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Rudi Dhooge - One of the best experts on this subject based on the ideXlab platform.
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genetic deletion of pde10a selectively impairs incentive salience attribution and decreases Medium Spiny Neuron excitability
Behavioural Brain Research, 2014Co-Authors: Elisabeth Piccart, Jeanfrancois De Backer, Laurie Lambot, Greet Vanhoof, David Gall, Serge N Schiffmann, Adam Raes, Rudi DhoogeAbstract:The striatum is the main input structure to the basal ganglia and consists mainly out of Medium Spiny Neurons. The numerous spines on their dendrites render them capable of integrating cortical glutamatergic inputs with a motivational dopaminergic signal that originates in the midbrain. This integrative function is thought to underly attribution of incentive salience, a process that is severely disrupted in schizophrenic patients. Phosphodiesterase 10A (PDE10A) is located mainly to the striatal Medium Spiny Neurons and hydrolyses cAMP and cGMP, key determinants of MSN signaling. We show here that genetic depletion of PDE10A critically mediates attribution of salience to reward-predicting cues, evident in impaired performance in PDE10A knockout mice in an instrumentally conditioned reinforcement task. We furthermore report modest impairment of latent inhibition in PDE10A knockout mice, and unaltered prepulse inhibition. We suggest that the lack of effect on PPI is due to the pre-attentional nature of this task. Finally, we performed whole-cell patch clamp recordings and confirm suggested changes in intrinsic membrane excitability. A decrease in spontaneous firing in striatal Medium Spiny Neurons was found. These data show that PDE10A plays a pivotal role in striatal signaling and striatum-mediated salience attribution. © 2014 Elsevier B.V.
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genetic deletion of pde10a selectively impairs incentive salience attribution and decreases Medium Spiny Neuron excitability
Behavioural Brain Research, 2014Co-Authors: Elisabeth Piccart, Jeanfrancois De Backer, Laurie Lambot, Greet Vanhoof, David Gall, Serge N Schiffmann, Adam Raes, Rudi DhoogeAbstract:The striatum is the main input structure to the basal ganglia and consists mainly out of Medium Spiny Neurons. The numerous spines on their dendrites render them capable of integrating cortical glutamatergic inputs with a motivational dopaminergic signal that originates in the midbrain. This integrative function is thought to underly attribution of incentive salience, a process that is severely disrupted in schizophrenic patients. Phosphodiesterase 10A (PDE10A) is located mainly to the striatal Medium Spiny Neurons and hydrolyses cAMP and cGMP, key determinants of MSN signaling. We show here that genetic depletion of PDE10A critically mediates attribution of salience to reward-predicting cues, evident in impaired performance in PDE10A knockout mice in an instrumentally conditioned reinforcement task. We furthermore report modest impairment of latent inhibition in PDE10A knockout mice, and unaltered prepulse inhibition. We suggest that the lack of effect on PPI is due to the pre-attentional nature of this task. Finally, we performed whole-cell patch clamp recordings and confirm suggested changes in intrinsic membrane excitability. A decrease in spontaneous firing in striatal Medium Spiny Neurons was found. These data show that PDE10A plays a pivotal role in striatal signaling and striatum-mediated salience attribution.
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impaired appetitively as well as aversively motivated behaviors and learning in pde10a deficient mice suggest a role for striatal signaling in evaluative salience attribution
Neurobiology of Learning and Memory, 2011Co-Authors: Elisabeth Piccart, Greet Vanhoof, Ronald De Hoogt, Ilse Gantois, Annelies Laeremans, Theo Meert, Lutgarde Arckens, Rudi DhoogeAbstract:Abstract Phosphodiesterase 10A (PDE10A) hydrolyzes both cAMP and cGMP, and is a key element in the regulation of Medium Spiny Neuron (MSN) activity in the striatum. In the present report, we investigated the effects of targeted disruption of PDE10A on spatial learning and memory as well as aversive and appetitive conditioning in C57BL/6 J mice. Because of its putative role in motivational processes and reward learning, we also determined the expression of the immediate early gene zif268 in striatum and anterior cingulate cortex. Animals showed decreased response rates in scheduled appetitive operant conditioning, as well as impaired aversive conditioning in a passive avoidance task. Morris water maze performance revealed not-motor related spatial learning and memory deficits. Anxiety and social explorative behavior was not affected in PDE10A-deficient mice. Expression of zif268 was increased in striatum and anterior cingulate cortex, which suggests alterations in the neural connections between striatum and anterior cingulate cortex in PDE10A-deficient mice. The changes in behavior and plasticity in these PDE10A-deficient mice were in accordance with the proposed role of striatal MSNs and corticostriatal connections in evaluative salience attribution.
