reactivation during sharp-wave ripples and their association with emotional valence.
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Laventure S and Benchenane K
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- Animals, Humans, Memory Consolidation physiology, Brain Waves physiology, Emotions physiology, Hippocampus physiology, Learning physiology, Memory physiology, Sleep physiology
- Abstract
Sleep is important for memory consolidation, and an abundant literature suggests that reactivation in the hippocampus during sleep is instrumental to this process. Yet, the current interpretation of activity during sharp-waves ripples (SWRs), as replay of wake experiences, relies on hypotheses that, while widely accepted, have only recently begun to be tested directly. Moreover, this theory has been mainly studied in the context of pure spatial learning, and it is still not clear how emotional valence can fit into this conceptual framework when considering reward- or punishment-based learning. In this review, we will present recent experimental arguments validating the interpretation of sleep replay as reactivation of awake experiences and examine the evidence showing that the emotional valence is also replayed during sleep in a coordinated fashion with hippocampal SWRs. Finally, we will detail recent experiments showing that brain-computer interfaces can be used to modify the emotional valence associated with sleep replay., (© 2019 Wiley Periodicals, Inc.)
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- 2020
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12. The Theta Rhythm Mixes and Matches Gamma Oscillations Cycle by Cycle.
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Bagur S and Benchenane K
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- Memory, Neurons, Temporal Lobe, Hippocampus, Theta Rhythm
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In the hippocampus, gamma power modulation by the theta rhythm is interpreted as the signature of temporally coordinated inputs that reflect ongoing processing. In this issue of Neuron, Lopes-Dos-Santos et al. (2018) develop a new methodology demonstrating that theta cycles can be viewed as individual computational units characterized by typical gamma profiles., (Copyright © 2018. Published by Elsevier Inc.)
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- 2018
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13. Harnessing olfactory bulb oscillations to perform fully brain-based sleep-scoring and real-time monitoring of anaesthesia depth.
- Author
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Bagur S, Lacroix MM, de Lavilléon G, Lefort JM, Geoffroy H, and Benchenane K
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- Algorithms, Anesthesia methods, Animals, Brain physiology, Electroencephalography methods, Electromyography, Hippocampus physiology, Male, Mice, Mice, Inbred C57BL, Olfactory Bulb metabolism, Sleep drug effects, Sleep Stages physiology, Sleep, REM physiology, Olfactory Bulb physiology, Sleep physiology, Wakefulness physiology
- Abstract
Real-time tracking of vigilance states related to both sleep or anaesthesia has been a goal for over a century. However, sleep scoring cannot currently be performed with brain signals alone, despite the deep neuromodulatory transformations that accompany sleep state changes. Therefore, at heart, the operational distinction between sleep and wake is that of immobility and movement, despite numerous situations in which this one-to-one mapping fails. Here we demonstrate, using local field potential (LFP) recordings in freely moving mice, that gamma (50-70 Hz) power in the olfactory bulb (OB) allows for clear classification of sleep and wake, thus providing a brain-based criterion to distinguish these two vigilance states without relying on motor activity. Coupled with hippocampal theta activity, it allows the elaboration of a sleep scoring algorithm that relies on brain activity alone. This method reaches over 90% homology with classical methods based on muscular activity (electromyography [EMG]) and video tracking. Moreover, contrary to EMG, OB gamma power allows correct discrimination between sleep and immobility in ambiguous situations such as fear-related freezing. We use the instantaneous power of hippocampal theta oscillation and OB gamma oscillation to construct a 2D phase space that is highly robust throughout time, across individual mice and mouse strains, and under classical drug treatment. Dynamic analysis of trajectories within this space yields a novel characterisation of sleep/wake transitions: whereas waking up is a fast and direct transition that can be modelled by a ballistic trajectory, falling asleep is best described as a stochastic and gradual state change. Finally, we demonstrate that OB oscillations also allow us to track other vigilance states. Non-REM (NREM) and rapid eye movement (REM) sleep can be distinguished with high accuracy based on beta (10-15 Hz) power. More importantly, we show that depth of anaesthesia can be tracked in real time using OB gamma power. Indeed, the gamma power predicts and anticipates the motor response to stimulation both in the steady state under constant anaesthetic and dynamically during the recovery period. Altogether, this methodology opens the avenue for multi-timescale characterisation of brain states and provides an unprecedented window onto levels of vigilance., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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14. Slow-wave sleep: From the cell to the clinic.
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Léger D, Debellemaniere E, Rabat A, Bayon V, Benchenane K, and Chennaoui M
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- Electroencephalography, Humans, Cognition physiology, Memory physiology, Sleep Stages physiology, Sleep, Slow-Wave physiology
- Abstract
In recent decades, increasing evidence has positioned slow-wave sleep (SWS) as a major actor in neurophysiological phenomena such as glucose metabolism, hormone release, immunity and memory. This proposed role for SWS, coupled with observations of impaired SWS in several pathologies as well as in aging, has led some researchers to implement methods that could specifically enhance SWS. This review aims to gather the current knowledge extending from the cell to the clinic, in order to construct an overview of what is currently known about so-called SWS. We slowly expand the view from the molecular processes underlying SWS to the cell unit and assembly to cortical manifestations. We then describe its role in physiology and cognition to finally assess its association with clinical aspects. Finally, we address practical considerations for several techniques that could be used to manipulate SWS, in order to improve our understanding of SWS and possibly help the development of treatments for SWS clinical disorders., (Copyright © 2018. Published by Elsevier Ltd.)
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- 2018
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15. Taming the oscillatory zoo in the hippocampus and neo-cortex: a review of the commentary of Lockmann and Tort on Roy et al.
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Bagur S and Benchenane K
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- Animals, Review Literature as Topic, Hippocampus physiology, Neocortex physiology, Respiration
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- 2018
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16. 4-Hz oscillations synchronize prefrontal-amygdala circuits during fear behavior.
