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A Reiner - One of the best experts on this subject based on the ideXlab platform.
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disrupted Striatal Neuron inputs and outputs in huntington s disease
CNS Neuroscience & Therapeutics, 2018Co-Authors: A Reiner, Yunping DengAbstract:Huntington's disease (HD) is a hereditary progressive neurodegenerative disorder caused by a CAG repeat expansion in the gene coding for the protein huntingtin, resulting in a pathogenic expansion of the polyglutamine tract in the N-terminus of this protein. The HD pathology resulting from the mutation is most prominent in the Striatal part of the basal ganglia, and progressive differential dysfunction and loss of Striatal projection Neurons and interNeurons account for the progression of motor deficits seen in this disease. The present review summarizes current understanding regarding the progression in Striatal Neuron dysfunction and loss, based on studies both in human HD victims and in genetic mouse models of HD. We review evidence on early loss of inputs to striatum from cortex and thalamus, which may be the basis of the mild premanifest bradykinesia in HD, as well as on the subsequent loss of indirect pathway Striatal projection Neurons and their outputs to the external pallidal segment, which appears to be the basis of the chorea seen in early symptomatic HD. Later loss of direct pathway Striatal projection Neurons and their output to the internal pallidal segment account for the severe akinesia seen late in HD. Loss of parvalbuminergic Striatal interNeurons may contribute to the late dystonia and rigidity.
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differential loss of thalamoStriatal and corticoStriatal input to Striatal projection Neuron types prior to overt motor symptoms in the q140 knock in mouse model of huntington s disease
Frontiers in Systems Neuroscience, 2014Co-Authors: Yunping Deng, Ting Wong, Jim Y Wan, A ReinerAbstract:Motor slowing and forebrain white matter loss have been reported in premanifest Huntington’s disease (HD) prior to substantial Striatal Neuron loss. These findings raise the possibility that early motor defects in HD may be related to loss of excitatory input to striatum. In a prior study, we showed that in the heterozygous Q140 knock-in mouse model of HD that loss of thalamoStriatal axospinous terminals is evident by 4 months, and loss of corticoStriatal axospinous terminals is evident at 12 months, before Striatal projection Neuron pathology. In the present study, we specifically characterized the loss of thalamoStriatal and corticoStriatal terminals on direct (dSPN) and indirect (iSPN) pathway Striatal projection Neurons, using immunolabeling to identify thalamoStriatal (VGLUT2+) and corticoStriatal (VGLUT1+) axospinous terminals, and D1 receptor immunolabeling to distinguish dSPN (D1+) and iSPN (D1-) synaptic targets. We found that the loss of corticoStriatal terminals at 12 months of age was preferential for D1+ spines, and especially involved smaller terminals, presumptively of the intratelencephalically projecting (IT) type. By contrast, indirect pathway D1- spines showed little loss of axospinous terminals at the same age. ThalamoStriatal terminal loss was comparable for D1+ and D1- spines at both 4 months and 12 months. Regression analysis showed that the loss of VGLUT1+ terminals on D1+ spines was correlated with a slight decline in open field motor parameters at 12 months. Our overall results raise the possibility that differential thalamic and cortical input loss to SPNs is an early event in human HD, with cortical loss to dSPNs in particular contributing to premanifest motor slowing.
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loss of corticoStriatal and thalamoStriatal synaptic terminals precedes Striatal projection Neuron pathology in heterozygous q140 huntington s disease mice
Neurobiology of Disease, 2013Co-Authors: Yunping Deng, Ting Wong, Courtney Brickeranthony, B Deng, A ReinerAbstract:Abstract Motor slowing, forebrain white matter loss, and Striatal shrinkage have been reported in premanifest Huntington's disease (HD) prior to overt Striatal Neuron loss. We carried out detailed LM and EM studies in a genetically precise HD mimic, heterozygous Q140 HD knock-in mice, to examine the possibility that loss of corticoStriatal and thalamoStriatal terminals prior to Striatal Neuron loss underlies these premanifest HD abnormalities. In our studies, we used VGLUT1 and VGLUT2 immunolabeling to detect corticoStriatal and thalamoStriatal (respectively) terminals in dorsolateral (motor) striatum over the first year of life, prior to Striatal projection Neuron pathology. VGLUT1 + axospinous corticoStriatal terminals represented about 55% of all excitatory terminals in striatum, and VGLUT2 + axospinous thalamoStriatal terminals represented about 35%, with VGLUT1 + and VGLUT2 + axodendritic terminals accounting for the remainder. In Q140 mice, a significant 40% shortfall in VGLUT2 + axodendritic thalamoStriatal terminals and a 20% shortfall in axospinous thalamoStriatal terminals were already observed at 1 month of age, but VGLUT1 + terminals were normal in abundance. The 20% deficiency in VGLUT2 + thalamoStriatal axospinous terminals persisted at 4 and 12 months in Q140 mice, and an additional 30% loss of VGLUT1 + corticoStriatal terminals was observed at 12 months. The early and persistent deficiency in thalamoStriatal axospinous terminals in Q140 mice may reflect a development defect, and the impoverishment of this excitatory drive to striatum may help explain early motor defects in Q140 mice and in premanifest HD. The loss of corticoStriatal terminals at 1 year in Q140 mice is consistent with prior evidence from other mouse models of corticoStriatal disconnection early during progression, and can explain both the measurable bradykinesia and Striatal white matter loss in late premanifest HD.
