The Experts below are selected from a list of 777 Experts worldwide ranked by ideXlab platform
Nigel J. M. Birdsall - One of the best experts on this subject based on the ideXlab platform.
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Progress toward a high-affinity allosteric enhancer at muscarinic M_1 receptors
Journal of Molecular Neuroscience, 2003Co-Authors: Sebastian Lazareno, Angela Popham, Nigel J. M. BirdsallAbstract:Loss of forebrain acetylcholine is an early Neurochemical Lesion in Alzheimer’s disease (AD). As muscarinic acetylcholine receptors are involved in memory and cognition, a muscarinic agonist could therefore provide a “replacement therapy” in this disease. However, muscarinic receptors occur throughout the CNS and the periphery. A selective locus of action of a muscarinic agonist is therefore crucial in order to avoid intolerable side effects. The five subtypes of muscarinic receptors, M_1–M_5, have distinct regional distributions with M_2 and M_3 receptors mediating most of the peripheral effects. M_1 receptors are the major receptor subtype in the cortex and hippocampus—the two brain regions most associated with memory and cognition. This localization has led to a, so far unsuccessful, search for a truly M_1-selective muscarinic agonist. However, acetylcholinesterase inhibitors, such as donepezil (Aricept), which potentiate cholinergic neurotransmission, do have a therapeutic role in the management of AD and so the M_1 receptor remains a viable therapeutic target. Our approach is to develop muscarinic allosteric enhancers—compounds that bind to the receptor at an “allosteric” site, which is distinct from the “primary” site to which ACh binds, and which enhance ACh affinity (or efficacy). Having discovered that a commercially available compound, WIN 62577, is an allosteric enhancer with micromolar potency at M_3 receptors, we report here some results of a chemical synthesis project to develop this hit. Modification of WIN 62577 has led to compounds with over 1000-fold increased affinity but, so far, none of these extremely potent compounds are allosteric enhancers.
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Progress toward a high-affinity allosteric enhancer at muscarinic M1 receptors.
Journal of Molecular Neuroscience, 2003Co-Authors: Sebastian Lazareno, Angela Popham, Nigel J. M. BirdsallAbstract:Loss of forebrain acetylcholine is an early Neurochemical Lesion in Alzheimer’s disease (AD). As muscarinic acetylcholine receptors are involved in memory and cognition, a muscarinic agonist could therefore provide a “replacement therapy” in this disease. However, muscarinic receptors occur throughout the CNS and the periphery. A selective locus of action of a muscarinic agonist is therefore crucial in order to avoid intolerable side effects. The five subtypes of muscarinic receptors, M1–M5, have distinct regional distributions with M2 and M3 receptors mediating most of the peripheral effects. M1 receptors are the major receptor subtype in the cortex and hippocampus—the two brain regions most associated with memory and cognition. This localization has led to a, so far unsuccessful, search for a truly M1-selective muscarinic agonist. However, acetylcholinesterase inhibitors, such as donepezil (Aricept), which potentiate cholinergic neurotransmission, do have a therapeutic role in the management of AD and so the M1 receptor remains a viable therapeutic target. Our approach is to develop muscarinic allosteric enhancers—compounds that bind to the receptor at an “allosteric” site, which is distinct from the “primary” site to which ACh binds, and which enhance ACh affinity (or efficacy). Having discovered that a commercially available compound, WIN 62577, is an allosteric enhancer with micromolar potency at M3 receptors, we report here some results of a chemical synthesis project to develop this hit. Modification of WIN 62577 has led to compounds with over 1000-fold increased affinity but, so far, none of these extremely potent compounds are allosteric enhancers.