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Karalis N, Dejean C, Chaudun F, Khoder S, Rozeske RR, Wurtz H, Bagur S, Benchenane K, Sirota A, Courtin J, and Herry C
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- Acoustic Stimulation adverse effects, Animals, Conditioning, Psychological physiology, Extinction, Psychological physiology, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Neural Pathways physiology, Amygdala physiology, Biological Clocks physiology, Fear physiology, Fear psychology, Optogenetics methods, Prefrontal Cortex physiology
- Abstract
Fear expression relies on the coordinated activity of prefrontal and amygdala circuits, yet the mechanisms allowing long-range network synchronization during fear remain unknown. Using a combination of extracellular recordings, pharmacological and optogenetic manipulations, we found that freezing, a behavioral expression of fear, temporally coincided with the development of sustained, internally generated 4-Hz oscillations in prefrontal-amygdala circuits. 4-Hz oscillations predict freezing onset and offset and synchronize prefrontal-amygdala circuits. Optogenetic induction of prefrontal 4-Hz oscillations coordinates prefrontal-amygdala activity and elicits fear behavior. These results unravel a sustained oscillatory mechanism mediating prefrontal-amygdala coupling during fear behavior.
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- 2016
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17. From necessity to sufficiency in memory research: when sleep helps to understand wake experiences.
- Author
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Lacroix MM, De Lavilléon G, and Benchenane K
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- Animals, Humans, Memory physiology, Neurons physiology, Optogenetics methods, Sleep physiology, Wakefulness physiology
- Abstract
Memory is the ability to adapt our behavior by using the stored information, previously encoded. The first investigations of the neuronal bases of the memory trace concerned its properties (location, cellular and molecular mechanisms, among others). However, to understand how this is achieved at the scale of neurons, we must provide evidence about the necessity of a neuronal subpopulation to support the memory trace, but also its sufficiency. Here, we will present past and recent studies that provide information about the neuronal nature of memories. We will show that research on sleep, when cells assembly supposedly carrying information from the past are replayed, could also provide valuable information about the memory processes at stake during wake., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
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- 2015
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18. Astroglial Connexin 43 Hemichannels Modulate Olfactory Bulb Slow Oscillations.
- Author
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Roux L, Madar A, Lacroix MM, Yi C, Benchenane K, and Giaume C
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- Adenosine A1 Receptor Antagonists pharmacology, Animals, Animals, Newborn, Biological Clocks drug effects, Biological Clocks genetics, Carbenoxolone pharmacology, Connexin 30, Connexin 43 genetics, Connexins deficiency, Connexins genetics, Excitatory Postsynaptic Potentials drug effects, Excitatory Postsynaptic Potentials genetics, Glutamic Acid metabolism, In Vitro Techniques, Membrane Potentials drug effects, Membrane Potentials genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net drug effects, Nerve Net physiology, Peptides pharmacology, Sodium Channel Blockers pharmacology, Synaptic Transmission drug effects, Synaptic Transmission genetics, Tetrodotoxin pharmacology, Xanthines pharmacology, Astrocytes metabolism, Biological Clocks physiology, Connexin 43 metabolism, Membrane Potentials physiology, Olfactory Bulb cytology, Olfactory Bulb physiology
- Abstract
An emergent concept in neurosciences consists in considering brain functions as the product of dynamic interactions between neurons and glial cells, particularly astrocytes. Although the role played by astrocytes in synaptic transmission and plasticity is now largely documented, their contribution to neuronal network activity is only beginning to be appreciated. In mouse olfactory bulb slices, we observed that the membrane potential of mitral cells oscillates between UP and DOWN states at a low frequency (<1 Hz). Such slow oscillations are correlated with glomerular local field potentials, indicating spontaneous local network activity. Using a combination of genetic and pharmacological tools, we showed that the activity of astroglial connexin 43 hemichannels, opened in an activity-dependent manner, increases UP state amplitude and impacts mitral cell firing rate. This effect requires functional adenosine A1 receptors, in line with the observation that ATP is released via connexin 43 hemichannels. These results highlight a new mechanism of neuroglial interaction in the olfactory bulb, where astrocyte connexin hemichannels are both targets and modulators of neuronal circuit function., Significance Statement: An emergent concept in neuroscience consists in considering brain function as the product of dynamic interactions between neurons and glial cells, particularly astrocytes. A typical feature of astrocytes is their high expression level of connexins, the molecular constituents of gap junction channels and hemichannels. Although hemichannels represent a powerful medium for intercellular communication between astrocytes and neurons, their function in physiological conditions remains largely unexplored. Our results show that in the olfactory bulb, connexin 43 hemichannel function is promoted by neuronal activity and, in turn, modulates neuronal network slow oscillations. This novel mechanism of neuroglial interaction could influence olfactory information processing by directly impacting the output of the olfactory bulb., (Copyright © 2015 the authors 0270-6474/15/3515339-14$15.00/0.)
- Published
- 2015
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19. Interaction Between Hippocampus and Cerebellum Crus I in Sequence-Based but not Place-Based Navigation.
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Iglói K, Doeller CF, Paradis AL, Benchenane K, Berthoz A, Burgess N, and Rondi-Reig L
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- Adult, Cerebellum blood supply, Female, Functional Laterality, Hippocampus blood supply, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Maze Learning physiology, Neural Pathways blood supply, Oxygen blood, User-Computer Interface, Young Adult, Cerebellum physiology, Hippocampus physiology, Neural Pathways physiology, Spatial Navigation physiology
- Abstract
To examine the cerebellar contribution to human spatial navigation we used functional magnetic resonance imaging and virtual reality. Our findings show that the sensory-motor requirements of navigation induce activity in cerebellar lobules and cortical areas known to be involved in the motor loop and vestibular processing. By contrast, cognitive aspects of navigation mainly induce activity in a different cerebellar lobule (VIIA Crus I). Our results demonstrate a functional link between cerebellum and hippocampus in humans and identify specific functional circuits linking lobule VIIA Crus I of the cerebellum to medial parietal, medial prefrontal, and hippocampal cortices in nonmotor aspects of navigation. They further suggest that Crus I belongs to 2 nonmotor loops, involved in different strategies: place-based navigation is supported by coherent activity between left cerebellar lobule VIIA Crus I and medial parietal cortex along with right hippocampus activity, while sequence-based navigation is supported by coherent activity between right lobule VIIA Crus I, medial prefrontal cortex, and left hippocampus. These results highlight the prominent role of the human cerebellum in both motor and cognitive aspects of navigation, and specify the cortico-cerebellar circuits by which it acts depending on the requirements of the task., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2015
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20. Explicit memory creation during sleep demonstrates a causal role of place cells in navigation.