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the group 2 metabotropic glutamate receptor agonist ly379268 rescues Neuronal neurochemical and motor abnormalities in r6 2 huntington s disease mice
Neurobiology of Disease, 2012Co-Authors: A Reiner, H B Wang, D C Lafferty, N Del Mar, Yunping DengAbstract:Abstract Excitotoxic injury to striatum by dysfunctional cortical input or aberrant glutamate uptake may contribute to Huntington's disease (HD) pathogenesis. Since corticoStriatal terminals possess mGluR2/3 autoreceptors, whose activation dampens glutamate release, we tested the ability of the mGluR2/3 agonist LY379268 to improve the phenotype in R6/2 HD mice with 120–125 CAG repeats. Daily subcutaneous injection of a maximum tolerated dose (MTD) of LY379268 (20 mg/kg) had no evident adverse effects in WT mice, and diverse benefits in R6/2 mice, both in a cohort of mice tested behaviorally until the end of R6/2 lifespan and in a cohort sacrificed at 10 weeks of age for blinded histological analysis. MTD LY379268 yielded a significant 11% increase in R6/2 survival, an improvement on rotarod, normalization and/or improvement in locomotor parameters measured in open field (activity, speed, acceleration, endurance, and gait), a rescue of a 15–20% cortical and Striatal Neuron loss, normalization of SP Striatal Neuron neurochemistry, and to a lesser extent enkephalinergic Striatal Neuron neurochemistry. Deficits were greater in male than female R6/2 mice, and drug benefit tended to be greater in males. The improvements in SP Striatal Neurons, which facilitate movement, are consistent with the improved movement in LY379268-treated R6/2 mice. Our data indicate that mGluR2/3 agonists may be particularly useful for ameliorating the morphological, neurochemical and motor defects observed in HD.
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differential localization of the glur1 and glur2 subunits of the ampa type glutamate receptor among Striatal Neuron types in rats
Journal of Chemical Neuroanatomy, 2007Co-Authors: Yunping Deng, Q. Chen, Wanlong Lei, J P Xie, H B Wang, A ReinerAbstract:Differences among the various Striatal projection Neuron and interNeuron types in cortical input, function, and vulnerability to degenerative insults may be related to differences among them in AMPA-type glutamate receptor abundance and subunit configuration. We therefore used immunolabeling to assess the frequency and abundance of GluR1 and GluR2, the most common AMPA subunits in striatum, in the main Striatal Neuron types. All Neurons projecting to the external pallidum (GPe), internal pallidum (GPi) or substantia nigra, as identified by retrograde labeling, possessed perikaryal GluR2, while GluR1 was more common in striato-GPe than striato-GPi perikarya. The frequency and intensity of immunostaining indicated the rank order of their perikaryal GluR1:GluR2 ratio to be striato-GPe>striatonigral>striato-GPi. Ultrastructural studies suggested a differential localization of GluR1 and GluR2 to Striatal projection Neuron dendritic spines as well, with GluR1 seemingly more common in striato-GPe spines and GluR2 more common in striato-GPi and/or striatonigral spines. Comparisons among projection Neurons and interNeurons revealed GluR1 to be most common and abundant in parvalbuminergic interNeurons, and GluR2 most common and abundant in projection Neurons, with the rank order for the GluR1:GluR2 ratio being parvalbuminergic interNeurons>calretinergic interNeurons>cholinergic interNeurons>projection Neurons>somatostatinergic interNeurons. Striosomal projection Neurons had a higher GluR1:GluR2 ratio than did matrix projection Neurons. The abundance of both GluR1 and GluR2 in Striatal parvalbuminergic interNeurons and projection Neurons is consistent with their prominent cortical input and susceptibility to excitotoxic insult, while differences in GluR1:GluR2 ratio among projection Neurons are likely to yield differences in Ca(2+) permeability, desensitization, and single channel current, which may contribute to differences among them in plasticity, synaptic integration, and excitotoxic vulnerability. The apparent association of the GluR1 subunit with synaptic plasticity, in particular, suggests striato-GPe Neuron spines as a particular site of corticoStriatal synaptic plasticity, presumably associated with motor learning.
Anthony R. West - One of the best experts on this subject based on the ideXlab platform.