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Towards a high-affinity allosteric enhancer at muscarinic M_1 receptors
Journal of Molecular Neuroscience, 2002Co-Authors: Sebastian Lazareno, Angela Popham, Nigel J. M. BirdsallAbstract:Loss of forebrain acetylcholine (ACh) is an early Neurochemical Lesion in Alzheimer’s Disease (AD), and muscarinic receptors for ACh are involved in memory and cognition, so a muscarinic agonist could provide ‘replacement therapy’ in this disease. Muscarinic receptors, which couple to G-proteins, occur throughout the CNS, and in the periphery they mediate the responses of the parasympathetic nervous system, so selectivity is crucial. The five subtypes of muscarinic receptor, M_1–M_5, have a distinct regional distribution, with M_2 and M_3 mediating most of the peripheral effects, M_2 predominating in hindbrain areas, and M_1 predominating in the cortex and hippocampus—the brain regions most associated with memory and cognition, which has lead to a search for a truly M_1-selective muscarinic agonist. That search has so far been unsuccessful, but acetylcholinesterase inhibitors such as donepezil (Aricept), which potentiate cholinergic neurotransmission, have a therapeutic role in the management of AD; so the M_1 receptor remains a therapeutic target. Our approach is to develop allosteric enhancers—compounds which bind to the receptor at an ‘allosteric’ site which is distinct from the ‘primary’ site to which the endogenous ligand binds, and which enhance the affinity (or efficacy) of the endogenous ligand. We have developed radioligand binding assays and analyses for the detection and quantitatitation of allosteric interactions of a test agent with labelled and unlabelled ‘primary’ ligands, and we report here some results of the initial phase of a chemical synthesis project to develop potent and selective allosteric enhancers at muscarinic M_1 receptors.
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Towards a high-affinity allosteric enhancer at muscarinic M1 receptors.
Journal of molecular neuroscience : MN, 2002Co-Authors: Sebastian Lazareno, Angela Popham, Nigel J. M. BirdsallAbstract:Loss of forebrain acetylcholine (ACh) is an early Neurochemical Lesion in Alzheimer's Disease (AD), and muscarinic receptors for ACh are involved in memory and cognition, so a muscarinic agonist could provide 'replacement therapy' in this disease. Muscarinic receptors, which couple to G-proteins, occur throughout the CNS, and in the periphery they mediate the responses of the parasympathetic nervous system, so selectivity is crucial. The five subtypes of muscarinic receptor, M1-M5, have a distinct regional distribution, with M2 and M3 mediating most of the peripheral effects, M2 predominating in hindbrain areas, and M1 predominating in the cortex and hippocampus--the brain regions most associated with memory and cognition, which has lead to a search for a truly M1-selective muscarinic agonist. That search has so far been unsuccessful, but acetylcholinesterase inhibitors such as donepezil (Aricept), which potentiate cholinergic neurotransmission, have a therapeutic role in the management of AD; so the M1 receptor remains a therapeutic target. Our approach is to develop allosteric enhancers--compounds which bind to the receptor at an 'allosteric' site which is distinct from the 'primary' site to which the endogenous ligand binds, and which enhance the affinity (or efficacy) of the endogenous ligand. We have developed radioligand binding assays and analyses for the detection and quantitatitation of allosteric interactions of a test agent with labelled and unlabelled 'primary' ligands, and we report here some results of the initial phase of a chemical synthesis project to develop potent and selective allosteric enhancers at muscarinic M1 receptors.
Sebastian Lazareno - One of the best experts on this subject based on the ideXlab platform.
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Progress toward a high-affinity allosteric enhancer at muscarinic M_1 receptors
Journal of Molecular Neuroscience, 2003Co-Authors: Sebastian Lazareno, Angela Popham, Nigel J. M. BirdsallAbstract:Loss of forebrain acetylcholine is an early Neurochemical Lesion in Alzheimer’s disease (AD). As muscarinic acetylcholine receptors are involved in memory and cognition, a muscarinic agonist could therefore provide a “replacement therapy” in this disease. However, muscarinic receptors occur throughout the CNS and the periphery. A selective locus of action of a muscarinic agonist is therefore crucial in order to avoid intolerable side effects. The five subtypes of muscarinic receptors, M_1–M_5, have distinct regional distributions with M_2 and M_3 receptors mediating most of the peripheral effects. M_1 receptors are the major receptor subtype in the cortex and hippocampus—the two brain regions most associated with memory and cognition. This localization has led to a, so far unsuccessful, search for a truly M_1-selective muscarinic agonist. However, acetylcholinesterase inhibitors, such as donepezil (Aricept), which potentiate cholinergic neurotransmission, do have a therapeutic role in the management of AD and so the M_1 receptor remains a viable therapeutic target. Our approach is to develop muscarinic allosteric enhancers—compounds that bind to the receptor at an “allosteric” site, which is distinct from the “primary” site to which ACh binds, and which enhance ACh affinity (or efficacy). Having discovered that a commercially available compound, WIN 62577, is an allosteric enhancer with micromolar potency at M_3 receptors, we report here some results of a chemical synthesis project to develop this hit. Modification of WIN 62577 has led to compounds with over 1000-fold increased affinity but, so far, none of these extremely potent compounds are allosteric enhancers.