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de Lavilléon G, Lacroix MM, Rondi-Reig L, and Benchenane K
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- Animals, CA1 Region, Hippocampal cytology, Electric Stimulation, Electrodes, Implanted, Goals, Humans, Male, Mice, Mice, Inbred C57BL, Patch-Clamp Techniques, Reward, Behavior, Animal physiology, CA1 Region, Hippocampal physiology, Medial Forebrain Bundle physiology, Sleep physiology, Spatial Memory physiology, Spatial Navigation physiology
- Abstract
Hippocampal place cells assemblies are believed to support the cognitive map, and their reactivations during sleep are thought to be involved in spatial memory consolidation. By triggering intracranial rewarding stimulations by place cell spikes during sleep, we induced an explicit memory trace, leading to a goal-directed behavior toward the place field. This demonstrates that place cells' activity during sleep still conveys relevant spatial information and that this activity is functionally significant for navigation.
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- 2015
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21. Connexin 30 sets synaptic strength by controlling astroglial synapse invasion.
- Author
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Pannasch U, Freche D, Dallérac G, Ghézali G, Escartin C, Ezan P, Cohen-Salmon M, Benchenane K, Abudara V, Dufour A, Lübke JH, Déglon N, Knott G, Holcman D, and Rouach N
- Subjects
- Animals, Astrocytes metabolism, Behavior, Animal, Connexin 30, Female, Hippocampus cytology, Hippocampus metabolism, Hippocampus pathology, Male, Memory physiology, Mice, Inbred C57BL, Mice, Knockout, Mutation genetics, Neuronal Plasticity physiology, Astrocytes pathology, Cell Movement physiology, Connexins metabolism, Glutamic Acid metabolism, Synapses physiology, Synaptic Transmission physiology
- Abstract
Astrocytes play active roles in brain physiology by dynamic interactions with neurons. Connexin 30, one of the two main astroglial gap-junction subunits, is thought to be involved in behavioral and basic cognitive processes. However, the underlying cellular and molecular mechanisms are unknown. We show here in mice that connexin 30 controls hippocampal excitatory synaptic transmission through modulation of astroglial glutamate transport, which directly alters synaptic glutamate levels. Unexpectedly, we found that connexin 30 regulated cell adhesion and migration and that connexin 30 modulation of glutamate transport, occurring independently of its channel function, was mediated by morphological changes controlling insertion of astroglial processes into synaptic clefts. By setting excitatory synaptic strength, connexin 30 plays an important role in long-term synaptic plasticity and in hippocampus-based contextual memory. Taken together, these results establish connexin 30 as a critical regulator of synaptic strength by controlling the synaptic location of astroglial processes.
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- 2014
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22. Plasticity of astroglial networks in olfactory glomeruli.
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Roux L, Benchenane K, Rothstein JD, Bonvento G, and Giaume C
- Subjects
- Animals, Mice, Astrocytes physiology, Neuronal Plasticity, Olfactory Bulb physiology
- Abstract
Several recent findings have shown that neurons as well as astrocytes are organized into networks. Indeed, astrocytes are interconnected through connexin-formed gap junction channels allowing exchanges of ions and signaling molecules. The aim of this study is to characterize astrocyte network properties in mouse olfactory glomeruli where neuronal connectivity is highly ordered. Dye-coupling experiments performed in olfactory bulb acute slices (P16-P22) highlight a preferential communication between astrocytes within glomeruli and not between astrocytes in adjacent glomeruli. Such organization relies on the oriented morphology of glomerular astrocytes to the glomerulus center and the enriched expression of two astroglial connexins (Cx43 and Cx30) within the glomeruli. Glomerular astrocytes detect neuronal activity showing membrane potential fluctuations correlated with glomerular local field potentials. Accordingly, gap junctional coupling of glomerular networks is reduced when neuronal activity is silenced by TTX treatment or after early sensory deprivation. Such modulation is lost in Cx30 but not in Cx43 KO mice, indicating that Cx30-formed channels are the molecular targets of this activity-dependent modulation. Extracellular potassium is a key player in this neuroglial interaction, because (i) the inhibition of dye coupling observed in the presence of TTX or after sensory deprivation is restored by increasing [K(+)](e) and (ii) treatment with a K(ir) channel blocker inhibits dye spread between glomerular astrocytes. Together, these results demonstrate that extracellular potassium generated by neuronal activity modulates Cx30-mediated gap junctional communication between glomerular astrocytes, indicating that strong neuroglial interactions take place at this first relay of olfactory information processing.
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- 2011
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23. The hippocampus: hub of brain network communication for memory.
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Battaglia FP, Benchenane K, Sirota A, Pennartz CM, and Wiener SI
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- Animals, Cell Communication physiology, Circadian Rhythm, Hippocampus cytology, Humans, Neocortex cytology, Neurons physiology, Sleep, Hippocampus physiology, Memory physiology, Neocortex physiology, Neural Pathways physiology
- Abstract
A complex brain network, centered on the hippocampus, supports episodic memories throughout their lifetimes. Classically, upon memory encoding during active behavior, hippocampal activity is dominated by theta oscillations (6-10Hz). During inactivity, hippocampal neurons burst synchronously, constituting sharp waves, which can propagate to other structures, theoretically supporting memory consolidation. This 'two-stage' model has been updated by new data from high-density electrophysiological recordings in animals that shed light on how information is encoded and exchanged between hippocampus, neocortex and subcortical structures such as the striatum. Cell assemblies (tightly related groups of cells) discharge together and synchronize across brain structures orchestrated by theta, sharp waves and slow oscillations, to encode information. This evolving dynamical schema is key to extending our understanding of memory processes., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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24. Oscillations in the prefrontal cortex: a gateway to memory and attention.
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Benchenane K, Tiesinga PH, and Battaglia FP
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- Animals, Brain Mapping, Electroencephalography, Humans, Attention physiology, Brain Waves physiology, Memory physiology, Periodicity, Prefrontal Cortex physiology
- Abstract
We consider the potential role of oscillations in the prefrontal cortex (PFC) in mediating attention, working memory and memory consolidation. Activity in the theta, beta, and gamma bands is related to communication between PFC and different brain areas. While gamma/beta oscillations mediate bottom-up and top-down interactions between PFC and visual cortices, related to attention, theta rhythms are engaged by hippocampal/PFC interplay. These interactions are dynamic, depending on the nature and relevance of the information currently being processed. The profound modifications of the PFC neuronal network associated with changes in oscillatory coherence are controlled by neuromodulators such as dopamine, which thereby allow or prevent the formation of cell assemblies for information encoding and storage., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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25. Spatial learning and action planning in a prefrontal cortical network model.