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regulation of Striatal Neuron activity by cyclic nucleotide signaling and phosphodiesterase inhibition implications for the treatment of parkinson s disease
Advances in neurobiology, 2017Co-Authors: Fernando E Padovanneto, Anthony R. WestAbstract:Cyclic nucleotide phosphodiesterase (PDE) enzymes catalyze the hydrolysis and inactivation of cyclic nucleotides (cAMP/cGMP) in the brain. Several classes of PDE enzymes with distinct tissue distributions, cyclic nucleotide selectivity, and regulatory factors are highly expressed in brain regions subserving cognitive and motor processes known to be disrupted in neurodegenerative diseases such as Parkinson’s disease (PD). Furthermore, small-molecule inhibitors of several different PDE family members alter cyclic nucleotide levels and favorably enhance motor performance and cognition in animal disease models. This chapter will explore the roles and therapeutic potential of non-selective and selective PDE inhibitors on neural processing in fronto-Striatal circuits in normal animals and models of DOPA-induced dyskinesias (LIDs) associated with PD. The impact of selective PDE inhibitors and augmentation of cAMP and cGMP signaling on the membrane excitability of Striatal medium-sized spiny projection Neurons (MSNs) will be discussed. The effects of cyclic nucleotide signaling and PDE inhibitors on synaptic plasticity of striatonigral and striatopallidal MSNs will be also be reviewed. New data on the efficacy of PDE10A inhibitors for reversing behavioral and electrophysiological correlates of L-DOPA-induced dyskinesias in a rat model of PD will also be presented. Together, these data will highlight the potential of novel PDE inhibitors for treatment of movement disorders such as PD which are associated with abnormal corticoStriatal transmission.
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review modulation of Striatal Neuron activity by cyclic nucleotide signaling and phosphodiesterase inhibition
Basal ganglia, 2013Co-Authors: Sarah Threlfell, Anthony R. WestAbstract:Abstract The cyclic nucleotides cAMP and cGMP are common signalling molecules synthesized in Neurons following the activation of adenylyl or guanylyl cyclase. In the striatum, the synthesis and degradation of cAMP and cGMP is highly regulated as these second messengers have potent effects on the activity of striatonigral and striatopallidal Neurons. This review will summarize the literature on cyclic nucleotide signalling in the striatum with a particular focus on the impact of cAMP and cGMP on the membrane excitability of Striatal medium-sized spiny output Neurons (MSNs). The effects of non-selective and selective phosphodiesterase (PDE) inhibitors on membrane activity and synaptic plasticity of MSNs will also be reviewed. Lastly, this review will discuss the implications of the effects PDE modulation on electrophysiological activity of Striatal MSNs as it relates to the treatment of neurological disorders such as Huntington's and Parkinson's disease.
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Interactions between Procedural Learning and Cocaine Exposure Alter Spontaneous and Cortically Evoked Spike Activity in the Dorsal Striatum.
Frontiers in neuroscience, 2010Co-Authors: Janie M. Ondracek, Ingo Willuhn, Heinz Steiner, Anthony R. WestAbstract:We have previously shown that cocaine enhances gene regulation in the sensorimotor striatum associated with procedural learning in a running-wheel paradigm. Here we assessed whether cocaine produces enduring modifications of learning-related changes in Striatal Neuron activity, using single-unit recordings in anesthetized rats 1 day after the wheel training. Spontaneous and cortically-evoked spike activity was compared between groups treated with cocaine or vehicle immediately prior to the running-wheel training or placement in a locked wheel (control conditions). We found that wheel training in vehicle-treated rats increased the average firing rate of spontaneously active Neurons without changing the relative proportion of active to quiescent cells. In contrast, in rats trained under the influence of cocaine, the proportion of spontaneously firing to quiescent cells was significantly greater than in vehicle-treated, trained rats. However, this effect was associated with a lower average firing rate in these spontaneously active cells, suggesting that training under the influence of cocaine recruited additional low-firing cells. Measures of cortically-evoked activity revealed a second interaction between cocaine treatment and wheel training, namely, a cocaine-induced decrease in spike onset latency in control rats (locked wheel). This facilitatory effect of cocaine was abolished when rats trained in the running wheel during cocaine action. These findings highlight important interactions between cocaine and procedural learning, which act to modify population firing activity and the responsiveness of Striatal Neurons to excitatory inputs. Moreover, these effects were found 24 hours after the training and last drug exposure indicating that cocaine exposure during the learning phase triggers long-lasting changes in synaptic plasticity in the dorsal striatum. Such changes may contribute to the transition from recreational to habitual or compulsive drug taking behavior.
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Opposite influences of endogenous dopamine D1 and D2 receptor activation on activity states and electrophysiological properties of Striatal Neurons: studies combining in vivo intracellular recordings and reverse microdialysis.
The Journal of Neuroscience, 2002Co-Authors: Anthony R. West, Anthony A. GraceAbstract:The tonic influence of dopamine D 1 and D 2 receptors on the activity of Striatal Neurons in vivo was investigated by performing intracellular recordings concurrently with reverse microdialysis in chloral hydrate-anesthetized rats. Striatal Neurons were recorded in the vicinity of the microdialysis probe to assess their activity during infusions of artificial CSF (aCSF), the D 1 receptor antagonist SCH 23390 (10 μm), or the D 2 receptor antagonist eticlopride (20 μm). SCH 23390 perfusion decreased the excitability of Striatal Neurons exhibiting electrophysiological characteristics of spiny projection cells as evidenced by a decrease in the maximal depolarized membrane potential, a decrease in the amplitude of up-state events, and an increase in the intracellular current injection amplitude required to elicit an action potential. Conversely, a marked depolarization of up- and down-state membrane potential modes, a decrease in the amplitude of intracellular current injection required to elicit an action potential, and an increase in the number of spikes evoked by depolarizing current steps were observed in Striatal Neurons after local eticlopride infusion. A significant increase in maximal EPSP amplitude evoked by electrical stimulation of the prefrontal cortex was also observed during local eticlopride but not SCH 23390 infusion. These results indicate that in intact systems, ongoing dopaminergic neurotransmission exerts a powerful tonic modulatory influence on the up- and down-state membrane properties of Striatal Neurons and controls their excitability differentially via both D 1 - and D 2 -like receptors. Moreover, a significant component of D 2 receptor-mediated inhibition of Striatal Neuron activity in vivo occurs via suppression of excitatory synaptic transmission.