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Progress toward a high-affinity allosteric enhancer at muscarinic M1 receptors.
Journal of Molecular Neuroscience, 2003Co-Authors: Sebastian Lazareno, Angela Popham, Nigel J. M. BirdsallAbstract:Loss of forebrain acetylcholine is an early Neurochemical Lesion in Alzheimer’s disease (AD). As muscarinic acetylcholine receptors are involved in memory and cognition, a muscarinic agonist could therefore provide a “replacement therapy” in this disease. However, muscarinic receptors occur throughout the CNS and the periphery. A selective locus of action of a muscarinic agonist is therefore crucial in order to avoid intolerable side effects. The five subtypes of muscarinic receptors, M1–M5, have distinct regional distributions with M2 and M3 receptors mediating most of the peripheral effects. M1 receptors are the major receptor subtype in the cortex and hippocampus—the two brain regions most associated with memory and cognition. This localization has led to a, so far unsuccessful, search for a truly M1-selective muscarinic agonist. However, acetylcholinesterase inhibitors, such as donepezil (Aricept), which potentiate cholinergic neurotransmission, do have a therapeutic role in the management of AD and so the M1 receptor remains a viable therapeutic target. Our approach is to develop muscarinic allosteric enhancers—compounds that bind to the receptor at an “allosteric” site, which is distinct from the “primary” site to which ACh binds, and which enhance ACh affinity (or efficacy). Having discovered that a commercially available compound, WIN 62577, is an allosteric enhancer with micromolar potency at M3 receptors, we report here some results of a chemical synthesis project to develop this hit. Modification of WIN 62577 has led to compounds with over 1000-fold increased affinity but, so far, none of these extremely potent compounds are allosteric enhancers.
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Towards a high-affinity allosteric enhancer at muscarinic M_1 receptors
Journal of Molecular Neuroscience, 2002Co-Authors: Sebastian Lazareno, Angela Popham, Nigel J. M. BirdsallAbstract:Loss of forebrain acetylcholine (ACh) is an early Neurochemical Lesion in Alzheimer’s Disease (AD), and muscarinic receptors for ACh are involved in memory and cognition, so a muscarinic agonist could provide ‘replacement therapy’ in this disease. Muscarinic receptors, which couple to G-proteins, occur throughout the CNS, and in the periphery they mediate the responses of the parasympathetic nervous system, so selectivity is crucial. The five subtypes of muscarinic receptor, M_1–M_5, have a distinct regional distribution, with M_2 and M_3 mediating most of the peripheral effects, M_2 predominating in hindbrain areas, and M_1 predominating in the cortex and hippocampus—the brain regions most associated with memory and cognition, which has lead to a search for a truly M_1-selective muscarinic agonist. That search has so far been unsuccessful, but acetylcholinesterase inhibitors such as donepezil (Aricept), which potentiate cholinergic neurotransmission, have a therapeutic role in the management of AD; so the M_1 receptor remains a therapeutic target. Our approach is to develop allosteric enhancers—compounds which bind to the receptor at an ‘allosteric’ site which is distinct from the ‘primary’ site to which the endogenous ligand binds, and which enhance the affinity (or efficacy) of the endogenous ligand. We have developed radioligand binding assays and analyses for the detection and quantitatitation of allosteric interactions of a test agent with labelled and unlabelled ‘primary’ ligands, and we report here some results of the initial phase of a chemical synthesis project to develop potent and selective allosteric enhancers at muscarinic M_1 receptors.