John Meitzen - One of the best experts on this subject based on the ideXlab platform.
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Biological Sex, Estradiol and Striatal Medium Spiny Neuron Physiology: A Mini-Review
Frontiers in Cellular Neuroscience, 2018Co-Authors: Amanda A. Krentzel, John MeitzenAbstract:The caudate-putamen, nucleus accumbens core and shell are important striatal brain regions for premotor, limbic, habit formation, reward, and other critical cognitive functions. Striatal-relevant behaviors such as anxiety, motor coordination, locomotion, and sensitivity to reward, all change with fluctuations of the menstrual cycle in humans and the estrous cycle in rodents. These fluctuations implicate sex steroid hormones, such as 17β-estradiol, as potent neuromodulatory signals for striatal Neuron activity. The Medium Spiny Neuron (MSN), the primary Neuron subtype of the striatal regions, expresses membrane estrogen receptors and exhibits sex differences both in intrinsic and synaptic electrophysiological properties. In this mini-review, we first describe sex differences in the electrophysiological properties of the MSNs in prepubertal rats. We then discuss specific examples of how the human menstrual and rat estrous cycles induce differences in striatal-relevant behaviors and neural substrate, including how female rat MSN electrophysiology is influenced by the estrous cycle. We then conclude the mini-review by discussing avenues for future investigation, including possible roles of striatal-localized membrane estrogen receptors and estradiol.
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sex differences in Medium Spiny Neuron excitability and glutamatergic synaptic input heterogeneity across striatal regions and evidence for estradiol dependent sexual differentiation
Frontiers in Endocrinology, 2018Co-Authors: Jinyan Cao, Jaime A Willett, David M Dorris, John MeitzenAbstract:Steroid sex hormones and biological sex influence how the brain regulates motivated behavior, reward, and sensorimotor function in both normal and pathological contexts. Investigations into the underlying neural mechanisms have targeted the striatal brain regions, including the caudate-putamen, nucleus accumbens core and shell. These brain regions are of particular interest to neuroendocrinologists given that they express membrane-associated but not nuclear estrogen receptors, and also the well-established role of the sex steroid hormone 17β-estradiol (estradiol) in modulating striatal dopamine systems. Indeed, output Neurons of the striatum, the Medium Spiny Neurons (MSNs), exhibit estradiol sensitivity and sex differences in electrophysiological properties. Here we review sex differences in rat MSN glutamatergic synaptic input and intrinsic excitability across striatal regions, including evidence for estradiol-mediated sexual differentiation in the nucleus accumbens core. In prepubertal animals, female MSNs in the caudate-putamen exhibit a greater intrinsic excitability relative to male MSNs, but no sex differences are detected in excitatory synaptic input. Alternatively, female MSNs in the nucleus accumbens core exhibit increased excitatory synaptic input relative to male MSNs, but no sex differences in intrinsic excitability were detected. Increased excitatory synaptic input onto female MSNs in the nucleus accumbens core is abolished after masculinizing estradiol or testosterone exposure during the neonatal critical period. No sex differences are detected in MSNs in prepubertal nucleus accumbens shell. Thus, despite possessing the same Neuron type, striatal regions exhibit heterogeneity in sex differences in MSN electrophysiological properties, which likely contribute to the sex differences observed in striatal function.
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nucleus accumbens core Medium Spiny Neuron electrophysiological properties and partner preference behavior in the adult male prairie vole microtus ochrogaster
Journal of Neurophysiology, 2018Co-Authors: Jaime A Willett, Ashlyn G Johnson, Andrea R Vogel, Heather B Patisaul, Lisa A Mcgraw, John MeitzenAbstract:This research represents the first assessment of prairie vole nucleus accumbens core Medium Spiny Neuron intrinsic electrophysiological properties and probes the relationship between cellular excit...