Peter Bossaerts - One of the best experts on this subject based on the ideXlab platform.
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CogSci - Neural Computations Supporting Cognition: Rumelhart Prize Symposium in Honor of Peter Dayan
Cognitive Science, 2017Co-Authors: Kenji Doya, Alexandre Pouget, John P. O'doherty, Peter BossaertsAbstract:Neural Computations Supporting Cognition: Rumelhart Prize Symposium in Honor of Peter Dayan Participants Kenji Doya (doya@oist.jap) John O’Doherty (jodoherty@caltech.edu) Neural Computation Unit, Okinawa Institute of Science and Technology, 1919-1 Tancha, Onna Okinawa 904-0495 Japan Division of the Humanities and Social Sciences, California Institute of Technology, MC 228-77 Pasadena, CA 91125 USA Alexandre Pouget (alex@cvs.rochester.edu) Peter Bossaerts (pbs@hss.caltech.edu) Departement de neuroscience fondementale, Universite de Geneve, 1 rue Michel-Servet CH-1211 Geneva 4, Switzerland Division of the Humanities and Social Sciences, California Institute of Technology, MC 228-77 Pasadena, CA 91125 USA Organizors Nathaniel Daw (daw@cns.nyu.edu) Center for Neural Science New York University New York, NY, 10003 Yael Niv (yael@princeton.edu) Princeton Neuroscience Institute and Psychology Department Princeton University, Princeton, NJ, 08544 Keywords: neural computation; reinforcement learning; inference; uncertainty and reward. After more than a decade from the discovery, however, there still remain questions to be answered, such as what Striatal Neuron firing represents, how and where an action is selected, and how negative reinforcement is realized. Here we review Peter Dayan's seminal contributions and recent developments. Motivation Principles of sound statistical inference underpin prominent accounts for a variety of cognitive phenomena, including perception, learning, and decision-making. Linking these building blocks of cognition to the biological substrate that supports them, recent work has investigated how the brain implements probabilistic inference and learning under uncertainty. The interplay between the psychological and biological levels of analysis has shed light on the structure of cognition and computation at both levels. This symposium builds on Peter Dayan’s seminal contributions to linking psychological, neural and computational phenomena. In particular, speakers will discuss recent work growing out of two areas where Dayan made early and fundamental contributions: the brain’s mechanisms for reinforcement learning, and neural representations supporting probabilistic inference under uncertainty. Fractionating model-based reinforcement- learning its component neural processes Author: John P. O’Doherty Abstract: It has recently been proposed that action- selection in the mammalian brain depends on at least two distinct mechanisms: a model-free reinforcement learning (RL) mechanism in which actions are selected on the basis of cached values acquired through trial and error, and a model-based RL system in which actions are chosen using values computed on-line by means of a rich cognitive model of the decision problem and knowledge of the current incentive value of goals. While much is now known about the putative neural substrates of the model-free RL system and its concomitant temporal difference prediction error, much less is known about how model-based RL is implemented at the neural level. In this talk I will review recent evidence from a series of functional neuroimaging studies in humans supporting the presence of neural signals within a wide expanse of cortex that are relevant to model- based RL. These include, a state-action based prediction error signal within a fronto-parietal network that could mediate learning of the cognitive model, a goal-value signal encoding the value of putative goal-outcomes within the Reinforcement learning and the basal ganglia Authors: Kenji Doya and Makoto Ito Abstract: The discovery of the parallel between the firing of dopamine Neurons and the temporal difference error signal of the reinforcement theory in the 1990s brought a breakthrough in understanding the function of the basal ganglia. Previously the most enigmatic part of the brain is now considered as the center for linking perception, action,
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neural computations supporting cognition rumelhart prize symposium in honor of peter dayan
Cognitive Science, 2012Co-Authors: Kenji Doya, John P Odoherty, Alexandre Pouget, Peter BossaertsAbstract:Neural Computations Supporting Cognition: Rumelhart Prize Symposium in Honor of Peter Dayan Participants Kenji Doya (doya@oist.jap) John O’Doherty (jodoherty@caltech.edu) Neural Computation Unit, Okinawa Institute of Science and Technology, 1919-1 Tancha, Onna Okinawa 904-0495 Japan Division of the Humanities and Social Sciences, California Institute of Technology, MC 228-77 Pasadena, CA 91125 USA Alexandre Pouget (alex@cvs.rochester.edu) Peter Bossaerts (pbs@hss.caltech.edu) Departement de neuroscience fondementale, Universite de Geneve, 1 rue Michel-Servet CH-1211 Geneva 4, Switzerland Division of the Humanities and Social Sciences, California Institute of Technology, MC 228-77 Pasadena, CA 91125 USA Organizors Nathaniel Daw (daw@cns.nyu.edu) Center for Neural Science New York University New York, NY, 10003 Yael Niv (yael@princeton.edu) Princeton Neuroscience Institute and Psychology Department Princeton University, Princeton, NJ, 08544 Keywords: neural computation; reinforcement learning; inference; uncertainty