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Towards a high-affinity allosteric enhancer at muscarinic M1 receptors.
Journal of molecular neuroscience : MN, 2002Co-Authors: Sebastian Lazareno, Angela Popham, Nigel J. M. BirdsallAbstract:Loss of forebrain acetylcholine (ACh) is an early Neurochemical Lesion in Alzheimer's Disease (AD), and muscarinic receptors for ACh are involved in memory and cognition, so a muscarinic agonist could provide 'replacement therapy' in this disease. Muscarinic receptors, which couple to G-proteins, occur throughout the CNS, and in the periphery they mediate the responses of the parasympathetic nervous system, so selectivity is crucial. The five subtypes of muscarinic receptor, M1-M5, have a distinct regional distribution, with M2 and M3 mediating most of the peripheral effects, M2 predominating in hindbrain areas, and M1 predominating in the cortex and hippocampus--the brain regions most associated with memory and cognition, which has lead to a search for a truly M1-selective muscarinic agonist. That search has so far been unsuccessful, but acetylcholinesterase inhibitors such as donepezil (Aricept), which potentiate cholinergic neurotransmission, have a therapeutic role in the management of AD; so the M1 receptor remains a therapeutic target. Our approach is to develop allosteric enhancers--compounds which bind to the receptor at an 'allosteric' site which is distinct from the 'primary' site to which the endogenous ligand binds, and which enhance the affinity (or efficacy) of the endogenous ligand. We have developed radioligand binding assays and analyses for the detection and quantitatitation of allosteric interactions of a test agent with labelled and unlabelled 'primary' ligands, and we report here some results of the initial phase of a chemical synthesis project to develop potent and selective allosteric enhancers at muscarinic M1 receptors.
Angela Popham - One of the best experts on this subject based on the ideXlab platform.
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Progress toward a high-affinity allosteric enhancer at muscarinic M_1 receptors
Journal of Molecular Neuroscience, 2003Co-Authors: Sebastian Lazareno, Angela Popham, Nigel J. M. BirdsallAbstract:Loss of forebrain acetylcholine is an early Neurochemical Lesion in Alzheimer’s disease (AD). As muscarinic acetylcholine receptors are involved in memory and cognition, a muscarinic agonist could therefore provide a “replacement therapy” in this disease. However, muscarinic receptors occur throughout the CNS and the periphery. A selective locus of action of a muscarinic agonist is therefore crucial in order to avoid intolerable side effects. The five subtypes of muscarinic receptors, M_1–M_5, have distinct regional distributions with M_2 and M_3 receptors mediating most of the peripheral effects. M_1 receptors are the major receptor subtype in the cortex and hippocampus—the two brain regions most associated with memory and cognition. This localization has led to a, so far unsuccessful, search for a truly M_1-selective muscarinic agonist. However, acetylcholinesterase inhibitors, such as donepezil (Aricept), which potentiate cholinergic neurotransmission, do have a therapeutic role in the management of AD and so the M_1 receptor remains a viable therapeutic target. Our approach is to develop muscarinic allosteric enhancers—compounds that bind to the receptor at an “allosteric” site, which is distinct from the “primary” site to which ACh binds, and which enhance ACh affinity (or efficacy). Having discovered that a commercially available compound, WIN 62577, is an allosteric enhancer with micromolar potency at M_3 receptors, we report here some results of a chemical synthesis project to develop this hit. Modification of WIN 62577 has led to compounds with over 1000-fold increased affinity but, so far, none of these extremely potent compounds are allosteric enhancers.
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Progress toward a high-affinity allosteric enhancer at muscarinic M1 receptors.