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Martinet LE, Sheynikhovich D, Benchenane K, and Arleo A
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- Animals, Hippocampus physiology, Models, Neurological, Nerve Net physiology, Rats, Cognition physiology, Learning physiology, Prefrontal Cortex physiology, Spatial Behavior physiology
- Abstract
The interplay between hippocampus and prefrontal cortex (PFC) is fundamental to spatial cognition. Complementing hippocampal place coding, prefrontal representations provide more abstract and hierarchically organized memories suitable for decision making. We model a prefrontal network mediating distributed information processing for spatial learning and action planning. Specific connectivity and synaptic adaptation principles shape the recurrent dynamics of the network arranged in cortical minicolumns. We show how the PFC columnar organization is suitable for learning sparse topological-metrical representations from redundant hippocampal inputs. The recurrent nature of the network supports multilevel spatial processing, allowing structural features of the environment to be encoded. An activation diffusion mechanism spreads the neural activity through the column population leading to trajectory planning. The model provides a functional framework for interpreting the activity of PFC neurons recorded during navigation tasks. We illustrate the link from single unit activity to behavioral responses. The results suggest plausible neural mechanisms subserving the cognitive "insight" capability originally attributed to rodents by Tolman & Honzik. Our time course analysis of neural responses shows how the interaction between hippocampus and PFC can yield the encoding of manifold information pertinent to spatial planning, including prospective coding and distance-to-goal correlates.
- Published
- 2011
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26. Principal component analysis of ensemble recordings reveals cell assemblies at high temporal resolution.
- Author
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Peyrache A, Benchenane K, Khamassi M, Wiener SI, and Battaglia FP
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- Animals, Probability, Sleep physiology, Time Factors, Wakefulness physiology, Action Potentials physiology, Models, Neurological, Neurons physiology, Principal Component Analysis
- Abstract
Simultaneous recordings of many single neurons reveals unique insights into network processing spanning the timescale from single spikes to global oscillations. Neurons dynamically self-organize in subgroups of coactivated elements referred to as cell assemblies. Furthermore, these cell assemblies are reactivated, or replayed, preferentially during subsequent rest or sleep episodes, a proposed mechanism for memory trace consolidation. Here we employ Principal Component Analysis to isolate such patterns of neural activity. In addition, a measure is developed to quantify the similarity of instantaneous activity with a template pattern, and we derive theoretical distributions for the null hypothesis of no correlation between spike trains, allowing one to evaluate the statistical significance of instantaneous coactivations. Hence, when applied in an epoch different from the one where the patterns were identified, (e.g. subsequent sleep) this measure allows to identify times and intensities of reactivation. The distribution of this measure provides information on the dynamics of reactivation events: in sleep these occur as transients rather than as a continuous process.
- Published
- 2010
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27. Coherent theta oscillations and reorganization of spike timing in the hippocampal- prefrontal network upon learning.
- Author
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Benchenane K, Peyrache A, Khamassi M, Tierney PL, Gioanni Y, Battaglia FP, and Wiener SI
- Subjects
- Action Potentials drug effects, Animals, Behavior, Animal, Dopamine pharmacology, Male, Neural Inhibition drug effects, Neural Inhibition physiology, Neural Pathways physiology, Neurons classification, Neurons drug effects, Principal Component Analysis, Rats, Rats, Long-Evans, Reward, Spectrum Analysis methods, Time Factors, Action Potentials physiology, Hippocampus physiology, Maze Learning physiology, Neurons physiology, Periodicity, Prefrontal Cortex physiology
- Abstract
To study the interplay between hippocampus and medial prefrontal cortex (Pfc) and its importance for learning and memory consolidation, we measured the coherence in theta oscillations between these two structures in rats learning new rules on a Y maze. Coherence peaked at the choice point, most strongly after task rule acquisition. Simultaneously, Pfc pyramidal neurons reorganized their phase, concentrating at hippocampal theta trough, and synchronous cell assemblies emerged. This synchronous state may result from increased inhibition exerted by interneurons on pyramidal cells, as measured by cross-correlation, and could be modulated by dopamine: we found similar hippocampal-Pfc theta coherence increases and neuronal phase shifts following local administration of dopamine in Pfc of anesthetized rats. Pfc cell assemblies emerging during high coherence were preferentially replayed during subsequent sleep, concurrent with hippocampal sharp waves. Thus, hippocampal/prefrontal coherence could lead to synchronization of reward predicting activity in prefrontal networks, tagging it for subsequent memory consolidation.
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- 2010
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28. Sequential Reinstatement of Neocortical Activity during Slow Oscillations Depends on Cells' Global Activity.
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Peyrache A, Benchenane K, Khamassi M, Wiener SI, and Battaglia FP
- Abstract
During Slow Wave Sleep (SWS), cortical activity is dominated by endogenous processes modulated by slow oscillations (0.1-1 Hz): cell ensembles fluctuate between states of sustained activity (UP states) and silent epochs (DOWN states). We investigate here the temporal structure of ensemble activity during UP states by means of multiple single unit recordings in the prefrontal cortex of naturally sleeping rats. As previously shown, the firing rate of each PFC cell peaks at a distinct time lag after the DOWN/UP transition in a consistent order. We show here that, conversely, the latency of the first spike after the UP state onset depends primarily on the session-averaged firing rates of cells (which can be considered as an indirect measure of their intrinsic excitability). This latency can be explained by a simple homogeneous process (Poisson model) of cell firing, with sleep averaged firing rates employed as parameters. Thus, at DOWN/UP transitions, neurons are affected both by a slow process, possibly originating in the cortical network, modulating the time course of firing for each cell, and by a fast, relatively stereotyped reinstatement of activity, related mostly to global activity levels.
- Published
- 2010
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29. Selective suppression of hippocampal ripples impairs spatial memory.