and reward. After more than a decade from the discovery, however, there still remain questions to be answered, such as what Striatal Neuron firing represents, how and where an action is selected, and how negative reinforcement is realized. Here we review Peter Dayan's seminal contributions and recent developments. Motivation Principles of sound statistical inference underpin prominent accounts for a variety of cognitive phenomena, including perception, learning, and decision-making. Linking these building blocks of cognition to the biological substrate that supports them, recent work has investigated how the brain implements probabilistic inference and learning under uncertainty. The interplay between the psychological and biological levels of analysis has shed light on the structure of cognition and computation at both levels. This symposium builds on Peter Dayan’s seminal contributions to linking psychological, neural and computational phenomena. In particular, speakers will discuss recent work growing out of two areas where Dayan made early and fundamental contributions: the brain’s mechanisms for reinforcement learning, and neural representations supporting probabilistic inference under uncertainty. Fractionating model-based reinforcement- learning its component neural processes Author: John P. O’Doherty Abstract: It has recently been proposed that action- selection in the mammalian brain depends on at least two distinct mechanisms: a model-free reinforcement learning (RL) mechanism in which actions are selected on the basis of cached values acquired through trial and error, and a model-based RL system in which actions are chosen using values computed on-line by means of a rich cognitive model of the decision problem and knowledge of the current incentive value of goals. While much is now known about the putative neural substrates of the model-free RL system and its concomitant temporal difference prediction error, much less is known about how model-based RL is implemented at the neural level. In this talk I will review recent evidence from a series of functional neuroimaging studies in humans supporting the presence of neural signals within a wide expanse of cortex that are relevant to model- based RL. These include, a state-action based prediction error signal within a fronto-parietal network that could mediate learning of the cognitive model, a goal-value signal encoding the value of putative goal-outcomes within the Reinforcement learning and the basal ganglia Authors: Kenji Doya and Makoto Ito Abstract: The discovery of the parallel between the firing of dopamine Neurons and the temporal difference error signal of the reinforcement theory in the 1990s brought a breakthrough in understanding the function of the basal ganglia. Previously the most enigmatic part of the brain is now considered as the center for linking perception, action,
Q. Chen - One of the best experts on this subject based on the ideXlab platform.
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differential localization of the glur1 and glur2 subunits of the ampa type glutamate receptor among Striatal Neuron types in rats
Journal of Chemical Neuroanatomy, 2007Co-Authors: Yunping Deng, Q. Chen, Wanlong Lei, J P Xie, H B Wang, A ReinerAbstract:Differences among the various Striatal projection Neuron and interNeuron types in cortical input, function, and vulnerability to degenerative insults may be related to differences among them in AMPA-type glutamate receptor abundance and subunit configuration. We therefore used immunolabeling to assess the frequency and abundance of GluR1 and GluR2, the most common AMPA subunits in striatum, in the main Striatal Neuron types. All Neurons projecting to the external pallidum (GPe), internal pallidum (GPi) or substantia nigra, as identified by retrograde labeling, possessed perikaryal GluR2, while GluR1 was more common in striato-GPe than striato-GPi perikarya. The frequency and intensity of immunostaining indicated the rank order of their perikaryal GluR1:GluR2 ratio to be striato-GPe>striatonigral>striato-GPi. Ultrastructural studies suggested a differential localization of GluR1 and GluR2 to Striatal projection Neuron dendritic spines as well, with GluR1 seemingly more common in striato-GPe spines and GluR2 more common in striato-GPi and/or striatonigral spines. Comparisons among projection Neurons and interNeurons revealed GluR1 to be most common and abundant in parvalbuminergic interNeurons, and GluR2 most common and abundant in projection Neurons, with the rank order for the GluR1:GluR2 ratio being parvalbuminergic interNeurons>calretinergic interNeurons>cholinergic interNeurons>projection Neurons>somatostatinergic interNeurons. Striosomal projection Neurons had a higher GluR1:GluR2 ratio than did matrix projection Neurons. The abundance of both GluR1 and GluR2 in Striatal parvalbuminergic interNeurons and projection Neurons is consistent with their prominent cortical input and susceptibility to excitotoxic insult, while differences in GluR1:GluR2 ratio among projection Neurons are likely to yield differences in Ca(2+) permeability, desensitization, and single channel current, which may contribute to differences among them in plasticity, synaptic integration, and excitotoxic vulnerability. The apparent association of the GluR1 subunit with synaptic plasticity, in particular, suggests striato-GPe Neuron spines as a particular site of corticoStriatal synaptic plasticity, presumably associated with motor learning.