Journal of Molecular Neuroscience, 2003Co-Authors: Sebastian Lazareno, Angela Popham, Nigel J. M. BirdsallAbstract:Loss of forebrain acetylcholine is an early Neurochemical Lesion in Alzheimer’s disease (AD). As muscarinic acetylcholine receptors are involved in memory and cognition, a muscarinic agonist could therefore provide a “replacement therapy” in this disease. However, muscarinic receptors occur throughout the CNS and the periphery. A selective locus of action of a muscarinic agonist is therefore crucial in order to avoid intolerable side effects. The five subtypes of muscarinic receptors, M1–M5, have distinct regional distributions with M2 and M3 receptors mediating most of the peripheral effects. M1 receptors are the major receptor subtype in the cortex and hippocampus—the two brain regions most associated with memory and cognition. This localization has led to a, so far unsuccessful, search for a truly M1-selective muscarinic agonist. However, acetylcholinesterase inhibitors, such as donepezil (Aricept), which potentiate cholinergic neurotransmission, do have a therapeutic role in the management of AD and so the M1 receptor remains a viable therapeutic target. Our approach is to develop muscarinic allosteric enhancers—compounds that bind to the receptor at an “allosteric” site, which is distinct from the “primary” site to which ACh binds, and which enhance ACh affinity (or efficacy). Having discovered that a commercially available compound, WIN 62577, is an allosteric enhancer with micromolar potency at M3 receptors, we report here some results of a chemical synthesis project to develop this hit. Modification of WIN 62577 has led to compounds with over 1000-fold increased affinity but, so far, none of these extremely potent compounds are allosteric enhancers.
-
Towards a high-affinity allosteric enhancer at muscarinic M_1 receptors
Journal of Molecular Neuroscience, 2002Co-Authors: Sebastian Lazareno, Angela Popham, Nigel J. M. BirdsallAbstract:Loss of forebrain acetylcholine (ACh) is an early Neurochemical Lesion in Alzheimer’s Disease (AD), and muscarinic receptors for ACh are involved in memory and cognition, so a muscarinic agonist could provide ‘replacement therapy’ in this disease. Muscarinic receptors, which couple to G-proteins, occur throughout the CNS, and in the periphery they mediate the responses of the parasympathetic nervous system, so selectivity is crucial. The five subtypes of muscarinic receptor, M_1–M_5, have a distinct regional distribution, with M_2 and M_3 mediating most of the peripheral effects, M_2 predominating in hindbrain areas, and M_1 predominating in the cortex and hippocampus—the brain regions most associated with memory and cognition, which has lead to a search for a truly M_1-selective muscarinic agonist. That search has so far been unsuccessful, but acetylcholinesterase inhibitors such as donepezil (Aricept), which potentiate cholinergic neurotransmission, have a therapeutic role in the management of AD; so the M_1 receptor remains a therapeutic target. Our approach is to develop allosteric enhancers—compounds which bind to the receptor at an ‘allosteric’ site which is distinct from the ‘primary’ site to which the endogenous ligand binds, and which enhance the affinity (or efficacy) of the endogenous ligand. We have developed radioligand binding assays and analyses for the detection and quantitatitation of allosteric interactions of a test agent with labelled and unlabelled ‘primary’ ligands, and we report here some results of the initial phase of a chemical synthesis project to develop potent and selective allosteric enhancers at muscarinic M_1 receptors.
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Towards a high-affinity allosteric enhancer at muscarinic M1 receptors.
Journal of molecular neuroscience : MN, 2002Co-Authors: Sebastian Lazareno, Angela Popham, Nigel J. M. BirdsallAbstract:Loss of forebrain acetylcholine (ACh) is an early Neurochemical Lesion in Alzheimer's Disease (AD), and muscarinic receptors for ACh are involved in memory and cognition, so a muscarinic agonist could provide 'replacement therapy' in this disease. Muscarinic receptors, which couple to G-proteins, occur throughout the CNS, and in the periphery they mediate the responses of the parasympathetic nervous system, so selectivity is crucial. The five subtypes of muscarinic receptor, M1-M5, have a distinct regional distribution, with M2 and M3 mediating most of the peripheral effects, M2 predominating in hindbrain areas, and M1 predominating in the cortex and hippocampus--the brain regions most associated with memory and cognition, which has lead to a search for a truly M1-selective muscarinic agonist. That search has so far been unsuccessful, but acetylcholinesterase inhibitors such as donepezil (Aricept), which potentiate cholinergic neurotransmission, have a therapeutic role in the management of AD; so the M1 receptor remains a therapeutic target. Our approach is to develop allosteric enhancers--compounds which bind to the receptor at an 'allosteric' site which is distinct from the 'primary' site to which the endogenous ligand binds, and which enhance the affinity (or efficacy) of the endogenous ligand. We have developed radioligand binding assays and analyses for the detection and quantitatitation of allosteric interactions of a test agent with labelled and unlabelled 'primary' ligands, and we report here some results of the initial phase of a chemical synthesis project to develop potent and selective allosteric enhancers at muscarinic M1 receptors.