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Girardeau G, Benchenane K, Wiener SI, Buzsáki G, and Zugaro MB
- Subjects
- Action Potentials physiology, Analysis of Variance, Animals, Behavior, Animal, Biophysics, Electric Stimulation methods, Electroencephalography methods, Hippocampus cytology, Male, Maze Learning physiology, Nerve Net physiology, Neurons physiology, Online Systems, Rats, Rats, Long-Evans, Spectrum Analysis methods, Evoked Potentials physiology, Hippocampus physiology, Memory Disorders physiopathology, Neural Inhibition physiology, Space Perception physiology
- Abstract
Sharp wave-ripple (SPW-R) complexes in the hippocampus-entorhinal cortex are believed to be important for transferring labile memories from the hippocampus to the neocortex for long-term storage. We found that selective elimination of SPW-Rs during post-training consolidation periods resulted in performance impairment in rats trained on a hippocampus-dependent spatial memory task. Our results provide evidence for a prominent role of hippocampal SPW-Rs in memory consolidation.
- Published
- 2009
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- View/download PDF
30. Replay of rule-learning related neural patterns in the prefrontal cortex during sleep.
- Author
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Peyrache A, Khamassi M, Benchenane K, Wiener SI, and Battaglia FP
- Subjects
- Action Potentials, Algorithms, Analysis of Variance, Animals, Electrodes, Implanted, Hippocampus physiology, Male, Memory physiology, Microelectrodes, Periodicity, Rats, Rats, Long-Evans, Time Factors, Wakefulness physiology, Maze Learning physiology, Prefrontal Cortex physiology, Sleep physiology
- Abstract
Slow-wave sleep (SWS) is important for memory consolidation. During sleep, neural patterns reflecting previously acquired information are replayed. One possible reason for this is that such replay exchanges information between hippocampus and neocortex, supporting consolidation. We recorded neuron ensembles in the rat medial prefrontal cortex (mPFC) to study memory trace reactivation during SWS following learning and execution of cross-modal strategy shifts. In general, reactivation of learning-related patterns occurred in distinct, highly synchronized transient bouts, mostly simultaneous with hippocampal sharp wave/ripple complexes (SPWRs), when hippocampal ensemble reactivation and cortico-hippocampal interaction is enhanced. During sleep following learning of a new rule, mPFC neural patterns that appeared during response selection replayed prominently, coincident with hippocampal SPWRs. This was learning dependent, as the patterns appeared only after rule acquisition. Therefore, learning, or the resulting reliable reward, influenced which patterns were most strongly encoded and successively reactivated in the hippocampal/prefrontal network.
- Published
- 2009
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31. Toward safer thrombolytic agents in stroke: molecular requirements for NMDA receptor-mediated neurotoxicity.
- Author
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Lopez-Atalaya JP, Roussel BD, Levrat D, Parcq J, Nicole O, Hommet Y, Benchenane K, Castel H, Leprince J, To Van D, Bureau R, Rault S, Vaudry H, Petersen KU, Santos JS, Ali C, and Vivien D
- Subjects
- Amino Acid Sequence, Animals, Catalytic Domain, Cells, Cultured, Drug-Related Side Effects and Adverse Reactions, Mice, Models, Molecular, Molecular Sequence Data, Neurons drug effects, Neurons metabolism, Plasminogen Activators metabolism, Protein Binding, Protein Structure, Quaternary, Receptors, N-Methyl-D-Aspartate chemistry, Receptors, N-Methyl-D-Aspartate genetics, Signal Transduction, Tissue Culture Techniques, Tissue Plasminogen Activator chemistry, Tissue Plasminogen Activator metabolism, Fibrinolytic Agents toxicity, Receptors, N-Methyl-D-Aspartate metabolism, Stroke metabolism
- Abstract
Current thrombolytic therapy for acute ischemic stroke with tissue-type plasminogen activator (tPA) has clear global benefits. Nevertheless, evidences argue that in addition to its prohemorrhagic effect, tPA might enhance excitotoxic necrosis. In the brain parenchyma, tPA, by binding to and then cleaving the amino-terminal domain (ATD) of the NR1 subunit of N-methyl-D-aspartate (NMDA) glutamate receptors, increases calcium influx to toxic levels. We show here that tPA binds the ATD of the NR1 subunit by a two-sites system (K(D)=24 nmol/L). Although tenecteplase (TNK) and reteplase also display two-sites binding profiles, the catalytically inactive mutant TNKS478A displays a one-site binding profile and desmoteplase (DSPA), a kringle 2 (K2) domain-free plasminogen activator derived from vampire bat, does not interact with NR1. Moreover, we show that in contrast to tPA, DSPA does not promote excitotoxicity. These findings, together with three-dimensional (3D) modeling, show that a critical step for interaction of tPA with NR1 is the binding of its K2 domain, followed by the binding of its catalytic domain, which in turn cleaves the NR1 subunit at its ATD, leading to a subsequent potentiation of NMDA-induced calcium influx and neurotoxicity. This could help design safer new generation thrombolytic agents for stroke treatment.
- Published
- 2008
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32. Ageing and amyloid-beta peptide deposition contribute to an impaired brain tissue plasminogen activator activity by different mechanisms.
- Author
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Cacquevel M, Launay S, Castel H, Benchenane K, Chéenne S, Buée L, Moons L, Delacourte A, Carmeliet P, and Vivien D
- Subjects
- Animals, Brain pathology, Enzyme-Linked Immunosorbent Assay, Humans, Immunohistochemistry, Mice, Mice, Transgenic, RNA, Messenger analysis, Reverse Transcriptase Polymerase Chain Reaction, Aging physiology, Alzheimer Disease enzymology, Amyloid beta-Peptides metabolism, Brain enzymology, Tissue Plasminogen Activator metabolism
- Abstract
Alzheimer's disease (AD) is the most common form of neurodegenerative disorder in the ageing population. It is characterized by the cerebral accumulation of toxic amyloid-beta peptide assemblies (Abeta). The serine protease plasmin, which is generated from the inactive zymogen plasminogen through its proteolytic cleavage by tissue- (tPA) or urokinase-type plasminogen activator, has been implicated in the catabolism of Abeta peptides. In this report, we studied the regulation of tPA activity in vivo during ageing in normal mice and in a mouse model of AD characterized by an exacerbated endogenous Abeta accumulation. We observed that cerebral tPA activity was decreased during ageing in normal mice and that this effect was worsened in mice overproducing Abeta peptides. These phenomena result, respectively, from a decrease in tPA expression and from an increase in the production of one of the tPA inhibitors, the plasminogen activator inhibitor type 1 (PAI-1). A similar study in sporadic AD and age-matched control brain tissues revealed that the tPA proteolytic activity was negatively correlated to Abeta peptides levels supporting the data observed in mice. Altogether, our data support a model in which amyloid deposition induces a decrease in tPA activity through the overproduction of PAI-1 by activated glial cells.