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Cellular distribution of the NMDA receptor NR2A/2B subunits in the rat striatum.
Brain research, 1996Co-Authors: Q. Chen, A ReinerAbstract:Using immunohistochemical double-labeling with a specific antibody recognizing both NR2A and NR2B subunits, we studied the cellular distribution of the NMDA receptor subunit NR2A/2B on all major known Striatal Neuron types. Among Striatal interNeurons, our results showed that none of somatostatin interNeurons was labeled for NR2A/2B subunits, 56% of parvalbumin interNeurons were double-labeled for NR2A/2B, and all identified cholinergic interNeurons were labeled for NR2A/2B. Among Striatal projections Neurons, 95% of striatonigral Neurons, 96% of enkephalin-containing Neurons, and 98% of calbindin-containing Striatal matrix Neurons were double-labeled for NR2A/2B. Our studies demonstrate that there is a differential distribution of the NMDA receptor NR2A/2B subunits on Striatal Neuron types. The paucity of NR2A/2B subunits on NMDA receptors on Striatal somatostatin interNeurons may confer resistance to NMDA receptor-mediated excitotoxicity on these Neurons.
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cellular expression of ionotropic glutamate receptor subunits on specific Striatal Neuron types and its implication for Striatal vulnerability in glutamate receptor mediated excitotoxicity
Neuroscience, 1996Co-Authors: Q. Chen, C L Veenman, A ReinerAbstract:Glutamate receptors are composed of subtype-specific subunits. Variation in the precise subunit composition of a receptor may result in significant functional differences. Thus, a precise knowledge of subunit composition on Striatal Neurons is a prerequisite for understanding the selective vulnerability of Striatal Neurons to excitatory amino acids. In the present study, we used an immunohistochemical double-labelling approach to localize ionotropic glutamate receptor subunits (NMDAR1, GluR1, GluR2/3, GluR4 and GluR5/6/7) on specific Striatal Neuron populations. Our results showed that Striatal cholinergic and somatostatin interNeurons were not labelled for the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate, receptor subunits GluR1, GluR2/3 and GluR4. Most cholinergic and somatostatin interNeurons (83.3% to 100%), however, were double-labelled for the N-methyl-D-aspartate receptor subunit NR1 and kainic acid receptor subunits GluR5/6/7. All parvalbumin interNeurons were labelled for GluR1 and GluR4, and 96% GluR1 positive and 95% GluR4 positive Neurons were also double-labelled as parvalbumin interNeurons. About half of all parvalbumin interNeurons co-localized with GluR2/3, and over 97% were labelled for NR1 and GluR5/6/7. Among Striatal projection Neurons, enkephalin-positive (mainly striatopallidal) Neurons, striatonigral Neurons (mainly substance P-positive) and calbindin-positive matrix Neurons were not immunostained for GluR1 or GluR4. In contrast, 95% to 100% of each of these types of projection Neurons were double-labelled for NR1, GluR2/3 and GluR5/6/7. Our results demonstrate that Striatal Neuron types differ in their expression of ionotropic glutamate receptor subunits and subtypes. The clear difference between Striatal interNeurons and projection Neurons in ionotropic glutamate receptor subtypes/subunits supports the idea that differential glutamate receptor expression mechanism may account for the selective vulnerability of Striatal projection Neurons to excitotoxicity, and that glutamate receptor-mediated excitotoxicity may be involved in the Striatal neurodegenerative diseases.
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Glutamate-Mediated Excitotoxic Death of Cultured Striatal Neurons Is Mediated by Non-NMDA Receptors
Experimental neurology, 1995Co-Authors: Q. Chen, Cynthia Harris, Charity Stewart Brown, Angela Howe, D. James Surmeier, A ReinerAbstract:Abstract Considerable interest has focused on the role of glutamate-mediated excitotoxicity in neurodegenerative disorders of the basal ganglia. The in vitro data on the receptor mechanisms involved in this process, however, have been inconclusive. Some studies have indicated that excitotoxins acting at NMDA receptors kill Striatal Neurons and others have indicated that NMDA receptor-mediated excitotoxic death of Striatal Neurons is minimal in the absence of cortex. In the present study, we used a pharmacological approach to carefully reexamine this issue in 2-week-old cultures of Striatal Neurons dissociated from E17 rat embryos. The sensitivity of these Neurons to glutamate agonists and antagonists was determined by monitoring cell loss in identified regions of the growth dishes. We found that glutamate killed Striatal Neurons with an EC50 of 100 μM. This loss was not mediated by NMDA receptors, since it was not reduced by the NMDA receptor antagonist APV (0.1-1.0 mM). Consistent with this result, up to 50 mM NMDA receptor-specific excitotoxin quinolinic acid (QA) did not affect Neuronal survival. Depolarizing the QA-exposed Neurons with 35 mM potassium chloride to enhance NMDA receptor activation by QA also did not produce Neuron loss. The metabotropic glutamate receptor antagonist AP3 (500 μM) also had no effect on the Striatal Neuron loss produced by 100 μM glutamate. In contrast, the non-NMDA antagonist GYKI 52466 (100 μM) did block the excitotoxic effect of glutamate (100 μM). Specific AMPA and KA receptor agonists and the non-NMDA antagonist GYKI 52466 revealed that the non-NMDA receptor-mediated excitotoxic effect of glutamate was mediated by KA receptors. These results suggest that cultured Striatal Neurons are directly vulnerable to non-NMDA glutamate agonists, but not to NMDA and metabotropic glutamate agonists. Thus, non-NMDA receptors may play a greater role in the excitotoxic death of Striatal Neurons in disease and experimental animal models than previously realized.