Francesca Billwiller - One of the best experts on this subject based on the ideXlab platform.
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Differential origin of the activation of dorsal and ventral dentate gyrus granule cells during paradoxical (REM) sleep in the rat
Brain Structure and Function, 2017Co-Authors: Francesca Billwiller, Leslie Renouard, Olivier Clément, Patrice Fort, Pierre-hervé LuppiAbstract:We recently demonstrated that granule cells located in the dorsal dentate gyrus (dDG) are activated by neurons located in the lateral supramammillary nucleus (SumL) during paradoxical sleep (PS) hypersomnia. To determine whether these neurons are glutamatergic and/or GABAergic, we combined FOS immunostaining with in situ hybridization of vesicular glutamate transporter 2 (vGLUT2, a marker of glutamatergic neurons) or that of the vesicular GABA transporter (vGAT, a marker of GABAergic neurons) mRNA in rats displaying PS hypersomnia (PSR). We found that 84 and 76 % of the FOS+ SumL neurons in PSR rats expressed vGLUT2 and vGAT mRNA, respectively. Then, we examined vGLUT2 and FOS immunostaining in the dorsal and ventral DG of PSR rats with a Neurochemical Lesion of the Sum. In PSR-Lesioned animals but not in sham animals, nearly all vGLUT2+ fibers and FOS+ neurons disappeared in the dDG, but not in the ventral DG (vDG). To identify the pathway (s) responsible (s) for the activation of the vDG during PS hypersomnia, we combined Fluorogold (FG) injection in the vDG of PSR rats with FOS staining. We found a large number of neurons FOS-FG+, specifically in the medial entorhinal cortex (ENTm). Altogether, our results suggest that SumL neurons with a unique dual glutamatergic and GABAergic phenotype are responsible for the activation of the dDG during PS hypersomnia, while vDG granule neurons are activated by ENTm cortical neurons. These results suggest differential mechanisms and functions for the activation of the dDG and the vDG granule cells during PS.
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The supramammillary nucleus and the claustrum activate the cortex during REM sleep
Science Advances, 2015Co-Authors: Leslie Renouard, Francesca Billwiller, Keiko Ogawa, Olivier Clément, Nutabi Camargo, Mouaadh Abdelkarim, Céline Scoté-blachon, Rouguy Touré, Paul-antoine Libourel, Pascal RavassardAbstract:Evidence in humans suggests that limbic cortices are more active during rapid eye movement (REM or paradoxical) sleep than during waking, a phenomenon fitting with the presence of vivid dreaming during this state. In that context, it seemed essential to determine which populations of cortical neurons are activated during REM sleep. Our aim in the present study is to fill this gap by combining gene expression analysis, functional neuroanatomy, and Neurochemical Lesions in rats. We find in rats that, during REM sleep hypersomnia compared to control and REM sleep deprivation, the dentate gyrus, claustrum, cortical amygdaloid nucleus, and medial entorhinal and retrosplenial cortices are the only cortical structures containing neurons with an increased expression of Bdnf, FOS, and ARC, known markers of activation and/or synaptic plasticity. Further, the dentate gyrus is the only cortical structure containing more FOS-labeled neurons during REM sleep hypersomnia than during waking. Combining FOS staining, retrograde labeling, and Neurochemical Lesion, we then provide evidence that FOS overexpression occurring in the cortex during REM sleep hypersomnia is due to projections from the supramammillary nucleus and the claustrum. Our results strongly suggest that only a subset of cortical and hippocampal neurons are activated and display plasticity during REM sleep by means of ascending projections from the claustrum and the supramammillary nucleus. Our results pave the way for future studies to identify the function of REM sleep with regard to dreaming and emotional memory processing.