- Published
- 2007
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33. Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory.
- Author
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Benchenane K, Castel H, Boulouard M, Bluthé R, Fernandez-Monreal M, Roussel BD, Lopez-Atalaya JP, Butt-Gueulle S, Agin V, Maubert E, Dantzer R, Touzani O, Dauphin F, Vivien D, and Ali C
- Subjects
- Animals, Behavior, Animal drug effects, Excitatory Amino Acid Agonists pharmacology, Female, Maze Learning drug effects, Mice, Models, Immunological, N-Methylaspartate pharmacology, Protein Structure, Tertiary, Tissue Plasminogen Activator deficiency, Memory drug effects, Receptors, N-Methyl-D-Aspartate chemistry, Receptors, N-Methyl-D-Aspartate metabolism, Tissue Plasminogen Activator metabolism, Vaccination
- Abstract
Fine-tuning of NMDA glutamatergic receptor signalling strategically controls crucial brain functions. This process depends on several ligands and modulators, one of which unexpectedly includes the serine protease tissue-type plasminogen activator (tPA). In vitro, tPA increases NMDA-receptor-mediated calcium influx by interacting with, and then cleaving, the NR1 subunit within its N-terminal domain. Owing to lack of in vivo evidence of the relevance and contribution of this mechanism in physiological and pathological brain processes, active immunisation was developed here in mice, to allow transient and specific prevention of the interaction of tPA with the NR1 subunit. Immunisation significantly reduced the severity of ischemic and excitotoxic insults in the mouse brain. Cognitive function was altered in some, but not all behavioural tasks affected in tPA-deficient mice. Our data demonstrate that in vivo, tPA controls neurotoxicity and the encoding of novel spatial experiences by binding to and cleaving the NMDA receptor NR1 subunit. Interesting therapeutic possibilities for several brain pathologies that involve excitotoxicity may now be envisaged.
- Published
- 2007
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34. Tissue-type plasminogen activator rescues neurones from serum deprivation-induced apoptosis through a mechanism independent of its proteolytic activity.
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Liot G, Roussel BD, Lebeurrier N, Benchenane K, López-Atalaya JP, Vivien D, and Ali C
- Subjects
- Analysis of Variance, Animals, Blotting, Western methods, Butadienes pharmacology, Cell Count methods, Cerebral Cortex cytology, Chromones pharmacology, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Interactions, Embryo, Mammalian, Enzyme Inhibitors, Immunohistochemistry methods, Mice, Morpholines pharmacology, Neuropeptides pharmacology, Nitriles pharmacology, Nuclear Proteins pharmacology, Serpins pharmacology, Time Factors, Tissue Plasminogen Activator metabolism, Neuroserpin, Apoptosis drug effects, Fibrinolytic Agents pharmacology, Neurons drug effects, Serum physiology, Tissue Plasminogen Activator administration & dosage
- Abstract
Although the mechanism of action of tissue-type plasminogen activator (tPA) in excitotoxic necrosis is well documented, whether this serine protease can influence the apoptotic cascade remains a subject of debate. Here, we report that tPA protects cultured cortical neurones against apoptotic cell death induced by serum deprivation, an effect associated with a reduction of caspase-3 activation. Interestingly, blocking tPA proteolytic activity by either tPA stop or neuroserpin did not prevent this neuroprotection. Similarly, prevention of the interaction between tPA and its receptor low-density lipoprotein receptor-related protein (LRP) could not alter tPA anti-apoptotic activity. Interestingly, the survival-promoting effect of tPA was blocked by the phosphatidylinositol-3 (PI-3) kinase inhibitor, LY294002, but not by the mitogen-activated protein (MAP) kinase inhibitor, U0126. In conclusion, the present demonstration of an anti-apoptotic effect of tPA, independent of its enzymatic activity, reveals an additional level of complexity in our understanding of this critical mediator of brain physiology and pathology.
- Published
- 2006
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35. Oxygen glucose deprivation switches the transport of tPA across the blood-brain barrier from an LRP-dependent to an increased LRP-independent process.
- Author
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Benchenane K, Berezowski V, Fernández-Monreal M, Brillault J, Valable S, Dehouck MP, Cecchelli R, Vivien D, Touzani O, and Ali C
- Subjects
- Animals, Brain Ischemia etiology, Cell Hypoxia, Cytoplasmic Vesicles chemistry, Endothelium, Vascular cytology, Endothelium, Vascular ultrastructure, Glucose physiology, Infarction, Middle Cerebral Artery complications, LDL-Receptor Related Proteins antagonists & inhibitors, Male, Mice, Protein Transport, Tissue Plasminogen Activator analysis, Tissue Plasminogen Activator pharmacology, Blood-Brain Barrier metabolism, Brain Ischemia metabolism, LDL-Receptor Related Proteins physiology, Tissue Plasminogen Activator metabolism
- Abstract
Background and Purpose: Despite uncontroversial benefit from its thrombolytic activity, the documented neurotoxic effect of tissue plasminogen activator (tPA) raises an important issue: the current emergency stroke treatment might not be optimum if exogenous tPA can enter the brain and thus add to the deleterious effects of endogenous tPA within the cerebral parenchyma. Here, we aimed at determining whether vascular tPA crosses the blood-brain barrier (BBB) during cerebral ischemia, and if so, by which mechanism., Methods: First, BBB permeability was assessed in vivo by measuring Evans Blue extravasation following intravenous injection at 0 or 3 hours after middle cerebral artery electrocoagulation in mice. Second, the passage of vascular tPA was investigated in an in vitro model of BBB, subjected or not to oxygen and glucose deprivation (OGD)., Results: We first demonstrated that after focal permanent ischemia in mice, the BBB remains impermeable to Evans Blue in the early phase (relative to the therapeutic window of tPA), whereas at later time points massive Evans Blue extravasation occurs. Then, the passage of tPA during these 2 phases, was investigated in vitro and we show that in control conditions, tPA crosses the intact BBB by a low-density lipoprotein (LDL) receptor-related protein (LRP)-dependent transcytosis, whereas OGD leads to an exacerbation of tPA passage, which switches to a LRP-independent process., Conclusions: We evidence 2 different mechanisms through which vascular tPA can reach the brain parenchyma, depending on the state of the BBB. As discussed, these data show the importance of taking the side effects of blood-derived tPA into account and offer a basis to improve the current thrombolytic strategy.