Yunping Deng - One of the best experts on this subject based on the ideXlab platform.
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disrupted Striatal Neuron inputs and outputs in huntington s disease
CNS Neuroscience & Therapeutics, 2018Co-Authors: A Reiner, Yunping DengAbstract:Huntington's disease (HD) is a hereditary progressive neurodegenerative disorder caused by a CAG repeat expansion in the gene coding for the protein huntingtin, resulting in a pathogenic expansion of the polyglutamine tract in the N-terminus of this protein. The HD pathology resulting from the mutation is most prominent in the Striatal part of the basal ganglia, and progressive differential dysfunction and loss of Striatal projection Neurons and interNeurons account for the progression of motor deficits seen in this disease. The present review summarizes current understanding regarding the progression in Striatal Neuron dysfunction and loss, based on studies both in human HD victims and in genetic mouse models of HD. We review evidence on early loss of inputs to striatum from cortex and thalamus, which may be the basis of the mild premanifest bradykinesia in HD, as well as on the subsequent loss of indirect pathway Striatal projection Neurons and their outputs to the external pallidal segment, which appears to be the basis of the chorea seen in early symptomatic HD. Later loss of direct pathway Striatal projection Neurons and their output to the internal pallidal segment account for the severe akinesia seen late in HD. Loss of parvalbuminergic Striatal interNeurons may contribute to the late dystonia and rigidity.
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differential loss of thalamoStriatal and corticoStriatal input to Striatal projection Neuron types prior to overt motor symptoms in the q140 knock in mouse model of huntington s disease
Frontiers in Systems Neuroscience, 2014Co-Authors: Yunping Deng, Ting Wong, Jim Y Wan, A ReinerAbstract:Motor slowing and forebrain white matter loss have been reported in premanifest Huntington’s disease (HD) prior to substantial Striatal Neuron loss. These findings raise the possibility that early motor defects in HD may be related to loss of excitatory input to striatum. In a prior study, we showed that in the heterozygous Q140 knock-in mouse model of HD that loss of thalamoStriatal axospinous terminals is evident by 4 months, and loss of corticoStriatal axospinous terminals is evident at 12 months, before Striatal projection Neuron pathology. In the present study, we specifically characterized the loss of thalamoStriatal and corticoStriatal terminals on direct (dSPN) and indirect (iSPN) pathway Striatal projection Neurons, using immunolabeling to identify thalamoStriatal (VGLUT2+) and corticoStriatal (VGLUT1+) axospinous terminals, and D1 receptor immunolabeling to distinguish dSPN (D1+) and iSPN (D1-) synaptic targets. We found that the loss of corticoStriatal terminals at 12 months of age was preferential for D1+ spines, and especially involved smaller terminals, presumptively of the intratelencephalically projecting (IT) type. By contrast, indirect pathway D1- spines showed little loss of axospinous terminals at the same age. ThalamoStriatal terminal loss was comparable for D1+ and D1- spines at both 4 months and 12 months. Regression analysis showed that the loss of VGLUT1+ terminals on D1+ spines was correlated with a slight decline in open field motor parameters at 12 months. Our overall results raise the possibility that differential thalamic and cortical input loss to SPNs is an early event in human HD, with cortical loss to dSPNs in particular contributing to premanifest motor slowing.
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loss of corticoStriatal and thalamoStriatal synaptic terminals precedes Striatal projection Neuron pathology in heterozygous q140 huntington s disease mice
Neurobiology of Disease, 2013Co-Authors: Yunping Deng, Ting Wong, Courtney Brickeranthony, B Deng, A ReinerAbstract:Abstract Motor slowing, forebrain white matter loss, and Striatal shrinkage have been reported in premanifest Huntington's disease (HD) prior to overt Striatal Neuron loss. We carried out detailed LM and EM studies in a genetically precise HD mimic, heterozygous Q140 HD knock-in mice, to examine the possibility that loss of corticoStriatal and thalamoStriatal terminals prior to Striatal Neuron loss underlies these premanifest HD abnormalities. In our studies, we used VGLUT1 and VGLUT2 immunolabeling to detect corticoStriatal and thalamoStriatal (respectively) terminals in dorsolateral (motor) striatum over the first year of life, prior to Striatal projection Neuron pathology. VGLUT1 + axospinous corticoStriatal terminals represented about 55% of all excitatory terminals in striatum, and VGLUT2 + axospinous thalamoStriatal terminals represented about 35%, with VGLUT1 + and VGLUT2 + axodendritic terminals accounting for the remainder. In Q140 mice, a significant 40% shortfall in VGLUT2 + axodendritic thalamoStriatal terminals and a 20% shortfall in axospinous thalamoStriatal terminals were already observed at 1 month of age, but VGLUT1 + terminals were normal in abundance. The 20% deficiency in VGLUT2 + thalamoStriatal axospinous terminals persisted at 4 and 12 months in Q140 mice, and an additional 30% loss of VGLUT1 + corticoStriatal terminals was observed at 12 months. The early and persistent deficiency in thalamoStriatal axospinous terminals in Q140 mice may reflect a development defect, and the impoverishment of this excitatory drive to striatum may help explain early motor defects in Q140 mice and in premanifest HD. The loss of corticoStriatal terminals at 1 year in Q140 mice is consistent with prior evidence from other mouse models of corticoStriatal disconnection early during progression, and can explain both the measurable bradykinesia and Striatal white matter loss in late premanifest HD.