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Sex Differences in Medium Spiny Neuron Excitability and Glutamatergic Synaptic Input: Heterogeneity Across Striatal Regions and Evidence for Estradiol-Dependent Sexual Differentiation
Frontiers Media S.A., 2018Co-Authors: John Meitzen, David M Dorris, Jaime A Willett, Jinyan CaoAbstract:Steroid sex hormones and biological sex influence how the brain regulates motivated behavior, reward, and sensorimotor function in both normal and pathological contexts. Investigations into the underlying neural mechanisms have targeted the striatal brain regions, including the caudate–putamen, nucleus accumbens core (AcbC), and shell. These brain regions are of particular interest to neuroendocrinologists given that they express membrane-associated but not nuclear estrogen receptors, and also the well-established role of the sex steroid hormone 17β-estradiol (estradiol) in modulating striatal dopamine systems. Indeed, output Neurons of the striatum, the Medium Spiny Neurons (MSNs), exhibit estradiol sensitivity and sex differences in electrophysiological properties. Here, we review sex differences in rat MSN glutamatergic synaptic input and intrinsic excitability across striatal regions, including evidence for estradiol-mediated sexual differentiation in the nucleus AcbC. In prepubertal animals, female MSNs in the caudate–putamen exhibit a greater intrinsic excitability relative to male MSNs, but no sex differences are detected in excitatory synaptic input. Alternatively, female MSNs in the nucleus AcbC exhibit increased excitatory synaptic input relative to male MSNs, but no sex differences in intrinsic excitability were detected. Increased excitatory synaptic input onto female MSNs in the nucleus AcbC is abolished after masculinizing estradiol or testosterone exposure during the neonatal critical period. No sex differences are detected in MSNs in prepubertal nucleus accumbens shell. Thus, despite possessing the same Neuron type, striatal regions exhibit heterogeneity in sex differences in MSN electrophysiological properties, which likely contribute to the sex differences observed in striatal function
Morgane Thomsen - One of the best experts on this subject based on the ideXlab platform.
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effects of muscarinic m1 receptor stimulation on reinforcing and neurochemical effects of cocaine in rats
Neuropsychopharmacology, 2020Co-Authors: Pia Weikop, Kathrine L Jensen, Morgane ThomsenAbstract:Cocaine addiction is a chronic illness characterized by maladaptive drug-induced neuroplastic changes that confer lasting vulnerability to relapse. Over several weeks we observed the effects of the M1 receptor-selective agonist VU0364572 in adult male rats that self-administer cocaine in a cocaine vs. food choice procedure. The drug showed unusual long-lasting effects, as rats gradually stopped self-administering cocaine, reallocating behavior towards the food reinforcer. The effect lasted as long as tested and at least 4 weeks. To begin to elucidate how VU0364572 modulates cocaine self-administration, we then examined its long-term effects using dual-probe in vivo dopamine and glutamate microdialysis in nucleus accumbens and medial prefrontal cortex, and ex vivo striatal dopamine reuptake. Microdialysis revealed marked decreases in cocaine-induced dopamine and glutamate outflow 4 weeks after VU0364572 treatment, without significant changes in dopamine uptake function. These lasting and marked effects of M1 receptor stimulation reinforce our interest in this target as potential treatment of cocaine addiction. M1 receptors are known to modulate Medium Spiny Neuron responses to corticostriatal glutamatergic signaling acutely, and we hypothesize that VU0364572 may oppose the addiction-related effects of cocaine by causing lasting changes in this system.
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muscarinic m1 receptor stimulation prevents and reverses addiction related effects of cocaine
bioRxiv, 2020Co-Authors: Pia Weikop, Kathrine L Jensen, Morgane ThomsenAbstract:Cocaine addiction is a chronic illness characterized by maladaptive drug-induced neuroplastic changes that confer lasting vulnerability to relapse. Over several weeks we observed the effects of the M1 receptor-selective agonist VU0364572 in adult male rats that self-administer cocaine in a cocaine vs. natural reinforcer choice procedure. The drug showed unusual long-lasting effects, as rats gradually stopped self-administering cocaine, reallocating behavior towards the food reinforcer. The effect lasted as long as tested and at least four weeks. To begin to elucidate how VU0364572 modulates cocaine self-administration, we then examined its long-term effects using dual-probe in vivo dopamine and glutamate microdialysis in nucleus accumbens and medial prefrontal cortex, and ex vivo striatal dopamine reuptake. Microdialysis revealed dramatic decreases in cocaine-induced dopamine and glutamate outflow four weeks after VU0364572 treatment, without significant changes in dopamine uptake function. These lasting and dramatic effects of M1 receptor stimulation reinforce our interest in this target as potential treatment of cocaine addiction. M1 receptors are known to modulate Medium Spiny Neuron responses to corticostriatal glutamatergic signaling acutely, and we hypothesize that VU0364572 may oppose the addiction-related effects of cocaine by causing lasting changes in this system.