- Published
- 2005
- Full Text
- View/download PDF
36. Arginine 260 of the amino-terminal domain of NR1 subunit is critical for tissue-type plasminogen activator-mediated enhancement of N-methyl-D-aspartate receptor signaling.
- Author
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Fernández-Monreal M, López-Atalaya JP, Benchenane K, Cacquevel M, Dulin F, Le Caer JP, Rossier J, Jarrige AC, Mackenzie ET, Colloc'h N, Ali C, and Vivien D
- Subjects
- Alanine chemistry, Amino Acid Sequence, Animals, Binding Sites, Calcium chemistry, Cell Line, Humans, Immunoblotting, Kinetics, Ligands, Mass Spectrometry, Mice, Microscopy, Video, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Neurons metabolism, Point Mutation, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Recombinant Proteins chemistry, Sequence Homology, Amino Acid, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Temperature, Time Factors, Transfection, Arginine chemistry, Receptors, N-Methyl-D-Aspartate chemistry, Receptors, N-Methyl-D-Aspartate metabolism, Signal Transduction, Tissue Plasminogen Activator chemistry
- Abstract
Tissue-type plasminogen activator (tPA) has been involved in both physiological and pathological glutamatergic-dependent processes, such as synaptic plasticity, seizure, trauma, and stroke. In a previous study, we have shown that the proteolytic activity of tPA enhances the N-methyl-D-aspartate (NMDA) receptor-mediated signaling in neurons (Nicole, O., Docagne, F., Ali, C., Margaill, I., Carmeliet, P., MacKenzie, E. T., Vivien, D., and Buisson, A. (2001) Nat. Med. 7, 59-64). Here, we show that tPA forms a direct complex with the amino-terminal domain (ATD) of the NR1 subunit of the NMDA receptor and cleaves this subunit at the arginine 260. Furthermore, point mutation analyses show that arginine 260 is necessary for both tPA-induced cleavage of the ATD of NR1 and tPA-induced potentiation of NMDA receptor signaling. Thus, tPA is the first binding protein described so far to interact with the ATD of NR1 and to modulate the NMDA receptor function.
- Published
- 2004
- Full Text
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37. 2,7-Bis-(4-amidinobenzylidene)-cycloheptan-1-one dihydrochloride, tPA stop, prevents tPA-enhanced excitotoxicity both in vitro and in vivo.
- Author
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Liot G, Benchenane K, Léveillé F, López-Atalaya JP, Fernández-Monreal M, Ruocco A, Mackenzie ET, Buisson A, Ali C, and Vivien D
- Subjects
- Animals, Cell Death drug effects, Cell Death physiology, Cells, Cultured, Cycloheptanes, Excitatory Amino Acid Agonists toxicity, In Vitro Techniques, Male, Mice, N-Methylaspartate toxicity, Neurons cytology, Neurotoxins toxicity, Rats, Rats, Sprague-Dawley, Signal Transduction drug effects, Signal Transduction physiology, Brain Ischemia drug therapy, Brain Ischemia metabolism, Serine Proteinase Inhibitors pharmacology, Tissue Plasminogen Activator antagonists & inhibitors, Tissue Plasminogen Activator metabolism
- Abstract
Tissue-type plasminogen activator (tPA) is available for the treatment of thromboembolic stroke in humans. However, adverse effects of tPA have been observed in animal models of ischemic brain injuries. In the present study, we have used a synthetic tPA inhibitor, named 2,7-bis-(4-amidino-benzylidene)-cycloheptan-1-one dihydrochloride (tPA stop), to investigate the role of endogenous tPA in the cerebral parenchyma. In mouse cortical cell cultures, we observed that although tPA stop reduced N-methyl-D-aspartic acid (NMDA)-mediated excitotoxic neuronal death, it failed to modulate alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazole propanoic acid or kainate-mediated necrosis. In addition, we found that tPA stop could prevent the deleterious effects of both endogenous and exogenous tPA during NMDA exposure. At the functional level, tPA stop was found to prevent tPA-dependent potentiation of NMDA receptor-evoked calcium influx. The relevance of those findings was strengthened by the observation of a massive reduction of NMDA-induced excitotoxic lesion in rats when tPA stop was co-injected. Altogether, these data demonstrate that the blockade of the endogenous proteolytic activity of tPA in the cerebral parenchyma could be a powerful neuroprotective strategy raised against brain pathologies associated with excitotoxicity.
- Published
- 2004
- Full Text
- View/download PDF
38. Is tissue-type plasminogen activator a neuromodulator?
- Author
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Fernández-Monreal M, López-Atalaya JP, Benchenane K, Léveillé F, Cacquevel M, Plawinski L, MacKenzie ET, Bu G, Buisson A, and Vivien D
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Animals, Calcium Signaling drug effects, Calcium Signaling physiology, Cell Line, Cerebral Cortex cytology, Cerebral Cortex metabolism, Chelating Agents pharmacology, Exocytosis drug effects, Exocytosis physiology, Glial Fibrillary Acidic Protein metabolism, Humans, Low Density Lipoprotein Receptor-Related Protein-1 metabolism, Mice, Microtubule-Associated Proteins metabolism, N-Methylaspartate pharmacology, Neurons drug effects, Neurotransmitter Agents pharmacology, Receptors, N-Methyl-D-Aspartate agonists, Receptors, N-Methyl-D-Aspartate metabolism, Synaptic Transmission drug effects, Synaptic Transmission physiology, Tissue Plasminogen Activator pharmacology, Brain metabolism, Brain Chemistry physiology, Neurons metabolism, Neurotransmitter Agents metabolism, Tissue Plasminogen Activator metabolism
- Abstract
In the last few years, it has been evidenced that serine proteases play key roles in the mammalian brain, both in physiological and pathological conditions. It has been well established that among these serine proteases, the tissue-type plasminogen activator (t-PA) is critically involved in development, plasticity, and pathology of the nervous system. However, its mechanism of action remains to be further investigated. By using pharmacological and immunological approaches, we have evidenced in the present work that t-PA should be considered as a neuromodulator. Indeed, we have observed that: (i). neuronal depolarization induces a release of t-PA; (ii). this release of t-PA is sensitive to exocytosis inhibition and calcium chelation; (iii). released t-PA modulates NMDA receptor signaling and (iv). astrocytes are able to recapture extracellular t-PA through a low-density lipoprotein (LDL) receptor-related protein (LRP)-dependent mechanism.