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the group 2 metabotropic glutamate receptor agonist ly379268 rescues Neuronal neurochemical and motor abnormalities in r6 2 huntington s disease mice
Neurobiology of Disease, 2012Co-Authors: A Reiner, H B Wang, D C Lafferty, N Del Mar, Yunping DengAbstract:Abstract Excitotoxic injury to striatum by dysfunctional cortical input or aberrant glutamate uptake may contribute to Huntington's disease (HD) pathogenesis. Since corticoStriatal terminals possess mGluR2/3 autoreceptors, whose activation dampens glutamate release, we tested the ability of the mGluR2/3 agonist LY379268 to improve the phenotype in R6/2 HD mice with 120–125 CAG repeats. Daily subcutaneous injection of a maximum tolerated dose (MTD) of LY379268 (20 mg/kg) had no evident adverse effects in WT mice, and diverse benefits in R6/2 mice, both in a cohort of mice tested behaviorally until the end of R6/2 lifespan and in a cohort sacrificed at 10 weeks of age for blinded histological analysis. MTD LY379268 yielded a significant 11% increase in R6/2 survival, an improvement on rotarod, normalization and/or improvement in locomotor parameters measured in open field (activity, speed, acceleration, endurance, and gait), a rescue of a 15–20% cortical and Striatal Neuron loss, normalization of SP Striatal Neuron neurochemistry, and to a lesser extent enkephalinergic Striatal Neuron neurochemistry. Deficits were greater in male than female R6/2 mice, and drug benefit tended to be greater in males. The improvements in SP Striatal Neurons, which facilitate movement, are consistent with the improved movement in LY379268-treated R6/2 mice. Our data indicate that mGluR2/3 agonists may be particularly useful for ameliorating the morphological, neurochemical and motor defects observed in HD.
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differential localization of the glur1 and glur2 subunits of the ampa type glutamate receptor among Striatal Neuron types in rats
Journal of Chemical Neuroanatomy, 2007Co-Authors: Yunping Deng, Q. Chen, Wanlong Lei, J P Xie, H B Wang, A ReinerAbstract:Differences among the various Striatal projection Neuron and interNeuron types in cortical input, function, and vulnerability to degenerative insults may be related to differences among them in AMPA-type glutamate receptor abundance and subunit configuration. We therefore used immunolabeling to assess the frequency and abundance of GluR1 and GluR2, the most common AMPA subunits in striatum, in the main Striatal Neuron types. All Neurons projecting to the external pallidum (GPe), internal pallidum (GPi) or substantia nigra, as identified by retrograde labeling, possessed perikaryal GluR2, while GluR1 was more common in striato-GPe than striato-GPi perikarya. The frequency and intensity of immunostaining indicated the rank order of their perikaryal GluR1:GluR2 ratio to be striato-GPe>striatonigral>striato-GPi. Ultrastructural studies suggested a differential localization of GluR1 and GluR2 to Striatal projection Neuron dendritic spines as well, with GluR1 seemingly more common in striato-GPe spines and GluR2 more common in striato-GPi and/or striatonigral spines. Comparisons among projection Neurons and interNeurons revealed GluR1 to be most common and abundant in parvalbuminergic interNeurons, and GluR2 most common and abundant in projection Neurons, with the rank order for the GluR1:GluR2 ratio being parvalbuminergic interNeurons>calretinergic interNeurons>cholinergic interNeurons>projection Neurons>somatostatinergic interNeurons. Striosomal projection Neurons had a higher GluR1:GluR2 ratio than did matrix projection Neurons. The abundance of both GluR1 and GluR2 in Striatal parvalbuminergic interNeurons and projection Neurons is consistent with their prominent cortical input and susceptibility to excitotoxic insult, while differences in GluR1:GluR2 ratio among projection Neurons are likely to yield differences in Ca(2+) permeability, desensitization, and single channel current, which may contribute to differences among them in plasticity, synaptic integration, and excitotoxic vulnerability. The apparent association of the GluR1 subunit with synaptic plasticity, in particular, suggests striato-GPe Neuron spines as a particular site of corticoStriatal synaptic plasticity, presumably associated with motor learning.