Michael V Sofroniew - One of the best experts on this subject based on the ideXlab platform.
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astrocyte kir4 1 ion channel deficits contribute to Neuronal dysfunction in huntington s disease model mice
Nature Neuroscience, 2014Co-Authors: Xiaoping Tong, Yan Ao, Guido C Faas, Sinifunanya E Nwaobi, Ji Xu, Martin D Haustein, Mark Anderson, Istvan Mody, Michelle L Olsen, Michael V SofroniewAbstract:In this study, the authors show that altered Medium Spiny Neuron excitability and symptom onset in Huntington's disease model mice is associated with decreased expression of Kir4.1 and impaired K+ handling by astrocytes. Exogenous expression of Kir4.1 could partially rescue motor function and prolong survival in HD mice.
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astrocyte kir4 1 ion channel deficits contribute to Neuronal dysfunction in huntington s disease model mice
Nature Neuroscience, 2014Co-Authors: Xiaoping Tong, Guido C Faas, Sinifunanya E Nwaobi, Michael V Sofroniew, Marti D Haustei, Mark Anderso, Istva Mody, Michelle L Olse, Alji S KhakhAbstract:Huntington's disease (HD) is characterized by striatal Medium Spiny Neuron (MSN) dysfunction, but the underlying mechanisms remain unclear. We explored roles for astrocytes, in which mutant huntingtin is expressed in HD patients and mouse models. We found that symptom onset in R6/2 and Q175 HD mouse models was not associated with classical astrogliosis, but was associated with decreased Kir4.1 K(+) channel functional expression, leading to elevated in vivo striatal extracellular K(+), which increased MSN excitability in vitro. Viral delivery of Kir4.1 channels to striatal astrocytes restored Kir4.1 function, normalized extracellular K(+), ameliorated aspects of MSN dysfunction, prolonged survival and attenuated some motor phenotypes in R6/2 mice. These findings indicate that components of altered MSN excitability in HD may be caused by heretofore unknown disturbances of astrocyte-mediated K(+) homeostasis, revealing astrocytes and Kir4.1 channels as therapeutic targets.
Xiaoping Tong - One of the best experts on this subject based on the ideXlab platform.
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astrocyte kir4 1 ion channel deficits contribute to Neuronal dysfunction in huntington s disease model mice
Nature Neuroscience, 2014Co-Authors: Xiaoping Tong, Yan Ao, Guido C Faas, Sinifunanya E Nwaobi, Ji Xu, Martin D Haustein, Mark Anderson, Istvan Mody, Michelle L Olsen, Michael V SofroniewAbstract:In this study, the authors show that altered Medium Spiny Neuron excitability and symptom onset in Huntington's disease model mice is associated with decreased expression of Kir4.1 and impaired K+ handling by astrocytes. Exogenous expression of Kir4.1 could partially rescue motor function and prolong survival in HD mice.
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astrocyte kir4 1 ion channel deficits contribute to Neuronal dysfunction in huntington s disease model mice
Nature Neuroscience, 2014Co-Authors: Xiaoping Tong, Guido C Faas, Sinifunanya E Nwaobi, Michael V Sofroniew, Marti D Haustei, Mark Anderso, Istva Mody, Michelle L Olse, Alji S KhakhAbstract:Huntington's disease (HD) is characterized by striatal Medium Spiny Neuron (MSN) dysfunction, but the underlying mechanisms remain unclear. We explored roles for astrocytes, in which mutant huntingtin is expressed in HD patients and mouse models. We found that symptom onset in R6/2 and Q175 HD mouse models was not associated with classical astrogliosis, but was associated with decreased Kir4.1 K(+) channel functional expression, leading to elevated in vivo striatal extracellular K(+), which increased MSN excitability in vitro. Viral delivery of Kir4.1 channels to striatal astrocytes restored Kir4.1 function, normalized extracellular K(+), ameliorated aspects of MSN dysfunction, prolonged survival and attenuated some motor phenotypes in R6/2 mice. These findings indicate that components of altered MSN excitability in HD may be caused by heretofore unknown disturbances of astrocyte-mediated K(+) homeostasis, revealing astrocytes and Kir4.1 channels as therapeutic targets.