- Published
- 2004
- Full Text
- View/download PDF
39. Equivocal roles of tissue-type plasminogen activator in stroke-induced injury.
- Author
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Benchenane K, López-Atalaya JP, Fernández-Monreal M, Touzani O, and Vivien D
- Subjects
- Animals, Cell Death drug effects, Disease Models, Animal, Fibrinolytic Agents adverse effects, Glutamic Acid metabolism, Humans, Neuroprotective Agents adverse effects, Neuroprotective Agents therapeutic use, Signal Transduction drug effects, Thrombolytic Therapy methods, Tissue Plasminogen Activator adverse effects, Transforming Growth Factor beta therapeutic use, Transforming Growth Factor beta1, Fibrinolytic Agents therapeutic use, Neuroglia drug effects, Neurons drug effects, Stroke complications, Stroke drug therapy, Tissue Plasminogen Activator therapeutic use
- Abstract
Stroke represents a major health problem in the ever-ageing population of industrialized nations. Each year, over three million people in the USA alone suffer from this affliction. Stroke, which results from the obstruction of an intra- or extra-cerebral artery, induces irreversible neuronal damage. The clot-busting drug tissue-type plasminogen activator (tPA) is the only FDA-approved therapy for acute stroke. Although tPA has been successfully used to treat myocardial infarction due to clot formation, its use in the treatment of occlusive cerebrovascular diseases remains controversial. Indeed, tPA is clearly beneficial as a thrombolytic agent. However, increasing evidence suggests that tPA could have direct and deleterious effects on neurons and glial cells.
- Published
- 2004
- Full Text
- View/download PDF
40. Selective blockade of endothelin-B receptors exacerbates ischemic brain damage in the rat.
- Author
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Chuquet J, Benchenane K, Toutain J, MacKenzie ET, Roussel S, and Touzani O
- Subjects
- Animals, Antihypertensive Agents administration & dosage, Blood Flow Velocity drug effects, Brain Ischemia chemically induced, Cerebrovascular Circulation drug effects, Disease Models, Animal, Excitatory Amino Acid Agonists administration & dosage, Excitatory Amino Acid Agonists toxicity, Gene Expression drug effects, Infarction, Middle Cerebral Artery pathology, Injections, Intraventricular, Male, N-Methylaspartate administration & dosage, N-Methylaspartate toxicity, Oligopeptides administration & dosage, Piperidines administration & dosage, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Receptor, Endothelin B, Receptors, Endothelin genetics, Antihypertensive Agents adverse effects, Brain Ischemia pathology, Endothelin Receptor Antagonists, Oligopeptides adverse effects, Piperidines adverse effects
- Abstract
Background and Purpose: Endothelins act through 2 receptors, namely, ET(A) and ET(B). In the cerebral circulation, ET(A) mediates marked and prolonged vasoconstriction, and its blockade increases cerebral blood flow (CBF) and reduces ischemic brain damage. However, the role of ET(B) receptors remains unclear. In this study we examined, in rats, the kinetics of expression of ET(B) and the effects of ET(B) blockade on changes in CBF and brain damage after focal cerebral ischemia and N-methyl-D-aspartate (NMDA)-induced excitotoxic injury., Methods: Rats were subjected to transient (60 minutes) focal cerebral ischemia or cortical injection of NMDA. The selective ET(B) antagonist BQ-788 was injected intracerebroventricularly 30 minutes before and 30 minutes after the onset of ischemia. Cortical perfusion was monitored by laser-Doppler flowmetry. The volume of infarction or NMDA-induced cortical lesion was assessed at 24 hours after the insult. The reverse transcription-polymerase chain reaction technique was used to assess ET(B) expression., Results: Cerebral ischemia failed to alter the expression of ET(B) mRNA in both acute and chronic stages. Administration of BQ-788 resulted in an increase in infarction volume (178%; P<0.05) accompanied by a decrease in residual CBF (-26.7% versus control; P<0.01). In these animals we found a positive correlation between the volume of infarction and the severity of the decrease in CBF. NMDA-induced cortical lesions were not affected by the administration of BQ-788., Conclusions: Our results suggest that the ET(B) antagonist BQ-788 induces deleterious effects that are mediated by the reduction of residual blood flow after ischemia and argue that the optimal therapeutic strategy in stroke would be to target the use of selective ET(A) antagonists and not mixed ET(A)/ET(B) antagonists.
- Published
- 2002
- Full Text
- View/download PDF
41. Matching gene expression with hypometabolism after cerebral ischemia in the nonhuman primate.
- Author
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Chuquet J, Benchenane K, Liot G, Fernández-Monreal M, Toutain J, Blanchet S, Eveno E, Auffray C, Piétu G, Buisson A, Touzani O, MacKenzie ET, and Vivien D
- Subjects
- Animals, Brain blood supply, Brain Ischemia metabolism, Cerebral Arteries metabolism, Cerebral Arteries pathology, Cloning, Molecular, Cluster Analysis, DNA, Complementary, Disease Models, Animal, Male, Oligonucleotide Array Sequence Analysis, Oxygen Consumption, Papio, Brain metabolism, Brain Ischemia genetics, Gene Expression Regulation
- Abstract
To correlate brain metabolic status with the molecular events during cerebral ischemia, a cDNA array was performed after positron emission tomography scanning in a model of focal cerebral ischemia in baboons. Cluster analysis for the expression of 74 genes allowed the identification of 4 groups of genes. In each of the distinct groups, the authors observed a marked inflection in the pattern of gene expression when the CMRo was reduced by 48% to 66%. These patterns of coordinated modifications in gene expression could define molecular checkpoints for the development of an ischemic infarct and a molecular definition of the penumbra.
- Published
- 2002
- Full Text
- View/download PDF
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