Leslie Renouard - One of the best experts on this subject based on the ideXlab platform.
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Differential origin of the activation of dorsal and ventral dentate gyrus granule cells during paradoxical (REM) sleep in the rat
Brain Structure and Function, 2017Co-Authors: Francesca Billwiller, Leslie Renouard, Olivier Clément, Patrice Fort, Pierre-hervé LuppiAbstract:We recently demonstrated that granule cells located in the dorsal dentate gyrus (dDG) are activated by neurons located in the lateral supramammillary nucleus (SumL) during paradoxical sleep (PS) hypersomnia. To determine whether these neurons are glutamatergic and/or GABAergic, we combined FOS immunostaining with in situ hybridization of vesicular glutamate transporter 2 (vGLUT2, a marker of glutamatergic neurons) or that of the vesicular GABA transporter (vGAT, a marker of GABAergic neurons) mRNA in rats displaying PS hypersomnia (PSR). We found that 84 and 76 % of the FOS+ SumL neurons in PSR rats expressed vGLUT2 and vGAT mRNA, respectively. Then, we examined vGLUT2 and FOS immunostaining in the dorsal and ventral DG of PSR rats with a Neurochemical Lesion of the Sum. In PSR-Lesioned animals but not in sham animals, nearly all vGLUT2+ fibers and FOS+ neurons disappeared in the dDG, but not in the ventral DG (vDG). To identify the pathway (s) responsible (s) for the activation of the vDG during PS hypersomnia, we combined Fluorogold (FG) injection in the vDG of PSR rats with FOS staining. We found a large number of neurons FOS-FG+, specifically in the medial entorhinal cortex (ENTm). Altogether, our results suggest that SumL neurons with a unique dual glutamatergic and GABAergic phenotype are responsible for the activation of the dDG during PS hypersomnia, while vDG granule neurons are activated by ENTm cortical neurons. These results suggest differential mechanisms and functions for the activation of the dDG and the vDG granule cells during PS.
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The supramammillary nucleus and the claustrum activate the cortex during REM sleep
Science Advances, 2015Co-Authors: Leslie Renouard, Francesca Billwiller, Keiko Ogawa, Olivier Clément, Nutabi Camargo, Mouaadh Abdelkarim, Céline Scoté-blachon, Rouguy Touré, Paul-antoine Libourel, Pascal RavassardAbstract:Evidence in humans suggests that limbic cortices are more active during rapid eye movement (REM or paradoxical) sleep than during waking, a phenomenon fitting with the presence of vivid dreaming during this state. In that context, it seemed essential to determine which populations of cortical neurons are activated during REM sleep. Our aim in the present study is to fill this gap by combining gene expression analysis, functional neuroanatomy, and Neurochemical Lesions in rats. We find in rats that, during REM sleep hypersomnia compared to control and REM sleep deprivation, the dentate gyrus, claustrum, cortical amygdaloid nucleus, and medial entorhinal and retrosplenial cortices are the only cortical structures containing neurons with an increased expression of Bdnf, FOS, and ARC, known markers of activation and/or synaptic plasticity. Further, the dentate gyrus is the only cortical structure containing more FOS-labeled neurons during REM sleep hypersomnia than during waking. Combining FOS staining, retrograde labeling, and Neurochemical Lesion, we then provide evidence that FOS overexpression occurring in the cortex during REM sleep hypersomnia is due to projections from the supramammillary nucleus and the claustrum. Our results strongly suggest that only a subset of cortical and hippocampal neurons are activated and display plasticity during REM sleep by means of ascending projections from the claustrum and the supramammillary nucleus. Our results pave the way for future studies to identify the function of REM sleep with regard to dreaming and emotional memory processing.